(12) United States Patent (10) Patent No.: US 8,026,396 B2 Mitsuda Et Al

USOO8026396 B2

(12) United States Patent (10) Patent No.: US 8,026,396 B2 Mitsuda et al. (45) Date of Patent: Sep. 27, 2011

(54) PROCESSES FOR THE PREPARATION OF E. E. 1886 OPTICALLY ACTIVE INTERMEDIATES EP 1418168 5, 2004 WO O 1922.63 12/2001 (75) Inventors: Masaru Mitsuda, Osaka (JP); Tadashi Moroshima, Osaka (JP); Kentaro OTHER PUBLICATIONS Tsukuya, Osaka (JP); Kazuhiko Office Action dated Dec. 30, 2009 received in copending U.S. Appl. Watabe, Osaka (JP); Masahiko No. 1 1/833,263. Yamada, Osaka (JP) Tomoskozi. Tetrahedron (1963) 19(12): 1969-1979 Abstract. Office Action dated Apr. 23, 2009 received in copending U.S. Appl. (73) Assignee: AstraZeneca AB, Sodertalje (SE) No.Engel 1 1/833,263.et al., “Photochemistry of azocyclopropane.” J Org Chem (*) Notice: Subject to any disclaimer, the term of this ECS1988) 53(2O):4748-4758. STN. Acc. No. 1971:435269, Filler et al., J. patent is extended or adjusted under 35 Chem. Soc., Section C: Organic (1971), 11, p. 2062-2068 (abstract). U.S.C. 154(b) by 0 days. Yasuri et al., “Vibrational circular dichroism of optically active cyclopropanes. 3. trans-2-Phenylcyclopropanecarboxylic acid (21) Appl. No.: 12/854,215 derivatives and related compounds.” J Am Chem Soc (1987) 109(8):2311-2320. (22) Filed: Aug. 11, 2010 Armstrong et al., “Stereocontrolled synthesis of 3-(trans-2- aminocyclopropyl)alanine, a key component of belactosin A.” (65) Prior Publication Data Organic Letters (2003) 5(13):2331-2334. Barbieri et al., “Chemo-enzymatic synthesis of (R)- and (S)-3,4- US 2010/0331575A1 Dec. 30, 2010 dichlorophenylbutanolide intermediate in the synthesis of sertraline.” Tetrahedron: Asymmetry (1999) 10:3931-3937. Related U.S. Application Data Wang et al., “Enantioselective synthesis of chiral cyclopropane com pounds through microbial transformations of trans-2- (63) Continuation of application No. 1 1/833.266, filed on arylcyclopropanecarbonitriles.” Tetrahedron Letters (2000)41:6501 Aug. 3, 2007, now Pat. No. 7,790,927. 6505. White “New reactions of polyfluoroaromatic compounds. Part II. (30) Foreign Application Priority Data Polyfluoroaralkyl amines.” J. ChemSoc. (1971) 2062-2068. Singh et al., “Development of a practical, safe, and high-yielding Aug. 5, 2006 (GB) ...... O61562O2 process for the preparation of enationerically pure trans cyclopropane carboxylic acid.” Organic Process Research & Devel (51) Int. Cl. opment (2002) 6:618-620. C07C 233/58 (2006.01) Notice of Allowance dated Sep. 7, 2010 received in copending U.S. (52) U.S. Cl...... 564/161; 564/190 Appl. No. 1 1/833,263. (58) Field of Classification Search ...... None * cited by examiner See application file for complete search history. Primary Examiner — Brian J Davis (56) References Cited (74) Attorney, Agent, or Firm — Pepper Hamilton LLP U.S. PATENT DOCUMENTS (57) ABSTRACT 4411,925. A 10/1983 Brennan et al. This invention relates to processes for the production of opti 4,590,292 A 5, 1986 Blackwell et al. 4.933.477 A 6, 1990 Goetz et al. cally active 2-(disubstituted aryl)cyclopropylamine com 5,225.602 A 7, 1993 Hoelderich et al. pounds and optically active 2-(disubstituted aryl)cyclopro 5,728,873 A 3, 1998 Kleemiss et al. pane carboxamide compounds which are useful 3. 4.58. St. intermediates for the preparation of pharmaceutical agents, ww- oeller et al. and in particular the compound 1S-(1C.2O.3f3(1S,2R), 7,790,927 B2 ck 9/2010 Mitsuda et al...... 564,307 5 B)-3-7-2-(3,4-difluorophenyl)-cyclopropylamino-5- FOREIGN PATENT DOCUMENTS (propylthio)-3H-1,2,3-triazolo 4,5-dipyrimidin-3-yl)-5-(2- DE 3909142 10, 1990 hydroxyethoxy)-cyclopentane-1,2-diol. DE 4315623 11, 1994 DE 19523868 1, 1997 2 Claims, No Drawings US 8,026,396 B2 1. 2 PROCESSES FOR THE PREPARATION OF (v) A process to obtain optically active cyclopropanecar OPTICALLY ACTIVE INTERMEDIATES boxylic acid derivative by cyclopropanation after deriving into optically active ester or amide via several steps using CROSS-REFERENCE TO RELATED benzaldehyde derivative as the starting material (WO01/ APPLICATIONS 92263); and (vi) A process to obtain optically active 2-dihydrofuranyl This application is a continuation of U.S. Ser. No. 1 1/833, cyclopropanecarboxylate derivative by reacting phospho 266 filed Aug. 3, 2007, which claims priority to Great Britain noacetic acid ester derivative with optically active dihy Application No. 0615620.2 filed Aug. 5, 2006, each of which drobenzofuranyl ethylene oxide derivative in the presence of is incorporated herein by reference in its entirety. 10 base (Organic Process Research & Development, Vol 6, p. 618 (2002)). FIELD OF THE INVENTION Examples of a process to produce optically active 2-aryl This invention relates to processes for the production of cyclopropylamine derivatives from optically active 2-aryl optically active 2-(disubstituted aryl)cyclopropylamine 15 cyclopropanecarboxylic acid are: derivatives and optically active 2-(disubstituted aryl)cyclo (vii) A process whereinbenzaldehydes is used as the start propane carboxamide derivative which are useful intermedi ing material and derived into optically active ester or amide ates for the preparation of pharmaceutical agents, and in via several steps, and thereafter optically active 2-aryl cyclo particular the compound 1S-(1C.2O.3 B(1S,2R).5B)-3- propane carboxylate ester is obtained by cyclopropanation. 7-2-(3,4-difluorophenyl)-cyclopropylamino-5-(propy This optically active carboxylic acid derivative is formed into lthio)-3H-1,2,3-triazolo 4.5-dpyrimidin-3-yl)-5-(2-hy acid azide, and optically active 2-aryl cyclopropylamine droxyethoxy)-cyclopentane-1,2-diol. This compound, and derivative is produced by Curtius rearrangement (WO01/ similar such compounds, are disclosed in WO 00/34283 and 92263). WO99/05143. These compounds are disclosed as P. (which In the process for the production of optically active 2-aryl is now usually referred to as PY) receptor antagonists. 25 cyclopropane carboxamides referred to in (i) above, only the Such antagonists can be used as, interalia, inhibitors of plate process to produce 2-phenylcyclopropane carboxamide from let activation, aggregation or degranulation. 2-phenylcyclopropane carboxylic acid is described and a pro cess for production for 2-(disubstituted aryl)cyclopropane BACKGROUND OF THE INVENTION carboxamide derivative is not disclosed. Moreover, in the 30 process (ii) above, there is mentioned the process for produc Some processes are known for the production of optically tion only of 2,2-dimethyl-3-phenylcyclopropane carboxam active 2-cyclopropane carboxamide derivatives, optically ide and 2,2-dimethyl-3-isopropylidene cyclopropane car active 2-aryl cyclopropylamine derivatives, and optically boxamide, and a process for production of 2-(disubstituted active 2-arylcyclopropane-1-carboxylate ester derivatives. aryl)cyclopropane carboxamide derivative is not disclosed. Examples of processes for the production of optically 35 Secondly, in a process for the production of optically active active 2-arylcyclopropane carboxamide derivatives are: 2-aryl cyclopropylamine derivative, optically active 2-aryl (i) A process wherein excess thionyl chloride is reacted cyclopropylamine derivative is produced by Curtius rear with optically active 2-phenylcyclopropane carboxylic acid rangement from optically active 2-arylcyclopropane car in benzene solvent to form corresponding acid chloride, and boxylic acid in the aforesaid process (iii), however, it is not after concentrating down excess thionyl chloride and benzene 40 suitable for a commercial preparation method from the view under reduced pressure, the acid chloride is isolated and point of safety because it is via an acid azide intermediate purified by distillation, and, by causing ammonia water to act having explosive properties. Moreover, in the process (iv), on this, 2-phenylcyclopropane carboxamide is obtained (J. optically active amine is produced from the optically active Am. Chem. Soc. Vol. 109, p. 2311 (1987), Journal of Medici carboxamide by a Hofmann rearrangement. However, it is not nal Chemistry Vol. 20, p. 771 (1977)); and 45 suitable for a commercial preparation method from the view (ii) A Process to obtain optically active 3-aryl-2-dimethyl point of economy because yield is low when the reaction is cyclopropane-1-carboxamide by causing ammonia water to carried out using the Sodium hypochlorite. Moreover, as for act on the corresponding acid chloride formed by reacting the aforesaid process (iv), only the process to produce opti thionyl chloride with optically active 3-aryl-2-dimethylcy cally active 2,2-dimethyl cyclopropylamine from optically clopropane-1-carboxylic acid (J. Org. Chem. Vol. 68, p. 621 50 active 2,2-dimethylcyclopropane carboxamide is mentioned, (2003)). and a process for production of 2-(disubstituted aryl)cyclo Examples of processes for the production of optically propane carboxamide derivative is not disclosed. active 2-aryl cyclopropylamine derivatives are: Thirdly, in a process for the production of optically active (iii) A process wherein chlorocarbonic acid ethyl ester is 2-arylcyclopropane carboxylate ester derivative, in the afore reacted with 2-aryl cyclopropane carboxylic acid to form 55 said process (V), optically active 3,4-difluorophenyl cyclo mixed acid anhydride, and by causing to act Sodium azide on propanecarboxylic derivative is obtained by cyclopropana this, corresponding acid azide is formed, and 2-aryl cyclopro tion after converting 3,4-difluoro benzaldehyde starting pylamine is obtained by Curtius rearrangement with this material into optically active ester or amide via several steps. (Journal of Medicinal Chemistry Vol. 20, p. 771 (1977), However, it is not commercially suitable from the viewpoint WO01/92263); and 60 of productivity and economy. For example, the starting mate (iv) A process to obtain corresponding 2,2-dimethylcyclo rial is expensive, the stereoselectivity is insufficient in the propylamine by causing chlorine, bromine or sodium cyclopropanation and also there are many numbers of steps. hypochlorite to act on the optically active 2.2-dimethylcyclo Moreover, in process (vi), only an example of preparing opti propane-1-carboxamide in the presence of base (Kokoku cally active dihydrofuranyl cyclopropanecarboxylate ester 5-3865); 65 from optically active dihydrobenzofuranyl ethylene oxide is Examples of a process for the production of optically active mentioned. It is not a process for the production of general 2-arylcyclopropane carboxylate ester derivatives are: optical activity 2-arylcyclopropane carboxylate ester. US 8,026,396 B2 3 Fourthly, a process to produce optically active 2-aryl cyclo propylamine derivative from optically active 2-arylcyclopro (7) pane carboxylate ester derivative using (vii) is not commer CO2H cially viable from a safety standpoint because the acid azide : intermediate has expulsion properties. Also, purification is : essential due to insufficient stereoselectivity during the cyclo F propanation, making this process unsuitable for commercial preparation because of poor productivity. F

Thus, the processes outlined are unsuitable for commercial 10 production. There is a need for a commercial process which by de-esterifying an optically active 2-arylcyclopropane car addresses areas such as safety, economy, productivity and the boxylate ester compound represented by general formula (6) like. (6) 15 SUMMARY OF THE INVENTION COR : The present invention provides processes for the produc : tion of an optically active cyclopropylamine compound rep F resented by general formula (2), or a salt thereof, F (2) wherein R is an optionally substituted Cocyclic or acyclic alkyl group, optionally substituted Co aryl group, or 25 optionally substituted C-o aralkyl group, and * denotes an asymmetric carbon centre, and wherein the compound of formula (6) is obtained by reacting an optically active styrene oxide compound represented by general formula (3) wherein each of R. R. R. and R is, independently, selected 30 from a hydrogenatom, optionally Substituted Co cyclic or (3) acyclic alkyl group, optionally Substituted Caryl group or O optionally Substituted Cz-o aralkyl group, and wherein * denotes an asymmetric carbon centre; characterised by the : reaction of an optically active cyclopropane carboxamide 35 compound represented by general formula (1) c.F (1) wherein * denotes an asymmetric carbon centre, or optically 40 active halohydrin compound represented by general formula (4)

(4) 45 OH wherein each of R', R. R. Rand * are the same as for the cyclopropylamine compound represented by general formula X (2)) with hypochlorite in water in the presence of 5-30 equiva lents of alkali metal hydroxide. The present invention also provides processes for the pro 50 F duction of an optically active 2-aryl cyclopropylamine com F pound represented by general formula (9), or a salt thereof, wherein X denotes a halogen atom, and * denotes an asym (9) 55 metric carbon centre, with a phosphonoacetic acid ester com NH2 pound represented by general formula (5)

(5) 60 O RO P-N-COR wherein * denotes an asymmetric carbon centre, and wherein an optically active 2-aryl cyclopropanecarboxylic acid com 65 wherein each RandR is, independently, a substituted Co pound represented by general formula (7), wherein * denotes cyclic oracyclic alkyl group, optionally Substituted Co aryl an asymmetric carbon centre, is obtained, group, or optionally Substituted Cz-o aralkyl group, in the US 8,026,396 B2 5 presence of base; and thereafter, the 2-aryl cyclopropanecar boxylic acid compound of formula (7) obtained is activated (17) by reaction with a carboxylic acid activator and thereafter reacting with ammonia to give the optically active 2-aryl R10 -(-CON:is cyclopropane carboxamide compound represented by : obtained general formula (8) wherein, R' is an aryl group substituted by 2 or more halogen atoms, and * denotes an asymmetric carbon centre. (8) 10 CONH2 DESCRIPTION OF EMBODIMENTS Efficient processes have now been discovered for the pro duction of optically active 2-aryl cyclopropylamine deriva 15 tives or salts thereof. The processes afford high optical purity by using a readily available optically active styrene oxide derivative as the starting material. Efficient processes for the wherein * denotes an asymmetric carbon centre, which is production of optically active cyclopropylamine derivative reacted with an oxidant to give the compound of formula (9). by a Hofmann rearrangement using sodium hypochlorite The present invention also provides processes for the pro have been discovered. These processes can be used safely and duction of optically active 2-aryl cyclopropane carboxamide inexpensively as commercial preparation methods. compound represented by general formula (12) Thus, according to the present invention there is provided a process for the production of optically active cyclopropy lamine derivatives (or compounds) represented by general 25 formula (2) or salts thereof (12) R7 -(-CON:is : (2)

30 wherein R is an aryl group substituted by 2 or more halogen atoms, and * denotes an asymmetric carbon centre, charac terized in that, an optically active 2-aryl cyclopropanecar 35 boxylic acid compound represented by general formula (10) (wherein R', R,R or R'denote a hydrogenatom, optionally Substituted Co cyclic or acyclic alkyl group, optionally Substituted Co aryl group, or optionally substituted Cz-o (10) aralkyl group, and * denotes an asymmetric carbon centre), 40 characterised by reacting optically active cyclopropane car R7 -(1-coilis : boxamide derivative (or compound) represented by general formula (1) wherein R is an aryl group substituted by 2 or more halogen 45 (1) atoms, and * denotes an asymmetric carbon centre, is reacted with a carboxylic acid activator with the formation of an optically active 2-aryl cyclopropanecarboxylic acid com pound represented by general formula (11) 50

(11) (wherein R', R. R. Rand * have the same said definitions) with hypochlorite in water in the presence of alkali metal 55 hydroxide of 5-30 equivalent. -(-),: Suitably, the hypochlorite is sodium hypochlorite; and in particular the quantity used of the hypochlorite is 1-5 mole equivalent with respect to compound of the formula (1). In a wherein R is an aryl group substituted by 2 or more halogen particular embodiment, there is provided a process for the atoms, Y is a carbonyl group activated group, and * denotes an 60 production of optically active cyclopropylamine derivatives asymmetric carbon centre, and thereafter this optically active or salts thereof wherein R', R, R is hydrogenatom and R is 2-aryl cyclopropanecarboxylic acid compound represented 3,4-difluorophenyl group. by general formula (11) is reacted with ammonia. In a further embodiment, there is provided is a process for The present invention also provides optically active 2-aryl 65 the production of an optically active 2-aryl cyclopropylamine cyclopropane carboxamide compounds represented by gen derivative (or compound) represented by general formula (9) eral formula (17) or a salt thereof, US 8,026,396 B2 7 (9) NH2 (5) : O : | F RO P-N-COR

F (wherein R or R denote optionally substituted Co cyclic (wherein * denotes an asymmetric carbon centre), wherein an oracyclic alkyl group, optionally Substituted Co aryl group optically active 2-aryl cyclopropanecarboxylic acid deriva 10 or optionally substituted Czo aralkyl group) in the presence tive (or compound) represented by general formula (7) of base, and optically active 2-aryl cyclopropane carboxam (7) ide derivative (or compound) represented by obtained general CO2H formula (8) : : 15 (8) F CONH F (wherein * denotes an asymmetric carbon centre) is obtained by de-esterifying the optically active 2-arylcyclopropane car boxylate ester derivative (or compound) represented by gen eral formula (6) (wherein * denotes an asymmetric carbon centre) which is (6) 25 obtained by reacting the obtained aforesaid 2-aryl cyclopro COR panecarboxylic acid derivative (or compound) with ammonia : : after being activated with carboxylic acid activator is reacted with oxidant. F 30 There is also provided a process for the production of optically an active 2-aryl cyclopropane carboxamide deriva F tive (or compound) represented by general formula (12) (wherein, R denotes optionally substituted Co cyclic or acyclic alkyl group, optionally Substituted Co aryl group, or optionally substituted C-o aralkyl group, and * denotes an 35 (12) asymmetric carbon centre) which is obtained by reacting the optically active styrene oxide derivative (or compound) rep R7 -(-CONH.: resented by general formula (3) (wherein R" denotes an aryl group substituted by 2 or more 40 halogen atoms, and * denotes an asymmetric carbon centre) (3) O characterized by reacting with ammonia, optically active 2-aryl cyclopropanecarboxylic acid derivative (or com : pound) represented by general formula (11) 45 (11) c.F

(wherein * denotes an asymmetric carbon centre) or optically 50 -s-s active halohydrin derivative (or compound) represented by or general formula (4) (wherein, R" denotes an aryl group substituted by 2 or more halogen atoms, Y denotes carbonyl group activated group, and * denotes an asymmetric carbon centre) which is (4) 55 obtained from an optically active 2-aryl cyclopropanecar OH boxylic acid derivative (or compound) represented by general X formula (10) :

60 F (10)

F R :

(wherein X denotes a halogen atom, and * denotes an asym 65 (wherein R" denotes an aryl group substituted by 2 or more metric carbon centre) with phosphonoacetic acid ester deriva halogen atoms, and * denotes an asymmetric carbon centre) tive (or compound) represented by general formula (5) by reacting with a carboxylic acid activator. US 8,026,396 B2 10 There is also provided a process for the production of an There is also provided a process for the production of an optically active 2-aryl cyclopropane carboxamide derivative optically active 2-aryl cyclopropane carboxamide derivative (or compound), wherein the reaction is carried out by using (or compound) to obtaina (1R,2R)-2-aryl cyclopropane car the compound of formula (10) obtained by de-esterifying an boxylate ester derivative (or compound) of formula (13) using optically active 2-aryl cyclopropane carboxylate ester deriva (S)-styrene oxide derivative formula (14) and (S)-halohydrin tive (or compound) represented by general formula (13) derivative (or compound) of formula (15). In particular, there is provided a process for the production of an optically active 2-aryl cyclopropane carboxamide derivative (or compound), (13) wherein R is 3,4-difluorophenyl group. 10 The present invention also provides an optically active : 2-arylcyclopropane carboxamide derivative (or compound) represented by general formula (17) (wherein R denotes optionally substituted Co cyclic or acyclic alkyl group, optionally Substituted Co aryl group, or 15 optionally substituted Coaralkyl group, and R and * have (17) the same said definitions). R -(-CON:: There is also provided a process for the production of an optically active 2-aryl cyclopropane carboxamide derivative (or compound), wherein the reaction is carried out by using (wherein R" denotes an aryl group substituted by 2 or more the compound of formula (13) obtained by reacting the opti halogen atoms, and * denotes an asymmetric carbon centre). cally active styrene oxide derivative represented by general In particular, in the optically active 2-arylcyclopropane carboxamide derivative (or compound) of formula (17), R' is formula (14) a 3,4-difluorophenyl group. 25 More particularly, the compound of formula (17) is a (1R, (14) 2R)-2-aryl cyclopropane carboxamide derivative (or com O pound). The present invention provides a process for preparing an -S optically active aminocyclopropane derivative (or com 30 pound) from inexpensive 3,4-difluorobenzene using a Hoff (wherein R7 and * have the same said definitions) or optically mann re-arrangement. In general, the process is a safe and active halohydrin derivative (or compound) represented by inexpensive way of preparing the optically active aminocy general formula (15) cloprane derivative which is useful as an intermediate in the manufacture of pharmaceuticals and pesticides. 35 The conversion of compounds of formula (14) to (2) com (15) prises 4 steps, namely in total: 1) cyclopropanation process, 2) deesterification process, 3) amidation process and 4) Hof mann rearrangement process. Hereinafter, the invention is R7 1: described in detail for each process. 40 Firstly, there will be described 1) cyclopropanation pro (wherein R and * have the same said definitions) with CCSS, phosphonoacetic acid ester derivative (or compound) repre sented by general formula (16) OH 45 O 1 X (16) 1< or R7 * -- O | (14) (15) COR O 9 / N1 | 50 RO R'O-P N1 COR -- 71-(1-coR is Red R : (wherein R denotes optionally substituted Co cyclic or (16) (13) acyclic alkyl group, optionally Substituted Co aryl group, or optionally substituted Coaralkyl group, and Rand * have 55 Step 1. Cyclopropanation Process the same said definitions) in the presence of base. There is In compounds represented by formula (14), R7 denotes an also provided a process for the production of an optically aryl group Substituted by 2 or more halogen atoms. Suitable active 2-aryl cyclopropane carboxamide derivative (or com values for R' include, for example, a 2,3-difluorophenyl pound) to obtain (1R,2R)-2-aryl cyclopropane carboxamide group, 3,4-difluorophenyl group, 2,4-difluorophenyl group, derivative (or compound) of formula (12) using a (1R,2R)-2- 60 2,3,4-trifluorophenyl group, 3,4,5-trifluorophenyl group, 2.3, aryl cyclopropanecarboxylic acid derivative (or compound) 4.5-tetrafluorophenyl group, 2,3,4,5,6-pentafluorophenyl of formula (10). The present invention also provides a process group, 2,3-dichlorophenyl group, 3,4-dichlorophenyl group, for the production of an optically active 2-aryl cyclopropane 2,4-dichlorophenyl group, 2,3,4-trichlorophenyl group, 3.4. carboxamide derivative (or compound) to obtain a (1R,2R)- 5-trichlorophenyl group, 2,3,4,5-tetrachlorophenyl group, 2-aryl cyclopropane carboxylic acid derivative (or com 65 2,3,4,5,6-pentachlorophenyl group, 2,3-dibromophenyl pound) formula (10) using a (1R,2R)-2-aryl cyclopropane group, 3,4-dibromophenyl group, 2,4-dibromophenyl group, carboxylate ester derivative (or compound) of formula (13). 2,3,4-tribromophenyl group, 3,4,5-tribromophenyl group, US 8,026,396 B2 11 12 2,3,4,5-tetrabromophenyl group, and a 2.3.4.5,6-pentabromo alkyl group, optionally substituted Co aryl group, or phenyl group. A 3,4-difluorophenyl group is preferred. More optionally substituted Co. aralkyl group, and R denotes over, * denotes an asymmetric carbon centre. In other words, optionally Substituted Co cyclic or acyclic alkyl group, a styrene oxide derivative formula (14) contains an asymmet optionally substituted Co aryl group, or optionally Substi ric carbon centre. This invention includes any optically active tuted C7-caralkyl group. Suitable values for an aryl group Substance or racemic mixture of the compound of formula Substituted by 2 or more halogenatoms, include, for example, (14). Preferably, it is optically active substance, and most a 2,3-difluorophenyl group, 3,4-difluorophenyl group, 2,4- preferably it is a compound whose absolute configuration of difluorophenyl group, 2,3,4-trifluorophenyl group, 3,4,5-tri asymmetric carbon centre is (S). fluorophenyl group, 2,3,4,5-tetrafluorophenyl group, 2.3.4.5, In the compound of formula (15), R denotes an aryl group 10 6-pentafluorophenyl group, 2,3-dichlorophenyl group, 3,4- Substituted by 2 or more halogen atoms, and X denotes a dichlorophenyl group, 2,4-dichlorophenyl group, 2,3,4- halogen atom. Suitable values for R7 include, for example, a trichlorophenyl group, 3,4,5-trichlorophenyl group, 2,3,4,5- 2,3-difluorophenyl group, 3,4-difluorophenyl group, 2,4-dif tetrachlorophenyl group, 2,3,4,5,6-pentachlorophenyl group, luorophenyl group, 2,3,4-trifluorophenyl group, 3,4,5-trif 2,3-dibromophenyl group, 3,4-dibromophenyl group, 2,4-di luorophenyl group, 2,3,4,5-tetrafluorophenyl group, 2.3.4.5, 15 bromophenyl group, 2,3,4-tribromophenyl group, 3,4,5-tri 6-pentafluorophenyl group, 2,3-dichlorophenyl group, 3,4- bromophenyl group, 2,3,4,5-tetrabromophenyl group, and dichlorophenyl group, 2,4-dichlorophenyl group, 2,3,4- 2,3,4,5,6-pentabromo phenyl group. Suitable values for a trichlorophenyl group, 3,4,5-trichlorophenyl group, 2,3,4,5- Co cyclic or acyclic alkyl group, include, for example, a tetrachlorophenyl group, 2,3,4,5,6-pentachlorophenyl group, methyl group, ethyl group, n-propyl group, i-propyl group, 2,3-dibromophenyl group, 3,4-dibromophenyl group, 2,4-di cyclopropyl group, n-butyl group, S-butyl group, i-butyl bromophenyl group, 2,3,4-tribromophenyl group, 3,4,5-tri group, t-butyl group, cyclobutyl group, n-pentyl group, neo bromophenyl group, 2,3,4,5-tetrabromophenyl group, and a pentyl group, cyclopentyl group, n-hexyl group, cyclohexyl 2,3,4,5,6-pentabromo phenyl group. A 3,4-difluorophenyl group, n-heptyl group, cyclohexylmethyl group, n-octyl group is preferred. group, and n-decyl group. Suitable values for an optionally Moreover, * denotes an asymmetric carbon centre. In other 25 Substituted Co aryl group include, for example, a phenyl words, the halohydrin derivative represented by general for group, o-methoxyphenyl group, m-methoxyphenyl group, mula (15) contains asymmetric carbon centre. The invention p-dimethoxyphenyl group, o-nitrophenyl group, m-nitrophe includes any optically active Substance or racemic mixture of nyl group, p-nitrophenyl group, o-chlorophenyl group, the compound of formula (15). Preferably it is optically active m-chlorophenyl group, p-chlorophenyl group, o-methylphe Substance, and most preferably it is a compound whose abso 30 nyl group, m-methylphenyl group, and p-methylphenyl lute configuration of asymmetric carbon centre is (S). group. Suitable values for an optionally Substituted C-o In the compound of formula (16), R denotes an optionally aralkyl group include, for example, a benzyl group, o-meth Substituted Co cyclic or acyclic alkyl group, optionally oxybenzyl group, m-methoxybenzyl group, p-methoxyben Substituted Co aryl group, or optionally substituted Cz-o Zyl group, o-nitrobenzyl, m-nitrobenzyl, p-nitrobenzyl, aralkyl group, and R denotes an optionally substituted Co 35 o-chlorobenzyl group, m-chlorobenzyl group, p-chloroben cyclic oracyclic alkyl group, optionally Substituted Co aryl Zyl group, o-methylbenzyl group, m-methylbenzyl group, group, or optionally Substituted C-o aralkyl group. Suitable and p-methylbenzyl group. It is generally preferred that R is values for a Co cyclic or acyclic alkyl group include for a 3,4-difluorophenyl group and R is an ethyl group. example, a methyl group, ethyl group, n-propyl group, i-pro Moreover, * denotes an asymmetric carbon centre. In other pyl group, cyclopropyl group, n-butyl group, S-butyl group, 40 words, an ester derivative represented by the formula (13) i-butyl group, t-butyl group, cyclobutyl group, n-pentyl contains asymmetric carbon centres. The invention includes group, neopentyl group, cyclopentyl group, n-hexyl group. any optically active Substance or racemic mixture of the com cyclohexyl group, n-heptyl group, cyclohexylmethyl group, pound of formula (13). Preferably it is an optically active n-octyl group, and n-decyl group. Suitable values for an Substance, and most preferably it is a compound whose abso optionally substituted Co aryl group include for example 45 lute configuration of asymmetric carbon centre is (1R,2R). phenyl group, o-methoxyphenyl group, m-methoxyphenyl The optically active halohydrin derivative represented by group, p-methoxyphenyl group, o-nitrophenyl group, m-ni the formula (15) which is a starting material of this invention trophenyl group, p-nitrophenyl group, o-chlorophenyl group, can be readily obtained, for example, by enantioselectively m-chlorophenyl group, p-chlorophenyl group, o-methylphe reacting a C-halomethyl arylketone derivative obtained by nyl group, m-methylphenyl group, and p-methylphenyl 50 reacting a benzene derivative with C-halo acetic acid chloride group. Suitable values for an optionally Substituted C-o in the presence of aluminum chloride. The optically active aralkyl group include, for example, a benzyl group, o-meth styrene oxide derivative of formula (14) can be readily oxybenzyl group, m-methoxybenzyl group, p-methoxyben obtained by epoxidation of an optically active C-halohydrin Zyl group, o-nitrobenzyl, m-nitrobenzyl, p-nitrobenzyl, derivative of formula (15). o-chlorobenzyl group, m-chlorobenzyl group, p-chloroben 55 A compound of formula (14) or of formula (15) is reacted Zyl group, o-methylbenzyl group, m-methylbenzyl group, with a compound of formula (16) in the presence of base and and p-methylbenzyl group. thereby converted to compound of formula (13). Examples of In particular one or both of Rand Rare methyl group or Suitable bases include, for example, an organolithium com ethyl group, and preferably both of R and R are methyl pound such as methyllithium, n-butyllithium, t-butyllithium, group or ethyl group. 60 phenyl lithium or the like, a Grignard reagent such as n-bu In the compound of formula (13), values of substituents R7. tylmagnesiumchloride, methyl magnesium bromide or the R originate from respective values in the styrene oxide like; an alkaline earth metal amide or alkali metal amide Such derivative of formula (14) or a halohydrin derivative repre as lithium amide, sodium amide, lithium diisopropyl amide, sented by the formula (15) and carboxylate ester derivative magnesium diisopropyl amide, lithium hexamethyl disi represented by general formula (16). In other words, R. 65 lazide, Sodium hexamethyl disilazide, potassium hexamethyl denotes an aryl group Substituted by 2 or more halogenatoms, disilaZide or the like; an alkali metal alkoxide Such as sodium and R denotes optionally substituted Clio cyclic or acyclic methoxide, sodium ethoxide, sodium-t-butoxide, lithium US 8,026,396 B2 13 14 methoxide, lithium ethoxide, lithium-t-butoxide, potassium Step 2. Deesterification Process t-butoxide or the like; an alkaline earth metal hydride or alkali The values of R. R. and * in the compound of formula metal hydride such as lithium hydride, sodium hydride, (13), including the suitable and preferred values, are the same potassium hydride, calcium hydride or the like. as those mentioned above in 1) cyclopropanation process. In A base of an alkali metal-t-butoxide, alkali metal hydride the compound of formula (10), the values of substituent R7 or the like is generally preferred. including the Suitable and preferred values, originate from the The quantity of base used differs depending on species of ester derivative of formula (13). In other words, R7 denotes an base used, species of Solvent and reaction conditions. A par aryl group Substituted by 2 or more halogen atoms. Suitable ticular quantity is a 1-5 fold molar ratio, preferably 1-3 fold values of an aryl group Substituted by 2 or more halogen 10 atoms include, for example, a 2,3-difluorophenyl group, 3,4- molar ratio with respect to compound of formula (14) or (15). difluorophenyl group, 2,4-difluorophenyl group, 2,3,4-trif The quantity of compound of formula (16) used differs luorophenyl group, 3,4,5-trifluorophenyl group, 2,3,4,5-tet depending on species of solvent and reaction conditions. A rafluorophenyl group, 2,3,4,5,6-pentafluorophenyl group, particular quantity is a 1-5 fold molar ratio, preferably 1-3 2,3-dichlorophenyl group, 3,4-dichlorophenyl group, 2,4- fold molar ratio with respect to compound of formula (14) or 15 dichlorophenyl group, 2,3,4-trichlorophenyl group, 3,4,5- (15). trichlorophenyl group, 2,3,4,5-tetrachlorophenyl group, 2.3, In general, a solvent is usually used in the reaction. 4.5,6-pentachlorophenyl group, 2,3-dibromophenyl group, Examples include, for example, dichloromethane, chloro 3,4-dibromophenyl group, 2,4-dibromophenyl group, 2,3,4- form, dichloroethane, benzene, toluene, diethyl ether, ethyl tribromophenyl group, 3,4,5-tribromophenyl group, 2,3,4,5- ene glycol dimethylether, methyl-t-butyl ether, diisopropyl tetrabromophenyl group or 2,3,4,5,6-pentabromophenyl ether, tetrahydrofuran, 1.4-dioxane, N,N-dimethylforma group. A 3,4-difluorophenyl group is generally preferred. mide, N-methylpyrrolidone, 1,3-dimethyl imidazolidinone, Moreover, * denotes an asymmetric carbon centre. In other dimethylsulfoxide, acetone, acetonitrile, ethyl acetate, iso words the carboxylic acid derivative of formulae (10) con propyl acetate ester, acetic acid-t-butyl, t-butanol, and the tains asymmetric carbon centres. The invention includes any like. The solvent may be used alone or as an admixture 25 optically active Substance or racemic mixture of the com thereof, and in this case, the mixed proportions thereofare not pound of formula (10). Preferably it is an optically active restricted. Substance, and most preferably it is a compound whose abso A solvent of toluene, ethylene glycol dimethylether, tet lute configuration of asymmetric carbon centre is (1R,2R). rahydrofuran or 1,4-dioxane is generally preferred. In this step, the compound of formula (13) is converted to Suitable values of the reaction temperature include values 30 the compound of formula (10) by deesterifying, and reaction selected from the range of -30°C. to boiling point of solvent conditions of deesterification of Compound (13) are not used, and a temperature in the range of 20°C.-90° C. Gener restricted. The reaction may be carried out using general ally, the reaction time required is usually 30 minutes to 24 deesterification conditions. Examples of conditions for dees hours. terification include a process of oxidative elimination of 35 p-methoxybenzyl ester using DDQ (2,3-dichloro-5,6-dicy On completion of the reaction, solvent may be removed by anobenzoquinone) and CAN (cerium nitrate), a process to distillation. The reaction mixture may then be added to water eliminate benzyl ester, t-butyl ester using iodotrimethylsi or water is added to it, and thereafter, it may be neutralized by lane, a process of reductive elimination of benzyl ester using addition of an appropriate quantity of acid. The compound of palladium catalyst under a hydrogen atmosphere, a process to formula (13) may be obtained by using procedures Such as 40 eliminate t-butyl ester using TFA (trifluoroacetic acid), a pro extraction with an organic Solvent such as toluene, ethyl cess to eliminate ester group by acid or alkali hydrolysis, or acetate, isopropyl acetate, diethyl ether, dichloromethane, the like. From the point of inexpensiveness and the point that chloroform or the like, washing with water and concentration. the process can be applied for most kinds of ester group, the The compound obtained may be purified further by column process to eliminate ester group by acid or alkali hydrolysis is chromatography or distillation. 45 preferred, and the process to eliminate ester group by alkali Examples of the acid used for neutralization after comple hydrolysis is more preferred. tion of the reaction include, but are not limited to, organic Suitable alkalis include an alkali metal hydroxide such as carboxylic acid such as formic acid, acetic acid, propionic lithium hydroxide, sodium hydroxide, potassium hydroxide, acid, trifluoroacetic acid, chloroacetic acid, dichloroacetic cesium hydroxide or the like; an alkaline earth metal hydrox acid, trichloroacetic acid, oxalic acid, benzoic acid, phthalic 50 ide Such as magnesium hydroxide, calcium hydroxide, acid, fumaric acid, mandelic acid or the like; an optically barium hydroxide or the like: an alkali metal carbonate such active organic carboxylic acid Such as tartaric acid, lactic as lithium carbonate, Sodium carbonate, potassium carbon acid, ascorbic acid, amino acid or the like; an organic Sulfonic ate, cesium carbonate or the like. An inorganic acid Such as acid Such as methanesulfonic acid, trifluoromethanesulfonic hydrochloric acid, Sulphuric acid, nitric acid, phosphoric acid, benzenesulfonic acid, p-toluenesulfonic acid, camphor 55 acid, perchloric acid or the like are generally preferred. Sulfonic acid or the like; an inorganic acid such as hydrochlo Suitable reaction solvents for deesterification include, for ric acid, Sulphuric acid, nitric acid, phosphoric acid, carbonic example, water, tetrahydrofuran, 1.4-dioxane, diethyl ether, acid or the like. Hydrochloric acid or sulfuric acid are gener methyl-t-butyl ether, toluene, benzene, N,N-dimethylforma ally preferred. mide, dimethylsulfoxide, dichloromethane, chloroform, Next, there will be described 2) deesterification process. 60 acetone, acetonitrile, butanol, propanol, ethanol, methanol, water and the like. The solvent may be used alone or as a mixture thereof, and in this case, the mixed proportions are not limited in particular. R71-(1-coR * , Her R7 -(1-coil* , In general, a solvent of toluene, tetrahydrofuran, ethanol or (13) (10) 65 methanol is preferred. Suitable reaction temperatures, include those selected from the range of -30°C. to boiling point of solvent used, and US 8,026,396 B2 15 16 preferably it is 0° C.-80° C. The reaction time is required formula (11). Preferably it is an optically active substance, usually to be 30 minutes to 27 hours. and most preferably it is a compound whose absolute con On completion of the reaction, the solvent may be removed figuration of asymmetric carbon centre is (1R,2R). by distillation, and thereafter the mixture added to water or In the compound of formula (12), values of substituent R' water is added to it as required. The mixture is neutralized by 5 originate from the ester derivative of formula (10). In other addition of acid. The compound of formula (10) may be words, R may denote an aryl group substituted by 2 or more obtained by procedures such as extraction with an organic halogen atoms. Suitable values for an aryl group Substituted Solvent such as toluene, ethyl acetate, isopropyl acetate, by 2 or more halogen atoms include a 2.3-difluorophenyl diethyl ether, dichloromethane, chloroform or the like; wash group, 3,4-difluorophenyl group, 2,4-difluorophenyl group, 10 2,3,4-trifluorophenyl group, 3,4,5-trifluorophenyl group, 2.3, ing with water, concentration and the like. The obtained com 4.5-tetrafluorophenyl group, 2,3,4,5,6-pentafluorophenyl pound may be further purified by column chromatography or group, 2,3-dichlorophenyl group, 3,4-dichlorophenyl group, crystallisation, or it may be used in the following step without 2,4-dichlorophenyl group, 2,3,4-trichlorophenyl group, 3.4. treatment. 5-trichlorophenyl group, 2,3,4,5-tetrachlorophenyl group, Suitable acids used for neutralization after completion of 15 2,3,4,5,6-pentachlorophenyl group, 2,3-dibromophenyl the reaction include, for example, an organic carboxylic acid group, 3,4-dibromophenyl group, 2,4-dibromophenyl group, Such as formic acid, acetic acid, propionic acid, trifluoroace 2,3,4-tribromophenyl group, 3,4,5-tribromophenyl group, tic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic 2,3,4,5-tetrabromophenyl group, 2,3,4,5,6-pentabromo phe acid, oxalic acid, benzoic acid, phthalic acid, fumaric acid, nyl group or the like. A 3,4-difluorophenyl group is generally mandelic acid or the like; an optically active organic carboxy preferred. lic acid Such as tartaric acid, lactic acid, ascorbic acid, amino Moreover, * denotes an asymmetric carbon centre. In other acid or the like; an organic Sulfonic acid such as methane words, the carboxylic acid derivative of formula (12) contains Sulfonic acid, trifluoromethanesulfonic acid, benzene asymmetric carbon centres. The invention includes any opti Sulfonic acid, p-toluenesulfonic acid, camphor Sulfonic acid cally active Substance or racemic mixture of the compound of or the like; an inorganic acid such as hydrochloric acid, Sul 25 formula (12). Preferably, it is an optically active substance, phuric acid, nitric acid, phosphoric acid, carbonic acid or the and most preferably it is a compound whose absolute con like. Hydrochloric acid and Sulfuric acid are generally pre figuration of asymmetric carbon centre is (1R,2R). ferred. The compound of formula (10) may be formed into the Next, a description will be given of 3) amidation process. compound of formula (11) by reacting with a carboxylic acid 30 activator to activate the carbonyl moiety. The activated com pound is converted to the compound of formula (12) by react ing with ammonia. Suitable carboxylic acid activators include, for example, a dehydrocondensation agent Such as dicyclohexylcarbodiimide (DCC) and carbonyldiimidazole; 35 chlorocarbonic acid esters such as methyl chlorocarbonate ester, ethyl chlorocarbonate ester, propyl chlorocarbonate ester, isopropyl chlorocarbonate ester, chlorocarbonate butyl ester, t-butyl chlorocarbonate, benzyl chlorocarbonate or the like; an acid anhydride Such as acetic anhydride, anhydrous 40 trifluoroacetic acid, anhydrous methanesulfonic acid, anhy Step 3. Amidation Process drous trifluoromethanesulfonic acid or the like; an carboxylic In the compound of formula (10), the values of substituent acid ester species such as carbonic acid di-t-butyl, dimethyl R" and * (including the suitable and preferred values) are the carbonate, diethyl carbonate or the like, acid chloride such as same as those mentioned above in 2) deesterification process. methanesulfonyl chloride, p-toluenesulphonyl chloride, In the compound of formula (11), values of substituent R7 45 phosphorus pentachloride, phosphorus trichloride, phospho originate from the ester derivative of formula (10). In other rus oxychloride, acetylchloride, propionyl chloride, pivaloyl words, R may represent an aryl group Substituted by 2 or chloride, benzoyl chloride, thionyl chloride, chlorosulfuric more halogen atoms. Suitable values for an aryl group Sub acid, oxalyl chloride; phosgene or the like, and a metal chlo stituted by 2 or more halogen atoms include a 2,3-difluo ride such as titanium chloride, aluminum chloride, ferric rophenyl group, 3,4-difluorophenyl group, 2,4-difluorophe 50 chloride or the like may be proposed. nyl group, 2,3,4-trifluorophenyl group, 3,4,5-trifluorophenyl Particular carboxylic acid activators are chlorocarbonate group, 2,3,4,5-tetrafluorophenyl group, 2,3,4,5,6-pentafluo ester, acid anhydride, carboxylic acid ester, acid chloride rophenyl group, 2,3-dichlorophenyl group, 3,4-dichlorophe except phosgene. In general thionyl chloride is preferred par nyl group, 2,4-dichlorophenyl group, 2,3,4-trichlorophenyl ticularly as it offers advantages from the point of handling and group, 3,4,5-trichlorophenyl group, 2,3,4,5-tetrachlorophe 55 post-treatment after reaction. nyl group, 2,3,4,5,6-pentachlorophenyl group, 2,3-dibro The quantity used of carboxylic acid activator differs mophenyl group, 3,4-dibromophenyl group, 2,4-dibro depending on species of base used and species of solvent and mophenyl group, 2,3,4-tribromophenyl group, 3,4,5- ofreaction conditions. In particular a 1-3 fold molar ratio may tribromophenyl group, 2,3,4,5-tetrabromophenyl group, 2.3, be used, and preferably a 1-1.5 fold molar ratio with respect to 4.5,6-pentabromo phenyl group or the like. A 3.4- 60 compound represented by the aforesaid formula (10). difluorophenyl group is generally preferred. Moreover, Y When reacting the compound of formula (10) with the denotes an activated carbonyl group activated group, and it is carboxylic acid activator, a base may be used in accordance derived from the carboxylic acid activator described later. with requirements. Suitable bases include, for example, an Moreover, * denotes an asymmetric carbon centre. In other organolithium compound such as methyllithium, n-butyl words the carboxylic acid derivative of formula (11) contains 65 lithium, t-butyllithium, phenyl lithium or the like, a Grignard asymmetric carbon centres. The invention includes any opti reagent Such as n-butyl magnesium chloride, methyl magne cally active substance or racemic mixture of the compound of sium bromide or the like, alkaline earth metal amide or alkali US 8,026,396 B2 17 18 metal amide Such as lithium amide, Sodium amide, lithium ethyl acetate, isopropyl acetate ester, diethyl ether, dichlo diisopropyl amide, magnesium diisopropyl amide, lithium romethane, chloroform or the like, washing with water, and hexamethyl disilazide, Sodium hexamethyl disilazide, potas concentration. The obtained compound may be further puri sium hexamethyl disilazide or the like, alkali metal alkoxide fied by column chromatography or crystallisation, or it may Such as Sodium methoxide, Sodium ethoxide, Sodium-t-bu be used in the following step without treatment. toxide, lithium methoxide, lithium ethoxide, lithium-t-butox The compound of formula (17) ide, potassium-t-butoxide or the like, alkaline earth metal hydride or alkali metal hydride such as lithium hydride, Sodium hydride, potassium hydride, calcium hydride or the (17) like, alkaline earth metal hydroxide or alkali metal hydroxide 10

Such as lithium hydroxide, Sodium hydroxide, potassium R -(-CON:: hydroxide, cesium hydroxide, magnesium hydroxide, cal cium hydroxide or the like, alkali metal carbonate Such as lithium carbonate, Sodium carbonate, potassium carbonate or produced by the aforesaid process is a novel compound, and the like, alkali metal bicarbonate such as lithium bicarbonate, 15 is therefore provided as a further feature of the present inven Sodium bicarbonate, potassium bicarbonate or the like, tion. Informula (17), R' denotes an aryl group substituted by organic tertiary amine Such as triethylamine, diisopropyl 2 or more halogen atoms. Suitable values for the aryl group ethylamine, DBU (1,8-diazabicyclo[5.4.0]undecene) or the substituted by 2 or more halogen atoms include a 2,3-difluo like, basic organic solvent such as N,N-dimethylformamide rophenyl group, 3,4-difluorophenyl group, 2,4-difluorophe or the like. nyl group, 2,3,4-trifluorophenyl group, 3,4,5-trifluorophenyl In particular, the base may be an alkali metal alkoxide, group, 2,3,4,5-tetrafluorophenyl group, 2,3,4,5,6-pentafluo alkaline earth metal hydride or alkali metal hydride, alkaline rophenyl group, 2,3-dichlorophenyl group, 3,4-dichlorophe earth metal hydroxide or alkali metal hydroxide, alkaline nyl group, 2,4-dichlorophenyl group, 2,3,4-trichlorophenyl earth carbonate or alkali metal carbonate, alkali metal bicar group, 3,4,5-trichlorophenyl group, 2,3,4,5-tetrachlorophe bonate, or organic tertiary amine. In general an alkaline earth 25 nyl group, 2,3,4,5,6-pentachlorophenyl group, 2,3-dibro metal hydroxide or alkali metal hydroxide, alkaline earth mophenyl group, 3,4-dibromophenyl group, 2,4-dibro carbonate or alkali metal carbonate, alkali metal bicarbonate, mophenyl group, 2,3,4-tribromophenyl group, 3,4,5- organic tertiary amine or the like is preferred. tribromophenyl group, 2,3,4,5-tetrabromophenyl group, 2.3, The quantity used of base differs depending on the species 4.5,6-pentabromo phenyl group or the like. A 3.4- of base used and species of solvent and reaction conditions. In 30 difluorophenyl group is generally preferred. particular a 1-3 fold molar ratio may be used, and preferably Moreover, * denotes an asymmetric carbon centre. In other a 1-1.5 fold molar ratio with respect to compound represented words, the carboxamide derivative of formulae (17) contains by the aforesaid formula (10). asymmetric carbon centres. The invention includes any opti Suitable forms of the ammonia used include, for example, cally active Substance or racemic mixture of the compound of liquid ammonia, ammonia gas, ammonia Solution in organic 35 formula (17). Preferably it is optically active substance, and Solvent and ammonia water. Particular examples are ammo most preferably it is a compound whose absolute configura nia gas, ammonia in an organic Solvent, ammonia water, and tion of asymmetric carbon centre is (1R,2R). ammonia water is generally preferred. Next, a description will be given of 4) Hofmann rearrange When the form of ammonia is ammonia water the concen ment process. tration of ammonia water used is not limited. In particular 40 5-30 wt % may be used, and 20-28 wt % is generally pre ferred. R1 RI R2 R2 The quantity of ammonia used differs depending on the R3 -> R3 form of used ammonia, species of solvent and reaction con CONH NH2 ditions. In particular, a 1-6 fold molar ratio may be used, and, 45 R4 R4 preferably, a 3-5 fold molar ratio with respect to compound : : represented by the aforesaid formula (10). (1) (2) Generally a solvent is usually used in the reaction. Suitable solvents include for example dichloromethane, chloroform, Step 4. Hofmann Rearrangement Step dichloroethane, benzene, toluene, diethyl ether, methyl-t-bu 50 In the compound of formula (1), R', R, R and Reach tyl ether, diisopropyl ether, tetrahydrofuran, 1.4-dioxane, independently denote hydrogen atom, optionally Substituted N,N-dimethylformamide, N-methylpyrrolidone, 1,3-dim Co cyclic or acyclic alkyl group, optionally Substituted ethyl imidazolidinone, dimethylsulfoxide, acetone, acetoni Co aryl group or optionally Substituted Cz-oaralkyl group, trile, ethyl acetate, isopropyl acetate ester and acetic acid-t- and they may be the same or different to each other. Suitable butyl and the like. 55 values of an optionally Substituted cyclic or acyclic alkyl The solvent may be used alone or by mixing, and in this group of carbon number 1-10 include a methyl group, ethyl case, the mixing proportion is not limited. Generally a solvent group, n-propyl group, i-propyl group, cyclopropyl group. of toluene, ethyl acetate and isopropyl acetate are preferred. n-butyl group, S-butyl group, i-butyl group, t-butyl group, Suitable reaction temperatures, include those selected cyclobutyl group, n-pentyl group, neopentyl group, cyclo from the range of -30°C. to boiling point of solvent used and 60 pentyl group, n-hexyl group, cyclohexyl group, n-heptyl preferably it is selected from the range of 0°C.-60° C. The group, cyclohexylmethyl group, n-octyl group, n-decyl group reaction time required is usually 10 minutes to 24 hours. and the like. Suitable values of an optionally Substituted Co On completion of the reaction, the solvent is removed by aryl group include a phenyl group, o-methoxyphenyl group, distillation in accordance with requirements, and thereafter m-methoxyphenyl group, p-dimethoxy phenyl group, o-ni the reaction mixture is added to water or water is added to it. 65 trophenyl group, m-nitrophenyl group, p-nitrophenyl group, The compound of formula (12) is obtained using procedures o-fluorophenyl group, m-fluorophenyl group, p-fluorophenyl Such as extraction with an organic solvent Such as toluene, group, o-chlorophenyl group, m-chlorophenyl group, p-chlo US 8,026,396 B2 19 20 rophenyl group, 2,3-difluorophenyl group, 3,4-difluorophe thylbenzyl group, p-methylbenzyl group and the like. nyl group, 2,4-difluorophenyl group, 2,3,4-trifluorophenyl Wherein preferably any of R', R, R and R is a 3,4-difluo group, 3,4,5-trifluorophenyl group, 2,3,4,5-tetrafluorophenyl rophenyl group, and more preferably, the Substituent other group, 2,3,4,5,6-pentafluorophenyl group, 2,3-dichlorophe than 3,4-difluorophenyl group is hydrogen atom. nyl group, 3,4-dichlorophenyl group, 2,4-dichlorophenyl Moreover, * denotes an asymmetric carbon centre. In other group, 2,3,4-trichlorophenyl group, 3,4,5-trichlorophenyl words, the compound represented by the formula (2) has group, 2,3,4,5-tetrachlorophenyl group, 2,3,4,5,6-pentachlo asymmetric carbon centre. The invention includes any opti rophenyl group, 2,3-dibromophenyl group, 3,4-dibromophe cally active Substance or racemic mixture of the compound of nyl group, 2,4-dibromophenyl group, 2,3,4-tribromophenyl formula (2). Preferably it is optically active substance, and group, 3,4,5-tribromophenyl group, 2,3,4,5-tetrabromophe 10 nyl group, 2,3,4,5,6-pentabromo phenyl group, o-methylphe most preferably it is a compound whose absolute configura nyl group, m-methylphenyl group, p-methylphenyl group tion of asymmetric carbon centre is (1R,2S). and the like. Suitable values of an optionally substituted C When oxidant is caused to act, there proceeds a so-called aralkyl group include a benzyl group, o-methoxybenzyl Hofmann rearrangement, and the compound of formula (1) is group, m-methoxybenzyl group, p-methoxybenzyl group, 15 converted to the compound of formula (2) while maintaining o-nitrobenzyl group, m-nitrobenzyl group, p-nitrobenzyl the stereochemistry of the asymmetric carbon centre repre group, o-chlorobenzyl group, m-chlorobenzyl group, p-chlo sented by *. For example, suitable oxidants include a high robenzyl group, o-methylbenzyl group, m-methylbenzyl valency iodine reagent exemplified by bis(trifluoroacetoxy) group, p-methylbenzyl group and the like. Preferably any of phenyl iodide, halide agent such as chlorine, bromine, iodine, R", R, R and R is a 3,4-difluorophenyl group, and more N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccin preferably the substituent except 3,4-difluorophenyl group is imide, sulphuryl chloride, sulphuryl bromide or the like, a hydrogen atom. hypochlorite species such as lithium hypochlorite, Sodium Moreover, * denotes an asymmetric carbon centre. In other hypochlorite, potassium hypochlorite, magnesium hypochlo words, the compound of formula (1) has asymmetric carbon rite, calcium hypochlorite or the like may be proposed, and centre. The invention includes any optically active Substance 25 chlorine, N-chloro succinimide, hypochlorite species or the or racemic mixture of the compound of formula (1). Prefer like. In general Sodium hypochlorite is preferred. ably it is optically active Substance, and most preferably it is The quantity of oxidant used differs depending on species a compound whose absolute configuration of asymmetric of oxidant used, species of reaction solvent and reaction con carbon centre is (1R,2R). ditions. In particular a 1-5 fold molar ratio may be used and In the compound of formula (2), values (including Suitable 30 preferably a 2-4 fold molar ratio with respect to the compound and preferred) for R', R. RandR' originate from the com of formula (1). Moreover, as regards the quantity used of the pound of formula (1). In other words, R. R. RandR each aforesaid oxidant, when a hypochlorite species is used as the independently denote a hydrogen atom, an optionally Substi oxidant, the quantity used is determined by effective chlorine tuted Co cyclic or an acyclic alkyl group, optionally Sub conversion. stituted Co aryl group, or optionally substituted Cz 35 In the reaction of compound of formula (1) and oxidant, a aralkyl group, and they may be the same or different to each base may be co-present in accordance with requirements. other. Suitable values for an optionally substituted Co Base may be added after mixing the compound of formulae cyclic or acyclic alkyl group include a methyl group, ethyl (1) and oxidant. Suitable bases include, for example, an orga group, n-propyl group, i-propyl group, cyclopropyl group. nolithium compound Such as methyllithium, n-butyllithium, n-butyl group, S-butyl group, i-butyl group, t-butyl group, 40 t-butyllithium, phenyl lithium or the like, Grignard reagent cyclobutyl group, n-pentyl group, neopentyl group, cyclo Such as n-butylmagnesium chloride, methyl magnesium bro pentyl group, n-hexyl group, cyclohexyl group, n-heptyl mide or the like, alkaline earth metal amide or alkali metal group, cyclohexylmethyl group, n-octyl group, n-decyl group amide such as lithium amide, Sodium amide, lithium diiso and the like. Suitable values for an optionally substituted propylamide, magnesium diisopropylamide, lithium hexam Co aryl group include a phenyl group, o-methoxyphenyl 45 ethyl disilazide, sodium hexamethyl disilazide, potassium group, m-methoxyphenyl group, p-dimethoxyphenyl group, hexamethyl disilazide or the like, alkali metal alkoxide such o-nitrophenyl group, m-nitrophenyl group, p-nitrophenyl as sodium methoxide, sodium ethoxide, sodium-t-butoxide, group, o-fluorophenyl group, m-fluorophenyl group, p-fluo lithium methoxide, lithium ethoxide, lithium-t-butoxide, rophenyl group, o-chlorophenyl group, m-chlorophenyl potassium-t-butoxide or the like, alkaline earth metal hydride group, p-chlorophenyl group, 2,3-difluorophenyl group, 3,4- 50 or alkali metal hydride such as lithium hydride, sodium difluorophenyl group, 2,4-difluorophenyl group, 2,3,4-trif hydride, potassium hydride, calcium hydride or the like, alka luorophenyl group, 3,4,5-trifluorophenyl group, 2,3,4,5-tet line earth metal hydroxide or alkali metal hydroxide such as rafluorophenyl group, 2,3,4,5,6-pentafluorophenyl group, lithium hydroxide, sodium hydroxide, potassium hydroxide, 2,3-dichlorophenyl group. 3,4-dichlorophenyl group, 2,4- cesium hydroxide, magnesium hydroxide, calcium hydrox dichlorophenyl group, 2,3,4-trichlorophenyl group, 3,4,5- 55 ide or the like, alkali metal carbonate such as lithium carbon trichlorophenyl group, 2,3,4,5-tetrachlorophenyl group, 2.3, ate, sodium carbonate, potassium carbonate or the like, alkali 4.5,6-pentachlorophenyl group, 2,3-dibromophenyl group, metal bicarbonate such as lithium bicarbonate, sodium bicar 3,4-dibromophenyl group, 2,4-dibromophenyl group, 2,3,4- bonate, potassium bicarbonate or the like, organic tertiary tribromophenyl group, 3,4,5-tribromophenyl group, 2,3,4,5- amine such as triethylamine, diisopropyl ethylamine, DBU tetrabromophenyl group, 2,3,4,5,6-penta bromo phenyl 60 (1,8-diazabicyclo[5.4.0]undecene) or the like. group, o-methylphenyl group, m-methylphenyl group, p-me In general an alkali metal hydroxide Such as Sodium thylphenyl group and the like. Suitable values for an option hydroxide is the preferred. ally substituted Czo aralkyl group include a benzyl group, The quantity of base used differs depending on species of o-methoxybenzyl group, m-methoxybenzyl group, p-meth base used, species of solvent and reaction conditions. In par oxybenzyl group, o-nitrobenzyl group, m-nitrobenzyl group, 65 ticular the reaction may be caused to proceed in high yield by p-nitrobenzyl group, o-chlorobenzyl group, m-chlorobenzyl using a 5-30 fold molar ratio, preferably 5-20 fold molar ratio group, p-chlorobenzyl group, o-methylbenzyl group, m-me with respect to compound represented by general formula (2). US 8,026,396 B2 21 22 In particular the concentration of the base in the reaction alkali metal hydroxide such as lithium hydroxide, sodium may be in the range of 5-30 wt %, more particularly in the hydroxide, potassium hydroxide, cesium hydroxide, magne range of 15-25 wt %. sium hydroxide, calcium hydroxide or the like, alkali carbon In generala solvent is usually used in the reaction. Suitable ate metal salt such as lithium carbonate, Sodium carbonate, Solvents include, for example, water, dichloromethane, chlo 5 potassium carbonate or the like, alkali metal bicarbonate Such roform, dichloroethane, benzene, toluene, diethyl ether, as lithium bicarbonate, sodium bicarbonate, potassium bicar methyl-t-butyl ether, tetrahydrofuran, 1,4-dioxane, N.N- bonate or the like, organic tertiary amine or the like Such as dimethylformamide, N-methylpyrrolidone, 1,3-dimethyl triethylamine, diisopropyl ethylamine, DBU (1,8-diazabicy cloS.4.0]undecene). imidazolidinone, dimethylsulfoxide, acetone, acetonitrile, In general an alkali metal hydroxide, alkaline earth metal ethyl acetate, acetic acid-t-butyl, t-butanol and the like. 10 hydroxide, alkali carbonate metal salt, alkaline earth metal The solvent may be used alone or as a mixture. In the case carbonate, alkali metal bicarbonate alkaline earth metal car of a mixture the proportion is not limited. In general, water is bonate, organic tertiary amine are preferred. preferred. Any of the embodiments described herein can be combined Suitable reaction temperatures include those selected from with any of the other embodiments described herein. the range of -30° C. to boiling point of solvent used and 15 In order that the invention disclosed herein may be more preferably it is selected from the range of 20° C.-60° C. The efficiently understood, examples are provided below. It reaction time required is usually 30 minutes to 24 hours. should be understood that these examples are for illustrative On completion of the reaction the solvent may be removed purposes only and are not to be construed as limiting the by distillation. The reaction mixture may be added to water or invention in any manner. water to it, and then the mixture is acidified by addition of acid. The Compound (2) is transferred to the aqueous layer, EXAMPLES and after having been caused to undergo liquid separation and washing with organic solvent Such as toluene, ethyl acetate, Example 1 isopropyl acetate, diethyl ether, dichloromethane, chloroform or the like, the aqueous layer is made basic using a base. The 25 Preparation of (2S)-2-(3,4-difluorophenyl)oxirane Compound of formula (2) is obtained using procedures Such as extraction with an organic solvent such as toluene, ethyl A mixture of (1S)-2-chloro-1-(3,4-difluorophenyl)-1- acetate, isopropyl acetate, diethyl ether, dichloromethane, ethanol (net 11.47 g, 59.5 mmol), toluene (25.23g), sodium chloroform or the like, washing with water and concentration. hydroxide (2.53 g, 1.06 molar equivalents) and water (24.25 Usually, on completion of the reaction, solvent is removed by 30 g) was stirred and heated at 40° C. for 1 hour. The organic distillation, and the compound of formula (2) may be layer was separated, washed with water, and concentrated obtained via procedures such as extraction with organic sol under reduced pressure. (2S)-2-(3,4-difluorophenyl)oxirane vent Such as toluene, ethyl acetate, isopropyl acetate, diethyl was obtained as resultant concentrate (net 8.94g, yield: 96%). ether, dichloromethane, chloroform or the like, washing with H-NMR in (400 MHz, CDC13) water and concentration without the step of transfering to the 35 8 2.71-2.73 (1H, dd, J=2.44 Hz, 5.37 Hz), 3.13-3.15 (1H, aqueous layer. The compound (2) may be obtained in the form m), 3.82-3.83 (1H, m), 701-7.27 (4H, m). of a salt of an acid. The compound may be further purified by column chromatography, distillation or crystallisation, or it Example 2 may be separated and purified in the form of a salt of an acid. Suitable acids used after completion of the reaction 40 Preparation of ethyl (1R,2R)-2-(3,4-difluorophenyl)- include, for example, an organic carboxylic acid Such as 1-cyclopropanecarboxylate formic acid, acetic acid, propionic acid, trifluoroacetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, Sodium t-butoxide (32.22 g, 1.25 molar equivalents) and oxalic acid, benzoic acid, phthalic acid, fumaric acid, man toluene (243.0 g) were charged into a reaction vessel. Triethyl delic acid or the like, optically active organic carboxylic acid 45 phosphonoacetate (78.06 g, 1.04 molar equivalents to Sodium Such as tartaric acid, lactic acid, ascorbic acid, amino acid or t-butoxide) was added to the mixture with stirring. A toluene the like, organic sulfonic acid Such as methanesulfonic acid, solution of (2S)-2-(3,4-difluorophenyl)oxirane (32.8 wt % trifluoromethanesulfonic acid, benzenesulfonic acid, p-tolu solution, net 41.83 g, 267.9 mmol) was added drop-wise to enesulfonic acid, camphor Sulfonic acid or the like, inorganic the mixture keeping the internal temperature between 60 to acid such as hydrochloric acid, Sulphuric acid, nitric acid, 50 80° C. After completion of addition, stirring was continued phosphoric acid, carbonic acid. Hydrochloric acid or Sulfuric for 11 hours at 80°C. After cooling to room temperature, the acid are generally preferred. mixture was washed with water, and the organic layer was Suitable bases used after completion of the reaction concentrated under reduced pressure. Ethyl (1R,2R)-2-(3,4- include, for example, an organolithium compound Such as difluorophenyl)-1-cyclopropanecarboxylate was obtained as methyllithium, n-butyllithium, t-butyllithium, phenyl lithium 55 resultant concentrate (net 49.11 g, yield: 81%). or the like, Grignard reagent such as n-butylmagnesium chlo 'H-NMR in (400 MHz, CDC13) ride, methyl magnesium bromide or the like, alkaline earth & 1.22-1.26 (1H, m), 1.26-1.30 (3H, t, J=7.1 Hz), 1.57-1.62 metal amide or alkali metal amide Such as lithium amide, (1H, m), 1.82-1.87 (1H, m), 2.45-2.50 (1H, m), 4.14-4.20 Sodium amide, lithium diisopropyl amide, magnesium diiso (2H, q, J=7.1 Hz), 6.82-6.91 (2H, m), 7.02-7.09 (1H, m) propylamide, lithium hexamethyl disilazide, Sodium hexam 60 ethyl disilazide, potassium hexamethyl disilazide or the like, Example 3 alkali metal alkoxide Such as sodium methoxide, sodium ethoxide, sodium-t-butoxide, lithium methoxide, lithium Preparation of (1R,2R)-2-(3,4-difluorophenyl)-1- ethoxide, lithium-t-butoxide, potassium-t-butoxide or the cyclopropanecarboxylic acid like, alkaline earth metal hydride or alkali metal hydride such 65 as lithium hydride, Sodium hydride, potassium hydride, cal Methanol (322.2 g) and 30% sodium hydroxide aqueous cium hydride or the like, alkaline earth metal hydroxide or solution (65.5 g, 1.8 molar equivalents) were added to a US 8,026,396 B2 23 24 solution of ethyl (1R,2R)-2-(3,4-difluorophenyl)-1-cyclo Example 5 propanecarboxylate (48.2 wt % toluene solution, net 61.22 g, 270.6 mmol). The mixture was heated at 65° C. with stirring Preparation of for 2 hours. The resultant mixture was concentrated under (1R,2S)-2-(3,4-difluorophenyl)-1-cyclopropanamine reduced pressure, then toluene and water were added to the 5 (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxa concentrate. The mixture was acidified with 35% hydrochlo mide (net 9.00 g, 45.64 mmol) and 30% sodium hydroxide ric acid. The organic layer was separated and concentrated aqueous solution (54.77 g, 9.00 molar equivalents) were under reduced pressure. (1R,2R)-2-(3,4-difluorophenyl)-1- charged into a reaction vessel and the mixture was stirred. cyclopropanecarboxylic acid was obtained as resultant con Aqueous 12% sodium hypochlorite solution (29.53 g, 2.25 centrate (net 52.55g, yield: 98%). 10 mol equivalents) was added to the stirred slurry maintaining H-NMR in (400 MHz, CDC13) the internal temperature at 30°C. The resultant mixture was & 1.33-1.38 (1H, m), 1.64-1.69 (1H, m), 1.83-1.88 (1H, m), stirred at 30° C. for 14 hours, then at 40°C. for 2 hours. After completion of the reaction, isopropyl acetate was poured to 2.54-2.59 (1H, m), 6.83-6.93 (2H, m), 7.04-7.10 (1H, m). the resultant mixture, then the organic layer was separated, Example 4 15 washed with water, and concentrated under reduced pressure. (1R,2S)-2-(3,4-difluorophenyl)-1-cyclopropanamine was Preparation of (1R,2R)-2-(3,4-difluorophenyl)-1- obtained as resultant concentrate (net 6.89 g, yield: 89%). cyclopropanecarboxamide 'H-NMR in (400 MHz, CDC13) 8 0.88-0.93 (1H, m), 1.03-1.08 (1H, m), 1.70 (2H, s), 1.79-1.84 (1H, m), 2.47-2.51 (1H, m), 6.72-6.79 (2H, m), Thionyl chloride (72.65 g, 1.21 molar equivalents) was 7.00-7.02 (1H, m). added to the stirred toluene solution of (1R,2R)-2-(3,4-dif Various modifications of the invention, in addition to those luorophenyl)-1-cyclopropanecarboxylic acid (18 wt %, net described herein, will be apparent to those skilled in the art 100.00 g,504.62 mmol). The mixture was stirred at 35° C. for from the foregoing description. Such modifications are also 6 hours, then concentrated under reduced pressure to give a 25 intended to fall within the scope of the appended claims. Each solution of (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropan reference (including, but not limited to, journal articles, U.S. ecarbonyl chloride. To a mixture of 28% ammonia aqueous and non-U.S. patents, patent application publications, inter solution (122.55 g, 4.00 molar equivalents), water (300.4 g) national patent application publications, gene bank accession and ethyl acetate (700.2 g), the solution of (1R,2R)-2-(3,4- numbers, and the like) cited in the present application is difluorophenyl)-1-cyclopropanecarbonyl chloride obtained 30 incorporated herein by reference in its entirety. above was gradually added with stirring below 10°C. The What is claimed is: reaction mixture was allowed to stir below 10°C. for 1 hour. 1. An optically active 2-aryl cyclopropane carboxamide The mixture was neutralized with 35% hydrochloric acid, compound represented by general formula (17) then the organic layer was separated and washed with water. The resultant solution was concentrated azeotropically under 35 reduced pressure to give a slurry of (1R,2R)-2-(3,4-difluo (17) rophenyl)-1-cyclopropanecarboxamide. The resultant slurry R10 -(-CONH: was heated to obtain a clear Solution, and cooled for crystal : lization. Hexane was added to the slurry, then the precipitates 40 were collected by filtration and dried to give (1R,2R)-2-(3,4- difluorophenyl)-1-cyclopropanecarboxamide (net 91.12 g, wherein, R' is 3,4-difluorophenyl group, and * denotes an asymmetric carbon centre. Yield: 92%). 2. A compound according to claim 1 wherein the com H-NMR in (400 MHz, CDC13) pound represented by the aforesaid formula (17) is (1R,2R)- 81.21-1.27(1H, m), 1.56-1.64 (3H, m), 2.47-2.49 (1H, m), 45 2-aryl cyclopropane carboxamide compound. 5.45 (1H, br), 5.63 (1H, br), 6.83-6.90 (2H, m), 7.03-7.10 (1H, m). k k k k k