CA2448499A1 - A novel process for the preparation of (is-cis) -4-(3, 4-dichlorophenyl) -1, 2, 3, 4 - tetrahydro-n-methyl-1-naphthalenamine - Google Patents
A novel process for the preparation of (is-cis) -4-(3, 4-dichlorophenyl) -1, 2, 3, 4 - tetrahydro-n-methyl-1-naphthalenamine Download PDFInfo
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- CA2448499A1 CA2448499A1 CA002448499A CA2448499A CA2448499A1 CA 2448499 A1 CA2448499 A1 CA 2448499A1 CA 002448499 A CA002448499 A CA 002448499A CA 2448499 A CA2448499 A CA 2448499A CA 2448499 A1 CA2448499 A1 CA 2448499A1
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- cis
- dichlorophenyl
- naphthalenamine
- tetrahydro
- methyl
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- 238000000034 method Methods 0.000 title claims description 20
- 238000002360 preparation method Methods 0.000 title claims description 7
- 238000005695 dehalogenation reaction Methods 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 239000003112 inhibitor Substances 0.000 claims abstract description 17
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 claims abstract description 10
- MGBVAZJASCWJGJ-UHFFFAOYSA-N 4-(3,4-dichlorophenyl)-n-methyl-3,4-dihydro-2h-naphthalen-1-imine Chemical compound C12=CC=CC=C2C(=NC)CCC1C1=CC=C(Cl)C(Cl)=C1 MGBVAZJASCWJGJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims abstract description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 18
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- VGKDLMBJGBXTGI-UHFFFAOYSA-N 4-(3,4-dichlorophenyl)-n-methyl-1,2,3,4-tetrahydronaphthalen-1-amine Chemical compound C12=CC=CC=C2C(NC)CCC1C1=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 claims description 4
- 150000003003 phosphines Chemical class 0.000 claims description 3
- FEVFLQDDNUQKRY-UHFFFAOYSA-N tris(4-methylphenyl) phosphite Chemical compound C1=CC(C)=CC=C1OP(OC=1C=CC(C)=CC=1)OC1=CC=C(C)C=C1 FEVFLQDDNUQKRY-UHFFFAOYSA-N 0.000 claims description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims 2
- 229910052697 platinum Inorganic materials 0.000 claims 1
- 229960002073 sertraline Drugs 0.000 abstract description 11
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 238000005984 hydrogenation reaction Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 150000002466 imines Chemical class 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000006227 byproduct Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229910002804 graphite Inorganic materials 0.000 description 4
- 239000010439 graphite Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 description 2
- JGMBHJNMQVKDMW-UHFFFAOYSA-N 4-(3,4-dichlorophenyl)-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1=C(Cl)C(Cl)=CC=C1C1C2=CC=CC=C2C(=O)CC1 JGMBHJNMQVKDMW-UHFFFAOYSA-N 0.000 description 2
- GLQPTZAAUROJMO-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)benzaldehyde Chemical compound C1=C(OC)C(OC)=CC=C1C1=CC=C(C=O)C=C1 GLQPTZAAUROJMO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229960002510 mandelic acid Drugs 0.000 description 2
- 229960003660 sertraline hydrochloride Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-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
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- -1 hydrochloride Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 150000003018 phosphorus compounds Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- BLFQGGGGFNSJKA-XHXSRVRCSA-N sertraline hydrochloride Chemical compound Cl.C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 BLFQGGGGFNSJKA-XHXSRVRCSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- IFXORIIYQORRMJ-UHFFFAOYSA-N tribenzylphosphane Chemical compound C=1C=CC=CC=1CP(CC=1C=CC=CC=1)CC1=CC=CC=C1 IFXORIIYQORRMJ-UHFFFAOYSA-N 0.000 description 1
- 150000005691 triesters Chemical class 0.000 description 1
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 description 1
- IGNTWNVBGLNYDV-UHFFFAOYSA-N triisopropylphosphine Chemical compound CC(C)P(C(C)C)C(C)C IGNTWNVBGLNYDV-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/70—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by reduction of unsaturated amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/86—Separation
- C07C209/88—Separation of optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
(1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (sertraline) is prepared by hydrogenating of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine in the presence of a dehalogenation inhibitor, e.g. triphenylphosphite or trimethylphosphite and a catalyst.
Description
A NOVEL PROCESS FOR THE PREPARATION OF (IS-CIS) -4-(3,4-DICHLOROPHENYL) -1,2,3, The present invention relates to a novel process for the preparation of (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (sertraline) comprising hydrogenation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalenylidene]methanamine.
BACKGROUND OF THE INVENTION
Seriraline, (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine, which has a structure of formula I
HN
i ~I
CI
I
is marketed in the form of its hydrochloride for the treatment of depression, obsessive-compulsive disorder and panic disorder.
The synthesis of sertraline is described in U.S. Patent no. 4,536,518. The process described comprises a condensation reaction of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone of formula II
O
I
I
I
CI
BACKGROUND OF THE INVENTION
Seriraline, (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine, which has a structure of formula I
HN
i ~I
CI
I
is marketed in the form of its hydrochloride for the treatment of depression, obsessive-compulsive disorder and panic disorder.
The synthesis of sertraline is described in U.S. Patent no. 4,536,518. The process described comprises a condensation reaction of 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone of formula II
O
I
I
I
CI
with monomethylamine yielding N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine. This is further hydrogenated in the presence of palladium on carbon catalyst to form a mixture of cis- and trans-racemates of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine with the isomeric ratio of 70:30. The desired product is the cis isomer, and accordingly the trans .
isomer is a not desired byproduct which is classified as an impurity in the final product. Other impurities formed in the reaction are e.g. dehalogenation products, the amount of which depends e.g. on the temperature and pressure used in the hydrogenation and the quality of the imine starting material. The removal of the dehalogenation products is difficult.
Different solutions have been suggested to increase the formation of cis isomer and to prevent the dehalogenation reaction in the hydrogenation. In the process described in US 5,082,970 trans-isomer is treated with a basic equilibration agent like potassium tert.-butoxide to change it to cis-isomer. This however, requires an additional step in the synthesis. In WO 99/47486 copper containing catalysts are used to improve the ratio, and results as high as 98.5 % in favor of cis compound have been achieved. Nothing has, however, been said about the dehalogenation products formed. In WO 99/57093 a hydrogenation process with a palladium catalyst which has been pretreated with alkali halide has been described. The process described gives a cis/trans ratio of 85-95/15-5 (in %). The amount of dehalogenation side products is said to be below 0.5 %.
In US 3,474,144 there has been described the use of triphenyl phosphite or tritolyl phosphite as dehalogenation inhibitors in the catalytic reduction of aromatic chloronitro compounds. It has also been mentioned that the use of the inhibitors does not affect the original isomer ratio. In EP 292 682 there has been used organic esters of phosphoric acid together with hydrocarbyl-silanes to inhibit the dehalogenation during the catalytic reduction of aromatic vitro-halo-derivatives. The degree of dehalogenation lower than 1 % was reported. In Kosak, Catal. Org. Synth., 1980, vol. date 1978, p. 107-117, there has been described the use of phosphorous acid and some related compounds as dehalogenation inhibitors in the hydrogenation of haloaromatic vitro compounds. However, the use of the inhibitors of the present invention in the preparation of sertraline or in the hydrogenation of imine compounds has not been described.
isomer is a not desired byproduct which is classified as an impurity in the final product. Other impurities formed in the reaction are e.g. dehalogenation products, the amount of which depends e.g. on the temperature and pressure used in the hydrogenation and the quality of the imine starting material. The removal of the dehalogenation products is difficult.
Different solutions have been suggested to increase the formation of cis isomer and to prevent the dehalogenation reaction in the hydrogenation. In the process described in US 5,082,970 trans-isomer is treated with a basic equilibration agent like potassium tert.-butoxide to change it to cis-isomer. This however, requires an additional step in the synthesis. In WO 99/47486 copper containing catalysts are used to improve the ratio, and results as high as 98.5 % in favor of cis compound have been achieved. Nothing has, however, been said about the dehalogenation products formed. In WO 99/57093 a hydrogenation process with a palladium catalyst which has been pretreated with alkali halide has been described. The process described gives a cis/trans ratio of 85-95/15-5 (in %). The amount of dehalogenation side products is said to be below 0.5 %.
In US 3,474,144 there has been described the use of triphenyl phosphite or tritolyl phosphite as dehalogenation inhibitors in the catalytic reduction of aromatic chloronitro compounds. It has also been mentioned that the use of the inhibitors does not affect the original isomer ratio. In EP 292 682 there has been used organic esters of phosphoric acid together with hydrocarbyl-silanes to inhibit the dehalogenation during the catalytic reduction of aromatic vitro-halo-derivatives. The degree of dehalogenation lower than 1 % was reported. In Kosak, Catal. Org. Synth., 1980, vol. date 1978, p. 107-117, there has been described the use of phosphorous acid and some related compounds as dehalogenation inhibitors in the hydrogenation of haloaromatic vitro compounds. However, the use of the inhibitors of the present invention in the preparation of sertraline or in the hydrogenation of imine compounds has not been described.
SUMMARY OF THE INVENTION
One object of the present invention is to provide an improved preparation method for cis-sertraline or a pharmaceutically acceptable acid addition salt thereof.
The other object of the present invention is the pharmaceutical composition comprising cis-sertraline or a pharmaceutically acceptable acid addition salt thereof made by the process of the invention.
These objects have been achieved by the inventor's surprising discovery that if some phosphorus compounds, specially esters of phosphorous acid, are used as dehalogenation inhibitors in the hydrogenation of the imine in the production of sertraline, the cis-trans ratio is improved. In addition the amount of dehalogenation products is diminished. The produced racemic cis-sertraline can be further resolved or crystallized directly to a pharmaceutically acceptable acid addition salt, e.g.
hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of cis-sertraline comprising hydrogenating N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine in the presence of a catalyst and a dehalogenation inhibitor to achieve cis-racemate of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine.
By using the hydrogenation process of the present invention the ratio of cisarans isomers is improved to as high as 97:3 and the formation of dehalogenation byproducts may be reduced to even less than 0.1 %. No further purification process is needed before resolution or crystallization. This is achieved by using the inhibitors of the invention in the hydrogenation process.
Cis-sertraline is prepared starting from 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenone (tetralone), which can be prepared by methods known in the art, e.g. as decsribed in US 5,019,655. Tetralone is reacted with monomethylamine to form an imine, which can be performed by methods known in the art, e.g. as described in US 4,536,518. The imine obtained is further hydrogenated to cis-racemate of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine in the presence of a catalyst and a dehalogenation inhibitor of the invention.
From this mixture, the cis-compound can be either resolved by e.g. mandelic acid or camphorsulphonic acid to afford cis-(+)-sertraline and crystallized as a base or a pharmaceutically acceptable acid addition salt, e.g. hydrochloride, or the racemic cis-sertraline can be crystallized as a base or as a pharmaceutically acceptable salt.
The hydrogenation of the imine is performed in the presence of a catalyst and an inhibitor, which is selected from the group consisting of hypophosphorous acid, esters of hypophosphorous acid, phosphorous acid, esters of phosphorous acid, phosphine and substituted phosphines. Suitable inhibitors are e.g. mono-,di-and triesters of phosphorous acid, preferably trimethyl phosphite, triphenyl phosphite or tritolyl phosphite. Examples of suitable phosphines are e.g.
trimethylphosphine, triethylphosphine, triisopropylphosphine, tritolylphosphine and tribenzylphosphine.
The amount of the inhibitor used in the process is typically 0.5 - IO mol %, preferably 3 - 5 mol %, based on the number of moles of the metal in the catalyst used. The catalyst used can be any suitable catalyst known in the art, e.g.
palladium on carbon, palladium on graphite, palladium on carbon paste or Pt02. The catalyst is typically used in the amount of 0.1 - 1.0 % (w/w, calculated as the pure metal in the catalyst) based on the weight of the imine used. The hydrogenation may be carried out in an organic solvent, which can be any suitable erotic or aprotic solvent or mixtures thereof. Examples of solvents are e.g. dimethylformamide (DMF), esters like ethyl acetate, chlorinated hydrocarbons like methylene chloride or chloroform, or alcohols like methanol, ethanol or isopropanol. Preferably a lower alcohol, e.g.
methanol or ethanol or their mixture with DMF is used as a solvent.
The reaction can be carried out at a temperature of 0-100 °C, preferably at 20 - 50 °C. The hydrogen pressure used is from 1 to 50 bar, preferably from 2 to 5 bar.
The reaction time can vary from half an hour to 24 hours depending on the catalyst used, on hydrogen pressure, on the reaction temperature and on the equipment used. Preferably the hydrogenation time is about 2 to 6 hours.
The following examples merely illustrate the invention and they are not to be construed as limiting.
Cis-( 1 S )( 1 R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenylidene]-methanamine (50 5 g), methanol (300 ml), palladium on graphite 5 % (2.5 g) and trimethyl phosphite (0.004 g) are charged into a reaction vessel. The mixture is hydrogenated at 5 bar overpressure of hydrogen for 5 hours at about 40 °C. The catalyst is removed by filtration and the cake is washed with methanol. The cisarans ratio is 97:3.
The amount of dehalogenation byproducts is < 0.1 %. The reaction mixture can be used directly in the resolution step or crystallized as HCl salt.
( 1 S-cis)-4-(3,4-dichlorophenyl)-1,2, 3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride (Sertraline hydrochloride) The reaction mixture containing the rasemic compound from the previous step is resolved by mandelic acid and finally crystallized as sertraline hydrochloride. The total yield is 19.8 g (70 % of theoretical (+)-enantiomer). Analytical results: HPLC-purity is 99.9 %, trans-isomer < 0.1 % and dehydrohalogenation products < 0.1 %.
Optical purity is 99.9 %.
Cis-( 1 S)( 1R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine N-[4-(3,4-Dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (40 g), dimethylformamide ( 150 ml), methanol ( 150 ml), palladium on graphite catalyst (4 g) and triphenyl phosphite (0.0010 g) are charged into a reaction vessel.
The mixture is hydrogenated for 5 hours under 5 bar overpressure of hydrogen at 20-°C. The catalyst is removed by filtration and the cake washed with methanol. The cisarans ratio is 96:4 and the amount of dehalogenation byproducts is 0.5 %.
One object of the present invention is to provide an improved preparation method for cis-sertraline or a pharmaceutically acceptable acid addition salt thereof.
The other object of the present invention is the pharmaceutical composition comprising cis-sertraline or a pharmaceutically acceptable acid addition salt thereof made by the process of the invention.
These objects have been achieved by the inventor's surprising discovery that if some phosphorus compounds, specially esters of phosphorous acid, are used as dehalogenation inhibitors in the hydrogenation of the imine in the production of sertraline, the cis-trans ratio is improved. In addition the amount of dehalogenation products is diminished. The produced racemic cis-sertraline can be further resolved or crystallized directly to a pharmaceutically acceptable acid addition salt, e.g.
hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of cis-sertraline comprising hydrogenating N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine in the presence of a catalyst and a dehalogenation inhibitor to achieve cis-racemate of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine.
By using the hydrogenation process of the present invention the ratio of cisarans isomers is improved to as high as 97:3 and the formation of dehalogenation byproducts may be reduced to even less than 0.1 %. No further purification process is needed before resolution or crystallization. This is achieved by using the inhibitors of the invention in the hydrogenation process.
Cis-sertraline is prepared starting from 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenone (tetralone), which can be prepared by methods known in the art, e.g. as decsribed in US 5,019,655. Tetralone is reacted with monomethylamine to form an imine, which can be performed by methods known in the art, e.g. as described in US 4,536,518. The imine obtained is further hydrogenated to cis-racemate of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine in the presence of a catalyst and a dehalogenation inhibitor of the invention.
From this mixture, the cis-compound can be either resolved by e.g. mandelic acid or camphorsulphonic acid to afford cis-(+)-sertraline and crystallized as a base or a pharmaceutically acceptable acid addition salt, e.g. hydrochloride, or the racemic cis-sertraline can be crystallized as a base or as a pharmaceutically acceptable salt.
The hydrogenation of the imine is performed in the presence of a catalyst and an inhibitor, which is selected from the group consisting of hypophosphorous acid, esters of hypophosphorous acid, phosphorous acid, esters of phosphorous acid, phosphine and substituted phosphines. Suitable inhibitors are e.g. mono-,di-and triesters of phosphorous acid, preferably trimethyl phosphite, triphenyl phosphite or tritolyl phosphite. Examples of suitable phosphines are e.g.
trimethylphosphine, triethylphosphine, triisopropylphosphine, tritolylphosphine and tribenzylphosphine.
The amount of the inhibitor used in the process is typically 0.5 - IO mol %, preferably 3 - 5 mol %, based on the number of moles of the metal in the catalyst used. The catalyst used can be any suitable catalyst known in the art, e.g.
palladium on carbon, palladium on graphite, palladium on carbon paste or Pt02. The catalyst is typically used in the amount of 0.1 - 1.0 % (w/w, calculated as the pure metal in the catalyst) based on the weight of the imine used. The hydrogenation may be carried out in an organic solvent, which can be any suitable erotic or aprotic solvent or mixtures thereof. Examples of solvents are e.g. dimethylformamide (DMF), esters like ethyl acetate, chlorinated hydrocarbons like methylene chloride or chloroform, or alcohols like methanol, ethanol or isopropanol. Preferably a lower alcohol, e.g.
methanol or ethanol or their mixture with DMF is used as a solvent.
The reaction can be carried out at a temperature of 0-100 °C, preferably at 20 - 50 °C. The hydrogen pressure used is from 1 to 50 bar, preferably from 2 to 5 bar.
The reaction time can vary from half an hour to 24 hours depending on the catalyst used, on hydrogen pressure, on the reaction temperature and on the equipment used. Preferably the hydrogenation time is about 2 to 6 hours.
The following examples merely illustrate the invention and they are not to be construed as limiting.
Cis-( 1 S )( 1 R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenylidene]-methanamine (50 5 g), methanol (300 ml), palladium on graphite 5 % (2.5 g) and trimethyl phosphite (0.004 g) are charged into a reaction vessel. The mixture is hydrogenated at 5 bar overpressure of hydrogen for 5 hours at about 40 °C. The catalyst is removed by filtration and the cake is washed with methanol. The cisarans ratio is 97:3.
The amount of dehalogenation byproducts is < 0.1 %. The reaction mixture can be used directly in the resolution step or crystallized as HCl salt.
( 1 S-cis)-4-(3,4-dichlorophenyl)-1,2, 3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride (Sertraline hydrochloride) The reaction mixture containing the rasemic compound from the previous step is resolved by mandelic acid and finally crystallized as sertraline hydrochloride. The total yield is 19.8 g (70 % of theoretical (+)-enantiomer). Analytical results: HPLC-purity is 99.9 %, trans-isomer < 0.1 % and dehydrohalogenation products < 0.1 %.
Optical purity is 99.9 %.
Cis-( 1 S)( 1R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine N-[4-(3,4-Dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (40 g), dimethylformamide ( 150 ml), methanol ( 150 ml), palladium on graphite catalyst (4 g) and triphenyl phosphite (0.0010 g) are charged into a reaction vessel.
The mixture is hydrogenated for 5 hours under 5 bar overpressure of hydrogen at 20-°C. The catalyst is removed by filtration and the cake washed with methanol. The cisarans ratio is 96:4 and the amount of dehalogenation byproducts is 0.5 %.
Cis-( 1 S)( 1R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenylidene]-methanamine (50 g), methanol (400 mI), palladium on graphite 5 % (5 g) and triphenyl phosphine (0.014 g) are charged into a reaction vessel. The mixture is hydrogenated at 5 bar overpressure of hydrogen for 3 hours at about 35 °C. The catalyst is removed by filtration and the cake is washed with methanol. The cisarans ratio is 97:3.
The amount of dehalogenation byproducts is 0.2 %. The reaction mixture can be used directly in the resolution step or crystallized as HCl salt.
The amount of dehalogenation byproducts is 0.2 %. The reaction mixture can be used directly in the resolution step or crystallized as HCl salt.
Claims (9)
1. A process for the preparation of cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl 1-naphthalenamine comprising hydrogenating N-[4-(3,4-dichlorophenyl)-3,4-dihydro 1(2H)-naphthalenylidene]methanamine in the presence of a catalyst and a dehalogenation inhibitor selected from the group consisting of hypophosphorous acid, esters of hypophosphorous acid, phosphorous acid, esters of phosphorous acid, phosphine and substituted phosphines, to obtain cis-racemate of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine.
2. A process according to claim 1 wherein said dehalogenation inhibitor is an ester of phosphorous acid.
3. Process according to claim 2 wherein said dehalogenation inhibitor is triphenyl phosphite or trimethyl phosphite or tritolyl phosphite.
4. A process according to any of claims 1 to 3 wherein the dehalogenation inhibitor is used in the amount of 0.5 to 10.0 mol % based on the number of moles of metal in the catalyst used.
5. A process according to claim 4 wherein the dehalogenation inhibitor is used 3 to 5 mol %
based on the number of moles of metal in the catalyst used.
based on the number of moles of metal in the catalyst used.
6. A process according to claim 1 wherein said catalyst is a palladium or a platinum catalyst.
7. A process according to claim 1 wherein the cis-racemate obtained is further resolved to obtain the (+)enantiomer of cis- 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine.
8. The process according to claim 7, further comprising crystallizing said (+)enantiomer of cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine as a base or as an acid addition salt.
9. The process according to claim 8 wherein the said acid addition salt is hydrochloride.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US29808801P | 2001-06-15 | 2001-06-15 | |
| FI20011271A FI20011271A0 (en) | 2001-06-15 | 2001-06-15 | Production Process |
| US60/298,088 | 2001-06-15 | ||
| FI20011271 | 2001-06-15 | ||
| PCT/FI2002/000518 WO2002102761A1 (en) | 2001-06-15 | 2002-06-14 | A novel process for the preparation of (is-cis) -4-(3, 4-dichlorophenyl) -1, 2, 3, 4 - tetrahydro-n-methyl-1-naphthalenamine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2448499A1 true CA2448499A1 (en) | 2002-12-27 |
Family
ID=26161186
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002448499A Abandoned CA2448499A1 (en) | 2001-06-15 | 2002-06-14 | A novel process for the preparation of (is-cis) -4-(3, 4-dichlorophenyl) -1, 2, 3, 4 - tetrahydro-n-methyl-1-naphthalenamine |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1401800A1 (en) |
| CA (1) | CA2448499A1 (en) |
| WO (1) | WO2002102761A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2242555T1 (en) * | 2003-04-14 | 2005-11-16 | Teva Pharmaceutical Industries Limited | HYDROGENATION OF INTERMEDIARIES OF IMINA OF SERTRALINA WITH CATALYSTS. |
| WO2005121074A2 (en) * | 2004-06-09 | 2005-12-22 | Ranbaxy Laboratories Limited | Processes for the preparation of sertraline hydrochloride |
| GB0526444D0 (en) * | 2005-12-23 | 2006-02-08 | Sandoz Ag | Sertraline acid addition salt, its prepartion and its use in the preparation of sertraline hydrochloride form ll |
| TR200808115T1 (en) * | 2006-04-28 | 2009-03-23 | Sandoz Ag | Process for the Preparation of 4 (S, R) - (3,4-dichlorophenyl) -3,4-dihydro-1 (2H) -naphthalen-1-ylidene] methylamine |
| CN111632400B (en) * | 2020-06-21 | 2022-04-05 | 赤峰制药股份有限公司 | Recrystallization purification method of enamine salt |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3474144A (en) * | 1966-08-17 | 1969-10-21 | Gaf Corp | Catalytic reduction of chloronitro aromatic compounds |
| US4020107A (en) * | 1975-04-07 | 1977-04-26 | E. I. Du Pont De Nemours And Co. | Catalytic reduction of halonitroaromatic compounds |
| US4536518A (en) * | 1979-11-01 | 1985-08-20 | Pfizer Inc. | Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine |
| IT1205040B (en) * | 1987-05-28 | 1989-03-10 | Rimar Chimica Spa | Catalytic reduction of aromatic nitro-halo-derivs. |
| HU226424B1 (en) * | 1998-05-05 | 2008-12-29 | Egis Gyogyszergyar Nyrt | Process for producing enantiomer mixture for preparation of sertraline |
| AU4363401A (en) * | 2000-03-14 | 2001-09-24 | Teva Pharma | Novel process for preparing (+)-cis-sertraline |
-
2002
- 2002-06-14 WO PCT/FI2002/000518 patent/WO2002102761A1/en not_active Application Discontinuation
- 2002-06-14 CA CA002448499A patent/CA2448499A1/en not_active Abandoned
- 2002-06-14 EP EP02743288A patent/EP1401800A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP1401800A1 (en) | 2004-03-31 |
| WO2002102761A1 (en) | 2002-12-27 |
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