USOO778604.4B2

(12) United States Patent (10) Patent No.: US 7,786,044 B2 Epp et al. (45) Date of Patent: Aug. 31, 2010

(54) 2-SUBSTITUTED-6-AMINO-5-ALKYL, (58) Field of Classification Search ...... 546/310; ALKENYLOR 504/260 ALKYNYL-4-PYRIMIDNECARBOXYLC See application file for complete search history. ACDS AND 6-SUBSTITUTED-4-AMNO-3- ALKYL, ALKENYL OR ALKYNYL (56) References Cited PCOL.INIC ACDS AND THEIR USE AS U.S. PATENT DOCUMENTS HERBCDES 6,297, 197 B1 10, 2001 Fields et al. (75) Inventors: Jeffrey B. Epp, Noblesville, IN (US); 6,784,137 B2 8, 2004 Balko et al. Paul R. Schmitzer, Indianapolis, IN 7,300,907 B2 11/2007 Epp et al. 7,314,849 B2 1, 2008 Balko et al. (US); Terry W. Balko, Greenfield, IN 2003.0114311 A1 6, 2003 Balko et al. (US); Carla N. Yerkes, Crawfordsville, 2004/O1986.08 A1 10, 2004 Balko et al. IN (US) 2007/O179059 A1 8, 2007 Epp et al. (73) Assignee: Dow AgroSciences LLC, Indianapolis, FOREIGN PATENT DOCUMENTS IN (US) WO WO2005/063721 7/2005 WO WO2007/0921.84 8, 2007 (*) Notice: Subject to any disclaimer, the term of this WO WO 2007/0921.84 8, 2008 patent is extended or adjusted under 35 WO WO 2009-046090 4/2009 U.S.C. 154(b) by 0 days. OTHER PUBLICATIONS (21) Appl. No.: 12/243,469 U.S. Appl. No. 12/200,945, filed Aug. 29, 2008, Jeffrey B. Epp et al. Bioorganic & Medicinal Chemistry Letters 2004, vol. 14, pp. 3869 (22) Filed: Oct. 1, 2008 3873. Journal of Organic Chemistry 1981, vol. 46, pp. 1413-1423. (65) Prior Publication Data Primary Examiner—Deepak Rao US 2009/OO88322 A1 Apr. 2, 2009 (74) Attorney, Agent, or Firm—Craig E. Mixan Related U.S. Application Data (57) ABSTRACT (60) Provisional application No. 60/997.210, filed on Oct. 2, 2007, provisional application No. 61/049,536, filed 6-Amino-4-pyrimidinecarboxylic acids having alkyl, alkenyl on May 1, 2008. oralkynyl Substituents in the 5-position and 4-aminopicolinic acids having alkyl, alkenyl or alkynyl Substituents in the (51) Int. C. 3-position, and their amine and acid derivatives, are potent C07D 213/79 (2006.01) herbicides demonstrating a broad spectrum of weed control. AOIN 43/40 (2006.01) (52) U.S. Cl...... 504/260; 546/310 11 Claims, No Drawings US 7,786,044 B2 1. 2 2-SUBSTITUTED-6-AMINO-5-ALKYL, R represents C-C alkyl, C-Chaloalkyl, C-C alkenyl, ALKENYLOR C-C haloalkenyl or ALKYNYL-4-PYRIMDNECARBOXYLC ACDS AND 6-SUBSTITUTED-4-AMNO-3- ALKYL, ALKENYL OR ALKYNYL PCOL.INIC ACIDS AND THEIR USE AS HERBCDES This application claims the benefit of U.S. Provisionals Application Ser. No. 60/997.210 filed on Oct. 2, 2007 and 10 Application Ser. No. 61/049,536 filed on May 1, 2008. This invention relates to certain novel 2-(substituted)-6-amino-5- (alkyl, alkenyl or alkynyl)-4-pyrimidine-carboxylates and 6-(Substituted)-4-amino-3-(alkyl, alkenyl or alkynyl) picoli wherein nates and their derivatives and to the use of these compounds 15 W represents Horhalogen; as herbicides. X represents H. halogen, nitro, cyano, formyl, C-C, alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, C-C, BACKGROUND OF THE INVENTION alkoxyalkyl, C-C alkylcarbonyl, C-C alkylthio. C-C, alkylsulfinyl, C-C alkylsulfonyl, C-C alkenyloxy, C-C, A number of pyrimidine carboxylic acids and their pesti alkynloxy, C-C alkenylthio, C-C alkynylthio, C-C, cidal properties have been described in the art. WO 2005/ haloalkyl, C-C halo-alkenyl, C-C haloalkynyl, C-C, 063721 A1, WO 2007/092184 A2 and U.S. Pat. No. 7,300, haloalkoxy, C-C haloalkoxyalkyl, C-C haloalkylcarbo 907 B2 disclose a genus of 2-substituted-6-amino-4- nyl, C-C haloalkylthio, C-C haloalkylsulfinyl, C-C, pyrimidinecarboxylic acids and their derivatives with halo-alkylsulfonyl, C-C trialkylsilyl, C-C haloalkeny halogen, cyano, thiocyanato, nitro, alkyl, haloalkyl, alkoxy, 25 thioalkyl and amino substituents in the 5-position and their loxy, C-C haloalkynyloxy, C-C haloalkenylthio, C-C, use as herbicides. haloalkynylthio. —C(O)OR7, —C(O)NRR-7, CRNOR7, A number of picolinic acids and their pesticidal properties —NRR, NROR, NRSOR, NRC(O)R. - NRC(O)OR. - NRC(O)NRR, or - NCRNRR: have been described in the art. U.S. Pat. Nos. 6,297,197 B1; Y represents H, halogen, C-C alkyl, C-C haloalkyl, 6,784,137 B2; and 7,314,849 B2 and US Patent Application 30 Publication 2004/0198608 A1 disclose a genus of 6-substi C-C alkoxy, C-C haloalkoxy, C-C alkenyl or C-C, tuted-4-aminopicolinic acids and their derivatives with halo haloalkenyl, or, when X and Y are taken together, represents gen, cyano, thiocyanato, nitro, alkyl, haloalkyl, alkoxy, —O(CH), CH, , or —O(CH)O— wherein n=1 or 2; and haloalkoxy, thioalkyl and aryloxy Substituents in the 3-posi Z represents H or halogen; tion and their use as herbicides. R and R independently represent H, C-C alkyl, C-C, 35 alkenyl, C-C alkynyl, hydroxy, C-C alkoxy, amino, C-C, SUMMARY OF THE INVENTION acyl, C-C carboalkoxy, C-C alkylcarbamyl, C-C alkyl Sulfonyl, C-C trialkylsilyl or C-C dialkyl phosphonyl or It has now been found that certain 2-(substituted)-6-amino RandR taken together with N representa 5- or 6-membered 5-(alkyl, alkenyl or alkynyl)-4-pyrimidinecarboxylic acids 40 saturated ring; and and 6-(substituted)-4-amino-3-(alkyl, alkenyl or alkynyl) Rs represents H or halogen; picolinic acids and their derivatives are superior herbicides R represents H. C-C alkyl or C-Chaloalkyl; and with a broad spectrum of weed control against Woody plants, R7 represents C-C alkyl or C-Chaloalkyl; grasses and sedges as well as broadleafweeds and with excel and agriculturally acceptable derivatives of the carboxylic lent selectivity to beneficial plant species. The compounds 45 acid group. further possess excellent toxicological or environmental pro Preferred compounds of formula (I) include the following files. classes: The invention includes compounds of Formula I: (1) Compounds of formula (I) wherein R is C-C alkyl, C-C haloalkyl, C-C alkenyl or C-C haloalkenyl, most 50 preferably wherein R is vinyl. (2) Compounds of formula (I) wherein R is cyclopropyl. (3) Compounds of formula (I) wherein R is

55 OH

60 wherein A represents N or CRs: R represents C-C alkyl, C-Chaloalkyl, C-C alkoxy alkyl, C-C alkylthioalkyl, C-C alkenyl, C-C haloalk (4) Compounds of class (3) wherein W represents H or F. enyl, C-C alkoxyalkenyl, C-C thioalkylalkenyl, C-C, 65 X represents H. halogen, C-C alkyl, C-C haloalkyl, alkynyl or C-C haloalkynyl, formyl, C-C alkylcarbonyl, C-C alkoxy, C-C haloalkoxy or —NRR-7, Y represents C-C haloalkylcarbonyl: C1 or halomethyl, and Z represents H or F. US 7,786,044 B2 3 4 (5) Compounds of formula (I) wherein R and Ra are H or Y represents H, halogen, C-C alkyl, C-C haloalkyl, C-C alkyl. C-C alkoxy, C-C haloalkoxy, C-C alkenyl or C-C, It will be appreciated by those skilled in the art that the haloalkenyl, or, when X and Y are taken together, represents most preferred compounds are generally those which are —O(CH2)CH2—, or —O(CH), O— wherein n=1 or 2; and comprised of combinations of the above preferred classes. Z represents H or halogen; The invention includes herbicidal compositions compris Rs represents H or halogen ing an herbicidally effective amount of a compound of For R represents H. C-C alkyl or C-Chaloalkyl; and mula I and agriculturally acceptable derivatives of the car R, represents C-C alkyl or C-C haloalkyl: boxylic acid group in a mixture with an agriculturally The amino group at the 6-position of the pyrimidine ring or acceptable adjuvant or carrier. The invention also includes a 10 the 4-position of the pyridine ring can be unsubstituted or method of use of the compounds and compositions of the Substituted with one or more C-C alkyl, C-C alkenyl, present invention to kill or control undesirable vegetation by C-C alkynyl, hydroxy, C-C alkoxy or amino Substituents. application of an herbicidal amount of the compound to the The amino group can be further derivatized as an amide, a Vegetation or to the locus of the vegetation as well as to the carbamate, a urea, a Sulfonamide, a silylamine or a phospho soil prior to emergence of the vegetation. 15 ramidate. Such derivatives are capable of breaking down into the amine. An unsubstituted amino group or one substituted DETAILED DESCRIPTION OF THE INVENTION with one or two alkyl substituents is preferred. The carboxylic acids of Formula Ia are believed to be the The herbicidal compounds of the present invention are compounds that actually kill or control undesirable vegeta derivatives of 6-amino-5-(alkyl, alkenyl or alkynyl)-4-pyri tion and are typically preferred. Analogs of these compounds midinecarboxylic acids or 4-amino-3-(alkyl, alkenyl or alky in which the acid group of the pyrimidine carboxylic acid or nyl) picolinic acids of the formula: picolinic acid is derivatized to form a related substituent that can be transformed within plants or the environment to an Ia acid group possess essentially the same herbicidal effect and NH2 25 are within the scope of the invention. Therefore, an "agricul turally acceptable derivative', when used to describe the car 1N R boxylic acid functionality at the 4-position of the pyrimidine ring or the 2-position of the pyridine ring, is defined as any l 2 OH salt, ester, acylhydrazide, imidate, thioimidate, amidine, R N 30 amide, orthoester, acylcyanide, acyl halide, thioester, thion oester, dithiolester, nitrile or any other acid derivative well O known in the art which (a) does not substantially affect the herbicidal activity of the active ingredient, i.e., the 2-(substi wherein tuted)-6-amino-5-(alkyl, alkenyl or alkynyl)-4-pyrimidin A represents N or CRs: 35 ecarboxylic acid or the 6-(substituted)-4-amino-3-(alkyl, alk R represents C-C alkyl, C-C haloalkyl, C-C alkoxy enyl or alkynyl) picolinic acid, and (b) is or can be alkyl, C-C alkylthioalkyl, C-C alkenyl, C-C haloalk hydrolyzed, oxidized or metabolized in plants or soil to the enyl, C-C alkoxyalkenyl, C-C thioalkylalkenyl, C-C, 4-pyrimidinecarboxylic acid or the picolinic acid of Formula Ia that, depending upon the pH, is in the dissociated or the alkynyl or C-C haloalkynyl, formyl, C-C alkylcarbonyl, undissociated form. The preferred agriculturally acceptable C-C haloalkylcarbonyl: 40 derivatives of the carboxylic acid are agriculturally accept R represents C-C alkyl, C-Chaloalkyl, C-C alkenyl, able salts, esters and amides. Likewise, an "agriculturally C-C haloalkenyl or acceptable derivative', when used to describe the amine func tionality at the 6- or 4-position, is defined as any salt, sily lamine, phosphorylamine, phosphinimine, phosphoramidate, 45 Sulfonamide, Sulfillimine, Sulfoximine, aminal, hemiaminal, amide, thioamide, carbamate, thiocarbamate, amidine, urea, imine, nitro, nitroso, azide, or any other nitrogen containing derivative well known in the art which (a) does not substan tially affect the herbicidal activity of the active ingredient, 50 i.e., the 2-(Substituted)-6-amino-5-(alkyl, alkenyl or alky nyl)-4-pyrimidinecarboxylic acid or the 6-(substituted)-4- amino-3-(alkyl, alkenyl or alkynyl) picolinic acid, and (b) is wherein or can be hydrolyzed in plants or soil to a free amine. N-OX W represents H or halogen; ides which are also capable of breaking into the parent pyri X represents H. halogen, nitro, cyano, formyl, C-C, 55 midine or pyridine are also covered by the scope of this alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, C-C, invention. alkoxyalkyl, C-C alkylcarbonyl, C-C alkylthio, C-C, Suitable salts include those derived from alkali or alkaline alkylsulfinyl, C-C alkylsulfonyl, C-C alkenyloxy, C-C, earth metals and those derived from ammonia and amines. alkynloxy, C-C alkenylthio, C-C alkynylthio, C-C, Preferred cations include Sodium, potassium, magnesium, and aminium cations of the formula: haloalkyl, C-C haloalkenyl, C-C haloalkynyl, C-C, 60 haloalkoxy, C-C haloalkoxyalkyl, C-C haloalkylcarbo RRRoNH' nyl, C-C haloalkylthio, C-C haloalkylsulfinyl, C-C, halo-alkylsulfonyl, C-C trialkylsilyl, C-C haloalkeny wherein Rs. R and Ro each, independently represents loxy, C-C haloalkynyloxy, C-C haloalkenylthio, C-C, hydrogen or C-C alkyl, C-C alkenyl or C-C alkynyl, haloalkynylthio. —C(O)OR7, C(O)NRR-7, CRNOR7, 65 each of which is optionally substituted by one or more —NRR-7, NROR7, NRSOR7, NRC(O)R7, hydroxy, C-C alkoxy, C-C alkylthio or phenyl groups, - NRC(O)OR. - NRC(O)NRR, or - NCRNRR: provided that Rs. R and Ro are sterically compatible. Addi US 7,786,044 B2 5 6 tionally, any two of Rs. Ro and Rio together may represent an 3-halopyridine of Formula II and an organometallic com aliphatic difunctional moiety containing 1 to 12 carbonatoms pound of type III in an inert solvent in the presence of a and up to two oxygen or Sulfur atoms. Salts of the compounds transition metal catalyst. of Formula I can be prepared by treatment of compounds of Formula I with a metal hydroxide, such as sodium hydroxide, 5 or an amine, such as ammonia, trimethylamine, diethanola Scheme 1 mine, 2-methylthiopropylamine, bisallylamine, 2-butoxy ethylamine, morpholine, cyclododecylamine, or benzy NR3R4 lamine. Amine salts are often preferred forms of the Q 10 w1N R-M compounds of Formula I because they are water-soluble and --- lend themselves to the preparation of desirable aqueous based l 2 OMe III herbicidal compositions. R N Suitable esters include those derived from C-C alkyl, C-C alkenyl or C-C alkynyl alcohols, such as methanol, O iso-propanol, butanol, 2-ethylhexanol, butoxyethanol, meth 15 II oxypropanol, allyl alcohol, propargyl alcohol or cyclohex NRR4 anol. Esters can be prepared by coupling of the 4-pyrimidine carboxylic acids or picolinic acids with the alcohol using any w1N R number of Suitable activating agents such as those used for peptide couplings such as dicyclohexylcarbodiimide (DCC) l 2 OMe or carbonyl diimidazole (CDI), by reacting the corresponding R N acid chloride of a 4-pyrimidinecarboxylic acid or picolinic acid of Formula I with an appropriate alcohol, by reacting the O corresponding 4-pyrimidinecarboxylic acid or picolinic acid of Formula I with an appropriate alcohol in the presence of an 25 acid catalyst or by transesterification. Suitable amides In this case W can be NorCRs; Q can be chlorine, bromine include those derived from ammonia or from C-C alkyl, or iodine; R can be alkyl, haloalkyl, alkenyl, haloalkenyl, or C-C alkenyl or C-C alkynyl mono- or di-substituted amines, such as but not limited to dimethylamine, diethano alkynyl group; and M can be tri-(C-C alkyl)tin or B(OR) lamine, 2-methylthiopropylamine, bisallylamine, 2-butoxy 30 (OR), where R and R2 are independent of one another, ethylamine, cyclododecyl-amine, benzylamine or cyclic or hydrogen, C-C alkyl, or when taken together form an eth aromatic amines with or without additional heteroatoms such ylene or propylene group; and “Catalyst” can be a transition as but not limited to aziridine, azetidine, pyrrolidine, pyrrole, metal catalyst, in particular a palladium catalyst Such as bis imidazole, tetrazole or morpholine. Amides can be prepared (triphenylphosphine)palladium(II) dichloride. The method by reacting the corresponding4-pyrimidinecarboxylic acidor 35 of Scheme 1 is illustrated in Examples 17, 18, 21, 22, 24, 25, picolinic acid chloride, mixed anhydride, or carboxylic ester 27, 28, and 30. of Formula I with ammonia or an appropriate amine. As shown in Scheme 2, many 2-(Substituted)-6-amino-5- The terms “alkyl”, “alkenyl and “alkynyl', as well as halo-4-pyrimidinecarboxylic acid esters of Formula II can be derivative terms such as “alkoxy”, “acyl”, “alkylthio' and made from compounds of Formula IV by reaction with a “alkylsulfonyl', as used herein, include within their scope 40 halogenating reagent Such as N-bromosuccinimide in a sol straight chain, branched chain and cyclic moieties. The terms vent such as chloroform or acetonitrile. In this case, Q can be “alkenyl and “alkynyl are intended to include one or more chlorine, bromine or iodine. The method of Scheme 2 is unsaturated bonds. illustrated in Example 16. The term “aryl', as well as derivative terms such as “ary loxy’, refers to a phenyl. 45 Unless specifically limited otherwise, the term “halogen Scheme 2 including derivative terms such as “halo” refers to fluorine, NRR4 chlorine, bromine, and iodine. The terms “haloalkyl.” “haloalkoxy' and “haloalkylthio' N1 n refer to alkyl and alkoxy groups substituted with from 1 to the 50 maximum possible number of halogen atoms. l 2 OMe -Halogenating > The compounds of Formula I can be made using well R N Agent known chemical procedures. Many procedural details for making compounds of Formula I can be found in the follow O IV ing patent applications: WO 2007/082076 A1: WO 2005/ 55 063721 A1; U.S. Pat. Nos. 7,300,907 B2; 6.297,197 B1; NRR4 6,784,137 B2; 7,314,849 B2; and US Patent Application Pub Q lication 2004/0198608 A1. Intermediates not specifically N1 N mentioned in the above patent applications are either com mercially available, can be made by routes disclosed in the 60 ul 2 OMe chemical literature, or can be readily synthesized from com R N mercial starting materials utilizing standard procedures. As shown in Scheme 1, many 2-(Substituted)-6-amino-5- II (alkyl, alkenyl or alkynyl)-4-pyrimidinecarboxylic acid esters or 6-(substituted)-4-amino-3-(alkyl, alkenyl or alky 65 nyl) picolinic acid esters of Formula I can be prepared by As shown in Scheme 3, many 2-(Substituted)-6-amino-4- reaction of an appropriately Substituted 5-halopyrimidine or pyrimidinecarboxylic acid esters of Formula I and IV can be US 7,786,044 B2 7 8 prepared by reaction of appropriately substituted 2-chloropy another, hydrogen, C-C alkyl, or when taken together form rimidines of Formula V and VI and an organometallic com an ethylene or propylene group; and “Catalyst” can be a pound of type VII in an inert solvent in the presence of a transition metal catalyst, in particular a palladium catalyst transition metal catalyst. such as bis(triphenylphosphine)-palladium(II) dichloride. The method of Scheme 4 is illustrated in Example 13. As shown in Scheme 5, many 2-chloro-6-amino-5-iodo-4- Scheme 3 pyrimidinecarboxylic acid esters pyrimidines of Formula NR3R4 NR3R4 VIII can be obtained by reaction of pyrimidines of Formula IX with amines of type X. Pyrimidines of Formula IX can be R R 10 prepared from compounds of Formula XI by reaction with N1 N R-M N1 N reagents such as phosphorous oxychloride either neat or in us 2 OMe --VII l|| 2 OMe the presence of a catalytic amount of dimethylformamide. C N R N The methods of Scheme 5 are illustrated in Examples 11 and 12. O O 15 V I NRR4 NRR4 Scheme 5 O N1 N R-M N1 N I 2 OMe VII 2 OMe HN C N R N POCl. 1. OMe -- O O O N H VI IV 25 O XI In this case R can be an alkyl, haloalkyl, alkenyl, haloalk C enyl, or alkynyl group; R can be an alkyl, haloalkyl, alkenyl, N I haloalkenyl or aryl group; M can be tri-(C-C alkyl)tin or HNRR4 B(OR)(OR), where R and R are independent of one 30 another, hydrogen, C-C alkyl, or when taken together form us 2 OMe X an ethylene or propylene group; and “Catalyst” can be a C N transition metal catalyst, in particular a palladium catalyst such as bis(triphenylphosphine) palladium(II) dichloride. O IX The methods of Scheme 3 are illustrated in Examples 15 and 35 19. NRR4 As shown in Scheme 4, many 2-chloro-6-amino-5-alkyl, I alkenyl or alkynyl-4-pyrimidinecarboxylic acid esters of For N1N mula V can be obtained by reaction of appropriately substi us 2 OMe tuted pyrimidines of Formula VIII and an organometallic 40 C N compound of type III in an inert solvent in the presence of a transition metal catalyst. VIII

Scheme 4 45 It is recognized that some reagents and reaction conditions NR3R4 disclosed herein or in the chemical literature for preparing I compounds of Formula I may not be compatible with certain N1 N R-M He functionalities present in the intermediates. In these III 2 OMe 50 instances, the incorporation of protection/deprotection C N sequences or functional group interconversions into the Syn thesis will aid in obtaining the desired products. The use and O choice of the protection groups will be apparent to one skilled VIII in chemical synthesis. NR3R4 55 One skilled in the art will recognize that, in Some cases, after the introduction of a given reagent as disclosed herein or N1 N R in the chemical literature, it may be necessary to perform additional routine synthetic steps not described in detail to us 2 OMe complete the synthesis of compounds of Formula I. One C N 60 skilled in the art will also recognize that it may necessary to O perform a combination of the steps disclosed herein or in the chemical literature in an order other than that implied by the V particular sequence presented to prepare the compounds of Formula I. In this case R can be an alkyl, haloalkyl, alkenyl, haloalk 65 Finally, one skilled in the art will also recognize that com enyl or alkynyl group; M can be tri-(C-C alkyl)tin or pounds of Formula I and the intermediates described herein or B(OR)(OR), where R and R2 are independent of one in the chemical literature can be subjected to various electro US 7,786,044 B2 10 philic, nucleophilic, radical, organometallic, oxidation, and herbicides or applied sequentially with the other herbicide or reduction reactions to add substituents or modify existing herbicides. Some of the herbicides that can be employed in Substituents. conjunction with the compounds of the present invention The compounds of Formula I have been found to be useful include: amide herbicides such as allidochlor, beflubutamid, as pre-emergence and post-emergence herbicides. They can benzadox, benzipram, bromobutide, cafenstrole, CDEA, be employed at non-selective (higher) rates of application to chlorthiamid, cyprazole, dimethenamid, dimethenamid-P, control a broad spectrum of the vegetation in an area or at diphenamid, epronaz, etnipromid, fentraZamide, flupoxam, lower rates of application for the selective control of undesir fomesafen, halosafen, isocarbamid, isoxaben, napropamide, able vegetation. Areas of application include pasture and naptalam, pethoxamid, propyZamide, quinonamid and teb rangelands, roadsides and rights of way, power lines and any 10 utam; anilide herbicides such as chloranocryl, cisanilide, industrial areas, as well as turf and ornamental environments clomeprop, cypromid, diflufenican, etobenzanid, fenasulam, where control of undesirable vegetation is desirable. Another flufenacet, flufenican, mefenacet, mefluidide, metamifop, use is the control of unwanted vegetation in crops such as monalide, naproanilide, pentanochlor, picolinafen and propa corn, rice and cereals. They can also be used to control unde nil, arylalanine herbicides such as benzoylprop, flamprop and sirable vegetation in tree crops such as citrus, apple, rubber, 15 flamprop-M; chloroacetanilide herbicides such as acetochlor, oil palm, forestry and others. It is usually preferred to employ alachlor, butachlor, butenachlor, delachlor, diethatyl, dimeth the compounds postemergence. It is further usually preferred achlor, metaZachlor, metolachlor, S-metolachlor, preti to use the compounds to control a wide spectrum of woody lachlor, propachlor, propisochlor, prynachlor, terbuchlor, the plants, broadleaf and grass weeds, and sedges. Use of the nylchlor and xylachlor; sulfonanilide herbicides such as compounds to control undesirable vegetation in established benZofluor, perfluidone, pyrimisulfan and profluaZol; Sul crops is especially indicated. While each of the 2-(substi fonamide herbicides such as asulam, carbasulam, fenasulam tuted)-6-amino-5-(alkyl, alkenyl or alkynyl)-4-pyrimidin and oryzalin; antibiotic herbicides such as bilanafos; benzoic ecarboxylate and 6-(substituted)-4-amino-3-(alkyl, alkenyl acid herbicides such as chloramben, dicamba,2,3,6-TBA and or alkynyl) picolinic compounds encompassed by Formula I tricamba; pyrimidinyloxybenzoic acid herbicides Such as is within the scope of the invention, the degree of herbicidal 25 bispyribac and pyriminobac, pyrimidinylthiobenzoic acid activity, the crop selectivity, and the spectrum of weed control herbicides such as pyrithiobac; phthalic acid herbicides such obtained varies depending upon the Substituents present. An as chlorthal; picolinic acid herbicides such as aminopyralid, appropriate compound for any specific herbicidal utility can clopyralid and picloram; quinolinecarboxylic acid herbicides be identified by using the information presented herein and Such as quinclorac and quinmerac, arsenical herbicides Such routine testing. 30 as cacodylic acid, CMA, DSMA, hexaflurate, MAA, The term herbicide is used herein to mean an active ingre MAMA, MSMA, potassium arsenite and sodium arsenite: dient that kills, controls or otherwise adversely modifies the benzoylcyclohexanedione herbicides such as mesotrione, growth of plants. An herbicidally effective or vegetation con sulcotrione, tefuryltrione and tembotrione; benzofuranyl trolling amount is an amount of active ingredient which alkylsulfonate herbicides such as benfuresate and ethofume causes an adversely modifying effect and includes deviations 35 sate; carbamate herbicides such as asulam, carboxazole chlo from natural development, killing, regulation, desiccation, rprocarb, dichlormate, fenasulam, karbutilate and terbucarb: retardation, and the like. The terms plants and vegetation carbanilate herbicides such as barban, BCPC, carbasulam, include germinant seeds, emerging seedlings and established carbetamide, CEPC, chlorbufam, chlorpropham, CPPC, des Vegetation. medipham, phenisopham, phenmedipham, phenmedipham Herbicidal activity is exhibited by the compounds of the 40 ethyl, propham and Swep; cyclohexene oxime herbicides present invention when they are applied directly to the plant Such as alloxydim, butroxydim, clethodim, cloproxydim, or to the locus of the plant at any stage of growth or before cycloxydim, profoxydim, Sethoxydim, tepraloxydim and planting or emergence. The effect observed depends upon the tralkoxydim; cyclopropylisoxazole herbicides such as isox plant species to be controlled, the stage of growth of the plant, achlortole and isoxaflutole; dicarboximide herbicides such as the application parameters of dilution and spray drop size, the 45 benzfendizone, cinidon-ethyl, flumezin, flumiclorac, flumi particle size of Solid components, the environmental condi oxazin and flumipropyn, dinitroaniline herbicides such as tions at the time of use, the specific compound employed, the benfluralin, butralin, dinitramine, ethalfluralin, fluchloralin, specific adjuvants and carriers employed, the Soil type, and isopropalin, methalpropalin, nitralin, oryzalin, pendimetha the like, as well as the amount of chemical applied. These and lin, prodiamine, profluralin and trifluralin; dinitrophenolher other factors can be adjusted as is known in the art to promote 50 bicides Such as dinofenate, dinoprop, dinosam, dinoseb, non-selective or selective herbicidal action. Generally, it is dinoterb, DNOC, etinofen and medinoterb; diphenyl ether preferred to apply the compounds of Formula I postemer herbicides such as ethoxyfen; nitrophenyl ether herbicides gence to relatively immature undesirable vegetation to Such as acifluorfen, aclonifen, bifenox, chlomethoxyfen, achieve the maximum control of weeds. chlornitrofen, etnipromid, fluorodifen, fluoroglycofen, fluo Application rates of about 1 to about 1,000 g/Ha are gen 55 ronitrofen, fomesafen, furyloxyfen, halosafen, lactofen, erally employed in postemergence operations; for preemer nitrofen, nitrofluorfen and oxyfluorfen: dithiocarbamate her gence applications, rates of about 10 to about 2,000 g/Haare bicides such as dazomet and metam; halogenated aliphatic generally employed. The higher rates designated generally herbicides such as alorac, chloropon, dalapon, flupropanate, give non-selective control of a broad variety of undesirable hexachloroacetone, iodomethane, methyl bromide, Vegetation. The lower rates typically give selective control 60 monochloroacetic acid, SMA and TCA; imidazolinone her and can be employed in the locus of crops. bicides such as imazamethabenZ, imaZamox, imazapic, The herbicidal compounds of the present invention are imazapyr, imaZaquin and imazethapyr; inorganic herbicides often applied in conjunction with one or more other herbi Such as ammonium Sulfamate, borax, calcium chlorate, cop cides to control a wider variety of undesirable vegetation. per Sulfate, ferrous Sulfate, potassium azide, potassium cyan When used in conjunction with other herbicides, the presently 65 ate, Sodium azide, Sodium chlorate and Sulfuric acid; nitrile claimed compounds can be formulated with the other herbi herbicides such as bromobonil, bromoxynil, chloroxynil, cide or herbicides, tank mixed with the other herbicide or dichlobenil, iodobonil, ioxynil and pyraclonil; organophos US 7,786,044 B2 11 12 phorus herbicides such as amiprofoS-methyl, anilofos, ben pyrazosulfuron, rimsulfuron, Sulfometuron, Sulfosulfuron Sulide, bilanafos, butamifos, 2,4-DEP, DMPA, EBEP, fos and trifloxysulfuron; triazinylsulfonylurea herbicides such as amine, glufosinate, glyphosate and piperophos; phenoxy chlorSulfuron, cinosulfuron, ethametSulfuron, iodosulfuron, herbicides such as bromofenoxim, clomeprop, 2,4-DEB, 2,4- metsulfuron, prosulfuron, thifensulfuron, triasulfuron, tribe DEP, difenopenten, disul, erbon, etnipromid, fenteracol and nuron, triflusulfuron and tritosulfuron; thiadiazolylurea her trifopsime; phenoxyacetic herbicides such as 4-CPA, 2,4-D, bicides such as buthiuron, ethidimuron, tebuthiuron, thiaz 3,4-DA, MCPA, MCPA-thioethyl and 2,4,5-T: phenoxybu afluoron and thidiaZuron; and unclassified herbicides such as tyric herbicides such as 4-CPB, 2,4-DB,3,4-DB, MCPB and acrolein, allyl alcohol, azafenidin, benazolin, bentaZone, ben 2,4,5-TB; phenoxypropionic herbicides such as cloprop, Zobicyclon, buthidazole, calcium cyanamide, cambendichlor, 4-CPP, dichlorprop, dichlorprop-P, 3,4-DP, fenoprop, meco 10 chlorfenac, chlorfemprop, chlorflurazole, chlorflurenol, cin propand mecoprop-P; aryloxyphenoxypropionic herbicides methylin, clomazone, CPMF, cresol, ortho-dichlorobenzene, Such as chlorazifop, clodinafop, clofop, cyhalofop, diclofop, dimepiperate, endothal, fluoromidine, fluridone, fluorochlo fenoxaprop, fenoxaprop-P, fenthiaprop, fluazifop, fluazifop ridone, flurtamone, fluthiacet, indanofan, methazole, methyl P. haloxyflop, haloxyfop-P, isoxapyrifop, metamifop, pro isothiocyanate, nipyraclofen, OCH, oxadiargyl, oxadiazon, paquizafop, quizalofop, quizalofop-P and trifop; phenylene 15 oxaziclomefone, pentachlorophenol, pentoxaZone, phenylm diamine herbicides such as dinitramine and prodiamine; ercury acetate, pinoxaden, prosulfalin, pyribenzoxim, pyrift pyrazolylherbicides such as benzofenap, pyrazolynate, pyra alid, quinoclamine, rhodethanil, Sulglycapin, thidiazimin, tri Sulfotole, pyrazoxyfen, pyroxasulfone and toprameZone; diphane, trimeturon, tripropindan and tritac. The herbicidal pyrazolylphenyl herbicides such as fluazolate and pyraflufen; compounds of the present invention can, further, be used in pyridazine herbicides such as credazine, pyridafol and pyri conjunction with glyphosate, glufosinate, dicamba, imida date; pyridaZinone herbicides such as brompyrazon, chlo Zolinones or 2,4-D on glyphosate-tolerant, glufosinate-toler ridazon, dimidazon, flufenpyr, metflurazon, norflurazon, ant, dicamba-tolerant, imidazolinone-tolerant or 2,4-D-toler oxapyrazon and pydanon; pyridine herbicides Such as ami ant crops. It is generally preferred to use the compounds of the nopyralid, cliodinate, clopyralid, dithiopyr, fluoroxypyr, invention incombination with herbicides that are selective for haloxydine, picloram, picolinafen, pyriclor, thiazopyr and 25 the crop being treated and which complement the spectrum of triclopyr; pyrimidinediamine herbicides such as iprymidam weeds controlled by these compounds at the application rate and tioclorim; quaternary ammonium herbicides such as employed. It is further generally preferred to apply the com cyperquat, diethamquat, difenZoquat, diguat, morfamquat pounds of the invention and other complementary herbicides and paraquat; thiocarbamate herbicides such as butylate, at the same time, either as a combination formulation or as a cycloate, di-allate, EPTC, esprocarb, ethiolate, isopolinate, 30 tank mix. methiobencarb, molinate, orbencarb, pebulate, prosulfocarb, The compounds of the present invention can generally be pyributicarb, sulfallate, thiobencarb, tiocarbazil, tri-allate employed in combination with known herbicide safeners, and Vemolate; thiocarbonate herbicides such as dimexano, Such as benoxacor, benthiocarb, brassinolide, cloquintocet EXD and proxan; thiourea herbicides such as methiuron; (mexyl), cyometrinil, daimuron, dichlormid, dicyclonon, triazine herbicides Such as dipropetryn, triaziflam and trihy 35 dimepiperate, disulfoton, fenchlorazole-ethyl, fenclorim, flu droxytriazine; chlorotriazine herbicides such as atrazine, razole, fluxofenim, furilazole, isoxadifen-ethyl, mefenpyr chlorazine, cyanazine, cyprazine, eglinazine, ipazine, meso diethyl, MG 191, MON 4660, naphthalic anhydride (NA), prazine, procyazine, proglinazine, propazine, Sebuthylazine, oxabetrinil, R291.48 and N-phenyl-sulfonylbenzoic acid simazine, terbuthylazine and trietazine; methoxytriazine her amides, to enhance their selectivity. They can additionally be bicides such as atraton, methometon, prometon, secbumeton, 40 employed to control undesirable vegetation in many crops simeton and terbumeton; methylthiotriazine herbicides such that have been made tolerant to or resistant to them or to other as ametryn, aZiprotryne, cyanatryn, desmetryn, dimetham herbicides by genetic manipulation or by mutation and selec etryn, methoprotryne, prometryn, simetryn and terbutryn; tri tion. For example, corn, wheat, rice, soybean, Sugarbeet, cot aZinone herbicides Such as ametridione, amibuzin, hexazi ton, canola, and other crops that have been made tolerant or none, isomethiozin, metamitron and metribuzin, triazole 45 resistant to compounds that are acetolactate synthase inhibi herbicides such as amitrole, cafenstrole, epronaz and tors in sensitive plants can be treated. Many glyphosate and flupoxam, triazolone herbicides such as amicarbazone, ben glufosinate tolerant crops can be treated as well, alone or in carbazone, carfentraZone, flucarbazone, propoxycarbazone, combination with these herbicides. Some crops (e.g. cotton) SulfentraZone and thiencarbazone-methyl, triazolopyrimi have been made tolerant to auxinic herbicides such as 2.4- dine herbicides such as cloranSulam, dicloSulam, florasulam, 50 dichlorophenoxyacetic acid. These herbicides may be used to flumetSulam, metoSulam, penoXSulam and pyroxSulam; treat Such resistant crops or other auxin tolerant crops. uracil herbicides Such as butafenacil, bromacil, flupropacil, While it is possible to utilize the 2-(substituted)-6-amino isocil, lenacil and terbacil; 3-phenyluracils; urea herbicides 5-(alkyl, alkenyl or alkynyl)-4-pyrimidinecarboxylate and Such as benzthiaZuron, cumyluron, cycluron, dichloralurea, 6-(Substituted)-4-amino-3-(alkyl, alkenyl or alkynyl) picoli diflufenZopyr, isonoruron, isouron, methabenzthiazuron, 55 nate compounds of Formula I directly as herbicides, it is monisouron and noruron; phenylurea herbicides such as ani preferable to use them in mixtures containing an herbicidally Suron, buturon, chlorbromuron, chloreturon, chlorotoluron, effective amount of the compound along with at least one chloroXuron, daimuron, difenoXuron, dimefuron, diuron, agriculturally acceptable adjuvant or carrier. Suitable adju fenuron, fluometuron, fluothiuron, isoproturon, linuron, vants or carriers should not be phytotoxic to valuable crops, methiuron, methyldymron, metobenzuron, metobromuron, 60 particularly at the concentrations employed in applying the metoxuron, monolinuron, monuron, neburon, parafluoron, compositions for selective weed control in the presence of phenobenzuron, Siduron, tetrafluoron and thidiaZuron; pyri crops, and should not react chemically with the compounds of midinylsulfonylurea herbicides such as amidosulfuron, azim Formula I or other composition ingredients. Such mixtures Sulfuron, benSulfuron, chlorimuron, cyclosulfamuron, ethox can be designed for application directly to weeds or their ysulfuron, flazasulfuron, flucetosulfuron, flupyrsulfuron, 65 locus or can be concentrates or formulations that are normally foramsulfuron, halosulfuron, imaZoSulfuron, mesosulfuron, diluted with additional carriers and adjuvants before applica nicosulfuron, orthosulfamuron, oxasulfuron, primisulfuron, tion. They can be solids, such as, for example, dusts, granules, US 7,786,044 B2 13 14 water dispersible granules, or wettable powders, or liquids, The diluted compositions usually applied to weeds or the Such as, for example, emulsifiable concentrates, Solutions, locus of weeds generally contain about 0.0001 to about 1 emulsions or Suspensions. weight percent active ingredient and preferably contain about Suitable agricultural adjuvants and carriers that are useful 0.001 to about 0.05 weight percent. in preparing the herbicidal mixtures of the invention are well known to those skilled in the art. The present compositions can be applied to weeds or their Liquid carriers that can be employed include water, tolu locus by the use of conventional ground or aerial dusters, ene, Xylene, petroleum naphtha, crop oil, acetone, methyl sprayers, and granule applicators, diffusion in standing water, ethyl ketone, cyclohexanone, trichloroethylene, perchloroet by addition to irrigation water, and by other conventional hylene, ethyl acetate, amyl acetate, butyl acetate, propylene 10 means known to those skilled in the art. glycol monomethyl ether and diethylene glycol monomethyl The following Examples are presented to illustrate the ether, methanol, ethanol, isopropanol, amyl alcohol, ethylene various aspects of this invention and should not be construed glycol, propylene glycol, glycerine, N-methyl-2-pyrrolidi as limitations to the claims. none, N,N-dimethyl alkylamides, dimethyl sulfoxide, liquid 15 fertilizers and the like. Water is generally the carrier of choice EXAMPLES for the dilution of concentrates. Suitable solid carriers include talc, pyrophyllite clay, silica, 1. Preparation of 4-Chloro-2,5-difluorophenylamine attapulgus clay, kaolin clay, kieselguhr, chalk, diatomaceous earth, lime, calcium carbonate, bentonite clay, Fuller's earth, cotton seed hulls, wheat flour, soybean flour, pumice, wood flour, walnut shell flour, lignin, and the like. It is usually desirable to incorporate one or more surface active agents into the compositions of the present invention. 25 Such surface-active agents are advantageously employed in C F both solid and liquid compositions, especially those designed to be diluted with carrier before application. The surface active agents can be anionic, cationic or nonionic in character Tin (II) chloride dihydrate (15.5 g. 68.7 mmol) was dis and can be employed as emulsifying agents, wetting agents, 30 solved in ethyl acetate (50 mL) and 1-chloro-2,5-difluoro-4- Suspending agents, or for other purposes. Typical Surface nitrobenzene (2.65 g, 13.7 mmol) was added dropwise. The active agents include salts of alkylsulfates, such as diethanol reaction mixture was then stirred at 70° C. for 1 h. The ammonium lauryl Sulfate; alkylarylsulfonate salts, such as reaction mixture was then carefully added to saturated aque calciumdodecyl-benzenesulfonate; alkylphenol-alkylene ous sodium bicarbonate and extracted with ethyl acetate. The oxide addition products, such as nonylphenol-Cs ethoxylate: 35 organic phase was washed several more times with water, alcohol-alkylene oxide addition products, such as tridecyl dried, filtered, concentrated and purified by flash chromatog alcohol-Cethoxylate: Soaps, such as sodium Stearate; alky raphy on silica gel (hexane/diethyl ether) to give the title lnaphthalene-Sulfonate salts, such as Sodium dibutylnaphtha compound as a white solid (1.65 g, 73.9% yield): 'H NMR lenesulfonate; dialkyl esters of SulfoSuccinate salts, such as 40 (CDC1) & 7.02 (dd. 1H), 6.57 (dd. 1H), 3.81 (brs, 2H). sodium di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as Sorbitol oleate; quaternary amines, such as lauryl trim 2. Preparation of ethyl-ammonium chloride; polyethylene glycol esters offatty 1-Bromo-4-chloro-2,5-difluorobenzene acids, such as poly-ethylene glycol Stearate; block copoly mers of ethylene oxide and propylene oxide; and salts of 45 mono and dialkyl phosphate esters. Other adjuvants commonly used in agricultural composi tions include compatibilizing agents, antifoam agents, sequestering agents, neutralizing agents and buffers, corro 50 C F sion inhibitors, dyes, odorants, spreading agents, penetration aids, Sticking agents, dispersing agents, thickening agents, freezing point depressants, antimicrobial agents, and the like. Anhydrous copper (II) bromide (2.7 g, 12.1 mmol) and The compositions may also contain other compatible compo t-butyl nitrite (1.56 g. 15.1 mmol) were combined in anhy nents, for example, other herbicides, plant growth regulants, 55 drous acetonitrile (25 mL). The resulting mixture was heated fungicides, insecticides, and the like and can be formulated to 65° C. and a solution of 4-chloro-2,5-difluoro-pheny with liquid fertilizers or solid, particulate fertilizer carriers lamine (1.65 g, 10.1 mmol) in anhydrous acetonitrile (2 mL) Such as ammonium nitrate, urea and the like. was added dropwise (vigorous gas evolution was noted). The concentration of the active ingredients in the herbi After the reaction mixture cooled to ambient temperature, it cidal compositions of this invention is generally from about 60 0.001 to about 98 percent by weight. Concentrations from was added to 2N HCl and extracted twice with diethyl ether. about 0.01 to about 90 percent by weight are often employed. The organic extracts were then combined, washed with 2N In compositions designed to be employed as concentrates, the HCl, washed with saturated sodium bicarbonate, dried, con active ingredient is generally present in a concentration from centrated and purified by flash chromatography on silica gel about 5 to about 98 weight percent, preferably about 10 to 65 (hexanes) to give the title compound as a white solid (1.11 g, about 90 weight percent. Such compositions are typically 48.4% yield): 'H NMR (CDC1) & 7.38 (dd, 2H), 7.21 (dd, diluted with an inert carrier, Such as water, before application. 2H). US 7,786,044 B2 15 16 3. Preparation of 2-(4-Chloro-2,5-difluorophenyl)-4, acetone (50 mL) and concentrated by rotary evaporation. The 4.5,5-tetramethyl-1,3,2-dioxaborolane residue was partitioned between ethyl acetate and water. The organic phase was dried and concentrated to yield the title compound (10 g, 99% yield) as a white solid: "H NMR (CDC1) & 7.75 (d. 1H), 7.32 (m, 1H), 7.19 (m, 1H), 5.23 (q, 1H), 1.95 (d. 1H), 1.48 (d. 3H). O Another compound prepared by the procedure of Example F BNo. 4 is: 10

C F

1-Bromo-4-chloro-2,5-difluorobenzene (1.11 g, 4.9 15 C F mmol) was dissolved in tetrahydrofuran (THF: 15 mL) and cooled to -10°C. A 2.0M solution of isopropyl-magnesium chloride (2.7 mL, 5.4 mmol) in THF was added dropwise via HO syringe. The reaction mixture was stirred at -10°C. for 1 h, allowed to warm toward 0°C. for 1 h, then cooled again to -10°C. A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3, 1-(2-Chloro-6-fluorophenyl)ethanol: "H NMR (300 MHz, 2-dioxaborolane (1.0 g, 5.4 mmol) in THF (1.0 mL) was then CDC1) & 7. 14-7.22 (m, 2H), 6.99 (m. 1H), 5.38 (m, 1H), 2.48 added dropwise and the reaction mixture was allowed to (m. 1H), 1.63 (dd. 3H, J=1, 7 Hz). warm to ambient temperature. The reaction mixture was then added to diethyl ether and extracted with 1N sodium hydrox 25 ide twice. The aqueous phases were combined, acidified to 5. Preparation of pH 3 with concentrated HCl, and extracted with dichlo 4-Bromo-1-chloro-2-(1-fluoroethyl)-benzene romethane twice. The organic phases were combined, dried, filtered and concentrated to give the title compound (0.97g, 72.3% yield) that was used without further purification: 'H 30 NMR (CDC1) & 7.45 (dd. 1H), 7.09 dd, 1H), 1.36 (s, 12H). Another compound prepared by the procedure of Example Br 3 is:

35 C

40 Bis(2-methoxyethyl)aminosulfur trifluoride (4.5g, 20.34 mmol) was added to a stirred solution of 1-(5-bromo-2-chlo C F rophenyl)ethanol (3.99 g, 16.95 mmol) in dichloromethane (50 mL) at 0°C. The resulting solution was stirred at 0°C. for 3 h. The reaction mixture was quenched with a 5% solution of 2-(4-Chloro-2-fluoro-5-methylphenyl)-4,4,5,5-tetramethyl 45 aqueous sodium bicarbonate (100 mL) and the resulting bub 1,3,2-dioxaborolane: "H NMR (CDC1) & 7.58 (d. 1H), 7.03 bling biphasic reaction mixture was vigorously stirred at 0°C. (d. 1H), 2.32 (s.3H), 1.35 (s, 12H). for 15 min. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane twice. The com 4. Preparation of 50 bined organic layers were washed with 1M hydrochloric acid, 1-(5-Bromo-2-chlorophenyl)-ethanol dried and concentrated by rotary evaporation. The product was purified by flash chromatography on silica gel (hexanes) to yield the title compound (2.65 g, 11.16 mmol. 65.8% yield) as a clear oil: "H NMR (CDC1) & 7.65 (d. 1H), 7.37 (m. 1H), Br 55 7.20 (m. 1H), 5.88 (dq, 1H), 1.61 (dd. 3H). Another compound prepared by the procedure of Example 5 is: C

60 HO

Sodium borohydride (1.182 g, 51.4 mmol) was added to a stirred solution of 1-(5-bromo-2-chlorophenyl)ethanone (10 C F g, 42.8 mmol) in methanol at 0°C. The resulting bubbling 65 white mixture was allowed to warm to ambient temperature and stirred for 2 h. The reaction mixture was quenched with US 7,786,044 B2 17 18 1-Chloro-3-fluoro-2-(1-fluoroethyl)benzene: "H NMR (300 Another compound prepared by the procedure of Example MHz, CDC1) & 7.15-7.26 (m, 2H), 7.02 (m, 1H), 6.12 (dq, 7 is: 1H, J–6, 46 Hz), 1.76 (ddd, 3H, J=1, 7, 23 Hz). 6. Preparation of 1-Chloro-2-difluoromethoxy-3-fluorobenzene

10 C F

C F 1N F O 15 6-Chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro F lan-2-yl)phenyl)-dimethylamine: "H NMR (CDC1) & 7.35 (m. 1H), 7.13 (m, 1H), 2.85 (d. 6H), 1.36 (s, 12H). 2-Chloro-6-fluorophenol (1.8 g. 12.33 mmol) was dis solved in dimethylformamide (DMF; 22 mL) and water (2.2 mL). Potassium carbonate (2.55 g, 18.5 mmol) and sodium 8. Preparation of 2-(4-Chloro-2,3-difluorophenyl)-4, chlorodifluoroacetate (4.7g, 30.8 mmol) were then added and 4.5.5-tetramethyl-1,3,2-dioxaborolane the solution was heated to 100° C. for 3 h. The cooled reaction mixture was then diluted with concentrated HCl (10 mL) and 25 the resulting solution was stirred for 2 h. The reaction mixture was diluted with diethyl ether, washed with water, washed twice with 1MNaOH, washed once with brine, dried, filtered and concentrated under vacuum to yield the title compound (1 30 g, 41% yield) that was used in Subsequent reactions without further purification. C F

7. Preparation of 2-4-Chloro-3-(1-fluoroethyl)phe 35 nyl-4-4.55-tetramethyl-1,3,2-dioxaborolane A 2.5M solution of n-butyllithium (2.69 ml, 6.73 mmol) in hexanes was added dropwise to a solution of 1-chloro-2,3- difluorobenzene (1 g, 6.73 mmol) in THF (25 mL) cooled to 40 -78°C. After 45 min at -78°C. 2-isopropoxy-4,4,5,5-tet ramethyl-1,3,2-dioxaborolane (1.253 g. 6.73 mmol) was added dropwise after which the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was 45 diluted with water and ethyl acetate, and the organic phase was extracted twice with water. The aqueous extracts were C combined, acidified with 12NHCl to pH3, and extracted with ethyl acetate. The organic extract was dried and concentrated under vacuum to yield the title compound as an oil product 50 (0.93 g, 50% yield): 'H NMR (CDC1) & 7.42 (m, 1H), 7.17 (m. 1H), 1.37 (s, 12H). 4-Bromo-1-chloro-2-(1-fluoroethyl)benzene (2.55 g, Another compound prepared by the procedure of Example 10.74 mmol) was dissolved in dry diethyl ether (50 mL) and 8 is: cooled to -75° C. n-Butyllithium (4.72 mL, 11.81 mmol) was added dropwise keeping the temperature below -70° C. The 55 reaction mixture was then stirred for 15 min, then 2-isopro poxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.197 g. 11.81 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was then diluted with water and diethyl ether. The aqueous phase 60 was acidified with 12N HCl and the product was then extracted with diethyl ether. The organic phase was dried and concentrated under vacuum to yield the title compound (1.55 g, 5.45 mmol, 50.7% yield) as a white solid: "H NMR 65 (CDC1) & 7.94 (d. 1H), 7.65 (m. 1H), 7.36 (m. 1H), 5.96 (dq, 1H), 1.64 (dd. 3H), 1.34 (s, 12H). US 7,786,044 B2 19 20 2-(4-Chloro-3-difluoromethoxy-2-fluorophenyl)-4.4.5.5- 11. Preparation of tetramethyl-1,3,2-dioxaborolane: "HNMR (CDC1) & 7.1 (m, 2,6-Dichloro-5-iodopyrimidine-4-carboxylic acid 1H), 7.02 (m, 1H), 6.8 (t, 1H), 1.23 (s, 12H). methyl ester

9. Preparation of 2-(4-Chloro-2-fluoro-3-(1-fluoroet hyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

10

5-Iodo-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-car 15 boxylic acid methyl ester (5.0 g, 17 mmol) was added to POCl (30 mL), treated with 0.5 mL DMF and heated to reflux C F for 3h. The excess POCl was removed under vacuum and the residue was stirred with ice and extracted with dichlo romethane. The dichloromethane extract was washed with water, dried and evaporated. The residue was chromato graphed on silica (5-15% ethyl acetate/hexane) to give the A 2.5M solution of n-butyllithium (13 mL, 33 mmol) was title compound (2.7g, 48% yield). MS: m/z 332. added to a stirred solution of diisopropylamine (5.0 mL. 35 12. Preparation of mmol) in THF (50 mL) at -78°C. The resulting colorless 6-Amino-2-chloro-5-iodopyrimidine-4-carboxylic solution was stirred at -78°C. for 20 min, warmed to 0°C. for 25 acid methyl ester 20 min, and then cooled back to -78°C. for 20 min. A solution of 1-chloro-3-fluoro-2-(1-fluoroethyl)benzene (4.8 g. 27 mmol. 1.0 equiv) in THF (20 mL) at -78°C. was transferred to the base solution via cannula. The resulting dark brown 30 solution was stirred at -78°C. for 2 h. 2-Isopropoxy-4.4.5.5- tetramethyl-1,3,2-dioxaborolane (8.3 mL, 41 mmol. 1.5 equiv) was added and the brown solution was slowly warmed to 23° C. over 20 h. The reaction mixture was diluted with 0.1M hydrochloric acid (300 mL) and extracted with dichlo 35 romethane thrice. The combined organic extracts were dried, 2,6-Dichloro-5-iodopyrimidine-4-carboxylic acid methyl filtered and concentrated by rotary evaporation to afford the ester (12g, 36 mmol) was dissolved in dry dimethylsulfoxide title compound as a brown oil that solidified into a semi-solid (DMSO; 100 mL) and treated with a stream of ammonia at upon standing (7.7 g., 94% yield). "H NMR (300 MHz, such a rate when combined with external water bath cooling 40 to keep the temperature in the range of 20-30°C. After 90 CDC1) & 7.62 (m. 1H), 7.17 (m. 1H), 6.13 (dq, 1H, J–6, 46 min, the ammonia addition was complete and excess ammo Hz), 1.75 (ddd, 3H, J=1, 7, 23 Hz), 1.36 (s, 12H). nia was removed from the mixture by Sparging with a stream of nitrogen for 20 min. The mixture was poured into water 10. Preparation of 5-Iodo-2,6-dioxo-1,2,3,6-tetrahy (200 mL) with stirring and the precipitated product was dropyrimidine-4-carboxylic acid methyl ester 45 extracted with ethyl acetate (75 mL) twice. The combined ethyl acetate extracts were washed twice with water (50 mL), once with saturated NaCl solution, dried and evaporated to give the title compound (10g, 89% yield) that was used without further purification. MS: M/Z=313. 50 13. Preparation of 6-Amino-2-chloro-5-vinylpyrimidine-4-carboxylic acid methyl ester

55

Methyl orotate (20.0 g, 118 mmol) was combined with iodine (12.8 g. 50 mmol) and periodic acid (4.8 g., 21 mmol) in methanol (250 mL) and heated at reflux for 20 h. After 60 cooling to ambient temperature, the Volatiles were removed by rotary evaporation. The solid residue was slurried in water, collected by filtration, washed well with water and dried under vacuum at 70° C. to provide the title compound (34g, 65 97% yield) as a solid. It was used without further purification. 6-Amino-2-chloro-5-iodopyrimidine-4-carboxylic acid MS: m/Z=296. methyl ester (10g, 32 mmol) was dissolved in 1,2-dichloro US 7,786,044 B2 21 22 ethane (100 mL), treated with vinyltributylstannane (11.6 palladium(II) dichloride (842 mg, 1.2 mmol) were combined mL, 12.6 g., 40 mmol) and sparged with a nitrogen stream for in 12 mL of 1,2-dimethoxyethane and 12 mL of water. The 10 min. Bis(triphenylphosphine)palladium(II) dichloride reaction mixture was heated at 80° C. for 2 hand the cooled (1.1 g, 1.6 mmol, 5 mole %) was added and the mixture was reaction mixture was partitioned between ethyl acetate and heated at reflux under a nitrogen atmosphere for 3 h. The mixture was cooled, stirred with 10% aqueous KHF for 30 water. The organic phase was washed with water, dried, and min, and filtered through diatomaceous earth to remove sol concentrated under vacuum. The product was purified by ids. The filter cake was washed with more 1,2-dichloroethane flash chromatography on silica gel to yield the title compound and ethyl acetate. The combined filtrates were washed with (2.0 g, 53.5% yield); mp 188-190° C.: "H NMR (CDC1) & water, washed with saturated NaHCO, washed with brine, 10 7.66 (dd. 1H), 7.22 (dd. 1H), 7.14 (s, 1H), 5.25 (brs, 2H), 4.0 dried, and evaporated. The crude material was chromato (s, 3H), 3.99 (s.3H). graphed on silica (5-20% ethyl acetate/dichloromethane con Other compounds prepared by the method of Example 15 taining 2% acetic acid) to give the title compound (4.5g, 70% include: yield). This material contained approximately 5% PPhs, but was used without further purification. MS: m/z 213. "H 15 6-Amino-2-(4-chloro-2-fluorophenyl)pyrimidine-4-car NMR (CDC1,) 86.77 (dd. 1H), 6.4(br2H), 5.70 (d. 1H), 5.61 boxylic acid methyl ester: mp 192-194°C. (d. 1H). 6-Amino-2-(4-chlorophenyl)pyrimidine-4-carboxylic acid 14. Preparation of methyl ester: mp decompose above 195°C. 6-Amino-2-chloropyrimidine-4-carboxylic acid 6-Amino-2-(4-chloro-3-methoxyphenyl)pyrimidine-4-car methyl ester boxylic acid methyl ester: mp 210-213°C. 6-Amino-2-(4-chloro-2-fluoro-5-methoxyphenyl)pyrimi dine-4-carboxylic acid methyl ester: mp 218-220° C. 25 16. Preparation of 6-Amino-5-bromo-2-(4-chloro-2- fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylic acid methyl ester 30 Ammonia was slowly bubbled through a solution of 2,6- dichloro-pyrimidine-4-carboxylic acid methyl ester (20.0 g, NH2 97 mmol, see H. Gershon, J. Org. Chem. 1962,27,3507-3510 Br for preparation) in DMSO (100 mL) cooled with an ice bath 35 N1N to maintain the temperature below 70° C. When the tempera O ture of the reaction solution began to decline, no additional N N ammonia was added. When the temperature of the reaction solution reached 44°C., the ice bath was removed. When the O temperature of the reaction solution reached 32°C., the reac 40 C F tion mixture was diluted with 200 mL of water and filtered. The filtered product was washed with water, washed with O N ethyl acetate, and dried under vacuum to provide the title compound (14.4g, 79% yield) that was used without further purification. Flash chromatography on silica gel yielded an 45 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimi analytically pure sample of the title compound: "H NMR dine-4-carboxylic acid methyl ester (778 mg, 2.5 mmol) and (DMSO-d) & 7.7 (brs, 2H), 7.00 (s, 1H), 3.84 (s.3H). N-bromosuccinimide (489 mg, 2.75 mmol) were combined in chloroform (10 mL) and heated at reflux for 12 h. The cooled 15. Preparation of 6-Amino-2-(4-chloro-2-fluoro-3- reaction mixture was concentrated and the product was puri methoxyphenyl)-pyrimidine-4-carboxylic acid 50 fied by flash chromatography on silica gel to yield the title methyl ester compound (752 mg, 77% yield): mp 173-175° C.: "H NMR (CDC1) & 7.66 (dd. 1H), 7.24 (dd. 1H), 5.73 (brs, 2H), 4.03 NH2 (s, 3H), 4.01 (d. 3H). N1N 55 Other compounds prepared by the method of Example 16 include: 2 O N N 6-Amino-5-bromo-2-(4-chloro-2-fluorophenyl)pyrimidine

O 4-carboxylic acid methyl ester: mp 186-188° C. C F 60 6-Amino-5-bromo-2-(4-chlorophenyl)pyrimidine-4-car ON boxylic acid methyl ester: mp: decompose above 154°C. 6-Amino-5-bromo-2-(4-chloro-3-methoxyphenyl)pyrimi dine-4-carboxylic acid methyl ester: mp 146-151° C. 6-Amino-2-chloropyrimidine-4-carboxylic acid methyl 65 ester (2.25 g, 12 mmol, 4-chloro-2-fluoro-3-methoxyphenyl 6-Amino-5-bromo-2-(4-chloro-2-fluoro-5-methoxyphenyl) boronic acid (3.27g, 16 mmol), and bis(triphenylphosphine) pyrimidine-4-carboxylic acid methyl ester: mp 197-200° C. US 7,786,044 B2 23 24 17. Preparation of 6-Amino-2-cyclopropyl-5-meth 6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphe ylpyrimidine-4-carboxylic acid ethyl ester (Com nyl)-pyrimidine-4-carboxylic acid methyl ester (1.5 g, 3.84 pound 1) mmol), tributyl (vinyl)tin (2.436 g, 7.68 mmol), bis(triph enylphosphine)palladium(II) dichloride (0.270 g., 0.384 mmol) were combined in 1,2-dichloroethane (4 mL) and NH2 heated at 130° C. for 15 minina CEM microwave reactor. The cooled reaction mixture was concentrated onto silica gel and N purified by flash chromatography on silica gel (ethyl acetate/ hexane gradient) to yield the title compound (1.06 g. 82% yield): mp 145-147°C.: "H NMR (CDC1) & 7.64 (m. 1H), - 9N-1 7.22 (m, 1H), 6.84 (dd. 1H), 5.68 (m, 2H), 5.43 (brs, 2H), O 3.99 (d. 3H), 3.95 (s, 3H). 6-Amino-5-bromo-2-cyclopropylpyrimidine-4-carboxy 15 Other compounds prepared by the method of Example 18 lic acid ethyl ester (300 mg, 1.05 mmol; see WO 2005/063721 include: A1 for preparation), tetramethyltin (93.7 mg, 5.24 mmol), and bis(triphenylphosphine)palladium(II) dichloride (74 mg. 0.105 mmol) were combined in 5 mL of 1,2-dichloroethane NH2 and heated in a CEM microwave reactor at 150° C. for 20 min. The resulting reaction mixture was filtered and concentrated. The product was purified by flash chromatography on silica N gel (ethyl acetate/hexane gradient) followed by a purification by reverse phase chromatography to yield the title compound (116 mg, 50% yield):mp 130-132° C.: "H NMR (DMSO-d) 25 v- 4. 9N-1 8 6.85 (brs, 2H), 4.27 (q, 2H), 1.94 (s.3H), 1.87(m, 1H), 1.28 O (t, 3H), 0.84 (d. 4H). Another compound prepared by the method of Example 17 1S 30 6-Amino-2-cyclopropyl-5-vinylpyrimidine-4-carboxylic acid ethyl ester (Compound 4): mp 155-157° C.: "H NMR NH2 (CDC1) & 6.69 (dd. 1H), 5.57 (dd. 1H), 5.52 (dd. 1H), 5.13 (brs, 1H), 4.39 (1, 2H), 2.07 (m. 1H), 1.38 (t, 3H), 1.07 (m, 35 2H), 0.96 (m. 1H).

C F 40 ON

6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-meth 45 ylpyrimidine-4-carboxylic acid methyl ester (Compound 2): C F mp 168-170° C.: "H NMR (CDC1,) & 7.60 (m, 1H), 7.21 (m, 1H), 5.21 (brs, 2H), 3.99 (d. 3H), 3.98 (s.3H), 2.29 (s.3H). 6-Amino-2-(4-chloro-2-fluorophenyl)-5-vinylpyrimidine-4- 18. Preparation of 6-Amino-2-(4-chloro-2-fluoro-3- 50 methoxyphenyl)-5-vinylpyrimidine-4-carboxylic carboxylic acid methyl ester (Compound 5): mp 137-139°C.: acid methyl ester (Compound 3) "H NMR (CDC1,) & 7.96 (m, 1H), 7.20 (m. 2H), 6.83 (dd. 1H), 5.67 (m, 2H), 5.42 (brs, 2H), 3.95 (s.3H).

55

60

C F C

65 6-Amino-2-(4-chlorophenyl)-5-vinylpyrimidine-4-carboxy lic acid methyl ester (Compound 6): mp 164-167° C. "H US 7,786,044 B2 25 26 NMR (CDC1) & 8.3 (m, 2H), 7.40 (m, 2H), 6.80 (m, 1H), 5.6 (m. 2H), 5.37 (brs, 2H), 3.96 (s, 3H).

N1 N 1S 4 O N

O C F

C ON

15 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(1- ethoxyvinyl)pyrimidine-4-carboxylic acid methyl ester (Compound 10): 'H NMR (CDC1) & 7.62 (dd. 1H), 7.2 (dd. 6-Amino-2-(4-chloro-3-methoxyphenyl)-5-vinylpyrimi 1H), 5.62 (brs, 2H), 4.5 (dd, 2H), 3.99 (d. 3H), 3.92 (q, 2H), dine-4-carboxylic acid methyl ester (Compound 7): mp 144 3.91 (s.3H), 1.37 (t, 3H). 148° C.: "H NMR (CDC1) & 7.92 (m, 2H), 7.40 (d. 1H), 6.78 (m. 1H), 5.6 (m, 2H), 5.39 (brs, 1H), 4.01 (s, 3H), 3.96 (s, 3H). ---. 25 NH N

F N

% On C O C 4-tert-Butoxycarbonylamino-6-(4-chlorophenyl)-5-fluoro 35 3-(1-fluorovinyl)-pyridine-2-carboxylic acid methyl ester On (utilized tributyl-(1-fluorovinyl)-stannane prepared accord ing to the procedures found in Bull. Chem. Soc. Jpn. 2002, 75(11), 2497-2502): 'H NMR (CDC1,) & 7.96 (m, 2H), 7.46 (m. 2H), 6.35 (brs, 1H), 5.25 (dd. 1H), 4.85 (dd. 1H), 3.96 (s, 40 3H). This compound is the starting material for Compound 30 6-Amino-2-(4-chloro-2-fluoro-5-methoxyphenyl)-5-vi in Example 29. nylpyrimidine-4-carboxylic acid methyl ester (Compound 8): mp 161-164° C.; H NMR (DMSO-d) & 7.52 (m, 2H), 6.65 19. Preparation of 6-Amino-2-(4-chloro-2,3-difluo (m. 1H), 5.50 (m, 2H), 3.88 (s.3H), 3.81 (s.3H). rophenyl)-5-vinyl-pyrimidine-4-carboxylic acid 45 methyl ester (Compound 11)

NH2 Sr. 50 2 O N N

O C F 55 C F O N

60 6-Amino-2-chloro-5-vinylpyrimidine-4-carboxylic acid 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(1- methyl ester (0.6 g. 2.81 mmol), 2-(4-chloro-2,3-difluo fluorovinyl)pyrimidine-4-carboxylic acid methyl ester (uti rophenyl)-4,4,5,5-tetramethyl-1,3,2dioxaborolane (1.0 g, lized tributyl-(1-fluorovinyl)Stannane prepared according to 3.65 mmol), bis(triphenylphosphine)-palladium(II) dichlo the procedures found in Bull. Chem. Soc. Jpn. 2002, 75(11), ride (197 mg, 0.28 mmol), and cesium fluoride (0.85 g, 5.6 2497-2502) (Compound 9): 'H NMR (CDC1) & 7.67 (dd, 65 mmol) were combined in 10 mL of 1,2-dimethoxyethane 1H), 7.22 (dd. 1H), 5.52 (brs, 2H), 5.23 (dd. 1H), 4.9 (dd. (DME) and 10 mL of water. The reaction mixture was heated 1H), 3.99 (d. 3H), 3.95 (s.3H). in a CEM microwave reactor at 100° C. for 15 min (other

US 7,786,044 B2 30 20. Preparation of 6-Amino-2-(4-chloro-2-fluoro-3- methoxyphenyl)-5-ethyl-pyrimidine-4-carboxylic acid methyl ester (Compound 21)

10 C C

15 C F On 6-Amino-2-(2,4-dichloro-3-methoxyphenyl)-5-vinylpyrimi dine-4-carboxylic acid methyl ester (Compound 18): 'H NMR (CDC1) & 7.38 (s.2H), 6.83 (dd. 1H), 5.63-5.7 (m, 2H), 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vi 5.53 (brs, 2H), 3.92 (s.3H), 3.91 s, 3H). nyl-pyrimidine-4-carboxylic acid methyl ester (200 mg 0.7 mmol) was dissolved in ethanol (10 mL), palladium hydrox ide (20% on carbon, 50 mg) was added, and the reaction mixture was stirred under an atmosphere of hydrogen for 4 h. 25 The catalyst was then filtered off, the filtrate concentrated, and the product purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) to yield the title compound (148 mg, 62% yield): mp 144-146° C.: "H NMR (CDC1) & 7.61 (m, 1H), 7.20 (m, 1H), 5.19 (brs, 2H), 3.99 (d. 3H), 3.98 (s, 3H), 2.68 (q, 2H), 1.28 (t, 3H). C F 21. Preparation of 6-Amino-2-(4-chloro-2-fluoro-3- 1N methoxyphenyl)-5-(E)-propenyl)pyrimidine-4-car 35 boxylic acid methyl ester (Compound 22)

6-Amino-2-(4-chloro-3-dimethylamino-2-fluorophenyl)-5- vinylpyrimidine-4-carboxylic acid methyl ester (Compound 40 19): "H NMR (CDC1) & 7.57 (dd. 1H), 7.2 (dd. 1H), 6.83 (dd, 1H), 5.62-5.70 (m, 2H), 5.42 (brs, 2H), 3.94 (s.3H), 2.9 (d. 6H). 45

C F On

6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphe nyl)-pyrimidine-4-carboxylic acid methyl ester (400 mg. 1.02 mmol), trans-propenyl boronic acid (2132 mg, 1.54 C mmol), bis(triphenylphosphine)palladium(II) dichloride (72 mg, 0.1 mmol), and cesium fluoride (311 mg, 2.05 mmol) were combined in 1,2-dimethoxyethane (2 mL) and water (2 mL) and heated at 100° C. for 15 min in a CEM microwave reactor. The cooled reaction mixture was partitioned between 60 ethyl acetate and water, and the organic phase was dried and concentrated. The product was purified by flash chromatog 6-Amino-2-4-chloro-3-(1-fluoroethyl)phenyl-5-vinylpyri raphy on silica gel (hexane/ethyl acetate gradient) then puri midine-4-carboxylic acid methyl ester (Compound 20): "H fied again by reverse phase HPLC to yield the title compound: NMR (CDC1) & 8.53 (m. 1H), 8.26 (m. 1H), 7.40 (m. 1H), 65 mp 133-135° C.: "H NMR (CDC1,) & 7.63 (m, 1H), 7.22 (m, 6.78 (dd. 1H), 5.99 (dt, 1H), 5.6-5.66 (m, 2H), 5.35 (brs, 2H), 1H), 6.43 (m, 1H), 6.12 (m, 1H), 5.35 (brs, 2H), 3.99 (d. 3H), 3.95 (s.3H), 1.69 (dd, 3H). 3.94 (s.3H), 1.94 (dd. 3H). US 7,786,044 B2 31 32 Another compound prepared by the method of Example 21 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-trim is: ethyl-silanylethynylpyrimidine-4-carboxylic acid methyl ester (1.2g, 2.94 mmol) was dissolved in methanol (20 mL) and potassium carbonate (0.203 g, 1.471 mmol) was added. After 1 h stirring at ambient temperature, the precipitate that formed was filtered off, washed with methanol, dissolved in dichloromethane and washed with water. The organic phase was dried and concentrated to yield the title compound (0.410 g, 41.5% yield); mp 174-176°C.: "H NMR (CDC1,) & 7.7 (m, 1H), 7.22 (m, 1H), 5.82 (brs, 2H), 4.01 (s.3H), 4.00 (dd. 3H), 3.85 (s, 1H). C F 24. Preparation of 4-Amino-6-(4-chlorophenyl)-5- On fluoro-3-methylpyridine-2-carboxylic acid methyl 15 ester (Compound 25) 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-((Z)- propenyl)pyrimidine-4-carboxylic acid methyl ester (Com pound 23):mp 91-93° C.: "H NMR (CDC1) & 7.67 (m. 1H), 7.22 (m. 1H), 6.38 (m, 1H), 6.07 (m. 1H), 5.32 (brs, 2H), 4.0 (d. 3H), 3.93 (s.3H). 22. Preparation of 6-Amino-2-(4-chloro-2-fluoro-3- methoxyphenyl)-5-trimethylsilanylethynylpyri midine-4-carboxylic acid methyl ester 25 NH2 Y \ 4-Amino-3-chloro-6-(4-chlorophenyl)-5-fluoropyridine N1N 2-carboxylic acid methyl ester (0.400g, 1.269 mmol), tetram ethylstannane (3.41 g, 19.04 mmol), and bis(triphenylphos % O N phine)palladium(II) dichloride (0.089 g, 0.127 mmol) were combined and heated to 130° C. for 25 min in a CEM micro O wave reactor. The cooled reaction mixture was concentrated C F 35 onto silica gel and purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) to yield the title com ON pound (0.143 g, 38.2% yield): 'H NMR (CDC1) & 7.88 (m, 2H), 7.41 (m, 2H), 4.41 (brs, 2H), 3.96 (s.3H), 2.36 (s.3H). 6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphe nyl)-pyrimidine-4-carboxylic acid methyl ester (1.0g, 2.56 40 25. Preparation of 4-Acetylamino-6-(4-chloro-2- mmol), trimethyl((tributylstannyl)ethynyl)silane (1.98 g. fluoro-3-methoxyphenyl)-3-methylpyridine-2-car 5.12 mmol), and bis(triphenylphosphine)palladium(II) boxylic acid methyl ester dichloride (0.18 g., 0.256 mmol) were combined in 1,2- dichloroethane (10 mL) and heated in a CEM microwave reactor at 110° C. for 15 min. The cooled reaction mixture 45 was concentrated under vacuum then purified by flash chro matography on silica gel (dichloromethane/ethyl acetate gra dient). A second purification by flash chromatography on silica gel (hexane/ethyl acetate gradient) yielded the title compound (0.829 g, 79% yield): mp 126-128°C. 50 23. Preparation of 6-Amino-2-(4-chloro-2-fluoro-3- methoxyphenyl)-5-ethynyl-pyrimidine-4-carboxylic acid methyl ester (Compound 24) 55 NH 2 N1 N O 60 4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-methox % N yphenyl)-pyridine-2-carboxylic acid methyl ester (500 mg. 1.29 mmol), tetramethyltin (924 mg, 5.17 mmol), bis(triph O enylphosphine)palladium(II) dichloride (91 mg 0.129 C F mmol), and tetrabutylammonium triphenyldifluorosilicate 65 (1.395g, 2.58 mmol) were combined in 2 mL of acetonitrile On and heated in a CEM microwave reactor at 110°C. for 15 min. The resulting reaction mixture was filtered and concentrated. US 7,786,044 B2 33 34 This intermediate product was purified by flash chromatog 28. Preparation of 4-Acetylamino-6-(4-chloro-2- raphy on silica gel (ethyl acetate/hexane gradient) to yield the fluoro-3-methoxyphenyl)-3-vinylpyridine-2-car title compound (419 mg, 88% yield). mp 182-184°C. boxylic acid methyl ester 26. Preparation of 4-tert-Butoxycarbonylamino-3- chloro-6-(4-chlorophenyl)-5-fluoropyridine-2-car boxylic acid methyl ester

10

15

4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-methox yphenyl)pyridine-2-carboxylic acid methyl ester (0.5g, 1.29 mmol), tributyl (vinyl)tin (0.821 g, 2.58 mmol), bis(triph enylphosphine)palladium(II) dichloride (0.091 g, 0.129 4-Amino-3-chloro-6-(4-chlorophenyl)-5-fluoropyridine mmol), and tetrabutylammonium triphenyldifluorosilicate 2-carboxylic acid methyl ester (3 g, 9.5 mmol) was dissolved 25 (1.4g, 2.58 mmol) were combined in acetonitrile (3 ml) and in dichloromethane (50 mL) and di-tert-butyl dicarbonate heated to 110°C. for 15 minina CEM microwave reactor. The (4.6 g., 21 mmol) was added at ambient temperature. After 1 h, the reaction mixture was concentrated and the product was cooled reaction mixture was concentrated onto silica gel and purified by flash chromatography on silica gel (ethyl acetate/ purified by flash chromatography on silica gel (ethyl acetate/ hexane gradient). This bis-protected intermediate (3.2g, 6.2 hexane gradient) to yield the title compound (0.293 g. 60% mmol) was then dissolved in dichloromethane (25 mL) and 30 yield) as a white solid, mp 143-145° C. "H NMR (CDC1) & trifluoroacetic acid (1.42g, 12.4 mmol) was added. The reac 7.66 (m. 1H), 7.22 (d. 1H), 7.12 (m. 1H), 6.85 (dd. 1H), 5.66 tion mixture was stirred for 4 hat ambient temperature then (dd. 1H), 5.57 (dd. 1H), 4.61 (brs, 2H), 3.97 (s.3H), 3.94 (d. concentrated under vacuum. The product was purified by 3H). flash chromatography on silica gel to yield the title compound Other compounds prepared by the method of Example 28 (2 g, 4.82 mmol, 50.7% yield for the two steps) as a white 35 include: solid: "H NMR (CDC1,) & 7.91 (m, 2H), 7.43 (m, 2H), 6.48 (brs, 1H), 4.0 (s.3H), 1.55 (s, 9H). 27. Preparation of 4-Amino-6-(4-chlorophenyl)-5- fluoro-3-vinylpyridine-2-carboxylic acid methyl 40 ester (Compound 26)

45

C

4-Acetylamino-6-(4-chloro-2-fluorophenyl)-3-vinylpyri 50 dine-2-carboxylic acid methyl ester. 29. Preparation of 4-Amino-6-(4-chloro-2-fluoro-3- methoxyphenyl)-3-methyl-pyridine-2-carboxylic acid methyl ester (Compound 27) 4-Amino-3-chloro-6-(4-chlorophenyl)-5-fluoropyridine 55 2-carboxylic acid methyl ester (0.5 g, 1.59 mmol), tributyl (vinyl)tin (1.01 g, 3.17 mmol), bis(triphenylphosphine)palla dium(II) dichloride (0.111 g, 0.159 mmol), and tetrabutylammonium triphenyldifluorosilicate (1.71 g, 3.17 mmol) were combined in acetonitrile (3 ml) and heated to 60 110° C. for 15 min in a CEM microwave reactor. The cooled reaction mixture was concentrated onto silica geland purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) twice to yield the title compound (46 mg, 5% yield) as an off-white solid, mp. 81-83° C. "H NMR (CDC1) & 7.9 65 (m. 1H), 7.43 (m, 1H), 6.89 (dd. 1H), 5.7 (dd. 1H), 5.57 (dd. 1H), 4.72 (brs, 2H), 3.93 (s.3H). US 7,786,044 B2 35 36 4-Acetylamino-6-(4-chloro-2-fluoro-3-methoxyphenyl)- NMR (CDC1) & 7.9 (m, 2H), 7.43 (m, 2H), 5.27 (dd. 1H), 3-methylpyridine-2-carboxylic acid methyl ester (369 mg, 4.84 (dd. 1H), 4.87 (brs, 2H). 1.0 mmol) was dissolved in methanol (10 mL) and acetyl chloride (1.07 mL, 15 mmol) was added. The reaction mix 30. Preparation of 4-Acetylamino-6-(4-chloro-2- ture was stirred overnight at ambient temperature and con fluoro-3-methoxyphenyl)-3-trimethylsilanylethy centrated under vacuum. The residue was partitioned nylpyridine-2-carboxylic acid methyl ester between ethyl acetate and aqueous sodium bicarbonate; and the organic phase was dried and concentrated. Purification by flash chromatography on silica gel (dichloromethane/ethyl acetate gradient) followed by a second purification by flash 10 chromatography (hexane/ethyl acetate gradient) yielded the title compound (292 mg, 88% yield) as a white solid, mp 122-125° C. "H NMR (CDC1) & 7.65 (m, 1H), 7.26 (s, 1H), 7.1 (m, 1H), 4.35 (brs, 2H), 3.99 (s.3H), 3.98 (d,3H), 2.31 (s, 3H). 15 Other compounds prepared by the method of Example 29 include:

4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-methox 25 yphenyl)-pyridine-2-carboxylic acid methyl ester (0.8 g. 2.061 mmol), trimethyl((tributylstannyl)ethynyl)silane (1.596 g. 4.12 mmol), and bis(triphenylphosphine)palladium (II) dichloride (0.145 g, 0.206 mmol) were combined in 1,2- dichloroethane (2 mL) and heated in a CEM microwave reac 30 tor at 130° C. for 15 min. The cooled reaction mixture was purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) to yield the title compound (0.196 g. 21.1% 4-Amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-vi yield). "H NMR (CDC1,) & 9.03 (s, 1H), 8.4 (brs, 1H), 7.67 nylpyridine-2-carboxylic acid methyl ester (Compound 28): (m. 1H), 7.24 (m. 1H), 4.0 (s.3H), 3.99 (d. 3H), 2.29 (s.3H), mp 118-121° C.: "H NMR (CDC1) & 7.67 (m. 1H), 7.24 (d. 35 1H), 7.13 (m. 1H), 6.86 (dd. 1H), 5.55-5.71 (m, 2H), 4.63 (br 0.36 (s, 9H). s, 2H), 3.99 (s.3H), 3.94 (s.3H) 31. Preparation of 4-Amino-6-(4-chloro-2-fluoro-3- methoxyphenyl)-3-ethynyl-pyridine-2-carboxylic acid methyl ester (Compound 31) 40

45

4-Amino-6-(4-chloro-2-fluorophenyl)-3-vinylpyridine-2- carboxylic acid methyl ester (Compound 29). "H NMR 50 (CDC1) & 8.0 (m, 1H), 7.2 (d. 1H), 7.1 (m, 2H), 6.8 (m. 1H), 5.6 (m, 2 h), 4.6 (s. 2H), 3.9 (s.3H).

55 4-Acetylamino-6-(4-chloro-2-fluoro-3-methoxyphenyl)- 3-trimethylsilanylethynylpyridine-2-carboxylic acid methyl ester (0.196 g., 0.437 mmol) was suspended in methanol (4.36 mL) and acetyl chloride (0.310 mL, 4.37 mmol) was added. The reaction mixture was stirred overnight at ambient tem 60 perature then concentrated to dryness. The residue was dis Solved in methanol (4.36 mL) and potassium carbonate (0.121 g, 0.873 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h, acidified with 2NHCl, and concentrated but not to dryness. The residue was parti 65 tioned between ethyl acetate and sodium bicarbonate; and the 4-Amino-6-(4-chlorophenyl)-5-fluoro-3-(1-fluorovinyl)py organic phase was dried and concentrated. The resulting ridine-2-carboxylic acid methyl ester (Compound 30): "H product was purified by flash chromatography on silica gel US 7,786,044 B2 37 38 (ethyl acetate/hexane gradient) to yield the title compound Another compound prepared by the method of Example 33 (0.109 g, 74.6% yield) as a yellow solid, mp 167-169°C.: "H is:

NMR (CDC1) & 7.7 (m, 1H), 7.24 (s, 1H), 7.18 (m, 1H), 5.08 (brs, 2H), 3.99 (s.3H), 3.97 (d. 3H), 3.84 (s, 1H). 32. Preparation of 5-Acetyl-6-amino-2-(4-chloro-2- fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylic acid methyl ester (Compound 32)

10

NH2 O N1 N 15 4-Amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3- 4. O N formylpyridine-2-carboxylic acid methyl ester (Compound 34): 'H-NMR (CDC1) & 10.27(s, 1H), 7.75 (t, J=8.6 Hz, 1H), O 7.28 (dd, J=8.61.9 Hz, 1H) 7.25 (d. J=1.7 Hz, 1H), 7.12 (m, C F 2H), 5.3 (s. 2H), 4.03 (s.3H)3.98 (d. J=1.0 Hz, 3H). O N 34. Preparation of 6-Amino-2-(4-chloro-2-fluoro-3- methoxy-phenyl)-5-difluoromethylpyrimidine-4- 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(1- carboxylic acid methyl ester (Compound 35) ethoxy-vinyl)pyrimidine-4-carboxylic acid methyl ester 25 (0.235 g, 0.616 mmol) was dissolved in THF (5 mL) and 2N NH2 F HCl (0.616 mL, 1.231 mmol) and stirred at ambient tempera ture for 3 h. The reaction mixture was concentrated, triturated with water, and filtered. The product was washed with metha ins, 2 O nol and dried under vacuum to yield the title compound 30 N N (0.205 g, 94% yield): 'H NMR (DMSO-d) & 7.7 (brs, 2H), 7.63 (dd. 1H), 7.42 (dd. 1H), 3.92 (s.3H), 3.85 (s.3H), 2.46 O (s, 3H). C F O 33. Preparation of 6-Amino-2-(4-chloro-2-fluoro-3- 35 N methoxyphenyl)-5-formyl-pyrimidine-4-carboxylic acid methyl ester (Compound 33) 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5- formylpyrimidine-4-carboxylic acid methyl ester (0.120. 40 0.35 mmol) was dissolved in dichloromethane (5 mL) and NH2 diethyl ether (3 mL) with gentle heating. After allowing the Solution to cool to ambient temperature, diethylaminosulfur trifluoride (0.5 g, 3.15 mmol) was added and the reaction N1 N mixture was gently heated to obtain a clear Solution. The O 45 reaction mixture was stirred overnight at ambient temperature 4 N then quenched with methanol and concentrated under vacuum. The product was purified by flash chromatography O on silica gel (ethyl acetate/hexane gradient) to yield the title C F compound (62 mg, 48% yield): 'H NMR (CDC1) & 7.69 (dd. 50 1H), 7.42 (t, 1H), 7.24 (dd. 1H), 5.83 (brs, 2H), 4.02 (s.3H), On 4.0 (d. 3H). Another compound prepared by the method of Example 34 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vi 1S nyl-pyrimidine-4-carboxylic acid methyl ester (0.500 g, 1.5 55 mmol) was dissolved in THF (3 mL) and water (3 mL). Osmium tetroxide (4 mg. 0.015 mmol) was added and the reaction mixture was stirred for 2 min. Sodium periodate (0.63 g, 3 mmol) was then added over a period of 2 min. The reaction mixture was stirred for 16 hat ambient temperature then poured into water (150 mL) and extracted with dichlo 60 romethane thrice. The combined organic layers were dried, filtered and concentrated to afford the title compound (490 mg, 98% yield) in sufficient purity for subsequent reactions. An analytical sample was obtained by reverse phase chroma tography: "H NMR (CDC1) & 10.31 (s, 1H), 8.72 (brs, 1H), 65 7.77 (dd. 1H), 7.23 (m. 1H), 6.03 (brs, 1H), 4.06 (s.3H), 4.01 (d. 3H). US 7,786,044 B2 39 40 4-Amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-difluo filtered and concentrated. The product was purified by flash romethylpyridine-2-carboxylic acid methyl ester (Com chromatography (hexane/ethyl acetate gradient) to provide pound 36): 'H-NMR (CDC1) & 7.76 (t, J=8.2 Hz, 1H), 7.40 the title compound (0.510g, 60.5% yield) as a yellow solid: (t, J=53.4 Hz, s, 1H) 7.23 (m, 1H), 7.14 (m, 1H), 5.09 (s. 2H), "H NMR (CDC1) & 7.63 (dd. 1H), 7.19 (dd. 1H), 6.74 (d. 1H), 3.99 (s.3H), 3.97 (s.3H). 5 6.32 (d. 1H), 5.34 (brs, 2H), 3.99 (d. 3H), 3.94 (s.3H), 2.41 (s, 3H). 35. Preparation of 6-Amino-5-((E)-2-bromovinyl)-2- (4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4- 37. Preparation of 6-Amino-5-(2-bromo-1-fluoroet carboxylic acid methyl ester (Compound 37) hyl)-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimi 10 dine-4-carboxylic acid methyl ester

Br NH2 Br 15 NH2 N1 N - O N N ins,O 4. N O 2O C F O C F O N O N 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vi 25 nylpyrimidine-4-carboxylic acid methyl ester (0.720g, 2.13 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vi mmol) was dissolved in chloroform (20 mL) and bromine nyl-pyrimidine-4-carboxylic acid methyl ester (0.611 g, (0.51 1 g, 3.2 mmol) was added. The reaction mixture was 1.809 mmol) and N-bromosuccinimide (0.386 g. 2.171 stirred at ambient temperature for 2 h then concentrated under mmol) were dissolved in dichloromethane (10 ml) and the vacuum. The product was dissolved in dichloromethane (20 30 reaction mixture was cooled to 0°C. Triethylamine trihydrof mL), treated with triethylamine (0.430 g, 4.26 mmol), stirred luoride (0.884 mL, 5.43 mmol) was then added dropwise and at ambient temperature for 2 h, and then concentrated under the reaction mixture was allowed to warm to ambient tem vacuum. The product was purified by flash chromatography perature and stirred overnight. Water and additional dichlo on silica gel (dichloromethane/ethyl acetate gradient) to pro romethane were added. Sodium bicarbonate (0.760 g, 9.05 vide the title compound (0.5 g. 56% yield over two steps) as 35 mmol) was added in several portions until no further gas a white solid, mp 171-173° C.: "H NMR (CDC1) & 7.66 (dd. evolution was noted. The organic phase was dried and con 1H), 7.22 (dd. 1H), 7.22 (d. 1H), 6.72 (d. 1H), 5.37 (brs, 2H), centrated under vacuum. The product was purified by flash 4.0 (s.3H), 3.97 (s.3H). chromatography on silica gel twice (first with dichlo romethane/ethyl acetate gradient followed by hexane/ethyl 36. Preparation of 6-Amino-2-(4-chloro-2-fluoro-3- 40 acetate gradient) to provide the title compound (352 mg, methoxyphenyl)-5-((E)-2-methylsulfanylvinyl)pyri 0.806 mmol. 44.6% yield) as a white solid, mp 144-146°C.: midine-4-carboxylic acid methyl ester "H NMR (CDC1) & 7.67 (dd. 1H), 7.23 (dd. 1H), 6.32 (ddd, (Compound 38) 1H), 5.77 (brs, 2H), 4.01 (s, 3H), 4.0 (d. 3H), 3.77-3.94 (m, 2H). 45 38. Preparation of 6-Amino-2-(4-chloro-2-fluoro-3- S methoxyphenyl)-5-(1-fluoroethyl)pyrimidine-4-car NH2 N boxylic acid methyl ester (Compound 39) N1 N 50 NH2 N 1 -o N

O C F 55 ins,2 O ON N N O C F 6-Amino-5-((E)-2-bromovinyl)-2-(4-chloro-2-fluoro-3- 60 methoxy-phenyl)pyrimidine-4-carboxylic acid methyl ester (0.915g, 2.196 mmol) was dissolved in DMSO (10 mL) and On sodium thiomethoxide (0.169 g, 2.416 mmol) was added. After 30 min at ambient temperature, the reaction mixture 6-Amino-5-(2-bromo-1-fluoroethyl)-2-(4-chloro-2- was diluted with water and extracted with ethyl acetate. The 65 fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid organic phase was diluted with petroleum ether to decrease methyl ester (324 mg. 0.742 mmol), tri-n-butyltin hydride the solubility of residual DMSO, washed with water thrice, (0.396 mL, 1.484 mmol), and 2,2'-azobisisobutyronitrile US 7,786,044 B2 41 42 (3.05 mg, 0.019 mmol) were combined in 1,2-dimethoxy Other compounds prepared by the method of Example 40 ethane (2.5 mL) and heated at 100° C. for 15 min in a CEM include: microwave reactor. The cooled reaction mixture was concen trated under vacuum then purified by flash chromatography on silica gel (dichloromethane/ethyl acetate gradient). A sec ond purification by flash chromatography on silica gel (hex ane/ethyl acetate gradient) yielded the title compound (162 mg, 61.0% yield) as a white solid, mp 150-152°C.: "H NMR OH (CDC1) & 7.64 (dd. 1H), 7.22 (dd. 1H), 6.26 (dq, 1H), 5.73 (brs, 2H), 4.00 (d. 3H), 3.98 (s.3H), 1.80 (dd. 3H). 10 C F 39. Preparation of 6-Amino-2-(4-chloro-2-fluoro-3- methoxyphenyl)-5-(1-methoxyethyl)pyrimidine-4- 6-Amino-2-(4-chloro-2-fluorophenyl)-5-vinylpyrimidine-4- carboxylic acid (Compound 40) 15 carboxylic acid (Compound 42): mp 167-169° C.: "H NMR (DMSO-d and drop of DO) & 7.91 (m. 1H), 7.51 (m. 1H), 7.40 (m. 1H), 6.65 (dd. 1H), 5.58 (m, 2H).

C F OH ON 25 C 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(1- 6-Amino-2-(4-chlorophenyl)-5-vinylpyrimidine-4-carboxy fluoroethyl)pyrimidine-4-carboxylic acid methyl ester (0.100 30 lic acid (Compound 43): 'H NMR (DMSO-d) & 13.6 (bs, g, 0.280 mmol) was dissolved/suspended in methanol (10 1H), 8.26 (d. 2H), 7.53 (d. 2H), 7.19 (bs, 2H), 6.66 (m, 1H), mL) and 2N sodium hydroxide (0.561 mL, 1.121 mmol) was 5.54 (m, 2H). 5.63 (dd. 1H), 5.56 (dd. 1H). added. The reaction mixture was stirred overnight at ambient temperature, acidified with 2N HCl, and concentrated. The precipitate that formed was filtered, washed with water, and 35 dried to provide the title compound (0.085g. 85% yield) as a white solid, mp 165-167° C.: "H NMR (DMSO-d and drop of DO) & 7.60 (dd. 1H), 7.39 (dd. 1H), 4.55 (q, 1H), 3.91 (s, 3H), 3.17 (s, 3H), 1.41 (dd. 3H). OH 40 40. Preparation of 6-Amino-2-(4-chloro-2-fluoro-3- methoxyphenyl)-5-vinylpyrimidine-4-carboxylic acid (Compound 41) C F NH2 45 N1 N 6-amino-2-(4-chloro-2,3-difluorophenyl)-5-vinylpyrimi dine-4-carboxylic acid (Compound 44): mp 170-172°C.: "H 2 OH N NMR (DMSO-d and drop of DO) & 7.76 (m. 1H), 7.51 (m, 50 1H), 6.63 (dd. 1H), 5.52-5.61 (m, 2H). O C F On 55 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vi nylpyrimidine-4-carboxylic acid methyl ester (200 mg, 0.59 OH mmol) was dissolved in methanol (15 mL) and 2N sodium hydroxide (1 mL, 2 mmol) was added. The reaction mixture 60 was stirred at ambient temperature for 2 h, acidified with a C slight excess of 2N HCl, and concentrated. The crystals that formed were filtered off, washed with water, washed with On diethyl ether, and dried under vacuum to yield the title com pound (136 mg, 71% yield): mp 167-168° C.: "H NMR 65 (DMSO-d and drop of DO) & 7.62 (m. 1H), 7.43 (m. 1H), 6-Amino-2-(4-chloro-3-methoxyphenyl)-5-vinylpyrimi 6.65 (dd. 1H), 5.67 (m, 2H), 3.92 (d. 3H). dine-4-carboxylic acid (Compound 45): 'H NMR (DMSO

US 7,786,044 B2 47 48 4-Amino-6-(4-chloro-2-fluorophenyl)-3-vinylpyridine-2- 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vi carboxylic acid (Compound 60), mp 209-211° C. "H NMR nyl-pyrimidine-4-carboxylic acid (36 mg) was dissolved in (MeOH-d) & 7.65 (m. 1H), 7.46 (m, 2H), 6.96 (d. 1H), 6.76 10 mL of dichloromethane by the addition of 1 mL of triethy (dd. 1H), 5.75 (dd. 1H), 4.68 (dd. 1H). lamine. The solvent and excess triethylamine were removed

under vacuum to yield the title compound in quantitative yield. 43. Preparation of Herbicidal Compositions 10 In the following illustrative compositions, parts and per centages are by weight. C 4-Amino-6-(4-chlorophenyl)-5-fluoro-3-vinylpyridine-2- 15 carboxylic acid (Compound 61): 'HNMR (DMSO-d) & 7.87 EMULSIFLABLE CONCENTRATES (m. 2H), 7.55 (m, 2H), 6.74 (dd. 1H), 5.52-5.56 (m, 2H). WT 9 41. Preparation of 6-Amino-2-(4-chloro-2-fluoro-3- Formulation A methoxyphenyl)-5-vinyl-pyrimidine-4-carboxylic Compound 1 26.2 acid butyl ester (Compound 62) Polyglycol 26-3 5.2 Nonionic emulsifier-(di-sec-butyl)- phenyl-poly(oxypropylene)block polymer with (oxyethylene). The polyoxyethylene content is about 12 moles. NH2 25 Witconate P12-20 (Anionic emulsifier- 5.2 calcium dodecylbenzene Sulfonate 60 wt.% active) N1 N Aromatic 100 (Xylene range aromatic 63.4 solvent) O Formulation B 4. N-1N1 30 Compound 3 3.5 O Sunspray 11N (paraffin oil) 40.0 C F Polyglycol 26-3 19.0 Oleic acid 1.O On Xylene range aromatic solvent 36.5 35 Formulation C 6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vi Compound 9 13.2 Stepon C-65 25.7 nyl-pyrimidine-4-carboxylic acid (0.150 g, 0.46 mmol), Ethiomeen T 25 7.7 iodobutane (0.111 g, 0.60 mmol), and lithium carbonate Ethiomeen T15 18.0 (0.044 g. 0.6 mmol) were combined in DMF (1.5 mL) and 40 Xylene range aromatic solvent 35.4 heated at 60° C. overnight. The cooled reaction mixture was Formulation D concentrated and partitioned between ethyl acetate and water. Compound 2 3O.O The organic phase was dried and concentrated. The product Agrimer A1-1OLC (emulsifier) 3.0 was purified by flash chromatography on silica gel (ethyl N-methyl-2-pyrrollidone 67.0 Formulation E acetate/hexane gradient) to yield the title compound (0.092g, 45 52.3% yield): 'H NMR (CDC1) & 7.65 (dd. 1H), 7.19 (dd, Compound 18 1O.O 1H), 7.75 (dd. 1H), 5.62-5.67 (m, 2H), 5.35 (brs, 2H), 4.34 (t, Agrimul 70-A (dispersant) 2.0 3H), 3.99 (dd, 3H), 1.74 (m, 2H), 1.45 (m, 2H), 0.97 (t, 3H). Amsul DMAP 60 (thickener) 2.0 Emulsogen M (emulsifier) 8.O Attagel 50 (Suspension aid) 2.0 42. Preparation of the triethylamine salt of 6-amino 50 2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinylpyri Crop oil 76.O midine-4-carboxylic acid (Compound 63) These concentrates can be diluted with water to give emul sions of Suitable concentrations for controlling weeds. 55 NH2

N1 N WETTABLE POWDERS

2 O "NHEt 60 WT 9 N Formulation F O C F Compound 44 26.O Polyglycol 26-3 2.0 O Polyfon H 4.0 N 65 Zeosyl 100 (Precipitated hydrated SiO2) 17.0 Barden clay + inerts S1.O US 7,786,044 B2 50

-continued -continued

WETTABLE POWDERS Formulation K

WT 9 WT 9 Formulation G Neka BA 77 2.0 Zinc Stearate 2.0 Compound 58 62.4 Barden Clay 87.O Polyfon H (sodium salt of lignin 6.O Sulfonate) 10 Sellogen HR (sodium naphthalene 4.0 All materials are blended and ground to a powder then Sulfonate) water is added and the clay mixture is stirred until a paste is Zeosyl 100 27.6 formed. The mixture is extruded through a die to provide Formulation H granules of proper size. Compound 59 1.4 15 Kunigel V1 (carrier) 3O.O Stepanol ME Dry (wetter) 2.0 Tosnanon GR31A (binder) 2.0 WATER SOLUBLE LIQUIDS Kaolin NK-300 Clay (filler) 64.6 Formulation L. The active ingredient is applied to the corresponding car WT 9 riers and then these are mixed and ground to yield wettable Compound 62 3.67 powders of excellent wettability and suspension power. By Monoethanolamine pH buffer O.S diluting these wettable powders with water it is possible to Water 95.83 obtain Suspensions of Suitable concentrations for controlling weeds. 25 The active ingredient is dissolved in an appropriate amount of water and the additional monoethanolamine is added as a buffer. A water-soluble surfactant may be added. Other aids WATERDISPERSIBLE GRANULES may be incorporated to improve physical, chemical and/or Formulation I 30 formulation properties. WT 9 44. Evaluation of General Postemergence Herbicidal Compound 57 26.0 Activity Sellogen HR 4.0 Polyfon H S.O 35 Seeds or nutlets of the desired test plant species were Zeosyl 100 17.0 planted in Sun Gro MetroMix R 306 planting mixture, which Kaolinite clay 48.0 typically has a pH of 6.0 to 6.8 and an organic matter content of about 30 percent, in plastic pots with a surface area of 103 The active ingredient is added to the hydrated silica, which square centimeters. When required to ensure good germina is then mixed with the other ingredients and ground to a 40 tion and healthy plants, a fungicide treatment and/or other powder. The powder is agglomerated with water and sieved to chemical or physical treatment was applied. The plants were provide granules in the range of -10 to +60 mesh. By dispers grown for 7-21 days in a greenhouse with an approximate 15 ing these granules in water it is possible to obtain Suspensions hour photoperiod which was maintained at about 23-29° C. of Suitable concentrations for controlling weeds. during the day and 22-28°C. during the night. Nutrients and 45 water were added on a regular basis and Supplemental light ing was provided with overhead metal halide 1000-Watt GRANULES lamps as necessary. The plants were employed for testing Formulation J when they reached the first or second true leaf stage. A weighed amount, determined by the highest rate to be WT 9 50 tested, of each test compound was placed in a 25 mL glass vial Compound 50 S.O and was dissolved in 4 mL of a 97:3 V/v (volume/volume) Celetom MP-88 95.0 mixture of acetone and dimethylsulfoxide (DMSO) to obtain concentrated Stock Solutions. If the test compound did not The active ingredient is applied in a polar solvent Such as dissolve readily, the mixture was warmed and/or Sonicated. N-methylpyrollidinone, cyclohexanone, gamma-butyrolac 55 The concentrated stock solutions obtained were diluted with 20 mL of an aqueous mixture containing acetone, water, tone, etc. to the Celetom MP 88 carrier or to other suitable isopropyl alcohol, DMSO, Atplus 411F crop oil concentrate, carriers. The resulting granules can be applied by hand, gran and Triton(R) X-155 Surfactant in a 48.5:39:10:1.5:1.0:0.02 ule applicator, airplane, etc. in order to control weeds. V/V ratio to obtain spray solutions containing the highest 60 application rates. Additional application rates were obtained by serial dilution of 12 mL of the high rate solution into a Formulation K solution containing 2 mL of 97:3 V/v (volume/volume) mix ture of acetone and dimethylsulfoxide (DMSO) and 10 mL of WT 9 an aqueous mixture containing acetone, water, isopropyl Compound 41 1.O 65 alcohol, DMSO, Atplus 411F crop oil concentrate, and Triton Polyfon H 8.0 X-155 Surfactant in a 48.5:39:10:1.5:1.0:0.02 v/v ratio to obtain /2x, 4x, /sx and /16x rates of the high rate. Com US 7,786,044 B2 51 52 pound requirements are based upon a 12 mL application volume at a rate of 187 L/ha. Formulated compounds were TABLE 1-continued applied to the plant material with an overhead Mandel track sprayer equipped with a 8002E nozzles calibrated to deliver Post-emergent Weed Control 187 L/ha over an application area of 0.503 square meters at a Rate spray height of 18 inches (43 cm) above the average plant Compound gai?ha CHEAL ABUTH EPHHL ECHCG ORYSA canopy height. Control plants were sprayed in the same man S4 28O 100 90 100 90 O ner with the solvent blank. 55 70 100 100 100 1OO 15 The treated plants and control plants were placed in a 56 140 95 8O 90 75 O greenhouse as described above and watered by Sub-irrigation 10 57 140 100 90 100 30 5 58 28O 50 90 90 50 O to prevent wash-off of the test compounds. After 14 days, the 59 140 100 100 100 1OO O condition of the test plants as compared with that of the 60 140 100 70 8O 35 15 untreated plants was determined visually and scored on a 61 140 100 100 95 NT 50 scale of 0 to 100 percent where 0 corresponds to no injury and 62 140 100 100 100 NT 25 100 corresponds to complete kill. 15 63 70 100 95 100 90 75 Some of the compounds tested, application rates CHEAL = lambsquarter (Chenopodium album) ABUTH = velvetleaf (Abution theophrasti) employed, plant species tested, and results are given in Table EPHHL = wild poinsettia (Euphorbia heterophyia) 1. ECHCG = barnyardgrass (Echinochloa crus-gaii) ORYSA = rice (Oryza sativa) TABLE 1. NT = not testsed Post-emergent Weed Control 45. Evaluation of General Preemergence Herbicidal Rate Activity Compound gai?ha CHEAL ABUTH EPHHL ECHCG ORYSA 25 1 28O 8O 15 100 O O Seeds of the desired test plant species were planted in a soil 2 28O 100 95 100 95 O matrix prepared by mixing a loam soil (43 percent silt, 19 3 70 100 100 100 95 15 4 140 100 100 100 O O percent clay, and 38 percent sand, with a pH of about 8.1 and 5 140 100 100 100 8O 5 an organic matter content of about 1.5 percent) and sand in a 6 28O 90 100 70 8O O 30 70 to 30 ratio. The soil matrix was contained in plastic pots 7 28O 95 60 70 O O with a surface area of 127 square centimeters. When required 8 28O 100 100 50 1OO O 9 140 95 90 100 90 O to ensure good germination and healthy plants, a fungicide 10 28O 40 50 75 O O treatment and/or other chemical or physical treatment was 11 70 100 100 100 90 O applied. 12 140 100 100 50 50 O 35 A weighed amount, determined by the highest rate to be 13 28O 100 90 60 O O 14 70 100 100 100 1OO 10 tested, of each test compound was placed in a 25 mL glass vial 15 140 100 100 100 1OO 5 and was dissolved in 6 mL of a 97:3 V/v (volume/volume) 16 140 95 100 8O O O mixture of acetone and DMSO to obtain concentrated stock 17 28O 100 100 100 1OO O solutions. If the test compound did not dissolve readily, the 18 140 100 100 40 90 O 40 mixture was warmed and/or Sonicated. The stock solutions 19 28O 100 100 100 85 85 2O 28O 100 85 100 70 O obtained were diluted with 18 mL of a 0.1% V/v aqueous 21 140 100 85 100 70 O solution of Tween(R) 20 surfactant to obtain spray solutions 22 70 95 85 100 95 O containing the highest application rate. Additional applica 23 70 95 85 100 95 10 24 140 85 8O 85 70 O tion rates were obtained by serial dilution of 12 mL of the high 25 28O 100 70 100 O O 45 rate solution into a solution containing 3 mL of 97:3 V/v 26 140 100 100 90 70 O mixture of acetone and DMSO and 9 mL of the 0.1% w/v. 27 28O 30 8O 100 O O aqueous solution of TweenR 20 surfactant to obtain /2x, 4x, 28 28O 75 85 90 75 O 29 28O 85 85 75 O 10 /8x and /16x rates of the high rate. Compound requirements 30 140 100 100 90 O O are based upon a 12 mL application volume at a rate of 187 31 140 95 95 100 8O O 50 L/ha. Formulated compounds were applied to the soil surface 32 28O 70 70 100 O O with an overhead Mandel track sprayer equipped with a 33 229 50 8O 100 O O 34 28O 90 100 95 95 O 8002E nozzles calibrated to deliver 187 L/ha over an appli 35 28O 85 75 90 O O cation area of 0.503 square meters at a spray height of 18 36 28O 95 100 95 95 O inches (43 cm) above the soil surface. Control pots were 37 28O 90 8O 90 O 10 55 sprayed in the same manner with the solvent blank. 38 28O 100 90 100 60 O 39 140 60 8O 85 30 O The treated pots and control pots were placed in a green 40 28O 100 85 100 90 35 house maintained with an approximate 15 hour photoperiod 41 70 100 100 100 1OO 65 and temperatures of about 23-29° C. during the day and 43 28O 100 90 100 90 35 44 70 100 100 100 1OO 15 22-28°C. during the night. Nutrients and water were added on 45 28O 95 O 60 60 O 60 a regular basis and Supplemental lighting was provided with 46 140 100 90 95 90 40 overhead metal halide 1000-Watt lamps as necessary. The 47 70 100 90 100 1OO 50 water was added by top-irrigation. After 20-22 days, the 49 140 100 65 100 NT O condition of the test plants that germinated and grew as com 50 28O 100 95 100 1OO 45 51 140 100 100 90 95 60 pared with that of the untreated plants that emerged and grew 52 140 95 95 100 90 65 65 was determined visually and scored on a scale of 0 to 100 53 140 100 90 100 90 O percent where 0 corresponds to no injury and 100 corre sponds to complete kill or no emergence. US 7,786,044 B2 53 54 Some of the compounds tested, application rates alkylsulfonyl, C-C trialkylsilyl, C-C haloalkeny employed, plant species tested, and results are given in Table loxy, C-C haloalkynyloxy, C-C haloalkenylthio. 2. C-C haloalkynylthio. —C(O)OR7 –C(O)NRR-7, —CRNOR7, NRR-7, NROR7, NRSOR, TABLE 2 - NRC(O)R - NRC(O)OR, NRC(O)NRR, or - NCRNRR: Pre-emergent Weed Control Y represents H, halogen, C-C alkyl, C-C haloalkyl, Rate C-C alkoxy, C-Chaloalkoxy, C-C alkenyl or C-C, Compound gai?ha CHEAL ABUTH EPHHL ECHCG ORYSA haloalkenyl, or, when X and Y are taken together, rep 10 1 140 OO 8O 100 8O 30 resents —O(CH2)CH2—, or —O(CH), O—wherein 2 140 8O 40 95 O 15 n=1 or 2; and 3 140 OO 8O 100 8O 30 Z represents H or halogen; 4 28O OO 90 100 50 O R and R independently represent H, C-C alkyl, C-C, 5 140 95 100 90 O 10 11 70 OO 100 100 1OO 95 alkenyl, C-C alkynyl, hydroxy, C-C alkoxy, amino, 14 140 OO 100 100 95 95 15 C-C acyl, C-C carboalkoxy, C-C alkylcarbamyl. 21 140 40 60 8O O O C-C alkylsulfonyl, C-C trialkylsilyl or C-C dialkyl 28 140 95 95 100 70 2O phosphonyl or RandR taken together with N represent 42 140 OO 100 100 30 10 43 140 OO 100 100 90 90 a 5- or 6-membered saturated ring; and 45 140 60 O O 10 30 Rs represents H or halogen; 53 140 OO 100 100 8O O R represents H. C-C alkyl or C-Chaloalkyl; and 55 140 OO 100 100 60 30 R7 represents C-C alkyl or C-Chaloalkyl; 59 140 OO 100 100 1OO O and agriculturally acceptable derivatives of the carboxylic CHEAL = lambsquarter (Chenopodium album) acid group. ABUTH = velvetleaf (Abution theophrasti) 2. A compound of claim 1 in which R and R indepen EPHHL = wild poinsettia (Euphorbia heterophyia) 25 ECHCG = barnyardgrass (Echinochloa crus-gaii) dently represent H or C-C alkyl. ORYSA = rice (Oryza sativa) 3. A compound of claim 1 in which the agriculturally acceptable derivatives of the carboxylic acid group are agri What is claimed is: culturally acceptable salts, esters and amides. 1. A compound of the formula I 4. A compound of claim 1 in which R is C-C alkyl, C-C, 30 haloalkyl, C-C alkenyl or C-C haloalkenyl. 5. A compound of claim 4 in which R is vinyl. NRR4 I 6. A compound of claim 1 in which R is cyclopropyl. Rs N R 7. A compound of claim 1 in which R is 35 2 OH R N

O wherein 40 R represents C-C alkyl, C-C haloalkyl, C-C alkoxy alkyl, C-C alkythioalkyl, C-C alkenyl, C-C haloalkenyl, C-C alkoxyalkenyl, C-C thioalkylalk enyl, C-C alkynyl or C-Chaloalkynyl, formyl, C-C, wherein alkylcarbonyl, C-C haloalkylcarbonyl: 45 W represents Horhalogen; R represents C-C alkyl, cyclopropyl, C-C haloalkyl, X represents H, halogen, nitro, cyano, formyl, C-C, C-C alkenyl, C-Chaloalkenyl or alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, C-C alkoxyalkyl, C-C alkylcarbonyl, C-C, alkylthio, C-C alkylsulfinyl, C-C alkylsulfonyl, 50 C-C alkenyloxy, C-C alkynloxy, C-C alkenylthio. C-C alkynylthio. C-Chaloalkyl, C-Chalo-alkenyl, C-C haloalkynyl, C-C haloalkoxy, C-C haloalkoxyalkyl, C-C haloalkyl-carbonyl, C-C, haloalkythio, C-Chaloalkylsulfinyl, C-C haloalkyl 55 Sulfonyl, C-C trialkylsilyl, C-C haloalkenyloxy, C-C haloalkynyloxy, C-C haloalkenylthio. C-C, wherein haloalkynylthio. - C(O)OR, —C(O)NRR, W represents H or halogen; —CRNOR, NRR, NROR, NRSOR, X represents H. halogen, nitro, cyano, formyl, C-C, - NRC(O)R - NRC(O)0R, NRC(O)NRR, or alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, 60 - NCRNRR: C-C alkoxyalkyl, C-C alkylcarbonyl, C-C, Y represents H, halogen, C-C alkyl, C-C haloalkyl, alkylthio, C-C alkylsulfinyl, C-C alkylsulfonyl, C-C alkoxy, C-Chaloalkoxy, C-C alkenyl or C-C, C-C alkenyloxy, C-C alkynloxy, C-C alkenylthio. haloalkenyl, or, when X and Y are taken together, rep C-C alkynylthio, C-Chaloalkyl, C-Chaloalkenyl, resents —O(CH2)CH2—, or —O(CH), O—wherein C-C haloalkynyl, C-C haloalkoxy, C-C 65 n = 1 or 2; and haloalkoxyalkyl, C-C haloalkyl-carbonyl, C-C, Z represents H or halogen; haloalkylthio, C-C haloalkylsulfinyl, C-C halo Rs represents H or halogen; US 7,786,044 B2 55 56 R represents H. C-C alkyl or C-C haloalkyl; and in which R, represents C-C alkyl or C-Chaloalkyl. Rs represents H or halogen; 8. A compound of claim 7 in which W represents H or F. W represents Hor F: X represents H. halogen, C-C alkyl, C-C haloalkyl, X represents H, halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy or —NRR-7, Y represents 5 C-C alkoxy, C-C haloalkoxy or —NRR-7; C1 or halomethyl, and Z represents H or F. Y represents C1 or halomethyl; 9. A compound having the formula Z represents H or F, and agriculturally acceptable deriva

tives of the carboxylic acid group. 10. An herbicidal composition comprising an herbicidally 10 effective amount of a compound according to claim 1, in a mixture with an agriculturally acceptable adjuvant or carrier. 11. A method of controlling undesirable vegetation which comprises contacting the vegetation or the locus thereof with 15 or applying to the Soil or irrigation water to prevent the emer gence of vegetation an herbicidally effective amount of a compound according to claim 1.

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