USOO8614320B2

(12) United States Patent (10) Patent No.: US 8,614,320 B2 Matsushita et al. (45) Date of Patent: *Dec. 24, 2013

(54) PREPARATION OF AMINOPYRIMIDINE 4,968,681. A 1 1/1990 Hubsch et al.

COMPOUNDS 2931. A 3: WaySS a (75) Inventors: Akio Matsushita, Ube (JP); Mizuho 3.03. A E. E. et al. Oda, Yamaguchi (JP); Yasuhiro 5,260,440 A 1 1/1993 Hirai et al. Kawachi, Yamaguchi (JP); Jun-ichi 5,278,313 A 1/1994 Thottathil et al.

Chika, Yamaguchi (JP) 3.-- I A E OlaReal ea. 5,681,957 A 10, 1997 Wolters et al. (73) Assignee: strences UK Limited, London 6,278,001 B1 8, 2001 Solladie et al. 6,331,641 B1 12/2001 Taoka et al. 6,579,984 B1 6/2003 Veith et al. (*) Notice: Subject to any disclaimer, the term of this 6,689,591 B2 2/2004 Muller et al. patent is extended or adjusted under 35 6,784, 171 B2 8/2004 Taylor et al. U.S.C. 154(b) by 0 days. (Continued) This patent is Subject to a terminal dis- FOREIGN PATENT DOCUMENTS claimer. EP O252476 1, 1988 (21) Appl. No.: 13/523,534 EP O319845 6, 1989 (22) Filed: Jun. 14, 2012 other instektions (65) Prior Publication Data Anne et al. "Enantioselective synthesss of key A-ring precursors of US 2012/O277432 A1 Nov. 1, 2012 lo, 25-dihydroxyvitamin D and analogues' Synlett 9:1435-1437 s (1999). O O Bhaskar Reddy et al. "Enantioselective synthesis of B-hydroxy Related U.S. Application Data Ö-lactones: a new approach to the synthetic congeners of 3-hydroxy (62) Division of application No. 12/889,186, filed on Sep. Insthylglutayneyme A reductase inhibitors" J. Org, Chem. 23,faroplication 2010, now No.Pat. 1No. 1/933,626, 8,222.412, filed which on Nov. is a division1, 2007 Blandin22(?). et al. "One-pot and sequential asymmetric hydrogenation of of application No. s Illed on Nov. 1, s B,6-diketoesters into functionalized 1,3-diols: From anti- to syn now Pat. No. 7,816,528, which is a division of stereoselectivity” European Journal of Organic Chemistry 12:3421 application No. 10/483,430, filed as application No. 3427 (1999). PCT/JP02/07129 on Jul 12, 2002, now Pat. No. Continued 7,304,156. (Continued) Primary Examiner — Venkataraman Balasubramanian (30) Foreign Application Priority Data (74) Attorney, Agent, or Firm — Morgan, Lewis & Bockius LLP Jul. 13, 2001 (JP) ...... 2001-213417 Jul. 13, 2001 (JP) ...... 2001-213418 (57) ABSTRACT - Oct. 9, 2001 (JP) ...... 2001-310900 A 2-(N-methyl-N-methanesulfonylamino)pyrimidine com Nov. 27, 2001 (JP) ...... 2001-360339 pound of the formula (3): R is a hydrocarbyl group), is Jan. 1 6. 2002 (JP) 2002-007O15 prepared by the steps of (I) reacting an isobutyrylacetate Feb. 1 9. 2002 (JP). 2002-042O76 ester with 4-fluorobenzaldehyde and urea in the presence of a • u. -- s 1- w 1 vs - F · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · protonic compound and a metal salt; (II) oxidizing the reac (51) Int. Cl t1Onoroduction product Ofof the Stestep (I); (III react1nging the OX1Cat1Onoroductoxidation produ cond 239/36 2006.O1 of the step (II) with an organic sulfonyl halide or an organic CO7D 239/42 (2OO 6. O sulfonyl anhydride; and (IV) reacting the reaction product of C07D 239/22 3:08: the step (III) with N-methyl-N-methanesulfonamide. A61 K3 1/505 (2006.01) A6IP3/06 (2006.01) (3) (52) U.S. Cl. F USPC ...... 544/315:544/316:544/330 (58) Field of Classification Search USPC ...... 544/315, 316,330 See application file for complete search history. (56) References Cited COR U.S. PATENT DOCUMENTS O lN1N S 4,613,610 A 9/1986 Wareing HC1 YN 4. 4,625,039 A 1 1/1986 Jewell, Jr. et al. O 4,645,858 A 2f1987 Lowrie et al. 4,650,890 A 3/1987 Jewell, Jr. et al. 4,677,211 A 6/1987 Jewell, Jr. et al. 4,957,971 A 9, 1990 Picard et al. 4 Claims, No Drawings US 8,614,320 B2 Page 2

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"An Improved General Synthesis of 4-Aryl-5- 7,732,171 B2 6, 2010 Blacker et al. Pyrimidinecarboxylates' J. Heterocyclic Chem. 18: 183 (1981). 7.816,528 B2 10/2010 Matsushita et al. Casini et al. “Carbonic anhydrase inhibitors with strong topical 7,842,807 B2 11/2010 Horbury et al. antiglaucoma properties incorporating a 4-(2-amino-pyrimidin-4-yl 7,888,083 B2 2/2011 Blacker et al. amino)-benzenesulfonamide scaffold” Journal of Enzyme Inhibition 7.989,643 B2 8/2011 Kooistra et al. and Medicinal Chemistry 17(1):9-18 (2002). 8,034,932 B2 10/2011 Butters et al. Castro et al. "A new synthesis of 3,5-dihydroxy-7-(1-pyrrolyl)-6- 8,063,213 B2 11/2011 Crabb et al. heptenoic acids, a family of HMGCoA reductase inhibitors with 2003, OO18199 A1 1/2003 Brodfuehrer et al. ----- 2005, 0124639 A1 6, 2005 Joshi et al. antifungal activity”& 8 Tetrahedron Letters 43:1851-1854 (2002). 2006, O293355 A1 12, 2006 Booth et al. De Luca et al. "Cellulose Beads: a New Versatile Solid Support for 2007/0093660 A1 4/2007 Tararov et al. Microwave-Assisted Synthesis. Preparation of Pyrazole and 2007/0105882 A1 5, 2007 Black et al. Isoxazole Libraries” J. Comb. Chem. 5(4):465-471 (2003). 2007,0255060 A1 11, 2007 Okada et al. Denmark et al. “The Chemistry of Trichlorosilyl Enolates. Aldol 2008. O188657 A1 8/2008 Lenger Addition Reactions of Methyl Ketones' J. Am. Chem. Soc. 122 2008/02O7903 A1 8, 2008 Butters et al. (37):8837-8847 (2000). 2008, 0221323 A1 9, 2008 Crabb et al. Dovlatyan et al. “Studies on functionally-substituted azines. 8. Syn 2009,0264654 A1 10, 2009 Newton et al. thesis and transformations of 1-arylsulfonylamido-4-methoxy-6- 2010/0222373 A1 9, 2010 Booth et al. methylpyrimidines' Chemistry of Heterocyclic Compounds 2010/0228028 A1 9, 2010 Butters et al. 36(11): 1306-1313(2000). 2012,005.9022 A1 3/2012 Booth et al. Evans et al. “Diastereoselective synthesis of protected syn 1,3-diols by base-catalyzed intramolecular conjugate addition of hemiacetal FOREIGN PATENT DOCUMENTS derived alkoxide nucleophiles' J. Org. Chem. 58:2446-2453 (1993). EP O3 19847 6, 1989 Feuerstein et al. "A new efficient tetraphosphine/palladium catalyst EP O742212 11, 1996 for the Heck reaction of arvlhalidesy with stvirenetyr or vinylethery deriva EP O521471 10, 2000 tives’ Tetrahedron Letters 43:2191-2194 (2002). EP 1193,259 4/2002 Grohe et al. “Synthese and Reaktionen von 2,4-Dichlorpyrimidin-5- GB 2244705 12/1991 carbon-Saureestem” Liebigs Ann. Chem. 1025-1035 (1973). JP 5-178841 7, 1993 Guetal. “Synthesis ofent-Haterumalide NA(ent-Oocydin A) Methyl JP 6-256318 9, 1994 Ester” Organic Letters 5(23):4385-4388 (2003). WO WO90,03973 4f1990 & 8 WO WO92fO1675 2, 1992 Hannah et al. “Structural studies on bioactive compounds. Part 29: WO WO93,08823 5, 1993 palladium catalysed arylations and alkynylations of sterically hin WO WO 96.14846 4f1996 dered immunomodulatory 2-amino-5-halo-4,6- WO WO 97/19917 6, 1997 (disubstituted)pyrimidines' Bioorg Med Chem. 8(4):739-750 WO WO 97.21687 6, 1997 (2000). WO WO99.07695 4f1999 Hauser et al. “Synthesis of 5-phenyl-4,6-dimethyl-2-pyrimidol and WO WOOOf 49014 8, 2000 WO WOOOf7873O 12/2000 derivatives from the cyclization of urea with 3-phenyl-2,4- WO WOO1/4100 1, 2001 pentanedione” Journal of Organic Chemistry 18(5): 588-593 (1953). WO WOO1,04336 1, 2001 Hiyama et al. “Synthesis of Artificial HMG-CoA Reductase Inhibi WO WOO1? 60804 8, 2001 tors Based on the Olefination Strategy” Bull. Chem. Soc. Jpn. 68 WO WOO1,727O6 10, 2001 (1):364-372 (1995). WO WOO1f85702 11, 2001 Kaneko et al. "Preparation of optically active 5,6-epoxyhexanoic WO WOO1/859.75 11, 2001 acid esters as materials for physiologically active Substances' WO WOO2,05519 1, 2002 WO WOO2,06266 1, 2002 Chemical Abstracts +Indexes, American Chemical Society, Colum WO WOO3,OO4450 1, 2003 bus, US 118(11):832 (1993). WO WOO3,OO6439 1, 2003 Littke et al. "A Versatile Catalyst for Heck Reactions of Aryl Chlo WO WOO3,O18555 3, 2003 rides and Aryl Bromides under Mild Conditions' J. Am. Chem. Soc. WO WOO3,059901 T 2003 123(29):6989-7000 (2001). WO WOO3,064382 8, 2003 Littke et al. “Heck reactions in the presence of P(t-Bu) : Expanded WO WOO3,O87112 10, 2003 Scope and milder reaction conditions for the coupling of aryl chlo W W SEl 58. rides' J. Org. Chem. 64:10-11 (1999). WO WO 2004/O 14872 2, 2004 Ma et al. “Lanthanide Triflate Catalyzed Biginelli Reaction, One-Pot WO WO 2004/052867 6, 2004 Synthesis of Dihydropyrimidinones under Solvent Free Conditions' WO WO 2004/O54986 T 2004 Journal of Organic Chemistry, 2000 65(12), 3864-3868. WO WO 2004f103977 12, 2004 Menges et al. “Oxidative Degradation of Y-Butyrolactons into 1,3- WO WO 2004f108691 12, 2004 Diols via a Criegee Rearrangement of PeroxoSulfonates. An WO WO 2005/023779 3, 2005 Enantioselective Synthesis of Compactin Lactone and its WO WO 2005/0284.50 3, 2005 Diastereomer Synlett 12:901-905 (1993). US 8,614,320 B2 Page 3

(56) References Cited Scialdone et al. “Building blocks for skipped polyols: syn-1,3- acetonides by chemoenzymatic synthesis from cycloheptatriene' OTHER PUBLICATIONS Tetrahedron Letters 36(1):43-46 (1995). Shao et al. “Asymmetric hydrogenation of 3,5-Dioxoesters catalyzed Miller et al. “Discovery of Aminopyridine-Based Inhibitors of Bac by Ru-binap complex: A short step asymmetric synthesis of 6-Sub terial Enoyl-ACP Reductase (FabI)” J. Med. Chem. 45(15):3246 stituted 5,6-dihydro-2-pyrones' Tetrahedron 49(10): 1997-2010 3256 (2002). (1993). Minami et al. “A Novel Enantioselective Synthesis of HMG Co-A Singer et al. “Catalytic, enantioselective dienolate additions to Reductase Inhibitor NK-104 and a Related Compound” Tetrahedron aldehydes: Preparation of optically-active acetoacetate aldol letters 33(49): 7525-7526 (1992). adducts” Journal of the American Chemical Society 117(49): 12360 Minami et al. “Stereoselective Reduction of B,6-Diketo Esters 12361 (1995). Derived From Tartaric Acid. A Facile Route to Optically Active Solladié et al. “Chrial Sulfoxides in Asymmetric Synthesis: 6-oxo-3,5-syn-isopropylidenedioxyhexanoate, a Versatile Synthetic Enantioselective Synthesis of the Lactonic Moiety of (+)-Compactin Intermediate of Artificial HMG Co-A Reductase Inhibitors’ Tetra and (+)-Mevinolin. Application of a Compactin Analogue” J. Org. hedron Letters 34(3):513-516 (1993). Chem. 60:7774-7777 (1995). Mohr et al. “Stereoselective synthesis of functionalized erythro? 1,3- Takahashi et al. “Synthesis of an artificial HMG-CoA reductase diols’ Tetrahedron Letters 28(4):391-394 (1987). inhibitor NK-104 via a hydrosilylation-cross-coupling reaction' Bul Moore et al. “Biosynthesis of the hypocholesterolemic agent letin of the Chemical Society of Japan 68(9): 2649-2656 (1995). mevinolin by Aspergillus terreus. Determination of the origin of Vanden Eynde et al. “Microwave-mediated Regioselective Synthesis carbon, hydrogen, and oxygen atoms by carbon-13 NMR and mass of Novel Pyrimido 1,2-alpyrimidines under Solvent-free Condi spectrometry” J. Am. Chem. Soc. 107(12): 3694-3701 (1985). tions’ Tetrahedron 57(9): 1785-1791 (2001). Prasadet al. “A novel diastereroselective synthesis of lactone moiety Virolleaud et al. "A straightforward synthesis of (E)-8-alkenyl-BY of compactin’ Tetrahedron Letters 25(23):2435-2438 (1984). unsaturated Ö-lactones by a tandem ring-closing/cross-coupling Presentation given at the 20th International Congress of Heterocyclic metathesis process” Tetrahedron Letters 44(44):8081-8084 (2003). Chemistry in Palermo, Aug. 1-5, 2005. Watanabe et al Bioorganic & Medicinal Chemistry, vol. 5, No. 2, Presentation given at the Gordon Conference on Heterocyclic Com 1997, pp. 437-444. pounds, Salve Regina University, Newport, Rhode Island, Jul. 4-9. Wess et al. “Stereoselective Synthesis of HR 780 a New Highly 2004. Potent HMG-CoA Reductase Inhibitor'. Tetrahedron Letters 31(18): Sakaki et al. "Lipase-catalyzed asymmetric synthesis of 6-(3-chloro 2545-2548 (1990). 2-hydroxypropyl)-1,3-dioxin-4-ones and their conversion to chiral Zakrzewski et al. “Synthesis of syn- and anti-3,5-Dihydroxy-6- 5,6-epoxyhexanoates’ Tetrahedron: Asymmetry 2(5):343-346 heptenoates from 2-Deoxy-d-ribose: Intermediates for Polyols Syn (1991). thesis' Synlett 2:215-218 (2003). US 8,614,320 B2 1. 2 PREPARATION OF AMNOPYRIMIDNE BACKGROUND OF THE INVENTION COMPOUNDS Bioorg. Med. Chem., 5,437 (1997) describes that the 2-(N- RELATED APPLICATIONS methyl-N-methanesulfonylamino)pyrimidine compound is employable as an intermediate compound for producing a This application is a Divisional of U.S. application Ser. No. cholesterol reducing agent (HMG-CoA reductase inhibitor: 12/889,186 filed Sep. 23, 2010, now allowed, which is a S-4522) having the following formula: Divisional application of U.S. application Ser. No. 1 1/933, 626 filed Nov. 1, 2007, now U.S. Pat. No. 7,816,528, which is 10 a Divisional application of U.S. application Ser. No. 10/483, 430, filed Jan. 12, 2004, now U.S. Pat. No. 7,304,156, which is a U.S. National Phase Application of International Appli cation No. PCT/JP02/07129, filed Jul. 12, 2002, which claims the benefit of Japanese Patent Application No. 2001-213417. 15 filed Jul. 13, 2001, Japanese Patent Application No. 2001 213418, filed Jul. 13, 2001, Japanese Patent Application No. 2001-310900, filed Oct. 9, 2001, Japanese Patent Application COO Cat No. 2001-360339, filed Nov. 27, 2001, Japanese Patent Application No. 2002-07015, filed Jan. 16, 2002, and Japa nese Patent Application No. 2002-042076, filed Feb. 19, 2002, all of which are herein incorporated by reference in their entireties.

FIELD OF THE INVENTION 25 and which is now generally known as the calcium salt of rosuvastatin or rosuvastatin calcium. The present invention relates to the preparation of ami WO 01/04100 describes a process for preparing the 2-(N- nopyrimidine compounds having the following formula (8): methyl-N-methanesulfonylamino)pyrimidine compound 30 which comprises the steps of: (8) reacting methyl isobutyrylacetate with 4-fluoro-benzoni trile to produce methyl 2-1-amino-1-(4-fluorophenyl)meth ylene-4-methyl-3-oxopentanate; and reacting the 2-1-amino-1-(4-fluorophenyl)methylene-4- 35 methyl-3-oxopentanate with N-cyano-N-methyl-methane sulfonamide which is obtained by reaction between N-meth ylmethanesulfonamide and cyanogen chloride, to produce 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N- 40 methanesulfonyl-N-methylamino)pyrimidine. It is described that the total yield (based on the amount of methyl isobutyrylacetate) is 45.5%. It appears that the process described in WO 01/04100 is disadvantageous for the industrial preparation, because the in the formula (8), R is a hydrocarbyl group, and each of R' 45 and R independently is a hydrogen atom, an alkyl group, an yield is not high and it is necessary to employ toxic cyanogen alkylsulfonyl group, or an arylsulfonyl group, more particu chloride as one of the starting compounds. larly to the preparation of a 2-(N-methyl-N-methanesulfony Accordingly, it is an object of the invention to provide a lamino)pyrimidine compound having the following formula novel process for preparing a 2-(N-methyl-N-methanesulfo (3): 50 nylamino)pyrimidine or an analogous amino-pyrimidine compound thereof, more particularly to provide a novel pro cess which provides the compound more conveniently and/or (3) without employing a toxic compound and/or provides the F compound in high yield and/or high purity. 55 It is another object of the invention to provide a novel process for preparing a 2-(N-methyl-N-methanesulfony lamino)pyrimidine compound or an analogous amino-pyri midine compound thereof which is favorably employable in COR 60 the industrial preparation. gS ulis 2 SUMMARY OF THE INVENTION HC1 SN N The present invention resides in a process for preparing a 65 2-(N-methyl-N-methanesulfonylamino)pyrimidine having wherein R represents a hydrocarbyl group. the formula (3): US 8,614,320 B2 3 4 The invention further resides in a dihydropyrimidinone (3) compound having the formula (4). F The invention furthermore resides in a method for prepar ing a dihydropyrimidinone compound of the formula (4), which comprises reacting an isobutyrylacetate ester having the formula (5):

COR 10 (5) gS ulis 2 HC1 YN N COR

15 R is a hydrocarbyl group. which comprises the steps of: in which R is a hydrocarbyl group, reacting a hydroxypyrimidine compound having the for with 4-fluorobenzaldehyde and urea in the presence of a mula (1): protonic compound and a metal salt. The invention furthermore resides in a method for prepar (1) ing an aminopyrimidine compound having the formula (8):

25

(8)

30

35 in which R is the same as above, with an organic sulfonylhalide having the formula (2): R'SOX (2) in which R' is a hydrocarbyl group and X is a halogen atom, or an organic Sulfonic anhydride having the formula (2a): 40 in which R" is the same as above, and reacting the resulting wherein R is a hydrocarbyl group, and each of R' and R' reaction product with N-methyl-N-methanesulfonamide. independently is hydrogen atom, an alkyl group, an alkylsul The invention also resides in a hydroxypyrimidine com 45 fonyl group, or an arylsulfonyl group, pound having the above-identified formula (1). The invention further resides in a method for preparing a which comprises reacting a 2-substituted pyrimidine com hydroxypyrimidine compound of the formula (1), which pound having the formula (6): comprises oxidizing a dihydropyrimidinone compound hav ing the formula (4): 50 (6)

(4)

55

60

65 wherein R is the same as above, and X is a halogenatom oran organic Sulfonyloxy group, with an amine compound having wherein R is a hydrocarbyl group. the formula (7): US 8,614,320 B2 6 (I) reacting an isobutyrylacetate ester of the formula (5) (7) with 4-fluorobenzaldehyde and urea in the presence of a protonic compound and a metal salt; (II) oxidizing the reaction product of the step (I); (III) reacting the oxidation product of the step (II) with an organic sulfonylhalide of the formula (2) or an organic Sul wherein each of R' and R is the same as above. fonic anhydride of the formula (2a); and The invention furthermore resides inahalogenopyrimidine (IV) reacting the reaction product of the step (III) with compound having the formula (9): 10 N-methyl-N-methanesulfonamide. In the above-mentioned process, the steps (III) and (IV) can be carried out continuously in the same reaction mixture. (9) DETAILED DESCRIPTION OF THE INVENTION 15 The representative process for the preparation of 2-(N- methyl-N-methanesulfonylamino)pyrimidine of the formula (3) according to the present invention is schematically illus trated as follows:

F

25 wherein R is a hydrocarbyl group, and Hal is a halogenatom. The invention furthermore resides in a method for prepar ing the halogenopyrimidine compound of the formula (9), CHO 30 which comprises reacting a hydroxypyrimidine compound of -- --e- the aforementioned formula (1) with a halogenating agent. (I) The invention furthermore resides in an organic Sulfony NH2 O loxypyrimidine compound having the formula (10): 1. COR 35 O NH2

(10)

F 40

45 OXIDATION HN 2 (II) 1s, H wherein each of R and R' independently is a hydrocarbyl 50 group. (4) The invention furthermore resides in a method for prepar ing an organic sulfonyloxypyrimidine compound of the for mula (10), which comprises reacting a hydroxypyrimidine F compound of the aforementioned formula (1) with an organic 55 sulfonyl halide having the formula (2):

R'SOX (2) wherein R is a hydrocarbyl group, and X is a halogen atom, 60 COR - - or an organic Sulfonic anhydride having the formula (2a): N1 N (III) + (IV)

HO l N 2 in which R" is the same as above. The invention furthermore resides in a process for prepar 65 ing a 2-(N-methyl-N-methanesulfonylamino)pyrimidine of (1) the formula (3) which comprises the steps of US 8,614,320 B2 7 8 -continued ferred is copper(I) chloride. The metal salts may contain F water of crystallization. The metal salts can be employed singly or in combination. The metal salt can be employed in an amount of prefer ably, 0.001 to 5 mol., more preferably 0.01 to 0.1 mol., per one mol. of the isobutyrylacetate ester. The 4-fluorobenzaldehyde can be employed in an amount COR of preferably, 0.5 to 10 mol., more preferably 0.9 to 1.1 mol. per one mol. of the isobutyrylacetate ester. g is 10 The urea can be employed in an amount of preferably, 0.5 S ul 2 to 10 mol., more preferably 1.5 to 2 mol., per one mol. of the HC1 YN N isobutyrylacetate ester. Ö The reaction can be performed in the presence or absence (3) of a solvent. There are no specific limitations with respect to 15 the solvent employed, so far as the solvent does not disturb the desired reaction. Examples of the employable solvents Each step in the above-illustrated reaction scheme is include alcohols such as methanol, ethanol, n-propyl alcohol, described below in more detail. isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl Step (I) alcohol, and t-butyl alcohol; ethers such as diethyl ether, In the step (I), an isobutyrylacetate ester of the following diisopropyl ether, tetrahydrofuran, and dimethoxyethane; formula (5): nitriles Such as acetonitrile, propionitrile, butyronitrile, and isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon (5) tetrachloride; aromatic hydrocarbons such as benzene, tolu 25 ene, and Xylene; halogenated aromatic hydrocarbons such as COR chlorobenzene, and nitrated aromatic hydrocarbons such as nitrobenzene. Preferred are methanol, ethanol, n-propyl alco hol, isopropyl alcohol, n-butyl alcohol, diisopropyl ether, tetrahydrofuran, dimethoxyethane, acetonitrile, butyroni 30 trile, isobutylonitrile, dichloromethane, dichloroethane, R is a hydrocarbyl group chloroform, toluene, Xylene, and chlorobenzene. Especially is reacted with 4-fluorobenzaldehyde and urea in the presence preferred are methanol, ethanol, and isopropyl alcohol. The of a protonic compound and a metal salt. Solvents can be employed singly or in combination. The hydrocarbyl group (i.e., hydrocarbon group) repre The solvent can be employed in an amount of preferably sented by R in the formulas of the compounds involved in the 35 0.1 to 10 liters, more preferably 0.3 to 2 liters, per one mole of reactions of the invention can be an alkyl group Such as the isobutyrylacetate ester. The amount may vary depending methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, on homogeneity and dispersability of the reaction mixture. nonyl, or decyl, more particularly an alkyl group having 1-6 The reaction can be conducted by reacting the isobutyry carbonatoms and especially an alkyl group having 1-4 carbon lacetate ester, 4-fluorobenzaldehyde, and urea, in a solvent in atoms; a cycloalkyl group Such as cyclopropyl, cyclobutyl, 40 the presence of a protonic compound and a metal salt under cyclopentyl, or cyclohexyl, an aralkyl group Such as benzyl, inert gas atmosphere. The reaction can be carried out at a phenylethyl, or phenylpropyl; oran aryl group Such as phenyl temperature of preferably -10 to 200°C., more preferably 30 or methylphenyl. The hydrocarbyl group can take any isomer to 100°C. There are no specific limitations with respect to the configurations such as normal, iso, and tertiary. The hydro Surrounding pressure. carbyl group can have one or more substituents, provided that 45 The resulting product of the reaction, that is, a dihydropy the substituents do not disturb the reaction involved. rimidinone compound of the formula (4), can be isolated and The protonic compound can be an inorganic acid or its salt purified according to the conventional procedures such as Such as hydrochloric acid, Sulfuric acid, potassium hydrogen distillation, crystallization, recrystallization, and column Sulfate, sodium hydrogen Sulfate, nitric acid, or phosphoric chromatography. acid; an organic Sulfonic acid Such as methanesulfonic acid, 50 Step (II) ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic In the step (II), a dihydropyrimidinone compound of the acid, or p-bromobenzenesulfonic acid; an organic carboxylic formula (4), that is, the reaction product of the step (I), is acid such as acetic acid, propionic acid, butyric acid, or ben oxidized to give a hydroxypyrimidine compound of the for Zoic acid; an alcohol Such as methanol, ethanol, or propanol. mula (1). Preferred are protonic acids such as hydrochloric acid, sulfu 55 The oxidation (or dehydrogenation oxidation) can be per ric acid, p-toluenesulfonic acid, and acetic acid. Most pre formed in various conventional manners. Preferred is oxida ferred is Sulfuric acid. The protonic compounds can be tion utilizing nitric acid, because this oxidation procedure is employed singly or in combination. easily carried out and the post-treatment of the reaction prod The protonic compound can be employed in an amount of uct is easy. preferably, 0.01 to 3 mol., more preferably 0.1 to 1 mol., per 60 The nitric acid can be employed in an amount of prefer one mol. of the isobutyrylacetate ester. ably 1 to 20 mol., more preferably 3 to 15 mol., per one mole The metal salt employed in the reaction can be copper(I) of the dihydropyrimidinone compound of the formula (4). chloride, copper(II) chloride, copper(II) acetate, iron(II) The nitric acid of a concentration of preferably 40 to 80%, chloride, iron(III) chloride, aluminum chloride, nickel(II) more preferably 50 to 70%, can be preferably employed. bromide, tin(IV) chloride, titanium tetrachloride, or magne 65 The oxidation can be performed in the presence or absence sium bromide. Preferred are copper(I) chloride, copper(II) of a solvent. There are no specific limitations with respect to chloride, iron(III) chloride and nickel(II) bromide. Most pre the solvent employed, so far as the solvent does not disturb the US 8,614,320 B2 10 desired reaction. Examples of the preferred solvents include nyl chloride, 1-naphthalenesulfonyl chloride, 2-naphthalene carboxylic acids such as acetic acid, propionic acid, and sulfonyl chloride, p-toluenesulfonyl fluoride, p-toluenesulfo butyric acid. The solvents can be employed singly or in com nyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2.4.6- bination. triisopropylbenzenesulfonyl chloride, The solvent can be employed in an amount of preferably p-methoxybenzenesulfonyl chloride, p-chlorobenzenesulfo 0.1 to 7 mL, more preferably 0.5 to 3 mL, per 1 g of the nyl chloride, and 2-mitrobenzenesulfonyl chloride. Preferred dihydropyrimidinone compound. The amount may vary are trifluoromethanesulfonyl fluoride, benzenesulfonyl chlo depending on homogeneity and dispersability of the reaction ride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl mixture. chloride, p-toluenesulfonyl chloride, 2,4,6-trimethylbenze The oxidation can be conducted by reacting the dihydro 10 pyrimidinone compound and nitric acid in a solvent under nesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chlo inert gas atmosphere. The oxidation can be carried out at a ride, p-methoxybenzenesulfonyl chloride, and p-chloroben temperature of preferably -10 to 100° C., more preferably 0 Zenesulfonyl chloride. Particularly preferred are to 50° C. There are no specific limitations with respect to the p-toluenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl Surrounding pressure. A reaction initiator Such as sodium 15 chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, and nitrite may be incorporated into the reaction system to accel p-methoxybenzenesulfonyl chloride. erate the oxidation rate. Examples of the sulfonic anhydrides include methane The resulting product of the reaction, that is, the hydroxy sulfonic anhydride, trifluoromethanesulfonic anhydride, ben pyrimidine compound of the formula (1), can be isolated and Zenesulfonic anhydride, and p-toluenesulfonic anhydride. purified according to the conventional procedures Such as Preferred are trifluoromethanesulfonic anhydride, benzene distillation, crystallization, recrystallization, and column sulfonic anhydride, and p-toluenesulfonic anhydride. Par chromatography. ticularly preferred are trifluoromethanesulfonic anhydride Steps (III) and (IV) and p-toluenesulfonic anhydride. In the steps (III) and (IV), a hydroxypyrimidine compound The sulfonylhalide or sulfonic anhydride can be employed of the formula (1), that is, the reaction product of the step (II), 25 in an amount of, preferably 0.1 to 20 mol., more preferably is reacted with an organic sulfonyl halide of the formula (2): 0.5 to 5 mol., most preferably 1 to 2 mol., per one mole of the hydroxypyrimidine compound. R'SOX (2) In the Subsequent step, N-methylmethanesulfonamide can or an organic Sulfonic anhydride of the formula (2a): be employed in an amount of, preferably 0.1 to 30 mol., more 30 preferably 1 to 5 mol., per one mol. of the hydroxypyrimidine compound. and reacting the resulting reaction product with N-methyl-N- The reactions of the steps (III) and (IV) can be preferably methanesulfonamide. performed in the presence of a base. Examples of the bases include alkali metal carbonates Such as Sodium carbonate and In the formulas (2) and (2a), R' is a hydrocarbyl group 35 which can have one or more substituents. Examples of the potassium carbonate; alkali metal hydrogencarbonates Such hydrocarbyl groups include alkyl groups such as methyl, as Sodium hydrogencarbonate; alkali metal hydroxides Such ethyl, propyl, butyl, pentyl, heptyl, octyl, nonyl, and decyl. as lithium hydroxide, sodium hydroxide and potassium more particularly an alkyl group having 1-6 carbonatoms and hydroxide; alkali metal alkoxides Such as Sodium methoxide, especially an alkyl group having 1-4 carbon atoms; fluori 40 Sodium t-butoxide, potassium t-butoxide, and sodium t-pen nated alkyl groups such as trifluoromethyl, nonafluorobutyl, toxide; and tertiary amines such as triethylamine, triisopro tridecafluorohexyl, heptadecafluorooctyl, and uncosafluoro pylamine, diisopropylethylamine, and pyridine. Preferred are decyl; cycloalkyl groups such as cyclopropyl, cyclobutyl, Sodium carbonate, potassium carbonate, potassium t-butox cyclopentyl, and cyclohexyl, aralkyl groups such as benzyl, ide, Sodium t-pentoxide, triethylamine, and pyridine. Particu phenylethyl, and phenylpropyl; and aryl groups, including 45 larly preferred are potassium carbonate, Sodium t-pentoxide, unsubstituted and Substituted phenyl ornaphthyl groups, such and triethylamine. Most preferred are potassium carbonate as phenyl, naphthyl, tolyl, Xylyl, mesityl, triisopropylphenyl, and sodium t-pentoxide. The bases can be employed singly or methoxyphenyl, chlorophenyl, and nitrophenyl. Thus, the in combination. hydrocarbyl group can have one or more Substituents, pro The base can be employed in an amount of preferably 0.1 vided that the substituents do not disturb the reaction 50 to 30 mol., more preferably 1 to 5 mol., per one mol. of the involved. The hydrocarbyl group can take any isomer con hydroxypyrimidine compound. The whole amount of the figurations such as normal, iso, and tertiary. A particularly base can be incorporated in the reaction system before the suitable value for R' when it is aryl includes, for example, a reaction begins, or the base can be portionwise added to the phenyl or naphthyl group (particularly phenyl) which is reaction system after the reaction begins. unsubstituted or bears 1, 2 or 3 substituents. The substituents 55 The reaction can be performed in the presence or absence may be independently selected from, for example, alkyl hav of a solvent. There are no specific limitations with respect to ing 1-4 carbon atoms, alkoxy having 1-4 carbon atoms, halo the solvent, so far as the solvent does not disturb the reaction. geno, and nitro. Examples of the solvents include water, ketones such as In the formula (2), X is a halogen atom such as fluorine, acetone, methyl ethyl ketone, and diethyl ketone; ethers such chlorine, bromine, and iodine. 60 as diethyl ether and tetrahydrofuran; esters such as ethyl Examples of the sulfonylhalides include methanesulfonyl acetate, propyl acetate, and butyl acetate; nitrites Such as fluoride, methanesulfonyl chloride, ethanesulfonyl chloride, acetonitrile and propionitrile; amides such as N,N-dimethyl 1-propanesulfonyl chloride, 2-propanesulfonyl chloride, tri formamide and N-methylpyrrolidone; sulfoxides such as fluoromethanesulfonyl fluoride, trifluoromethanesulfonyl dimethylsulfoxide; ureas such as N,N'-dimethylimidazoli chloride, nonafluorobutanesulfonyl fluoride, tridecafluoro 65 none. Preferred are acetone, tetrahydrofuran, ethyl acetate, hexanesulfonyl fluoride, heptadecafluorooctanesulfonyl butyl acetate, acetonitrile, N,N-dimethylformamide, and fluoride, uncosafluorodecanesulfonyl fluoride, benzenesulfo dimethylsulfoxide. Particularly preferred are ethyl acetate, US 8,614,320 B2 11 12 butyl acetate and acetonitrile. Most preferred are butyl acetate chlorinating agent, an organic Sulfonyl halide of the formula and acetonitrile. The solvents can be employed singly or in (2): combination. R'SOX (2) The solvent can be employed in an amount of preferably in which R' has the same meaning as above and X is a halogen 0.01 to 100 liters, more preferably 0.5 to 5 liters, per one mole atom, or an organic Sulfonic anhydride of the formula (2a): of the hydroxypyrimidine compound. The amount may vary (RSO).O (2a) depending on homogeneity and dispersability of the reaction in which R' has the same meaning as above. mixture. Examples of the halogenating agents include phosphorus The reaction can be performed by reacting the hydroxypy 10 oxychloride and thionyl chloride. The halogenating agents rimidine compound and the organic Sulfonyl halide or Sul can be employed singly or in combination. fonic anhydride in a solvent in the presence of a base with The halogenating agent can be employed in an amount of preferably 0.1 to 50 mol., more preferably 1 to 20 mol., most stirring under inert gas atmosphere. The base can be added preferably 1.5 to 10 mol., per one mol. of the hydroxypyri portionwise. The reaction can be carried out at a temperature midine compound. of preferably -30 to 250° C., more preferably 0 to 150° C. 15 Examples of the organic sulfonyl halides and Sulfonic There are no specific limitations with respect to the surround anhydrides are those described hereinbefore. ing pressure. The organic sulfonyl halide or sulfonic anhydride can be The resulting product of the reaction, that is, the 2-(N- employed in an amount of preferably 0.1 to 20 mol., more methyl-N-methanecarbonsulfonylamino)pyrimidine com preferably 0.5 to 5 mol., most preferably 1 to 2 mol., per one pound of the formula (3), can be isolated and purified accord mol. of the hydroxypyrimidine compound. ing to the conventional procedures Such as distillation, The reaction can be performed in the presence or absence crystallization, recrystallization, and column chromatogra of a solvent. There are no specific limitations with respect to phy. the solvent, so far as the solvent does not disturb the reaction. The 2-(N-methyl-N-methanesulfonylamino)pyrimidine Examples of the solvents include aromatic hydrocarbons 25 Such as toluene; halogenated aromatic hydrocarbons such as compound of the formula (3) and other pyrimidine com chlorobenzene, nitrated hydrocarbons such as nitrobenzene: pounds of the formula (8) can be prepared from a hydroxy halogenated aliphatic hydrocarbons such as methylene chlo pyrimidine compound of the formula (1) via a 2-substituted ride and 1,2-dichloroethane; amides such as N,N-dimethyl pyrimidine compound of the formula (6) in the following formamide; water (not for a halogenating agent); nitriles Such steps (V) and (VI): 30 as acetonitrile and propionitrile; carboxylic acid esters such as ethyl acetate, propyl acetate, butyl acetate, ketones such as acetone, methyl ethyl ketone, diethyl ketone; and ethers such as diethyl ether and tetrahydrofuran. Preferred are butyl acetate, toluene, methylene chloride, acetonitrile, chloroben Zene, nitrobenzene, and N,N-dimethylformamide. The sol vents can be employed singly or in combination. The solvent can be employed in the reaction utilizing the halogenating agent in an amount of preferably 0.01 to 10 liters, more preferably 0.1 to 2 liters, per one mole of the hydroxypyrimidine compound. The amount may vary depending on homogeneity and dispersability of the reaction mixture. The solvent can be employed in the reaction utilizing the sulfonyl chloride or sulfonic anhydride in an amount of pref erably 0.1 to 50 liters, more preferably 0.5 to 2 liters, per one mole of the hydroxypyrimidine compound. The amount may vary depending on homogeneity and dispersability of the reaction mixture. The reaction can be carried out by reacting the hydroxy pyrimidine compound and the halogenating agent, in a sol vent with stirring under inert gas atmosphere. The reaction can be carried out at a temperature of preferably 0 to 200°C., more preferably 50 to 120° C. There are no specific limita tions with respect to the Surrounding pressure. The reaction can be carried out by reacting the hydroxy pyrimidine compound and the Sulfonyl halide or Sulfonyl anhydride in a solvent with stirring under inert gas atmo (8) sphere. The reaction can be carried out at a temperature of preferably -30 to 200° C., more preferably 0 to 50° C. There 60 are no specific limitations with respect to the Surrounding In the formula (8), R has the same meaning as described pressure. above, and each of R' and R independently is a hydrogen The resulting product of the reaction, that is, a 2-substi atom, an alkyl group, an alkylsulfonyl group, or arylsulfonyl tuted pyrimidine compound Such as a chloropyrimidine com group. pound or a sulfonyloxypyrimidine compound, can be isolated Step (V) 65 and purified according to the conventional procedures such as In the step (V), a hydroxypyrimidine compound of the distillation, crystallization, recrystallization, and column formula (1) is reacted with a halogenating agent such as a chromatography. US 8,614,320 B2 13 14 Step (VI) ethylammonium iodide, and hexadecyltrimethylammonium In the step (VI), the 2-substituted pyrimidine compound, chloride. Preferred are tetrabutylammonium chloride, tet Such as a chloropyrimidine compound or a Sulfonyloxypyri rabutylammonium bromide, tetrabutylammonium iodided, midine compound prepared in the step (V) is reacted with an benzyltriethylammonium chloride, and hexadecyltrimethy amine compound having the formula (7): 5 lammonium chloride. Most preferred are tetrabutylammo nium bromide, benzyltriethylammonium chloride, and hexa decyltrimethylammonium chloride. The phase transfer catalyst can be employed in an amount (7) of 0.01 to 0.5 mol., preferably 0.05 to 0.2 mol., per one mol. of the 2-substituted pyrimidine compound. 10 The resulting product of the reaction, that is, a 2-(N-me thyl-N-methanesulfonylamino)pyrimidine compound of the formula (3) or other aminopyrimidine compounds of formula (8), can be isolated and purified according to the conventional wherein each of R and R is the same as above. procedures such as distillation, crystallization, recrystalliza Examples of the groups of R' and R include a hydrogen 15 tion, or column chromatography. atom, alkyl groups such as methyl, ethyl, propyl, butyl, pentyl The present invention is further described by the following and hexyl; alkylsulfonyl groups such as methanesulfonyl; and non-limiting examples. arylsulfonyl groups such as benzenesulfonyl and p-toluene sulfonyl. Example 1 The amine compound can be employed in an amount of preferably 0.1 to 30 mol., more preferably 1 to 5 mol., per one Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- mol. of the 2-substituted pyrimidine compound. methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone The reaction is preferably performed in the presence of a base. Examples of the bases are those described hereinbefore. In a 500 mL-Volume glass flask equipped with a stirrer, a The base can be preferably employed in an amount of, 25 thermometer and a reflux condenser were placed 28.8 g (0.2 preferably 0.1 to 30 mol., more preferably 1 to 5 mol., per one mol.) of methyl isobutyrylacetate, 24.8 g (0.2 mol.) of 4-fluo mol. of the 2-substituted pyrimidine compound. robenzaldehyde, 21.0 g (0.35 mol.) of urea, 200 mg (2 mmol.) The reaction can be performed in the presence or absence of copper(I) chloride, 2 mL of sulfuric acid, and 200 mL of of a solvent. There are no specific limitations with respect to methanol. The content of the flask was heated to 64-65°C. for the solvent, so far as the solvent does not disturb the reaction. 30 24 hours under reflux with stirring, to carry out the reaction. Examples of the solvents include water, ketones such as There was precipitated crystalline product. The crystalline acetone, methyl ethyl ketone, and diethyl ketone; ethers such product was collected on a filter paper and washed with as diethyl ether and tetrahydrofuran; esters such as ethyl methanol to obtain 49.7 g of 4-(4-fluorophenyl)-6-isopropyl acetate, propyl acetate, and butyl acetate; nitriles Such as 5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone as a acetonitrile and propionitrile; amides such as N,N-dimethyl 35 colorless crystalline product having the below-mentioned formamide and N-methylpyrrolidone; sulfoxides such as characteristics. The yield was 85% (based on the amount of dimethylsulfoxide; ureas such as N,N-dimethylimidazolidi methyl isobutyrylacetate). none. Preferred are acetone, tetrahydrofuran, ethyl acetate, m.p.: 223-225° C. butyl acetate, acetonitrile, N,N-dimethylformamide, and UV (CHCN, m): 1943, 278.6 dimethylsulfoxide. Particularly preferred are ethyl acetate, 40 IR (KBr, cm): 3296, 3229, 3137, 2963, 1685, 1629, butyl acetate and acetonitrile. The solvents can be employed 1504,1225, 1097. singly or in combination. H-NMR (DMSO-de, 6 (ppm)): 1.14 (6H, dd, J=6.8, 6.9 The solvent can be employed in an amount of preferably HZ), 3.52 (3H, s), 4.0–4.2 (1H, m), 5.15 (1H, d, J-34 Hz), 0.01 to 100 liters, more preferably 0.5 to 5 liters, per one mole 7.1-7.2 (2H, m), 7.2-7.3 (2H, m), 7.76 (1H, d, J=3.2 Hz), 8.91 of the 2-substituted pyrimidine compound. The amount may 45 (1H, s). vary depending on homogeneity and dispersability of the HRMS: 292.1247 (theoretical value (CHFN.O.(M+)) reaction mixture. 292.1223) The reaction can be conducted by reacting the 2-substi tuted pyrimidine compound and the amine compound in a Example 2 Solvent in the presence of a base with stirring under inert gas 50 atmosphere. The reaction can be carried out at a temperature Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- of preferably-20 to 250° C., more preferably 25 to 150° C. methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone There are no specific limitations with respect to the surround ing pressure. The procedures of Example 1 were repeated except for The reaction can be conducted in two separate liquid 55 replacing 200 mg (2 mmol.) of copper(I) chloride with 5.41 g phases in the presence of a phase transfer catalyst. Examples (20 mmol.) of iron(III) chloride.hexahydrate. There was of the phase transfer catalysts include tetramethylammonium obtained 35.6 g of 4-(4-fluorophenyl)-6-isoproply-5-meth chloride, tetramethylammonium bromide, tetraethylammo oxycarbonyl-3,4-2(1H)-dihydropyrimidinone. The yield was nium fluoride, tetraethylammonium chloride, tetraethylam 61% (based on the amount of methyl isobutyrylacetate). monium bromide, tetrapropylammonium bromide, tetrapro 60 pylammonium iodide, tetrabutylammonium fluoride, Example 3 tetrabutylammonium chloride, tetrabutylammonium bro mide, tetrabutylammonium iodide, tetrapentylammonium Preparation of 4-(4-fluorophenyl)-2-hydroxy-6-iso bromide, tetrahexylammonium bromide, tetraheptylammo propyl-5-methoxycarbonylpyrimidine nium bromide, tetraoctylammonium bromide, benzyldimeth 65 yltetradecylammonium chloride, benzyltriethylammonium In a 50 mL-Volume glass flask equipped with a stirrer and chloride, phenyltrimethylammonium chloride, phenyltrim a thermometer was placed 11 mL (144 mmol.) of nitric acid US 8,614,320 B2 15 16 (60-61%, sp.gr. 1.38). To the nitric acid was slowly added at mixture was poured into 162 mL of water. The aqueous mix room temperature 4.00 g (13.7 mmol.) of 4-(4-fluorophenyl)- ture was neutralized by adding 61 g of aqueous Sodium 6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimi hydroxide solution (48 wt.%) to precipitate a crystalline dinone prepared in the same manner as in Example 1, and the product. The crystalline product was collected by filtration mixture was subjected to reaction for 30 minutes at room and dried to obtain 27.6 g of 4-(4-fluorophenyl)-2-hydroxy temperature. After the reaction was complete, the reaction 6-isopropyl-5-methoxy-carbonylpyrimidine as a colorless mixture was neutralized by placing the mixture in 140 mL of crystalline product. The yield was 91% (based on the amount saturated aqueous Sodium hydrogen carbonate solution. The of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2 reaction mixture was then extracted with ethyl acetate. The (1H)-dihydro-pyrimidinone). organic liquid portion was separated and concentrated under 10 reduced pressure. The residue was crystallized from toluene. Example 6 The crystalline product was collected on a filter and washed with toluene to obtain 3.64 g of 4-(4-fluorophenyl)-2-hy Preparation of 4-(4-fluorophenyl)-2-hydroxy-6-iso droxy-6-isopropyl-5-methoxycarbonylpyrimidine as a color propyl-5-methoxycarbonylpyrimidine less crystalline product having the below-mentioned charac 15 teristics. The yield was 92% (based on the amount of 4-(4- fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)- In a 2 L-volume glass flask equipped with a stirrer and a dihydropyrimidinone). thermometer was placed 323.3 g (3.09 mol.) of nitric acid m.p.: 193°C. (decomposed) (60-61%, sp.gr. 1.38). The concentrated nitric acid was then UV (CHCN, m): 196.6, 243.2,317.9 cooled to 10° C. To the nitric acid was added 2.36 g (34.2 IR (KBr, cm): 2991, 2887, 1717, 1653, 1589, 1433, mmol.) of sodium nitrite, and was further added slowly 100 g 1280, 1223. (342 mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5-methoxy H-NMR (DMSO-de, 6 (ppm)): 1.23 (6H, d, J=6.8 Hz), carbonyl-3,4-2(1H)-dihydropyrimidinone prepared in the 3.0-3.2 (1H, m), 3.56 (3H, s), 7.3-7.4 (2H, m), 7.5-7.6 (2H, same manner as in Example 1. The mixture was subjected to m), 12.25 (1H, brs). 25 reaction for 2 hours at a temperature of 10-12°C. After the HRMS: 290.1054 (theoretical value (CHFN.O.(M+)) reaction was complete, 970 mL of water was poured into the 290.1067) reaction mixture. The aqueous mixture was then neutralized by adding 257 g of aqueous sodium hydroxide Solution (48 Example 4 wt.%) to precipitate a crystalline product. The crystalline 30 product was collected by filtration and dried to obtain 93.3g Preparation of 4-(4-fluorophenyl)-2-hydroxy-6-iso of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxy propyl-5-methoxycarbonylpyrimidine carbonylpyrimidine as a colorless crystalline product. The yield was 94% (based on the amount of 4-(4-fluorophenyl)- In a 50 mL-Volume glass flask equipped with a stirrer and 6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimi a thermometer were placed 2.92 g (10 mmol.) of 4-(4-fluo 35 dinone). rophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihy dropyrimidinone prepared in the same manner as in Example Example 7 1 and 5 mL of acetic acid. To the mixture was slowly added 3.74 mL (50 mmol.) of nitric acid (60-61%, sp.gr. 1.38). To Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- the mixture was further added 0.07 g (1 mmol.) of sodium 40 methoxycarbonyl-2-(N-methyl-N-methanesulfonyl nitrite, and the reaction was carried out for one hour at room amino)pyrimidine temperature. After the reaction was complete, the reaction mixture was neutralized by placing the mixture in 50 mL of In a 200 mL-Volume glass flask equipped with a stirrer, a saturated aqueous Sodium hydrogen carbonate solution. The thermometer and a reflux condenser were placed 5.81 g (20 reaction mixture was then extracted with ethyl acetate. The 45 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5- organic liquid portion was separated and concentrated under methoxycarbonylpyrimidine, 3.59 g (26 mmol.) of potassium reduced pressure. The residue was crystallized from toluene. carbonate (available from Asahi Glass Works, Co., Ltd., Lot The crystalline product was collected on a filter and washed No. 1111632, particle size distribution: 75-250 um: 14%, 75 with toluene to obtain 2.61 g of 4-(4-fluorophenyl)-2-hy um pass: 86%), and 40 mL of butyl acetate. To the mixture droxy-6-isopropyl-5-methoxycarbonyl-pyrimidine as a col 50 was slowly added 4.19 g (22 mmol.) of p-toluenesulfonyl orless crystalline product. The yield was 90% (based on the chloride under stirring, and the reaction was carried out at 40° amount of 4-(4-fluorophenyl)-6-iso-propyl-5-methoxycar C. for 4 hours. Subsequently, the reaction mixture was cooled bonyl-3,4-2(1H)-dihydropyrimidinone). to room temperature. To the cooled reaction mixture were added 2.84 g (26 mmol.) of N-methylmethanesulfonamide Example 5 55 and 4.15 g (30 mmol.) of potassium carbonate (same as above). The mixture was heated to 110-125° C. for 2 hours Preparation of 4-(4-fluorophenyl)-2-hydroxy-6-iso under refluxing to carry out a reaction. After the reaction was propyl-5-methoxycarbonylpyrimidine complete, the mixture was cooled to room temperature. To the cooled mixture were added 25 mL of water and 20 mL of In a 200 mL-Volume glass flask equipped with a stirrer and 60 acetone, and the organic liquid portion was separated. The a thermometer was placed 54.0 g (735 mmol.) of nitric acid organic liquid portion was washed with a saturated aqueous (60-61%, sp.gr. 1.38). To the nitric acid was slowly added at Sodium chloride Solution and dried over anhydrous magne room temperature 30.6 g (105 mmol.) of 4-(4-fluorophenyl)- sium sulfate. The dry organic liquid portion was filtered and 6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimi concentrated under reduced pressure. The residue was crys dinone prepared in the same manner as in Example 1, and the 65 tallized from heptane, to obtain 6.58g of 4-(4-fluorophenyl)- mixture was subjected to reaction for 30 minutes at room 6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methane temperature. After the reaction was complete, the reaction Sulfonylamino)pyrimidine as a pale yellow crystalline US 8,614,320 B2 17 18 product. The yield was 86% (based on the amount of 4-(4- The resulting mixture was placed under reduced pressure to fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbon distill methanol off. To the residue were added 96.5 kg of ylpyrimidine). acetone and 96.5 kg of water. The aqueous residue was then neutralized by addition of acetic acid to precipitate a crystal Example 8 line product. The crystalline product was collected on a filter paper and washed with a acetone/water mixture, to give 17.9 Preparation of 4-(4-fluorophenyl)-6-isoproply-5- kg of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-meth methoxycarbonyl-2-(N-methyl-N-methanesulfonyl oxycarbonylpyrimidine. amino)pyrimidine 3) In a 200 L-volume glass-lined reaction vessel equipped 10 with a stirrer, a thermometer and a reflux condenser were In a 1000 mL-volume glass flask equipped with a stirrer, a placed 17.9 kg (62.0 mol.) of 4-(4-fluorophenyl)-2-hydroxy thermometer and a reflux condenser were placed 50.0 g (172 6-isopropyl-5-methoxycarbonylpyrimidine prepared as mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5- above, 107.7 kg of butyl acetate, 11.1 kg (80.3 mol.) of methoxycarbonylpyrimidine, 20.8 g (189 mmol.) of sodium potassium carbonate (available from Asahi Glass Works, Co., t-pentoxide, and 344 mL of acetonitrile, and the resulting 15 Ltd., Lot No. 1111632, particle size distribution: 75-250 um: mixture was stirred at 0-10°C. for 30 minutes. To the mixture 14%, 75 um pass: 86%), and 12.9 kg (67.7 mol.) of p-tolu was slowly added 36.1 g (189 mmol.) of p-toluenesulfonyl enesulfonyl chloride. The mixture was heated at 60° C. for 2 chloride, and the reaction was carried out at for 5 hours at hours, to carry out reaction. Subsequently, the reaction mix room temperature. Subsequently, the reaction mixture was ture was cooled to room temperature. To the cooled mixture cooled to a temperature of 0-10°C. To the cooled reaction were added 8.8 kg (80.6 mol.) of N-methylmethanesulfona mixture were added 28.2 g (258 mmol.) of N-methyl mide and 12.9 kg (93.3 mol.) of potassium carbonate, and the methanesulfonamide and 26.5 g (241 mmol.) of sodium resulting mixture was heated at 122-125° C. for 3 hours, for t-pentoxide. The mixture was kept at 0-10°C. for one hour carrying reaction. After the reaction was complete, the reac and then heated to 75-82°C. for 2 hours under refluxing, to tion mixture was cooled to room temperature. To the cooled carry out a reaction. After the reaction was complete, the 25 mixture were added acetone and water, and the organic liquid mixture was cooled to room temperature. To the cooled mix portion was separated. The organic liquid portion was then ture was added 344 mL of water. The aqueous mixture was washed successively with aqueous Sodium hydroxide solu cooled to 0-10° C. and stirred for one hour, precipitating a tion (3 wt.%) and a saturated aqueous sodium chloride solu crystalline product. The crystalline product was collected by tion. The washed organic liquid portion was concentrated filtration and dried, to obtain 45.3 g of 4-(4-fluorophenyl)-6- 30 under reduced pressure. Isopropyl alcohol and water were isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesul added to the residue, resulting in precipitation of a crystalline fonylamino)pyrimidine as a pale yellow crystalline product. product. The crystalline product was filtered on a filter paper The yield was 68% (based on the amount of 4-(4-fluorophe and washed with isopropyl alcohol. The washed crystalline nyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimi product and 85.7 kg of acetone were placed in a 200L-volume dine). 35 glass lined reaction vessel equipped with a stirrer, athermom eter and a reflux condenser. The mixture was stirred at 50-55° Example 9 C., to dissolve the crystalline product in acetone. The insoluble was removed with a line filter. Subsequently, 58.3 Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- kg of water was added to the solution, to precipitate a crys methoxycarbonyl-2-(N-methyl-N-methanesulfony 40 talline product. The crystalline product was collected on a lamino)pyrimidine from methyl isobutyrylacetate, filterpaper and washed with an acetone/water mixture, to give 4-fluorobenzaldehyde and urea 19.5 kg of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbo nyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine. 1) In a 200 L-volume glass-lined reaction vessel equipped with a stirrer, a thermometer and a reflux condenser were 45 Example 10 placed 24.4 kg (169 mol.) of methyl isobutyrylacetate, 20.0 kg (161 mol.) of 4-fluorobenzaldehyde, 16.9 kg (282 mol.) of Preparation of 2-chloro-4-(4-fluorophenyl)-6-isopro urea, 0.2 kg (2 mol.) of copper(I) chloride, 3.0 kg of sulfuric pyl-5-methoxycarbonylpyrimidine acid, and 80.4 kg of methanol. The mixture was heated to 64-66° C. for 20 hours under refluxing, to carry out reaction. 50 In a 25 mL-Volume glass flask equipped with a stirrer, a After the reaction was complete, the reaction mixture was thermometer and a reflux condenser were placed 1.00 g (3.43 cooled to room temperature, to precipitate a crystalline prod mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5- uct. The crystalline product was collected on a filter paper and methoxycarbonylpyrimidine and 3.4 mL (3.7 mmol.) of washed with methanol to obtain 43.4 kg of 4-(4-fluorophe phosphorus oxychloride. The mixture was heated to 100-106° nyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropy 55 C. for 1.5 hours under refluxing, to carry out reaction. After rimidinone as a colorless crystalline product. the reaction was complete, the reaction mixture was cooled to 2) In a 200 L-volume glass-lined reaction vessel equipped room temperature, and poured into an ice/water mixture. The with a stirrer and a thermometer were placed 62.5 kg (615.6 resulting aqueous mixture was neutralized with a saturated mol.) of diluted nitric acid and 0.5 kg (6.8 mol.) of sodium aqueous sodium hydrogen carbonate solution. The neutral nitrite. To the mixture was slowly added under chilling 20.0 60 ized aqueous mixture was extracted with ethyl acetate. The kg (68.4 mmol.) of the 4-(4-fluorophenyl)-6-isopropyl-5- ethyl acetate portion was separated, washed with a saturated methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone prepared aqueous sodium chloride solution, and dried over anhydrous as above. The resulting mixture was Subjected to reaction at a magnesium sulfate. The dried ethyl acetate portion was fil low temperature (10° C.). After the reaction was complete, tered and concentrated under reduced pressure, to obtain 1.03 the reaction mixture was neutralized by addition of an aque 65 g of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxy ous methanol Solution of sodium hydroxide. Subsequently, an carbonylpyrimidine as a colorless crystalline product having aqueous sodium hydroxide solution was added to the mixture. the below-mentioned characteristics. The yield was 97% US 8,614,320 B2 19 20 (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6- Example 13 isopropyl-5-methoxycarbonylpyrimidine). m.p.:99-101° C. Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- UV (CHCN, m): 1947,276.5 methoxycarbonyl-2-methanesulfonyloxypyrimidine IR (KBr, cm): 2980, 1728, 1542, 1508, 1227, 1086. In a 100 mL-volume glass flask were placed 10.0 g (34.4 'H-NMR (DMSO-de, 8(ppm)): 1.33 (6H, d, J=6.8 Hz), mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5- 3.1-3.2 (1H, m), 3.76 (3H, s), 7.15 (2H, t, J=8.5 Hz), 7.6-7.7 methoxycarbonylpyrimidine, 5.22 g (58.5 mmol.) of triethy (2H, m). lamine, and 34 mL of acetonitrile. The mixture in the flask HRMS: 3080695 (theoretical value (CHCIFNO, 10 was chilled to 0-5°C. in an ice bath. To the chilled mixture (M+)) 308.0728) was slowly added 5.12 g (44.7 mmol.) of methanesulfonyl chloride, and the resulting mixture was subjected to reaction Example 11 at 20-25°C. for 2 hours. After the reaction was complete, to 15 the reaction mixture was added 60 mL of water. The aqueous Preparation of 2-chloro-4-(4-fluorophenyl)-6-isopro reaction mixture was extracted with toluene and the toluene pyl-5-methoxycarbonylpyrimidine portion was separated. The toluene portion was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium Sulfate. The dried mixture was filtered In a 25 mL-Volume glass flask equipped with a stirrer, a and concentrated under reduced pressure. The residue was thermometer and a reflux condenser were placed 1.00 g (3.43 crystallized from methanol, to give 11.3 g of 4-(4-fluorophe mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5- nyl)-6-isopropyl-5-methoxycarbonyl-2-methanesulfony methoxycarbonylpyrimidine, 0.5 mL (3.9 mmol.) of thionyl loxypyrimidine as a colorless crystalline product having the chloride, 3.44 mL of toluene, and 0.11 mL of N,N-dimethyl below-mentioned characteristics. The yield was 89% (based formamide. The mixture was heated to 80°C. for 3 hours, to 25 on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl carry out reaction. After the reaction was complete, the reac 5-methoxycarbonylpyrimidine). tion mixture was cooled to room temperature, and poured into m.p.: 110-111° C. an ice/water mixture. The resulting aqueous mixture was UV (CHCN, m): 193.7, 276.8 neutralized with a saturated aqueous sodium hydrogen car IR (KBr, cm): 2980, 1724, 1562, 1391, 1250, 1175, bonate solution. The neutralized aqueous mixture was 30 1079,971. extracted with ethyl acetate. The ethyl acetate portion was 'H-NMR (CDC1, 8 (ppm)): 1.33 (6H, d. J=6.6 Hz), 3.20 separated, washed with a saturated aqueous sodium chloride (1H, m), 3.60 (3H, s), 7.1-7.2 (2H, s), 7.6-7.8 (2H, m). Solution, and dried over anhydrous magnesium sulfate. The HRMS: 368.0842 (theoretical value (CHFNOS dried ethyl acetate portion was filtered and concentrated (M+))368.0892) under reduced pressure, to obtain 0.80 g of 2-chloro-4-(4- 35 fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine as Example 14 a colorless crystalline product. The yield was 76% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5- Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- methoxycarbonylpyrimidine). methoxycarbonyl-2-(p-toluenesulfonyloxy)-pyrimi 40 dine Example 12 In a 200 mL-volume glass flask were placed 27.6 g (95.1 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5- Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- methoxycarbonylpyrimidine, 12.5 g (123 mmol.) of triethy methoxycarbonyl-2-(N-methyl-N-methanesulfonyl 45 lamine, and 95 mL of acetonitrile. The mixture of the flask amino)pyrimidine was chilled to 0-5°C. in an ice bath. To the chilled mixture was slowly added 20.0 g (105 mmol.) of p-toluenesulfonyl In a 25 mL-Volume glass flask equipped with a stirrer, a chloride, and the resulting mixture was subjected to reaction thermometer and a reflux condenser were placed 546 mg (5 at 20-25°C. for one hour. After the reaction was complete, to mmol.) of N-methylmethanesulfonamide, 551 mg (5 mmol.) 50 the reaction mixture was added 95 mL of water. The aqueous of sodium t-pentoxide, 10 mL of acetonitrile, and 309 mg (1 reaction mixture was extracted with toluene and the toluene mmol.) of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-meth portion was separated. The toluene portion was washed with oxycarbonylpyrimidine. The mixture was heated to 81-82°C. a saturated aqueous sodium chloride solution and dried over for 3 hours under refluxing, to carry out reaction. After the anhydrous magnesium Sulfate. The dried mixture was filtered reaction was complete, the reaction mixture was cooled to 55 and concentrated under reduced pressure. The residue was room temperature. To the cooled mixture was added 10 mL of crystallized from methanol, to give 35.9 g of 4-(4-fluorophe water, and the aqueous mixture was extracted with ethyl nyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfony acetate. The ethyl acetate portion was separated, and dried loxy)-pyrimidine as a colorless crystalline product having the over anhydrous magnesium sulfate. The dried ethyl acetate below-mentioned characteristics. The yield was 85% (based portion was filtered and concentrated under reduced pressure. 60 on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl The residue was purified by silica gel column chromatogra 5-methoxycarbonylpyrimidine). phy (column: Wako Gel C-200, eluent: hexane/ethyl acetate m.p. 94-96° C. (2:1, volume ratio)). There was obtained 339 mg of 4-(4- UV (CH.sub.3CN, m): 1949, 275.2 fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-me IR (KBr, cm): 2961, 1734, 1539, 1389, 1352, 1247, thyl-N-methanesul-fonylamino)pyrimidine. The yield was 65 1090,980. 89% (based on the amount of 2-chloro-4-(4-fluorophenyl)-6- 'H-NMR (CDC1, 8 (ppm)): 1.23 (6H, d, J=6.8 Hz), 2.45 isopropyl-5-methoxycarbonylpyrimidine). (3H, s), 3.0-3.2 (1H, m), 3.74 J=8.5 Hz). US 8,614,320 B2 21 22 HRMS: 444.1155 (theoretical value (CHFNOS There was obtained 39.9 g of 4-(4-fluorophenyl)-6-isopro (M+)) 444. 1194) pyl-5-methoxycarbonyl-2-(p-methoxybenzenesulfo-nyloxy) pyrimidine as a colorless crystalline product having the Example 15 below-mentioned characteristics. The yield was 91% (based Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl methoxycarbonyl-2-benzenesulfonyloxypyrimidine 5-methoxycarbonylpyrimidine). H-NMR (CDC1, 8 (ppm)): 1.25 (6H, d, J=6.8 Hz), 3.0- The procedures of Example 13 were repeated except for 3.2(1H, m), 3.74 (3H, s), 3.88 (3H, s), 6.99 (2H, dd, J-2.0,9.0 replacing p-toluenesulfonyl chloride with 18.5 g (105 mmol.) Hz), 7.0–7.2 (2H, m), 7.5-7.7 (2H, m), 8.07 (2H, dd, J–2.2, 9.0 of benzenesulfonyl chloride. 10 Hz). There was obtained 39.3 g of 4-(4-fluorophenyl)-6-isopro pyl-5-methoxycarbonyl-2-benzenesulfonyloxypyrimidine as Example 19 a pale yellow crystalline product having the below-mentioned characteristics. The yield was 96% (based on the amount of Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycar 15 methoxycarbonyl-2-(p-chlorobenzenesulfonyloxy)- bonylpyrimidine). pyrimidine 'H-NMR (CDC1, 8 (ppm)): 1.21 (6H, d, J–6.4 Hz), 3.0- 3.1 (1H, m), 3.73 (3H, s), 7.1-7.2 (2H, m), 7.5-7.7 (5H, m), The procedures of Example 13 were repeated except for 8.1-8.2 (2H, m). replacing p-toluenesulfonyl chloride with 22.2 g (105 mmol.) of p-chlorobenzenesulfonyl chloride. Example 16 There was obtained 39.9 g of 4-(4-fluorophenyl)-6-isopro Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- pyl-5-methoxycarbonyl-2-(p-chlorobenzenesulfonyloxy)py methoxycarbonyl-2-(2,4,6-trimethylbenzenesulfony rimidine as a colorless crystalline product having the below loxy)pyrimidine mentioned characteristics. The yield was 89% (based on the 25 amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5- The procedures of Example 13 were repeated except for methoxycarbonylpyrimidine). replacing p-toluenesulfonyl chloride with 23.0 g (105 mmol.) H-NMR (CDC1, 8 (ppm)): 1.23 (6H, d, J=6.6 Hz), 3.0- of 2,4,6-trimethylbenzenesulfonyl chloride. 3.2 (1H, m), 3.74 (3H, s), 7.1-7.2 (2H, m), 7.5-7.7 (4H, m), There was obtained 37.7 g of 4-(4-fluorophenyl)-6-isopro 8.0-8.1 (2H, m). pyl-5-methoxycarbonyl-2-(2,4,6-trimethylbenzen-esulfony 30 loxy)pyrimidine as a pale yellow crystalline product having Example 20 the below-mentioned characteristics. The yield was 84% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6- Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- isopropyl-5-methoxycarbonylpyrimidine). methoxycarbonyl-2-(2-nitrobenzenesulfonyloxy)- H-NMR (CDC1, 8 (ppm)): 1.17 (6H, d, J=6.8 Hz), 2.34 35 pyrimidine (3H, s), 2.67 (6H, s), 3.0-3.1 (1H, m), 3.73 (3H, s), 7.00 (2H, s), 7.0–7.2 (2H, m), 7.4-7.5 (2H, m). The procedures of Example 13 were repeated except for replacing p-toluenesulfonyl chloride with 23.3 g (105 mmol.) Example 17 of 2-nitrobenzenesulfonyl chloride. 40 There was obtained 28.0 g of 4-(4-fluorophenyl)-6-isopro Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- pyl-5-methoxycarbonyl-2-(2-nitrobenzenesulfony-loxy)py methoxycarbonyl-2-(2,4,6-triisopropylbenzenesulfo rimidine as an opaque crystalline product having the below nyloxy)pyrimidine mentioned characteristics. The yield was 62% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5- The procedures of Example 13 were repeated except for 45 methoxycarbonylpyrimidine). replacing p-toluenesulfonyl chloride with 31.8g (105 mmol.) H-NMR (CDC1, 8 (ppm)): 1.17 (6H, d, J=6.8 Hz), 3.0- of 2,4,6-triisopropylbenzenesulfonyl chloride. 3.2 (1H, m), 3.75 (3H, s), 7.1-7.2 (2H, m), 7.5-7.6 (2H, m), There was obtained 47.1 g of 4-(4-fluorophenyl)-6-isopro 7.7-8.0 (3H, m), 8.33 (1H, dd, J=1.7, 8.1 Hz). pyl-5-methoxycarbonyl-2-(2,4,6-triisopropylben-Zenesulfo nyloxy)pyrimidine as a pale yellow crystalline product hav 50 Example 21 ing the below-mentioned characteristics. The yield was 89% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6- Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- isopropyl-5-methoxycarbonylpyrimidine). methoxycarbonyl-2-(N-methyl-N-methanesulfony 'H-NMR (CDC1, 8 (ppm)): 1.12 (6H, d, J=6.6 Hz), 1.19 lamino)pyrimidine (12H, d, J=6.8 Hz), 1.27 (6H, d, J=7.1 Hz), 2.8-2.95 (1H, m), 55 2.95-3.1 (1H, m), 3.73 (3H, s), 4.1-4.3 (2H, m), 7.0–7.1 (2H, In a 25 mL-Volume glass flask equipped with a stirrer, a m), 7.20 (2H, s), 7.4-7.5 (2H, m). thermometer and a reflux condenser were placed 196 mg (1.8 mmol.) of N-methylmethanesulfonamide, 198 mg (1.8 Example 18 mmol.) of sodium t-pentoxide, 7.5 mL of acetonitrile, and 60 667 mg (1.5 mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5- Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine. The methoxycarbonyl-2-(p-methoxybenzenesulfony mixture was heated to 81-82°C. for 1.5 hours under refluxing, loxy)-pyrimidine to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the The procedures of Example 13 were repeated except for 65 cooled mixture was added 10 mL of water, and the aqueous replacing p-toluenesulfonyl chloride with 21.7 g (105 mmol.) mixture was extracted with ethyl acetate. The ethyl acetate of p-methoxybenzenesulfonyl chloride. portion was separated, and dried over anhydrous magnesium US 8,614,320 B2 23 24 sulfate. The dried ethyl acetate portion was filtered and con mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5- centrated under reduced pressure. The residue was purified by methoxycarbonylpyrimidine, 3.0 g (30.0 mmol.) of triethy silica gel column chromatography (column: Wako Gel C-200, lamine, and 150 mL of toluene. The mixture in the flask was eluent: hexane/ethyl acetate (2:1, volume ratio)). There was obtained 428 mg of 4-(4-fluorophenyl)-6-isopropyl-5-meth chilled to 0°C. in an ice bath. To the chilled mixture was oxycarbonyl-2-(N-methyl-N-methanesul-fonylamino)-pyri slowly added 8.46 g (30.0 mmol.) of trifluoromethane midine. The yield was 75% (based on the amount of 4-(4- Sulfonic anhydride, and the resulting mixture was Subjected fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p- to reaction for 3 hours at the same temperature. After the toluenesulfonyloxy)pyrimidine). reaction was complete, to the reaction mixture was added 90 mL of water. From the aqueous reaction mixture, an organic Example 22 10 liquid portion was separated. The organic liquid portion was concentrated under reduced pressure. The residue was puri Preparation of (2-amino-4-(4-fluorophenyl)-6-iso fied by silica gel column chromatography (column: Wako Gel propyl-5-methoxycarbonylpyrimidine C-200, eluent: hexane/ethyl acetate (8:2, volume ratio)). There was obtained 8.46 g of 4-(4-fluorophenyl)-6-isopro In a 25 mL-Volume glass flask equipped with a stirrer, a 15 pyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxy thermometer and a gas inlet were placed under ice-chilling pyrimidine having the below-mentioned characteristics as a 1.00 g (2.71 mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5- colorless oil. The yield was 74% (based on the amount of methoxycarbonyl-2-methanesulfonyloxypyrimidine and 8.1 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycar mL of tetrahydrofuran. The mixture was stirred at room tem bonylpyrimidine). perature for 12 hours under gaseous ammonia atmosphere, IR (KBr, cm): 3421, 2978, 1737, 1570, 1429, 1222, for carrying out reaction. After the reaction was complete, 10 1136,973, 851 mL of water was added to the reaction mixture. The aqueous 'H-NMR (CDC1, 6 ppm)): 1.33 (6H, d, J=6.6 Hz), 3.1-3.2 mixture was then subjected to extraction with toluene. The (1H, m), 3.80 (3H, s), 7.1-7.2 (2H, m), 7.7-7.8 (2H, m) toluene portion was separated, washed with a saturated aque HRMS: 422.0585 (theoretical value (CHFNOS ous Sodium chloride solution, and dried over anhydrous mag 25 (M+)) 422.0560) nesium sulfate. The dried toluene portion was filtered and concentrated under reduced pressure. The residue was puri Example 25 fied by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (2:1, volume ratio)). Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- There was obtained 0.63 g of 2-amino-4-(4-fluorophenyl)-6- 30 methoxycarbonyl-2-trifluoromethanesulfonyloxy isopropyl-5-methoxycarbonylpyrimidine. The yield was pyrimidine 80% (based on the amount of 4-(4-fluorophenyl)-6-isopro pyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine). In a 300 mL-Volume glass flask equipped with a stirrer, a 6-isopropyl-5-methoxycarbonylpyrimidine thermometer and a reflux condenser were placed 2.9 g (10.0 35 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5- Example 23 methoxycarbonylpyrimidine, 1.7 g (16.8 mmol.) of triethy lamine, and 50 mL of toluene. The mixture in the flask was Preparation of (4-(4-fluorophenyl)-6-isopropyl-5- chilled to 0°C. in an ice bath. To the chilled mixture was methoxycarbonyl-2-N-methylaminopyrimidine slowly added 2.4 g (14.1 mmol.) of trifluoromethanesulfonyl 40 chloride, and the resulting mixture was subjected to reaction In a 50 mL-Volume glass flask equipped with a stirrer, a for 3 hours at the same temperature. After the reaction was thermometer and a dropping funnel was placed 6.00 g (16.3 complete, to the reaction mixture was added 30 mL of water. mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbo From the aqueous reaction mixture, an organic liquid portion nyl-2-methanesulfonyloxypyrimidine. Into the flask was was separated. The organic liquid portion was concentrated slowly dropped under ice-chilling 5.06 g (65.2 mmol) of 45 under reduced pressure. The residue was purified by silica gel aqueous 40 wt.% methylamine Solution. The resulting mix column chromatography (column: Wako Gel C-200, eluent: ture was stirred for one hour at the same temperature for hexane/ethyl acetate (8:2, volume ratio)). There was obtained carrying out reaction. After the reaction was complete, 16 mL 2.8g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl of water was added to the reaction mixture. The aqueous 2-trifluoromethanesulfonyloxypyrimidine having the below mixture was then subjected to extraction with toluene. The 50 mentioned characteristics as a colorless oil. The yield was toluene portion was separated, washed with a saturated aque 66% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy ous Sodium chloride solution, and dried over anhydrous mag 6-isopropyl-5-methoxycarbonylpyrimidine). nesium sulfate. The dried toluene portion was filtered and concentrated under reduced pressure to give 4.81 g of 4-(4- Example 26 fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-N-methy 55 laminopyrimidine. The yield was 97% (based on the amount Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- of 4-(4-fluoro-phenyl)-6-isopropyl-5-methoxycarbonyl-2- methoxycarbonyl-2-(N-methyl-N-methanesulfony methanesulfonyloxypyrimidine). lamino)pyrimidine

Example 24 60 In a 50 mL-Volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 3.0 g (7 Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbo methoxycarbonyl-2-trifluoromethanesulfonyloxy nyl-2-trifluoromethanesulfonyloxypyrimidine, 1.13 g (10.5 pyrimidine mmol.) of N-methylmethanesulfonamide, 1.45 g (10.5 65 mmol.) of potassium carbonate (available from Wako Juny In a 300 mL-Volume glass flask equipped with a stirrer, a aku Co., Ltd., special grade), and 14 mL ofbutyl acetate. The thermometer and a reflux condenser were placed 8.7 g (30.0 mixture was heated to 122-125° C. for 3 hours under reflux US 8,614,320 B2 25 26 ing, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the (3) reaction mixture were added 10 mL of water and 7 mL of acetone, and the organic liquid portion was separated. The organic liquid portion was washed with a saturated aqueous Sodium chloride Solution and concentrated under reduced pressure. The residue was purified by silica gel column chro matography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (5:1, volume ratio)). There was obtained 2.1 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N- 10 methyl-N-methanesul-fonylamino)pyrimidine as a white crystalline product. The yield was 78% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-tri fluoromethanesulfonyloxypyrimidine). 15 in which R is selected from the group consisting of an alkyl Example 27 group having from 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl-alkyl group Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- having an alkyl moiety of from 1 to 3 carbon atoms, an methoxycarbonyl-2-(N-methyl-N-methanesulfony aryl group and a methylphenyl group, which comprises lamino)pyrimidine the steps of: (I) reacting an isobutyrylacetate ester of the following In a 50 mL-Volume glass flask equipped with a stirrer, a formula (5): thermometer and a reflux condenser were placed 1.1 g (2.5 25 mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbo nyl-2-(p-toluenesulfonyloxy)-pyrimidine, 0.55 g (5.0 mmol.) (5) of N-methylmethanesulfonamide, 0.69 g (5.0 mmol.) of potassium carbonate (available from Wako Junyaku Co., Ltd., COR special grade), 0.32 g (1.0 mmol.) of tetrabutylammonium 30 bromide, 20 mL of toluene and 5 mL of water. The mixture was heated to 85°C. for 28 hours under refluxing, to carry out reaction. After the reaction was complete, the reaction mix wherein R is the same as above, ture was cooled to room temperature. To the reaction mixture 35 were added 10 mL of water and 7 mL of acetone, and the with organic liquid portion was separated. The organic liquid por 4-fluorobenzaldehyde and urea in the presence of a pro tion was analyzed by high performance liquid chromatogra tonic compound selected from the group consisting of an phy. It was confirmed that 0.6 g of 4-(4-fluorophenyl)-6- inorganic acid or a salt thereof, an organic Sulfonic acid, isopropyl-5-methoxycarbonyl-2-(N-methyl-N- 40 an organic carboxylic acid and an alcohol; and methanesulfonylamino)pyrimidine was produced. The yield a metal salt selected from the group consisting of copper(I) was 63% (based on the amount of 4-(4-fluorophenyl)-6-iso chloride, copper(II) chloride, copper(II) acetate, iron(II) propyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)-pyri chloride, iron(III) chloride, aluminum chloride, nickel midine). (II) bromide, tin(VI) chloride, titanium tetrachloride, 45 and magnesium bromide; INDUSTRIALUTILITY (II) oxidizing the reaction product of the step (I); (III) reacting the oxidation product of the step (II) with The pyrimidine compound, particularly, 2-(N-methyl-N- an organic Sulfonylhalide having the formula (2): methanesulfonylamino)pyrimidine compound, prepared by 50 the invention is of value as an intermediate compound for the R'SOX (2) production of a cholesterol reducing agent (HMG-CoA in which R' is selected from the group consisting of an alkyl reductase agent). The compound of formula (3) can be con group having from 1 to 10 carbon atoms, a cycloalkyl verted to an HMG CoA reductase inhibitor by the processes 55 group having 3 to 6 carbon atoms, an aryl-alkyl group disclosed in European Patent Application Publication No. having an alkyl moiety of from 1 to 3 carbon atoms, an 0521471, Bioorg. Med. Chem., 5, 437 (1997) and Interna aryl group and a methylphenyl group, and X is a halogen tional Patent Application No. WO 00/49014. The disclosures atom, or an organic sulfonic anhydride having the for of these references are incorporated herein by reference to mula (2a): demonstrate how a compound of formula (3) or formula (8) can be converted to an HMG CoA reductase inhibitor, in 60 particular, rosuvastatin or a pharmaceutically acceptable salt thereof. Such as rosuvastatin calcium. in which R" has the same meaning as above; and (IV) reacting the reaction product of the step (III) with The invention claimed is: 65 N-methyl-N-methanesulfonamide. 1. A process for preparing a 2-(N-methyl-N-methanesulfo 2. A process for preparing a 2-(N-methyl-N-methanesulfo nylamino)pyrimidine compound having the formula (3): nylamino)pyrimidine compound having the formula (3): US 8,614,320 B2 27 28

(3) (3)

10

15 in which R is selected from the group consisting of an alkyl in which R is selected from the group consisting of an alkyl group having from 1 to 10 carbon atoms, a cycloalkyl group having from 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl-alkyl group group having 3 to 6 carbon atoms, an aryl-alkyl group having an alkyl moiety of from 1 to 3 carbon atoms, an having an alkyl moiety of from 1 to 3 carbon atoms, an aryl group and a methylphenyl group, which comprises aryl group and a methylphenyl group, which comprises the steps of: the steps of: reacting a hydroxypyrimidine compound having the for reacting a hydroxypyrimidine compound having the for mula (1): mula (1): 25

(1) (1) 30

35

40

45 in which R is the same as above, in which R is the same as above, with an organic Sulfonylhalide having the formula (2): with an organic Sulfonylhalide having the formula (2): R'SOX (2) R'SOX (2) 50 in which R' is selected from the group consisting of an alkyl in which R' is selected from the group consisting of an alkyl group having from 1 to 10 carbon atoms, a cycloalkyl group having from 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl-alkyl group group having 3 to 6 carbon atoms, an aryl-alkyl group having an alkyl moiety of from 1 to 3 carbon atoms, an having an alkyl moiety of from 1 to 3 carbon atoms, an 55 aryl group and a methylphenyl group and X is a halogen aryl group and a methylphenyl group; and X is a halogen atom, or an organic sulfonic anhydride having the for atom, or an organic Sulfonic anhydride having the for mula (2a): mula (2a):

60 in which R" has the same meaning as above, and reacting in which R' has the same meaning as above, and the resulting reaction product with N-methyl-N-meth reacting the resulting reaction product with N-methyl anesulfonamide, followed by conversion of the com N-methanesulfonamide, wherein R is a substituted or pound of formula (3) to rosuvastatin or a pharmaceuti unsubstituted aryl group. 65 cally acceptable salt thereof. 3. A process for preparing a 2-(N-methyl-N-methanesulfo 4. The process for preparing a 2-(N-methyl-N-methane nylamino)pyrimidine compound having the formula (3): Sulfonylamino)pyrimidine compound having the formula (3): US 8,614,320 B2 29 30 with 4-fluorobenzaldehyde and urea in the presence of a

(3) protonic compound selected from the group consisting of an inorganic acid or a salt thereof, an organic Sulfonic acid, an organic carboxylic acid and an alcohol; and a metal salt selected from the group consisting of copper(I) chloride, copper(II) chloride, copper(II)acetate, iron(II) chloride, iron(III) chloride, aluminum chloride, nickel (II) bromide, tin(VI) chloride, titanium tetrachloride, and magnesium bromide; 10 (II) oxidizing the reaction product of the step (I); (III) reacting the oxidation product of the step (II) with an organic Sulfonylhalide having the formula (2):

15 R'SOX (2) in which R is selected from the group consisting of an alkyl in which R' is selected from the group consisting of an alkyl group having from 1 to 10 carbon atoms, a cycloalkyl group having from 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl-alkyl group group having 3 to 6 carbon atoms, an aryl-alkyl group having an alkyl moiety of from 1 to 3 carbon atoms, an having an alkyl moiety of from 1 to 3 carbon atoms, an aryl group and a methylphenyl group, which comprises aryl group and a methylphenyl group, and X is a halogen the steps of: atom, or an organic sulfonic anhydride having the for (I) reacting an isobutyrylacetate ester of the following mula (2a): formula (5): 25 in which R" has the same meaning as above; and (5) (IV) reacting the reaction product of the step (III) with N-methyl-N-methanesulfonamide to provide the COR compound having the formula (3), followed by converting the compound having the for 30 mula (3) to rosuvastatin or a pharmaceutically accept able salt thereof. wherein R is the same as above, k k k k k