WO2014102808A1 - A process for preparation of trans (lr,2r)-cyclo hexane 1, 2-dicarboxylic acid - Google Patents
A process for preparation of trans (lr,2r)-cyclo hexane 1, 2-dicarboxylic acid Download PDFInfo
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- WO2014102808A1 WO2014102808A1 PCT/IN2013/000149 IN2013000149W WO2014102808A1 WO 2014102808 A1 WO2014102808 A1 WO 2014102808A1 IN 2013000149 W IN2013000149 W IN 2013000149W WO 2014102808 A1 WO2014102808 A1 WO 2014102808A1
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- Prior art keywords
- dicarboxylic acid
- cyclohexane
- compound
- trans
- iii
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000004805 Cyclohexane-1,2-dicarboxylic acid Substances 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 20
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 claims description 13
- 239000010410 layer Substances 0.000 claims description 13
- 239000007868 Raney catalyst Substances 0.000 claims description 12
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 12
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- QSAWQNUELGIYBC-UHFFFAOYSA-N cyclohexane-1,2-dicarboxylic acid Chemical compound OC(=O)C1CCCCC1C(O)=O QSAWQNUELGIYBC-UHFFFAOYSA-N 0.000 claims description 10
- 239000001530 fumaric acid Substances 0.000 claims description 10
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 10
- MBDNRNMVTZADMQ-UHFFFAOYSA-N sulfolene Chemical compound O=S1(=O)CC=CC1 MBDNRNMVTZADMQ-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 7
- 239000012044 organic layer Substances 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- YDUGVOUXNSWQSW-UHFFFAOYSA-N 3-bromo-1h-pyridin-2-one Chemical compound OC1=NC=CC=C1Br YDUGVOUXNSWQSW-UHFFFAOYSA-N 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 3
- 229960002863 lurasidone hydrochloride Drugs 0.000 abstract description 6
- NEKCRUIRPWNMLK-SCIYSFAVSA-N lurasidone hydrochloride Chemical compound Cl.C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 NEKCRUIRPWNMLK-SCIYSFAVSA-N 0.000 abstract description 6
- 239000000164 antipsychotic agent Substances 0.000 abstract description 4
- 201000000980 schizophrenia Diseases 0.000 abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 12
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- QSAWQNUELGIYBC-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-dicarboxylic acid Chemical compound OC(=O)[C@@H]1CCCC[C@H]1C(O)=O QSAWQNUELGIYBC-PHDIDXHHSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- -1 (1R,2R) cyclohexane- 1,2-dicarboxylic acid compound Chemical class 0.000 description 4
- 229960001432 lurasidone Drugs 0.000 description 4
- PQXKDMSYBGKCJA-CVTJIBDQSA-N lurasidone Chemical class C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 PQXKDMSYBGKCJA-CVTJIBDQSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 0 *[C@](CCCC1)[C@@]1C(O)=O Chemical compound *[C@](CCCC1)[C@@]1C(O)=O 0.000 description 2
- IXLVUUFUDRJUSL-RPBOFIJWSA-N 5-[[4-(3-acetamidophenyl)phenyl]methyl]-n-[(1s,2r)-2-phenylcyclopropyl]-1,3-oxazole-4-carboxamide Chemical compound CC(=O)NC1=CC=CC(C=2C=CC(CC3=C(N=CO3)C(=O)N[C@@H]3[C@H](C3)C=3C=CC=CC=3)=CC=2)=C1 IXLVUUFUDRJUSL-RPBOFIJWSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- VKNBTPZMAOWQOW-TYYBGVCCSA-N (E)-but-2-enedioic acid 2,5-dihydrothiophene 1,1-dioxide Chemical compound O=S1(=O)CC=CC1.OC(=O)\C=C\C(O)=O VKNBTPZMAOWQOW-TYYBGVCCSA-N 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N monoethyl amine Natural products CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/36—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by hydrogenation of carbon-to-carbon unsaturated bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- 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
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Definitions
- the solid material obtained from example- 1 was dissolved in 900 ml of methanol and was transferred to autoclave along with 30 g of Raney nickel under hydrogen gas pressure at room temperature and was maintained for 15-18 hours at room temperature. TLC was checked for the content of cyclohex-4-ene-l ,2-dicarboxylic acid (NMT 0.5 %). When TLC was complied, reaction mass was filtered to remove the Raney nickel and the filtrate was concentrated under reduced pressure to yield solid 725 to750 g. The recovered Raney nickel may be recycled for further use.
Abstract
A commercially viable process for industrial preparation of trans-(l R,2R)-cyclohexane 1,2- dicarboxylic acid represented by compound of Formula-I, wherein the compound has more than 99% HPLC purity. The compound of Formula-I is a key intermediate in preparation of Lurasidone hydrochloride which is a well known antipsychotic agent used for treatment of schizophrenia.
Description
A PROCESS FOR PREPARATION OF TRANS (lR,2R)-CYCLO HEXANE
1, 2-DICARBOXYLIC ACID
FIELD OF INVENTION
The invention relates to a process for preparation of trans-(lR,2R)-cyclohexane 1 ,2-dicarboxylic acid. More particularly, the invention relates to a commercially viable process for industrial preparation of trans-(lR,2R)-cyclohexane 1 ,2-dicarboxylic acid represented by compound of Formula-I, wherein the compound has more than 99% HPLC purity. The compound of Formula- I is a key intermediate in preparation of Lurasidone hydrochloride which is a well known antipsychotic agent used for treatment of schizophrenia.
( I )
BACKGROUND OF THE INVENTION
Lurasidone hydrochloride is chemically known as ( 3aR,4S,7R,7aS)-2-{(lR,2R) -2-[4-(l ,2- benzisothiazole-3-yl)piperazin-l-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H- isoindole-1, 3-dione hydrochloride having the structure represented as formula- A
Lurasidone Hydrochloride (A)
Lurasidone hydrochloride is an antipsychotic agent useful for the treatment of schizophrenia and is disclosed in PCT/JP2004/09095 by Dainippon Sumitomo Pharma Co. Ltd. of Japan. PCT application PCT/JP2004/01 1035 by Dainippon Sumitomo Pharma Co. Ltd. discloses a process for preparation of hydrochloric salts of Lurasidone.
US Patent 5532,372 discloses a process for preparation of Lurasidone Hydrochloride by using racemic trans 1,2-cyclohexane dicarboxylic acid as intermediate.
The compound trans (lR,2R)cyclohexane-l ,2-dicarboxylic acid represented by compound of Formula-I is one of the important intermediate in the synthesis of Lurasidone.
(I)
Among the prior arts, the preparation and properties of the racemic trans (1R,2R) cyclohexane- 1,2-dicarboxylic acid compound was disclosed in Australian Journal of Chemistry, 1986, 39, 591-604 and Justus Liebigs Ann.Chem., 1949,564, 96 as depicted below in Scheme-I.
Scheme-I
cyclohexane- 1,2- dicarboxylic acid racemic
The prior art discloses the heating of the fumaric acid and 3-sulfolene in acetic acid in a sealed container at 100° C for 40 hours to give trans-cyclohex-4-ene-l,2-dicarboxylic acid which on further hydrogenation using 10% palladium carbon in methanol media yields racemic trans cyclohexane 1 ,2- dicarboxylic acid.
Resolution of the trans- 1,2- (1R,2R) cyclohexane- 1 ,2-dicarboxylic acid using chiral resolving agent selected from the group comprising (R)-l-phenylethylamine, alpha-methylbenzylamine etc was reported in the literature ACOC Chemical Research Communications, Vol. 9, 1999, page
25-30.
W02012/131606 discloses the resolution and preparation of the Antipsychotic agent Lurasidone as depicted below in scheme-II.
SCHEME - II :
dicar
( 1 R,2R)cyclohexane- 1 ,2-dicarboxylic acid
The prior art methods of preparation of trans-(lR,2R)-cyclohexane 1 ,2-dicarboxylic acid conventionally comprise the steps of- i). resolution of trans racemic cyclohexane-1, 2-dicarboxylic acid;
ii). breaking the salt to isolate the technically pure resolved product; and
iii). improving the purity by hexane washing to get the chemically pure product.
Wherein, the process follows resolution of trans-racemic cyclohexane-1 , 2-dicarboxylic acid in the reaction with R-l -phenylethylamine in ethanol as a solvent to give corresponding salt. The obtained salt is broken using hydrochloric acid to give the technically pure trans (1R,2R) cyclohexane 1 ,2-di carboxylic acid. The purity of the obtained compound is further improved by hexane washing.
However, this process is very costly and commercially not viable for large scale preparations of the compound due non-recovery and wastage of the amine after breaking the salt. Therefore, a large quantity of R-l-phenylethylamine is required which increases the cost of the product and makes it commercially non-viable for industrial preparation.
OBJECTS OF THE INVENTION
The primary object of the invention is to provide a process for preparation of trans-(lR,2R) cyclohexane 1, 2-dicarboxylic acid.
Another object of the invention is to provide a process for preparation of trans- (1R,2R) cyclohexane 1,2-di carboxylic acid which is commercially viable and capable of being used in industrial preparation of trans- (1R,2R) cyclohexane 1,2-di carboxylic acid with more than 99% purity.
SUMMARY OF THE INVENTION
Accordingly, a process for preparation of trans-(lR,2R) cyclohexane 1 ,2-dicarboxylic acid compound represented by Formula -I is disclosed. The obtained compound-I has more than 99% purity.
In preferred embodiment of the invention, the resolution agent R-l -phenyl ethyl amine used in resolution steps of the process is also recovered with high purity at the end of the process and can be re-used in the next process cycle.
(I)
In an exemplary embodiment, 3- sulfolene and fumaric acid are used as starting material and the process comprises following steps: treating 3 -sulfolene with fumaric acid to obtain cyclohex-4-ene-l,2-dicarboxylic acid; ii) reducing the obtained cyclohex-4-ene-l ,2-dicarboxylic acid with economically available Raney nickel in presence of methanol to obtain racemic cyclohexane- 1,2- dicarboxylic acid compound - II;
(Π)
resolution of racemic cyclohexane-l,2-dicarboxylic acid (compound-II) with R-l- phenylethylamine to obtain corresponding salt represented by compound - III;
(III)
iv). breaking the salt (compound-Ill) in strong basic conditions to separate the trans-
(lR,2R)-cyclohexane-l,2-dicarboxylic acid (compound-I) and R-1 -phenyl ethyl amine.
(I)
The process of the invention is represented in below scheme III:
Scheme-Ill: aney Ni
Methanol
3-sulfolene fumaric acid
cyclohex-4-ene- 1 ,2-dicarboxylic acid
( 1 R,2R)cyclohexane- 1 ,2-dicarboxylic acid (I)
DETAILED DESCRIPTION OF THE INVENTION
Detailed embodiments of the present invention are disclosed herein below. However, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which can be embodied in various forms. The scope of the invention is not limited to the disclosed embodiments and terms and phrases used herein are not intended to be limiting but rather to provide an understandable description of the invention. The invention is defined by claims appended hereto. The present invention provides a process for preparation of trans-(lR,2R) cyclohexane 1,2- dicarboxylic acid compound represented by Formula-I. The compound-I is a key intermediate useful in preparation of Lurasidone and its salts.
(I)
The obtained compound-I has more than 99% purity.
In preferred embodiment of the invention, the resolution agent R-l-phenylethylamine used in resolution steps of the process is also recovered with high purity at the end of the process and can be re-used in the next process cycle.
The process starts with reaction between 3- sulfolene and fumaric acid and comprises following steps:
i) . treating 3-sulfolene with fumaric acid to obtain cyclohex-4-ene-l,2-dicarboxylic acid; ii) . reducing the obtained cyclohex-4-ene-l,2-dicarboxylic acid with Raney nickel in presence of methanol to obtain racemic cyclohexane- 1 ,2-dicarboxylic acid compound-II;
(Π)
resolution of racemic cyclohexane- 1 ,2-dicarboxylic acid (compound-II) with R-l phenylethylamine to obtain corresponding salt represented by compound - III;
(HI)
iv). breaking the salt (compound-Ill) in strong basic conditions to separate the trans-
(I)
In a conventional process known in the prior art, the reduction in step ii) of the process is done with reducing agents palladium and carbon. Whereas, present process comprises reduction of cyclohex-4-ene-l,2-dicarboxylic acid into racemic cyclohexane- 1 ,2-dicarboxylic acid compound-II with Raney nickel in presence of methanol. The usage of Raney nickel as reducing agent makes this step more commercially viable for industrial scale preparations. The Raney nickel is recovered and successfully recycled.
Recycling of recovered Raney nickel and separation of R-l-phenylethylamine using strong basic conditions thereby giving the good recovery of the same is also an important feature of the invention.
The process of the invention is represented below in Scheme-Ill.
Scheme-III-
cyclohexane- 1 ,2- dicarboxylic acid
Different steps of the process are further elaborated herein below.
Step-1: Treating 3-sulfolene with fumaric acid to obtain cyclohex-4-ene-l,2-dicarboxylic acid.
This step comprises treating 3-sulfolene with fumaric acid in acetic acid under nitrogen atmosphere with stirring at below 1 10° C for 15-16 hours. Removing the excess of solvent under reduced pressure at below 50° C and co-distilling with toluene to obtain the crude. Treating the obtained crude with ethyl acetate to get cyclohex-4-ene-l,2-dicarboxylic acid.
Step-2: Reducing the obtained cyclohex-4-ene-l,2-dicarboxylic acid with Raney nickel in presence of methanol to obtain racemic cyclohexane-l,2-dicarboxylic acid compound-II.
The cyclohex-4-ene-l ,2-dicarboxylic acid obtained in step-1 is dissolved in methanol and subjected to reduction reaction in presence of Raney Nickel under hydrogen gas pressure. The filtrate is concentrated under reduced pressure to obtain Racemic eyclohexane 1 ,2-dicarboxylic acid (Compound - II ).
Step-3: Resolution of racemic cyclohexane-l,2-dicarboxylic acid (compound-II) with R-l- phenylethylamine to obtain corresponding salt represented by compound - III.
This comprises racemic eyclohexane 1 ,2-dicarboxylic acid resolution with R-1- phenyl amine to obtain (lR,2R)cyclohexane-l,2-dicarboxylic acid phenyl ethyl amine salt.
(III)
Step-4: Breaking the salt (compound-Ill) in strong basic conditions to separate the trans- (lR,2R)-cyclohexane-l,2-dicarboxylic acid (compound-I) and R-l-phenyl ethyl amine.
This comprises breaking of the (lR,2R)cyclohexane-l,2-dicarboxylic acid phenyl ethyl amine salt (compound-Ill) with aqueous sodium hydroxide solution. Extraction of resolving agent in chloroform. Separation of chloroform layer and aqueous layer. Recovering the resolving agent from chloroform layer. Adjusting the pH of the aqueous layer with hydrochloric acid making it strong acidic and extracting with ethyl acetate. Concentrating the organic layer (ethyl acetate layer) under vacuum at below 40° C and co-distilling with cyclohexane to obtain the crude compound. Stirring the obtained crude material in cyclohexane at room temperature. Filtering the resulting solid, washing with cyclohexane and drying at about 50° C to obtain trans-(lR,2R)- cyclohexane 1 ,2-dicarboxylic acid (compound-I) having purity above 99 % by HPLC.
(I)
Examples:
Various embodiments of the invention are further exemplified with the help of given examples. However, these examples are only for the purpose of explanation of the process to a person of ordinary skill and various parameters of the examples are illustrative only and should not be taken as limitation to the claims.
Example-1:
Preparation of cyclohex-4-ene-l,2-dicarboxylic acid.
100 g (0.846 M) of 3-sulfolene, 63 g (0.542 M) of fumaric acid and 650 ml of acetic acid were taken in a clean and dry autoclave and stirred at room temperature. The mass temperature was slowly raised to 100 - 110° C and maintained for 15-16 hrs under stirring. After maintenance, TLC was checked for the content of the fumaric acid (NMT 0.5 %). When TLC was complied,
acetic acid was removed up to traces under vacuum below 50° C to get the crude. The crude material was slowly cooled to room temperature and charged with 100 ml of ethyl acetate and slowly heated to 45-50°C and stirred for 30 minutes. The reaction mass was slowly cooled to room temperature and stirred for 30 minutes and again cooled to 20-25° C and maintained and filtered. The cake was washed with chilled 50 ml of ethyl acetate and dried to get cyclohex-4- ene-l,2-dicarboxylic acid as a solid.
Example-2:
Preparation of racemic cyclohexane-l,2-dicarboxylic acid compound-II
(II)
The solid material obtained from example- 1 was dissolved in 900 ml of methanol and was transferred to autoclave along with 30 g of Raney nickel under hydrogen gas pressure at room temperature and was maintained for 15-18 hours at room temperature. TLC was checked for the content of cyclohex-4-ene-l ,2-dicarboxylic acid (NMT 0.5 %). When TLC was complied, reaction mass was filtered to remove the Raney nickel and the filtrate was concentrated under reduced pressure to yield solid 725 to750 g. The recovered Raney nickel may be recycled for further use.
Example-3:
Resolution of racemic cyclohexane-l,2-dicarboxylic acid (compound-II) to obtain (lR,2R)cyclohexane-l,2-dicarboxylic acid phenyl ethyl amine salt (compound-Ill)
(III)
625 ml of methanol and 100 g (0.58 M) of the solid compound obtained from example-2 were taken in a dry flask and stirred. After stirring at room temperature for 30 minutes, 56.2 g (0.46 M) of R-l- phenyl ethylamine was added and stirred for 2 hours at room temperature. The reaction mass was cooled to 3-7° C and maintained at 3-7° C for 2-3 hours. The solid was filtered, washed with 25 ml of chilled methanol and dried at about 50° C to obtain the product as solid
Example-4:
Separation of trans-(lR,2R)-cyclohexane-l,2-dicarboxylic acid (compound-I)
phenyl ethyl amine.
(I)
100 g (0.34 M) of the compound obtained from example-3 was taken in 300 ml of chloroform, and 400 ml of DM water was added at room temperature. pH of the reaction mass was adjusted to 10-11 by using sodium hydroxide (NaOH). The reaction mass was stirred for about 30 minutes. Aqueous and organic layers were separated. Aqueous layer was again extracted with chloroform and the combined chloroform layers were taken for recovery of R-l- phenylethylamine . The pH of the aqueous layer was adjusted to 1 to 2 using hydrochloric acid and the aqueous layer was then extracted twice with 80 ml of ethyl acetate. The combined ethyl acetate layer was dried over sodium sulphate. The dried organic layer( Ethyl acetate layer) was concentrated under vacuum at below 40°C and was co-distilled with 0.5 V of cyclohexane to
obtain the crude. The resulting crude material was added 1.0 V of cyclohexane and stirred for lhr at room temperature. The resulting mass was filtered, washed with 0.2V of cyclohexane and dried at about 50° C to obtain the product of HPLC purity more than 99 %.
Claims
1. A process for preparation of trans-(lR,2R)-cyclohexane 1 ,2-dicarboxylic acid compound-I with more than 99% HPLC purity
comprising the steps of:
i). treating 3-sulfolene with fumaric acid under pressure to obtain cyclohex-4-ene- 1 , 2- dicarboxylic acid;
cyclohexane- 1 ,2-dicarboxylic acid compound-II;
(II)
iii). resolution of racemic cyclohexane- 1 ,2-dicarboxylic acid (compound-II) to obtain corresponding salt-Ill;
(III)
iv). separating trans-(lR,2R)-cyclohexane-l,2-dicarboxylic acid (compound-I) and R-l-phenylethylamine and obtaining compound-I with more than 99% purity
(I)
2. A process as claimed in claim 1, wherein said reduction in step ii) is done with Raney nickel in presence of methanol.
3. A process as claimed in claim 1, wherein said resolution is step iii) is done with R-l- phenylethylamine in methanol at room temperature.
4. A process as claimed in claim 1, wherein said salt-III obtained in step iii) is (lR,2R)cyclohexane-l,2-dicarboxylic acid phenyl ethyl amine salt.
5. A process as claimed in claim 1, wherein said separation in step iv) is done by breaking (lR,2R)cyclohexane-l,2-dicarboxylic acid phenyl ethyl amine salt in strong basic conditions at pH between 10-1 1.
6. A process as claimed in claim 5, wherein said strong basic pH is obtained by sodium hydroxide.
7. A process as claimed in claim 5, wherein said separation comprises recovering free R-l- phenylethylamine from organic layer and extracting crude compound-I from the aqueous layer.
8. A process as claimed in claim 7, wherein pH of the aqueous layer is adjusted between 1-2 with hydrochloric acid before extraction.
9. A process as claimed in claim 7, wherein said compound-I is extracted in ethyl acetate.
10. A process as claimed in claim 1 , wherein said trans-(lR,2R)-cyclohexane-l ,2- dicarboxylic acid (compound-I) is washed and purified with cyclohexane.
1 1. A process as claimed in claim 1, wherein said R-l-phenylethylamine is separated from organic layer under strong basic conditions.
Γ2.
13. A trans-(lR,2R)-cyclohexane 1 ,2-dicarboxylic acid compound (I) obtained by the process as claimed in claim 1.
14. A trans-(lR,2R)-cyclohexane 1 ,2-dicarboxylic acid compound (I) as claimed in claim 13 wherein the compound has more than 99% HPLC purity.
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|---|---|---|---|
| IN5441CH2012 | 2012-12-25 | ||
| IN5441/CHE/2012 | 2012-12-25 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5532372A (en) | 1990-07-06 | 1996-07-02 | Sumitomo Pharmaceuticals Company, Ltd. | Imide derivatives, and their production and use |
| WO2012131606A1 (en) | 2011-04-01 | 2012-10-04 | Ranbaxy Laboratories Limited | Process for the preparation of an antipsychotic agent |
-
2013
- 2013-03-12 WO PCT/IN2013/000149 patent/WO2014102808A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5532372A (en) | 1990-07-06 | 1996-07-02 | Sumitomo Pharmaceuticals Company, Ltd. | Imide derivatives, and their production and use |
| WO2012131606A1 (en) | 2011-04-01 | 2012-10-04 | Ranbaxy Laboratories Limited | Process for the preparation of an antipsychotic agent |
Non-Patent Citations (6)
| Title |
|---|
| ACOC CHEMICAL RESEARCH COMMUNICATIONS, vol. 9, 1999, pages 25 - 30 |
| AUSTRALIAN JOURNAL OF CHEMISTRY, vol. 39, 1986, pages 591 - 604 |
| FUJIMA YOSHITO ET AL: "Synthesis of (S)-3-(N-Methylamino)-1-(2-thienyl)propan-1-ol: Revisiting Eli Lilly's Resolution-Racemization-Recycle Synthesis of Duloxetine for Its Robust Processes", ORGANIC PROCESS RESEARCH AND DEVELOPMENT, CAMBRIDGE, GB, vol. 10, no. 5, 1 January 2006 (2006-01-01), pages 905 - 913, XP002447767 * |
| GOODRIDGE RICHARD J ET AL: "Preparations and crystal structures of the 2-oxides of some octahydro-3,2,1-benzoxathiazines and octahydro-2H-3,1,2-benzoxazaphosphorines", AUSTRALIAN JOURNAL OF CHEMISTRY, CSIRO - COMMONWEALTH SCIENTIFIC AND INDUSTRIAL RESEARCH ORGANIZATION, AUSTRALIA, vol. 39, no. 4, 1 January 1986 (1986-01-01), pages 591 - 604, XP008162584, ISSN: 0004-9425 * |
| JUSTUS LIEBIGS ANN.CHEM., vol. 564, 1949, pages 96 |
| KIMURA K ET AL: "Resolution of trans-1,2-cyclohexanedicarboxylic acid with (R)-1-phenylethylamine", ACGC CHEMICAL RESEARCH COMMUNICATIONS, WOLLONGONG, AU, 1 January 1999 (1999-01-01), pages 25 - 30, XP008162587, ISSN: 1020-5586 * |
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