WO2003043996A1 - A method for preparing of chiral 2,2-dimethylcyclopropanecarboxyl derivatives - Google Patents
A method for preparing of chiral 2,2-dimethylcyclopropanecarboxyl derivatives Download PDFInfo
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- WO2003043996A1 WO2003043996A1 PCT/KR2002/002179 KR0202179W WO03043996A1 WO 2003043996 A1 WO2003043996 A1 WO 2003043996A1 KR 0202179 W KR0202179 W KR 0202179W WO 03043996 A1 WO03043996 A1 WO 03043996A1
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- Prior art keywords
- group
- derivatives
- dimethylcyclopropanecarboxyl
- formula
- preparation
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 23
- 230000003287 optical effect Effects 0.000 claims abstract description 48
- BFNMOMYTTGHNGJ-UHFFFAOYSA-N 2,2-dimethylcyclopropane-1-carboxylic acid Chemical compound CC1(C)CC1C(O)=O BFNMOMYTTGHNGJ-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 28
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 22
- -1 heterocycle compound Chemical class 0.000 claims abstract description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 66
- 238000002360 preparation method Methods 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 23
- 238000002425 crystallisation Methods 0.000 claims description 20
- 230000008025 crystallization Effects 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- BFNMOMYTTGHNGJ-SCSAIBSYSA-N (1s)-2,2-dimethylcyclopropane-1-carboxylic acid Chemical compound CC1(C)C[C@@H]1C(O)=O BFNMOMYTTGHNGJ-SCSAIBSYSA-N 0.000 claims description 5
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- BFNMOMYTTGHNGJ-BYPYZUCNSA-N (1r)-2,2-dimethylcyclopropane-1-carboxylic acid Chemical compound CC1(C)C[C@H]1C(O)=O BFNMOMYTTGHNGJ-BYPYZUCNSA-N 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 239000012043 crude product Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- QQNQOWHUBGUGQI-UHFFFAOYSA-N 2,2-dimethylcyclopropane-1-carbonyl chloride Chemical compound CC1(C)CC1C(Cl)=O QQNQOWHUBGUGQI-UHFFFAOYSA-N 0.000 description 9
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 7
- 239000011259 mixed solution Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 229940086542 triethylamine Drugs 0.000 description 6
- 0 *C(*)(*1)C(*)(*)NC1=* Chemical compound *C(*)(*1)C(*)(*)NC1=* 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 1
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 1
- OJOFMLDBXPDXLQ-SECBINFHSA-N (4r)-4-benzyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@@H]1CC1=CC=CC=C1 OJOFMLDBXPDXLQ-SECBINFHSA-N 0.000 description 1
- UMURLIQHQSKULR-UHFFFAOYSA-N 1,3-oxazolidine-2-thione Chemical class S=C1NCCO1 UMURLIQHQSKULR-UHFFFAOYSA-N 0.000 description 1
- WGJCBBASTRWVJL-UHFFFAOYSA-N 1,3-thiazolidine-2-thione Chemical class SC1=NCCS1 WGJCBBASTRWVJL-UHFFFAOYSA-N 0.000 description 1
- VDWVNBNZIIUVRW-UHFFFAOYSA-N CC(C(c1ccccc1)O1)N(C([I]2C(C)(C)C2)=O)C1=O Chemical compound CC(C(c1ccccc1)O1)N(C([I]2C(C)(C)C2)=O)C1=O VDWVNBNZIIUVRW-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 1
- DYDCUQKUCUHJBH-REOHCLBHSA-N L-Cycloserine Chemical group N[C@H]1CONC1=O DYDCUQKUCUHJBH-REOHCLBHSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- YSVZGWAJIHWNQK-UHFFFAOYSA-N [3-(hydroxymethyl)-2-bicyclo[2.2.1]heptanyl]methanol Chemical compound C1CC2C(CO)C(CO)C1C2 YSVZGWAJIHWNQK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000010669 acid-base reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- DHSUYTOATWAVLW-WFVMDLQDSA-N cilastatin Chemical compound CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O DHSUYTOATWAVLW-WFVMDLQDSA-N 0.000 description 1
- 229960004912 cilastatin Drugs 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- ITATYELQCJRCCK-QMMMGPOBSA-N methyl (2s)-2-hydroxy-2-phenylacetate Chemical compound COC(=O)[C@@H](O)C1=CC=CC=C1 ITATYELQCJRCCK-QMMMGPOBSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 229940073569 n-methylephedrine Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000002728 pyrethroid Substances 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The present invention relates to a method for preparing chiral 2,2-dimethylcyclopropanecarboxyl derivatives. More particularly, it relates to a method comprising the steps of reacting (RS)-2,2-dimethylcyclopropanecarboxylic acid with an optical resolving agent to obtain diastereomer, and resolving the diastereomer by recrystalization or chromatography to obtain (S)-2,2-dimethylcyclopropanecarboxyl derivatives and (R)-2,2-dimethylcyclopropanecarboxyl derivatives having optical purity, wherein the optical resolving agent is a chiral heterocycle compound.
Description
A METHOD FOR PREPARING OP CHIRAL 2,2- DIMETHYLCYCLOPROPANECARBOXYL DERIVATIVES
Technical field The present invention is related to the method for the preparation of chiral 2 , 2-dimethylcyclopropanecarboxyl derivatives represented by formula 1. More particularly, the present invention is related to the method for the preparation of optically pure (R)-2,2- dimethylcyclopropanecarboxyl derivatives (la) and (s)-2,2- dimethylcyclopropanecarboxyl derivatives (lb) , comprising the following steps of: reacting (RS)-2,2- dimethylcyclopropanecarboxylic acid (2) with optical resolving agent to synthesize diastereomers ,-and resolving the said diastereomers by crystallization or chromatography to obtain optically pure (R)-2,2- dimethylcyclopropanecarboxyl derivatives (la) and (s)-2,2- dimethylcyclopropanecarboxyl derivatives (lb) ;
Wherein, said optical resolving agent is chiral heterocycle compound represented by the formula 3. formula 1
Y is 0, S or N-R5 (wherein, R5 is Cι-C6 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy group or halogen atom) ; R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen atom, Cι-C3 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy group or halogen atom, R6-0-CH2 group (wherein R6 is L-CS alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy group or halogen atom) ;and R1 and R3 are combined to form C4-C8 carbocycle, or heterocycle compound containing 0, N or S . Wherein, it is excepted that all of R1, R2, R3 and R4 are H.)
Background of the Invention 2, 2-dimethyleyelopropanecarboxylic acid with optical activity is used in the preparation of pyrethroid insecticide having low toxicity in mammals (UK Patent No. 1,260,847). Further, it is also applied to agricultural chemicals and medicines as an essential material which is being used as the core intermediate of Cilastatin in preventing the solution of carbapenem antibiotic at kidneys (European Patent No. 48,301, European Patent No. 48,025).
Recently, many researches are being performed in order to prepare 2, 2-dimethylcyclopropanecarboxylic acid having various uses into a material with high yield and
pure optical activity. In order to prepare such 2, 2- dimethylcyclopropanecarboxylic acid, first, 2, 2- dimethylcyclopropanecarboxyl derivative, the intermediate of 2, 2-dimethylcyclopropanecarboxylic acid synthesis must be easily synthesized, and must have an optical activity of high purity.
Chiral amine, the most commonly used as optical resolving agent, forms salt when undergoing acid base reaction with (RS)-2, 2-dimethylcyclopropanecarboxylic acid, and the thus obtained salt is crystallized to be resolved into a diastereomer, chiral 2, 2- dimethylcyclopropanecarboxyl derivative. Then, it is hydrolyzed to obtain 2, 2-dimethylcyclopropanecarboxylic acid with optical activity. Such chiral amine can be exemplified by (S) -1-phenylethyl amine (UK Patent No. 1,260,847), quinine (US Patent No. 4,539,208), and 2- diphenylethyl amine (US Patent No. 4,542,235). However, chiral amine has a disadvantage that it should be crystallized several times in order to reach a high optical purity level and it has a low yield. In addition, there is another disadvantage that even though it is possible to prepare 2-diphenylethyl amine of high optical purity and high yield, it is impossible to prepare optical resolving agent, chiral 2-diphenylethyl amine from the natural product and it is expensive.
In another preparation method, chiral alcohol is used as optical resolving agent. This chiral alcohol reacts with (RS) -2, 2-dimethylcyclopropanecarboxylic acid to obtain chiral ester. The thus obtained chiral ester is crystallized to be separated into a diastereomer, chiral 2, 2-dimethylcyclopropanecarboxyl derivative. Then, it is hydrolyzed to obtain 2, 2-dimethylcyclopropanecarboxylic acid with optical activity. Such chiral alcohol can be exemplified by L-menthol (US Patent No. 4,487,956), methyl (S) -mandelate (US Patent No. 5,243,070), and L-N-methyl ephedrine (JP Patent No. 60-56,942). However, chiral alcohol has a disadvantage that it should be crystallized several times in order to reach a high optical purity level and it has a low yield. Further, chical alcohol is expensive.
Therefore, in order to minimize the above disadvantages, a novel optical resolving agent which can be easily synthesized by itself is required to obtain a chiral 2, 2-dimethylcyclopropanecarboxyl derivative with high yield and high purity. Accordingly, the present invention introduced the chiral heterocycle compound of formula 3, which can be easily prepared in various methods and is used in various asymmetric conversion reactions (Ager, D. J. , Prakash, I., Schaad D. Chem . Rev. 1996, 96, 846-859/ Ager, D. J., Prakash, I., Aldrichimic Acta, 1997, 30, 3; Nicolas,
E., Russel, K. C, Hruby, V. J. J. Org . Chem. 1993, 58, 766; Pridgen, L. N. , Prol, J. J". Org. Chem . 1989, 54, 3231; Hsiao, C. L. , Liu, L. , Miller, J., J". Org. Chem . , 1987, 52, 2201; Cardillo, G. , Damico, A., Orena, M., Sandri, S., J". Org. Chem. , 1988, 53 , 2354; Orena, M. , Porzi, Z., Samdri, S., Tetraheάron Lett . , 1992, 33 , 3797; Coppola, G. M. , Schuster, H. F., Asymmetric Synthesis : Construction of Chiral Molecules Using Aminoaciάs, Wiley, New York, 1987; Seyden-Penne, J. , Chiral Auxiliaries and Ligands in Asymmetric Synthesis, Wiley Interscience, 1995) . However, no example has been reported wherein the chiral heterocycle compound of formula 3 has been used in the preparation of chiral 2, 2-dimethylcyclopropanecarboxyl derivative of high purity.
Summary of the Invention
Hereupon, the present inventors made an effort in preparing an optical active 2, 2- dimethylcyclopropanecarboxyl derivative with optical activity and high purity, and thus, obtained a diastereomer by reacting (RS)-2, 2-dimethylcyclopropanecarboxylic acid
(2) with a chiral heterocycle compound of formula 3 as an optical resolving agent. The thus obtained diastereomers are crystallized or chromatographed to resolve the diastereomer and prepare an optically pure (R)-2, 2-
dimethylcyclopropanecarboxyl derivative (la) and (S)-2, 2- dimethylcyclopropanecarboxyl derivative (lb) . Further, the present invention has been completed by finding out that this derivative has a high yield and an optical activity of high purity.
It is an object of the present invention to provide a method for preparing (R) or (S)-2, 2- dimethylcyclopropanecarboxyl derivatives represented by formula 1. It is another object of the present invention to provide (R) or (S)-2, 2-dimethylcyclopropanecarboxyl derivatives represented by formula 1.
Best Mode of Carrying Out The Invention The present invention provides the method for the preparation of (R) or (S) -2, 2-dimethylcyclopropanecarboxyl derivatives represented by formula 1. More particularly, the present invention is related to the method for the preparation of optically pure (R)-2,2- dimethylcyclopropanecarboxyl derivatives (la) and (s)-2,2- dimethylcyclopropanecarboxyl derivatives (lb) , comprising the following steps of: reacting (RS)-2,2- dimethylcyclopropanecarboxylic acid (2) with optical resolving agent to synthesize diastereomers ,-and resolving the said diastereomers by crystallization or chromatography
to obtain optically pure (R)-2,2- dimethylcyclopropanecarboxyl derivatives (la) and (s)-2,2- dimethylcyclopropanecarboxyl derivatives (lb) ;
Wherein, said optical resolving agent is chiral heterocycle compound represented by the formula 3. formula 1
Y is 0, S or N-R5 (wherein, Rs is Cι-C6 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy group or halogen) ; R1, R2, R3 and R4 are independently selected from the group consisting of H, C - 5 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy group or halogen atom, R6-0-CH2 group (wherein, R6 is C!-C6 alkyl group, aryl group unsubstituted or substituted by Ci- C6 alkoxy group or halogen atom) ; and R1 and R3 are combined to form C-C8 carbocycle, or heterocycle compound containing O, N or S. Wherein, it is excepted that all of R1, R2, R3 and R4 are H.)
More particularly, the said method is comprised of : 1) reacting (RS) -2, 2-dimethylcyclopropanecarboxylic
acid (2) with optical resolving agent represented by formula 3 to synthesize diastereomers (step l.);and
2) resolving the said diastereomers by crystallization or chromatography to obtain optically pure (R) -2 , 2-dimethylcyclopropanecarboxyl derivatives (la) and
(s) -2 , 2-dimethylcyclopropanecarboxyl derivatives (lb) (step
2) .
The said step 1, reaction (RS)-2,2- dimethylcyclopropanecarboxylic acid (2) with optical resolving agent represented by formula 3 to synthesize diastereomers is accomplished by the known method in the art to implement. In the said reaction, various activating agents are used to increase the reactivity of (RS)-2,2- dimethylcyclopropanecarboxylic acid (2) . For example, activating agent selected from the group consisting of phosgene, phosphorus tribromide, phosphorus trichloride, oxalyl chloride and thionyl chloride is reacted with (RS) - 2 , 2-dimethylcyclopropanecarboxylic acid (2) to synthesize acyl halide. Another activating agent selected from the group consisting of ethyl chloroformate, methyl chloroformate, isobutyl chloriformate and methanesulfonyl chloride is reacted with (RS)-2,2- dimethylcyclopropanecarboxylic acid (2) to synthesize anhydride. Also, (RS) -2 , 2-dimethylcyclopropanecarboxylic
acid (2) is reacted with N,N' -dicyclohexylcarbodiimide (DCC) or known coupling reagent to synthesize carbodiimide. Also, (RS) -2, 2-dimethylcyclopropanecarboxylic acid (2) is activated by N,N' -carbonyldiimidazole, 2-ethoxy-N- ethoxycarbonyl-1, 2-dihydroquinoline (EDDQ) or triphenyl phosphine/carbon tetrachloride, thereafter easily reacted in the presence of base.
In the example of the present invention,' (RS)-2,2- dimethylcyclopropanecarboxylic acid (2) is converted to (RS) -2, 2-dimethylcyclopropanecarbonyl chloride by using thionyl chloride or oxalyl chloride as halogen compound. Amine used in the amidation reaction is tertiary C!-C4 alkyl amine. Particularly, the amine is selected from the group consisting of triethyl amine, tripropyl amine, triisopropyl amine and tributyl amine. Preferably, triethyl amine is used.
(RS) -2 , 2-dimethylcyclopropanecarbonyl chloride activated in the step 1 is reacted with chiral heterocycle compound represented by formula 3, optical resolving agent to synthesize Diastereomers of (RS)-2,2- dimethylcyclopropanecarboxyl derivatives . The said optical resolving agent, the compound represented by formula 3 is selected from the group consisting of the compounds represented by the formula 3a or 3b.
formula 3a
formula 3b
(wherein, R1, R2, R3 and R4 are as defined in the above . )
Particularly, 1, 3-oxazolidine-2-one derivatives, 1,3- oxazolidine-2-thione derivatives, 1, 3-thiazolidine-2-thione derivatives and 1, 3-imidazolidine-2-one derivatives, the compound of the formula 3a or 3b in which the X is 0 and the Y is O, the X is 0 and the Y is S, the X is S and the Y is S and the X is 0 and the Y is N-R5, respectively are used as the said optical resolving agent. Preferably, 1,3- oxazolidine-2-one derivatives are used.
More particularly, the said chiral heterocycle compound is the compound represented by the formula 3a;
One of the R1 and R2 is selected from the group consisting of Cι-C3 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkyl group, Cι-Cβ alkoxy group or halogen atom, or R6-0-CH2 group (wherein R6 is Cι-C3 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy group or halogen atom) . The other is hydrogen.
Preferably, the X is 0 and the Y is O; One of the R1 and R2 is selected from the group consisting of alkyl group containing methyl group, isopropyl group and t-butyl group, benzyl group containing benzyl group, 4-methoxybenzyl group and 4-chlorobenzyl group, aryl group containing phenyl group and 4-methoxyphenyl group; the other is hydrogen; and both R3 and R4 are hydrogen.
More preferably, the X is O and the Y is 0; one of the R1 and R2 is methyl group, benzyl group or phenyl group; the other is hydrogen atom; and both R3 and R4 are hydrogen .
The said chiral heterocycle compound is the compound represented by the formula 3b;
R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen atom, Cx-C6 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy group or halogen atom or R6-0-CH2 group (wherein R6 is Cι-C6 alkyl group, aryl group unsubstituted or substituted by Cι-C3
alkoxy group or halogen atom; and R1 and R3 are combined to form C4-C8 carbocycle, or heterocycle compound containing 0, N or S.
Preferably, the X is 0 and the Y is O; R1 and R3 is independently methyl group or phenyl group; and both R2 and R4 are hydrogen.
The prepared diastereomers are resolved to optically pure (R) -2 , 2 -dimethylcyclopropanecarboxyl derivatives (la) and (s) -2 , 2 -dimethylcyclopropanecarboxyl derivatives (lb) by crystallization or chromatography.
Chromatography is operated due to the difference of affinity to the stationary phase attached to the column in the two diastereomers. The condition of chromatography resolution (developing solvent, stationary phase, flowing rate) is selected for those skilled in the art to implement. According to the example of the present invention, the prepared diastereomers are resolved more easily than the ones prepared by using other optical resolving agent. Crystallization is the method using the difference of the solubility of two diastereomers in solvent. According to the example, preferably, the crystallization is accomplished in one or more solvents selected from the group consisting of alcohol containing methanol , ethanol and isopropanol, or hydrocarbon containing hexane, heptane
and cyclopropane, but the solvent is not limited to them.
More preferably, the said crystallization is accomplished in methanol, isopropanol, mixed solvent of hexane and dichloromethane, or mixed solvent of hexane and ethyl acetate. In the crystallization using the said solvent, one of the (R) -2 , 2-dimethylcyclopropanecarboxyl derivatives
(la) and (s) -2 , 2-dimethylcyclopropanecarboxyl derivatives
(lb) is selectively resolved from (RS)-2,2- dimethylcyclopropanecarboxyl derivatives. Crystallization was accomplished one time repeatedly in order that (R) or (S) -2 , 2-dimethylcyclopropanecarboxyl derivatives may be resolved with more selective and improved optical purity.
As shown in the Scheme 1, particularly illustrating the present invention, carboxylic group of (RS)-2,2- dimethylcyclopropanecarboxylic acid (2) is activated by the activating agent, thereafter activated carboxylic group is reacted with chiral heterocycle compound (3), optical resolving agent in the presence of base to synthesize the diastereomers . The prepared diastereomers are resolved by crystallization or chromatography to prepare optically pure (R) -2 , 2-dimethylcyclopropanecarboxyl derivatives (la) and (s) -2 , 2-dimethylcyclopropanecarboxyl derivatives (lb). Scheme 1
la lb
(wherein, X, Y, R1, R2, R3 and R4 are as defined in the above . )
Also, (R) -2 , 2-dimethylcyclopropanecarboxylic acid and (s) -2 , 2-dimethylcyclopropanecarboxylic acid are prepared by hydrolyzing (R) -2 , 2-dimethylcyclopropanecarboxyl derivatives (la) and (s) -2 , 2-dimethylcyclopropanecarboxyl derivatives (lb) , respectively. Also, if necessary, (R) - 2, 2-dimethylcyclopropanecarboxyl derivatives (la) and (s) - 2 , 2-dimethylcyclopropanecarboxyl derivatives (lb), as an intermediate are directly reacted with other compound to synthesize useful compound.
The present invention provides (R) or (S)-2,2- dimethylcyclopropanecarboxyl derivatives represented by formula 1. formula 1
(wherein, X, Y, R1, R2, R3 and R4 are as defined in the above . )
Preferably, the present invention provides (R) or (S) -2 , 2-dimethylcyclopropanecarboxyl derivatives, the compound of formula 1 in which the X is 0 and the Y is 0; one of the R1 and R2 is selected from the group consisting of alkyl group containing methyl group, isopropyl group, t- butyl group and cyclohexyl group, benzyl group containing benzyl group, 4-methoxybenzyl group and 4-chlorobenzyl group, aryl group containing phenyl group and 4- methoxyphenyl group; the other is hydrogen atoms; and both R3 and R4 are hydrogen. More preferably, the compound represented by formula 4a, formula 4b and formula 4c is provided, formula 4a
formula 4b
formula 4c
The present invention will be explained in more detail with reference to the following examples. However, the following examples are provided only to illustrate the present invention, and the present invention is not limited to them.
Step 1: activation of carboxyl group of (RS)-2,2- dimethylcyclopropanecarboxylic acid <EXAMPLE 1> Preparation of (RS) -2.2-dimethylcyclopropanecarbonyl chloride
In a 100ml flask, (RS)-2,2- dimethylcyclopropanecarboxylic acid (12g, 105mmol) was dissolved in hexane (12g), two drops of dimethylacetamide . The said solution was heated to 70°C, therein thionyl chloride (23.8g, 200mmol) and hexane (50g) were added slowly dropwise with stirring. The said mixed solution was
additionally stirred for 4 hours at 70 °C, thereafter hexane and excess thionyl chloride was removed under reduced pressure. The crude product was evaporated to obtain pure
(RS) -2, 2-dimethylcyclopropanecarbonyl chloride (12.6g, yield : 91%)
XH NMR(CDC13) : δ 1.18 (m, 1H) , 1.28 (s, 6H) , 1.37 (m, 1H) ,
2.15 (dd, 1H)
step 2 preparation of (RS) -2,2- dimethylcyclopropanecarboxyl derivatives
<EXAMPLE 2>
Preparation of 3- ( (RS) -2 ' , 2 ' -dimethylcyclopropanecarboxyl) - (S) -4-benzyl-l, 3-oxazolidine-2-one
(S) -4-benzyl-l, 3-oxazolidine-2-one (1.06g, 5.99mmol) , (RS) -2 , 2-dimethylcyclopropanecarbonyl chloride (1.03g, 7.77mmol) prepared in the said example 1, lithium chloride (0.28g, 6.60mmol) and triethyl amine(0.90g,
8.91mmol) were added to 5ml of tetrahydrofuran at 0°C, thereafter the solution was heated to the room temperature and stirred for 6 hours at the same temperature. The solvent (tetrahydrofuran) was removed under reduced pressure. The resultant solution was dissolved in the 10ml of ethyl acetate, thereafter the solution was washed with IN of NaOH solution, dried with magnesium sulfate and filtered. The filterate was concentrated under reduced pressure. The crude product was purified by chromatography (developing solvent: mixed solution of hexane and ethyl acetate) to obtain 3- ( (RS) -2 ', 2 ' - dimethylcyclopropanecarboxyl) - (S) -4-benzyl-l , 3-oxazolidine- 2-one(1.54g, yield : 94%).
XH NMR(CDC13) : δ 0.96 (m, 1H) , 1.16 (s, 1.5H) , 1.20 (s, 1.5H), 1.27(s, 1.5H), 1.30(s, 1.5H), 1.35(m, 1H) , 2.80(m, 2H) , 3.30 (m, 1H) , 4.14 (m, 2H) , 4.65 (m, 1H) , 7.29 (m, 5H)
<EXAMPLE 3>
Preparation of 3- ( (RS) -2 ' , 2 ' -dimethylcyclopropanecarboxyl) -
(R) -4-benzyl-l, 3-oxazolidine-2-one (R) -4-benzyl-l, 3-oxazolidine-2-one (1. OOg, 5.65mmol),
(RS) -2 , 2-dimethylcyclopropanecarbonyl chloride (0.97g, 7.32mmol) prepared in the said example 1, lithium chloride (0.26g, 6.10mmol) and triethyl amine(0.85g,
8.41mmol) were added to 5ml of tetrahydrofuran at 0°C, thereafter the solution was heated to the room temperature and stirred for 5 hours at the same temperature. The solvent (tetrahydrofuran) was removed under reduced pressure. The resultant solution was dissolved in the 10ml of ethyl acetate, thereafter the solution was washed with IN of NaOH solution, dried with magnesium sulfate and filtered. The filterate was concentrated under reduced pressure. The crude product was purified by chromatography (developing solvent: mixed solution of hexane and ethyl acetate) to obtain 3- ( (RS) -2 ', 2 ' - dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3 -oxazolidine- 2-one(1.43g, yield : 93%).
XH NMR(CDC13) : δ 0.96 (m, 1H) , 1.16 (s, 1.5H) , 1.20 (s, 1.5H), 1.27(s, 1.5H), 1.30(s, 1.5H), 1.35(m, 1H) , 2.80(m, 2H) , 3.30 (m, 1H) , 4.14 (m, 2H) , 4.65 (m, 1H) , 7.29 (m, 5H)
<EXAMPLE 4>
Preparation of 3 - ( (RS) -2 ' , 2 ' -dimethylcyclopropanecarboxyl) -
(S) -4 -phenyl- l, 3 -oxazolidine-2 -one
(S) -4 -phenyl - l , 3 -oxazolidine-2 -one (1 . O Og, 6 . 13mmol) , (RS) -2 , 2 -dimethylcyclopropanecarbonyl chloride ( 1 . 05g,
7.92mmol) prepared in the said example 1, lithium chloride (0.28g, 6.60mmol) and triethyl amine (0.93g, 9.21mmol) were added to 5ml of tetrahydrofuran at 0°C, thereafter the solution was heated to the room temperature and stirred for 7 hours at the same temperature. The solvent (tetrahydrofuran) was removed under reduced pressure. The resultant solution was dissolved in the 10ml of ethyl acetate, thereafter the solution was washed with IN of NaOH solution, dried with magnesium sulfate and filtered. The filterate was concentrated under reduced pressure. The crude product was purified by chromatography
(developing solvent: mixed solution of hexane and ethyl acetate) to obtain 3- ( (RS) -2 ', 2 ' - dimethylcyclopropanecarboxyl) - (S) -4-phenyl-l, 3-oxazolidine- 2-one(1.45g, yield : 91%).
XH NMR(CDC13) : δ 0.90(m, 1H) , 0.96(s, 1.5H) , 1.15(s, 1.5H), 1.24 (m, 1H) , 1.29(s, 1.5H) , 1.30.(s, 1.5H) , 2.82 (m, 1H) , 4.27 (m, 1H) , 4.70 (m, 1H) , 5.48 (m, 1H) , 7.35 (m, 5H)
<EXAMPLE 5>
Preparation of 3- ( (RS) -2 ' , 2 ' -dimethylcyclopropanecarboxyl) - (4S, 5R) -4-methyl-5-phenyl-1, 3-oxazolidine-2-one
(4S, 5R) -4-methyl-5-phenyl-l, -oxazolidine-2-one (1.06g,
5.99mmol) , (RS) -2 , 2-dimethylcyclopropanecarbonyl chloride (1.03g, 7.77mmol) prepared in the said example 1,
lithium chloride (0.28g, 6.60mmol) and triethyl amine(0.90g,
8.91mmol) were added to 5ml of tetrahydrofuran at 0°C, thereafter the solution was heated to the room temperature and stirred for 5 hours at the same temperature. The solvent (tetrahydrofuran) was removed under reduced pressure. The resultant solution was dissolved in the 10ml of ethyl acetate, thereafter the solution was washed with IN of NaOH solution, dried with magnesium sulfate and filtered. The filterate was concentrated under reduced pressure. The crude product was purified by chromatography (developing solvent: mixed solution of hexane and ethyl acetate) to obtain 3- ( (RS) -2 ', 2' - dimethylcyclopropanecarboxyl) - (4S, 5R) -4 -methyl-5-phenyl - 1, 3-oxazolidine-2-one (1.56g, yield : 95%). XH NMR(CDC13) : δ 0.89 (dd, 3H) , 0.93 (m, 1H) , 1.12 (s, 1.5H), 1.16(S, 1.5H), 1.27(s, 1.5H) , 1.30(m, 1H) , 1.32(s, 1.5H), 2.75 (dd, 0.5H), 2.94 (dd, 0.5H) , 4.80 (m, 1H) , 5.66 (d, 1H) , 7.37 (m, 5H)
step 3j optical resolution of (RS) -2,2- dimethylcyclopropanecarboxyl derivatives
<EXAMPLE 6>
Optical resolution of 3- ( (RS) -2 ' , ' - dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine- 2 -one by crystallization 1
3- ( (RS) -2' ,2' -dimethylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3-oxazolidine-2-one (2. OOg, 7.32mmol) prepared in the example 3 was refluxed and dissolved in 35.0ml of hexane and 4.00ml of ethyl acetate, thereafter the solution was slowly cooled and crystallized. The resultant crude product was filtered to obtain crystal (0.62g, 31.0%). The crystal was analyzed by HPLC . The result showed that 3- ( (S) -2' , 2' -dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3- oxazolidine-2-one and 3-((R)-2',2'- dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine-
2-one were mixed in a molar ratio of 98.5 : 1.5. (column :
Kromasil, developing solvent : ethyl acetate/hexane = 1/10)
^■H NMR(CDC13) : δ 0.92 (m, 1H) , 1.20 (s, 3H) , 1.29(s, 3H) ,
1.35 (m, 1H) , 2.71(dd, 1H) , 2.79 (dd, 1H) , 3.28 (dd, 1H) , 4.15 (m, 2H) , 4.65 (m, 1H) , 7.31 (m, 5H)
<EXAMPLE 7>
Optical resolution of 3- ( (RS) -2 ' , 2' - dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3 -oxazolidine- 2 -one by crystallization 2
3- ( (RS) -2', 2' -dimethylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3-oxazolidine-2-one (4. OOg, 14.7mmol) prepared in the example 3 was refluxed and dissolved in 12.0ml of isopropanol, thereafter the solution was slowly cooled and crystallized. The crude product was filtered to obtain
crystal (1.60g, 40.0%). The crystal was analyzed by HPLC . The result showed that 3-((S)-2', 2'- dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine- 2-one and 3- ( (R) -2 ', 2 ' -dimethylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3 -oxazolidine-2 -one were mixed in a molar ratio of 97.5 : 2.5. (column : Kromasil, developing solvent : ethyl acetate/hexane = 1/10)
XH NMR(CDC13) : δ 0.92 (m, 1H) , 1.20 (s, 3H) , 1.29(s, 3H) , 1.35 (m, 1H) , 2.71(dd, 1H) , 2.79 (dd, 1H) , 3.28 (dd, 1H) , 4.15 (m, 2H) , 4.65 (m, 1H) , 7.31 (m, 5H)
<EXAMPLE 8>
Optical resolution of 3- ( (RS) -2 ' , 2 ' - dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine- 2 -one by crystallization 3
2. OOg of crude product, in which 3-((S)-2' ,2'- dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l , 3 -oxazolidine- 2-one and 3- ( (R) -2',2' -dimethylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3-oxazolidine-2-one were mixed in a molar ratio of 91.0:9.0 was refluxed and dissolved in 12.0ml of isopropanol, thereafter the solution was slowly cooled to the room temperature and crystallized. The crude product was filtered to obtain crystal (1.40g, 70.0%). The crystal was analyzed by HPLC. The result showed that 3-((S)-2', 2'- dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine-
2-one and 3- ( (R) -2 ' , 2 ' -dimrthylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3-oxazolidine-2-one were mixed in a molar ratio of 99.9 : 0.1. Crystallization was accomplished one time repeatedly in order to reach more selective and improved optical resolution. (column : Kromasil, developing solvent : ethyl acetate/hexane = 1/10)
^Η NMR(CDC13) : δ 0.92 (m, 1H) , 1.20(s, 3H) , 1.29(s, 3H) , 1.35 (m, 1H) , 2.71 (dd, 1H) , 2.79 (dd, 1H) , 3.28 (dd, 1H) , 4.15 (m, 2H) , 4.65 (m, 1H) , 7.31 (m, 5H)
<EXAMPLE 9>
Optical resolution of 3-((RS)-2',2'- dimethylcyclopropanecarboxyl) - (S) -4-benzyl-l, 3-oxazolidine- 2 -one by crystallization 2. OOg of 3- ( (RS) -2', 2' -dimethylcyclopropanecarboxyl) - (S) -4-benzyl-l, 3-oxazolidine-2 -one prepared in the example 2 was refluxed and dissolved in 10.0ml of methanol, thereafter the solution was slowly cooled to the room temperature and crystallized. The resultant crude product was filtered to obtain crystal (0.74g, 37.0%). The crystal was analyzed by HPLC. The result showed that 3-((S)-2', 2'- dimethylcyclopropanecarboxyl) - (S) -4-benzyl-l, 3-oxazolidine- 2-one and 3- ( (R) -2 ', 2' -dimethylcyclopropanecarboxyl) - (S) -4- benzyl-1, 3 -oxazolidine-2 -one were mixed in a molar ratio of 5.0 : 95.0. (column : Kromasil, developing solvent : ethyl
acetate/hexane = 1/10)
XH NMR(CDC13) : δ 0.92 (m, IH) , 1.20 (s, 3H) , 1.29(s, 3H) , 1.35 (m, IH) , 2.71 (dd, IH) , 2.79 (dd, IH) , 3.28 (dd, IH) , 4.15 (m, 2H) , 4.65(m, IH) , 7.31 (m, 5H)
<EXAMPLE 10 >
Optical resolution of 3- ( (RS) -2' , 2' - dimethylcyclopropanecarboxyl) - (R) -4-phenyl-l, 3-oxazolidine- 2 -one by crystallization 1 2. OOg of 3- ( (RS) -2', 2' -dimethylcyclopropanecarboxyl) -
(R) -4-phenyl-l, 3 -oxazolidine-2 -one prepared in the example
4 was refluxed and dissolved in mixed solution of 20.0ml of hexane and 6.00ml of ethyl acetate, thereafter the solution was slowly cooled to the room temperature and crystallized. The resultant crude product was filtered to obtain crystal (0.50g, 25%) . The crystal was analyzed by HPLC. The result showed that 3-((S)-2', 2 ' -dimethylcyclopropanecarboxyl) - (R) -4-phenyl-l, 3-oxazolidine-2 -one and 3-((R)-2',2'- dimethylcyclopropanecarboxyl) - (R) -4-phenyl-l , 3 -oxazolidine- 2-one were mixed in a molar ratio of 6.0 : 94.0. (column : Kromasil, developing solvent : ethyl acetate/hexane = 1/4)
XH NMR(CDC13) : δ 0.90 (m, IH) , 1.15 (s, 3H) , 1.25(m, IH) , 1.29(s, 3H) , 2.82(dd, IH) , 4.27(m, IH) , 4.70(m, IH) , 5.48(m, IH) , 7.35 (m, 5H)
< EXAMPLE 11>
Optical resolution of 3- ( (RS) -2 ' ,2' - dimethylcyclopropanecarboxyl) - (R) -4-phenyl-l, 3-oxazolidine- 2-one by crystallization 2 2. OOg of crude product, in which 3-((S)-2',2'- dimethylcyclopropanecarboxyl) - (R) -4-phenyl-l , 3 -oxazolidine- 2-one and 3- ( (R) -2 ', 2 ' -dimethylcyclopropanecarboxyl) - (R) -4- phenyl-1 , 3 -oxazolidine-2 -one were mixed in a molar ratio of 82.0:18.0 was refluxed and dissolved in 30.0ml of isopropanol, thereafter the solution was slowly cooled to the room temperature and crystallized. The crude product was filtered to obtain crystal (0.64g, 32%). The crystal was analyzed by HPLC. The result showed that 3-((S)-2', 2'- dimethylcyclopropanecarboxyl) - (R) -4-phenyl-l , 3 -oxazolidine- 2-one and 3- ( (R) -2' ,2' -dimethylcyclopropanecarboxyl) - (R) -4- phenyl-1, 3 -oxazolidine-2 -one were mixed in a molar ratio of 99.0 : 1.0. (column : Kromasil, developing solvent : ethyl acetate/hexane = 1/4)
XH NMR(CDC13) : δ 0.89 (m, IH) , 0.90 (s, 3H) , 1.23 (m, IH) , 1.29(s, 3H) , 2.87(dd, IH) , 4.26 (m, IH) , 4.70(m, IH) , 5.44(m, IH) , 7.35 (m, 5H)
<EXAMPLE 12>
Optical resolution of 3- ( (RS) -2 ' , 2 ' - dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3 -oxazolidine-
2-one by chromatography l.OOg of 3- ( (RS) -2 ', 2' -dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine-2-one prepared in the example 3 was resolved by chromatography to obtain 3-((S)-2',2'- dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l , 3 -oxazolidine- 2-one(0.45g, 1.65mmol) and 3- ( (R) -2' , 2 ' - dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine- 2-one(0.46g, 1.68mmol) . (the condition of chromatography resolution: Si02 230~400 mesh, developing solvent: ethyl acetate/hexane=l/7) .
3- ( (S) -2' ,2' -dimethylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3 -oxazolidine-2 -one; 1H NMR(CDC13): δ 0.93 (m, IH) , 1.20(s, 3H) , 1.30(s, 3H) , 1.35(m, IH) , 2.75 (m, 2H) , 3.30(m, IH) , 4.14 (m, 2H) , 4.64 (m, IH) , 7.29 (m, 5H) 3- ( (R) -2',2' -dimethylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3 -oxazolidine-2 -one; 1H NMR(CDC13): δ 0.97 (m, IH) , 1.16(s, 3H) , 1.27(s, 3H) , 1.35(m, IH) , 2.85(m, 2H) , 3.30(m, IH) , 4.14 (m, 2H) , 4.66 (m, IH) , 7.29 (m, 5H)
<EXAMPLE 13>
Optical resolution of 3- ( (RS) -2' ,2" - dimethylcyclopropanecarboxyl) - (S) -4-phenyl-l, 3-oxazolidine- 2-one by chromatography
0.50g of 3- ( (RS) -2 ', 2' -dimethylcyclopropanecarboxyl) - (S) -4-phenyl-l, 3-oxazolidine-2-one was resolved by
chromatography to obtain 3-((S)-2',2'- dimethylcyclopropanecarboxyl) - (S) -4-phenyl-l, 3 -oxazolidine- 2-one(0.21g, 0.81mmol) and 3-((R)-2',2'- dimethylcyclopropanecarboxyl) - (S) -4-phenyl-l, 3-oxazolidine- 2-one(0.22g, 0.85mmol) . (the condition of chromatography resolution: Si02 230~400 mesh, developing solvent: ethyl acetate/hexane=l/4) .
3- ( (S) -2',2' -dimethylcyclopropanecarboxyl) - (s) -4- phenyl-1, 3 -oxazolidine-2 -one; XH NMR(CDC13): δ 0.90 (m, IH) , 1.15(s, 3H) , 1.25(m, IH) , 1.29(s, 3H) , 2.82(dd, IH) , 4.27(m, IH) , 4.70(m, IH) , 5.48(m, IH) , 7.35(m, 5H)
3- ( (R) -2' , 2 ' -dimethylcyclopropanecarboxyl) - ( S) -4- phenyl-1,3 -oxazolidine-2 -one; ^Η NMR(CDC13): δ 0.89 (m, IH) , 0.90(s, 3H) , 1.23(m, IH) , 1.29(s, 3H) , 2.87(dd, IH) , 4.26(m, IH) , 4.70 (m, IH) , 5.44 (m, IH) , 7.35 (m, 5H)
<EXAMPLE 14>
Optical resolution of 3- ( (RS) -2 ' , 2 ' - dimethylcyclopropanecarboxyl) - (4S,5R) -4-methyl-5-phenyl- 1, 3 -oxazolidine-2 -one by chromatography
1. Og of 3- ( (RS) -2 ' , 2 ' -dimethylcyclopropanecarboxyl) -
(4S, 5R) -4-methyl-5-phenyl-l, 3 -oxazolidine-2 -one was resolved by chromatography to obtain 3-((S)-2',2'- dimethylcyclopropanecarboxyl) - (4S,5R) -4-methyl-5-phenyl- 1, 3 -oxazolidine-2 -one (0.43g, 1.58mmol) and 3-((R)-2',2'-
dimethylcyclopropanecarboxyl) - (4S,5R) -4 -methyl-5 -phenyl - 1, 3 -oxazolidine-2 -one (0.44g, 1.61mmol) . (the condition of chromatography resolution: Si02 230~400 mesh, developing solvent: ethyl acetate/hexane=l/6) . 3-((S)-2',2' -dimethylcyclopropanecarboxyl) - (4S, 5R) -4- methyl-5-phenyl-l,3-oxazolidine-2-one; 1H NMR(CDC13) : δ 0.89(d, 3H) , 0.93(m, IH) , 1.16(s, 3H) , 1.27(s, 3H) , 1.28 (m, IH) , 2.94 (dd, IH) , 4.80 (m, IH) , 5.65 (d, IH) , 7.37 (m, 5H)
3- ( (R) -2' ,2' -dimethylcyclopropanecarboxyl) - ( 4S,5R) -4- methyl-5-phenyl-l,3-oxazolidine-2-one; XH NMR(CDC13) : δ 0.88(d, 3H) , 0.92(m, IH) , 1.12(s, 3H) , 1.32(s, 3H) , 1.33(m, IH) , 2.75 (dd, IH) , 4.74 (m, IH) , 5.67 (d, IH) , 7.37 (m, 5H)
step 4 : hydrolysis of (R) or (S) -2,2- dimethylcyclopropanecarboxyl derivatives <EXAMPLE 15>
Preparation of (S) -2, 2 -dimethylcyclopropanecarboxylic acid via hydrolysis
Crude product (2. OOg, 32mmol) , in which 3-((S)-2' ,2'- dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine- 2-one and 3- ( (R) -2' ,2' -dimethylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3 -oxazolidine-2 -one were mixed in a molar ratio of 99.9:0.1 was dissolved in mixed solution of 20ml of tetrahydrofuran and 6ml of H20, thereafter the solution was
cooled to 0°C. 30% H202 solution (2.8g, 29mmol) and 10% LiOH
solution (0.9g, 16.9mmol) were subsequently added dropwise therein. The solution was stirred for 4 hours, thereafter 30.0% sodium sulfite solution was added to remove excess H20, and concentrated under reduced pressure to remove tetrahydrofuran. Dichloromethane was added to the resultant acqueous solution, and extracted to recycle (4R) -4-benzyl- 1, 3-oxazolidine-2-one . The solution was acidified with 2N hydrochloric acid solution, and extracted with ethyl acetate. The extract was dried with magnesium sulfate, and filtered to obtain a filterate. The filterate was concentrated and evaporated under reduced pressure to obtain pure (S) -2 , 2 -dimethylcyclopropanecarboxylic acid(749mg, 90%, [a] D 20=147 (c=l, CHC13) . XH NMR(CDC13) : δ 0.92 (m, IH) , 1.12 (m, IH) , 1.17 (s, 3H) , 1.24(s, 3H) , 1.50 (m, IH)
Industrial applicability
As described above, in accordance with the present invention, a pure (R) or (S)-2, 2- dimethylcyclopropancarboxyl derivative (la, lb) with high purity, which is easily synthesized by itself is prepared by using a chiral heterocycle compound of formula 3 as a novel optical resolving agent. This compound is reacted with activated (RS)-2, 2 -dimethylcyclopropancarbonyl chloride, and the thus obtained diastereomer is
crystallized or chromatographed to prepare a pure (R) or (S)-2, 2-dimethylcyclopropancarboxyl derivative (la, lb). Chiral heterocycle compound of formula 3 is used as a novel optical resolving agent in the preparation method of the present invention to synthesize 2, 2- dimethylcyclopropancarboxyl derivatives of high purity, which can be industrially mass produced, and this is hydrolyzed to obtain (R) or (S)-2, 2- dimethylcyclopropancarboxylic acid.
Claims
1. A method for the preparation of optically pure (R) -2, 2-dimethylcyclopropanecarboxyl derivatives (la) and (s) -2 , 2 -dimethylcyclopropanecarboxyl derivatives (lb) , comprising the following steps of: reacting (RS)-2,2- dimethylcyclopropanecarboxylic acid with an optical resolving agent to synthesize diastereomers ;and resolving the said diastereomers by crystallization or chromatography to obtain optically pure (R)-2,2- dimethylcyclopropanecarboxyl derivatives (la) and (s)-2,2- dimethylcyclopropanecarboxyl derivatives (lb) ; wherein, said optical resolving agent is chiral heterocycle compound represented by the formula 3.
Scheme 1
Y is O, S or N-R5 (wherein, R5 is Cι-C6 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy group or halogen) ; R1, R2, R3 and R4 are independently
selected from the group consisting of H, Cι-C6 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy groups or halogen atom, R6-0-CH2 group (wherein R6 is Cι-C6 alkyl group, aryl groups unsubstituted or substituted by Cx-Cg alkoxy group or halogen atom) ; and R1 and R3 are combined to form C4-C8 carbocycle, or heterocycle compound containing O, N or S . Wherein, it is excepted that all of R1, R2, R3 and R4 are H.
2. The method for the preparation of claim 1, wherein said method is related to preparing pure (R)-2,2- dimethylcyclopropanecarboxylic acid and (S)-2,2- dimethylcyclopropanecarboxylic acid by hydrolyzing (R)-2,2- dimethylcyclopropanecarboxyl derivatives (la) and (S) - 2,2- dimethylcyclopropanecarboxyl derivatives (lb) , respectively .
3. The method for the preparation of claim 1, wherein said optical resolving agent is selected from the group consisting of the compounds represented by the formula 3a or 3b. formula 3a
(wherein, R , R , R and R are as defined in claim
1.)
4. The method for the preparation of claim 1, wherein said optical resolving agent is the compound of formula 3, in which X is O and Y is 0.
5. The method for the preparation of claim 4, one of the R1 and R2 is selected from the group consisting of alkyl group containing methyl group, isopropyl group and t- butyl group; benzyl group containing benzyl group, 4- methoxybenzyl group and 4-chlorobenzyl group; and aryl group containing phenyl group and 4-methoxyphenyl group; the other is hydrogen; and both R3 and R4 are hydrogen.
6. The method for the preparation of claim 4, one of the R1 and R2 is methyl group, benzyl group or phenyl group; the other is hydrogen; and both R3 and R4 are hydrogen .
7. The method for the preparation of claim 4, wherein R1 and R3 are independently methyl group or phenyl group; and both R2 and R4 are hydrogen.
8. The method for the preparation of claim 1, wherein said crystallization is accomplished' in one or more solvents selected from the group consisting of alcohol containing methanol, ethanol and isopropanol, and hydrocarbon containing hexane, heptane and cyclopropane.
9. The method for the preparation of claim 8, wherein said crystallization is accomplished in methanol, isopropanol, mixed solvent of hexane and dichloromethane, or mixed solvent of hexane and ethyl acetate .
10. (R) or (S) -2, 2 -dimethylcyclopropanecarboxyl derivatives represented by formula 1. formula 1
11. The derivatives of claim 10, wherein X is O and Y is 0.
12. The derivatives of claim 11, wherein X is O and Y is 0; one of the R1 and R2 is selected from the group consisting of alkyl group containing methyl group, isopropyl group, t-butyl group and cyclohexyl group, benzyl group containing benzyl group, 4-methoxybenzyl group and 4- chlorobenzyl group, aryl group containing phenyl group and 4-methoxyphenyl group, the other is hydrogen; and both R3 and R4 are hydrogen.
13. The derivatives of claim 11, wherein said derivatives are represented by formula 4a. formula 4a
14. The derivatives of claim 11, wherein said derivatives are represented by formula 4b. formula 4b
15. The derivatives of claim 11, wherein said derivatives are represented by formula 4c. formula 4c
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2002353630A AU2002353630A1 (en) | 2001-11-22 | 2002-11-21 | A method for preparing of chiral 2,2-dimethylcyclopropanecarboxyl derivatives |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2001-0073114A KR100441137B1 (en) | 2001-11-22 | 2001-11-22 | A method for preparing of chiral 2,2-dimethylcyclopropanecarboxyl derivatives |
| KR2001/73114 | 2001-11-22 |
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| PCT/KR2002/002179 WO2003043996A1 (en) | 2001-11-22 | 2002-11-21 | A method for preparing of chiral 2,2-dimethylcyclopropanecarboxyl derivatives |
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| Country | Link |
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| KR (1) | KR100441137B1 (en) |
| AU (1) | AU2002353630A1 (en) |
| WO (1) | WO2003043996A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4479005A (en) * | 1982-12-16 | 1984-10-23 | The Dow Chemical Company | Selective preparation of isomers and enantiomers of cyclopropane carboxylic acids |
| JPS6056936A (en) * | 1983-09-06 | 1985-04-02 | Sumitomo Chem Co Ltd | Production of optically active 2,2-dimethylcyclopropane carboxylic acid and its derivative |
| EP0171894A1 (en) * | 1984-07-18 | 1986-02-19 | Imperial Chemical Industries Plc | Insecticidal enantiomeric pair of a phenoxybenzyl cyclopropanecarboxylate derivative, and process for its preparation |
| US5273903A (en) * | 1991-03-06 | 1993-12-28 | Lonza Ltd. | Biotechnological process for the production of S-(+)-2,2-dimethylcyclopropanecarboxamide |
-
2001
- 2001-11-22 KR KR10-2001-0073114A patent/KR100441137B1/en not_active IP Right Cessation
-
2002
- 2002-11-21 WO PCT/KR2002/002179 patent/WO2003043996A1/en not_active Application Discontinuation
- 2002-11-21 AU AU2002353630A patent/AU2002353630A1/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4479005A (en) * | 1982-12-16 | 1984-10-23 | The Dow Chemical Company | Selective preparation of isomers and enantiomers of cyclopropane carboxylic acids |
| JPS6056936A (en) * | 1983-09-06 | 1985-04-02 | Sumitomo Chem Co Ltd | Production of optically active 2,2-dimethylcyclopropane carboxylic acid and its derivative |
| EP0171894A1 (en) * | 1984-07-18 | 1986-02-19 | Imperial Chemical Industries Plc | Insecticidal enantiomeric pair of a phenoxybenzyl cyclopropanecarboxylate derivative, and process for its preparation |
| US5273903A (en) * | 1991-03-06 | 1993-12-28 | Lonza Ltd. | Biotechnological process for the production of S-(+)-2,2-dimethylcyclopropanecarboxamide |
Non-Patent Citations (1)
| Title |
|---|
| ROOS JURGEN ET AL.: "Synthesis of (1R, cis, alpha S)-cypermethrine via lipase catalyzed kinetic resolution of racemic m-phenoxybenzaldehyde cyanohydrin acetate", TETRAHEDRON ASYMMETRY, vol. 9, no. 6, 1998, pages 1043 - 1049 * |
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| Publication number | Publication date |
|---|---|
| AU2002353630A1 (en) | 2003-06-10 |
| KR100441137B1 (en) | 2004-07-21 |
| KR20030042373A (en) | 2003-05-28 |
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