CA2116464C - Process for the preparation of an optically pure aminoalcohol - Google Patents
Process for the preparation of an optically pure aminoalcoholInfo
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- CA2116464C CA2116464C CA002116464A CA2116464A CA2116464C CA 2116464 C CA2116464 C CA 2116464C CA 002116464 A CA002116464 A CA 002116464A CA 2116464 A CA2116464 A CA 2116464A CA 2116464 C CA2116464 C CA 2116464C
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- dichlorophenyl
- cyano
- propionic acid
- formula
- acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A process is described for the preparation of (+)-2-(3,4-dichlorophenyl)-4-hydroxybutylamine (I) by reaction of 3,4-dichlorophenylacetonitrile (II) with an alkali metal halogenoacetate, treatment of the 3-cyano-3-(3,4-dichlorophenyl)propionic acid (III) with D-(-)-N-methylglucamine, with second-order asymmetric conversion, hydrolysis of the D-(-)-N-methylglucamine salt of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid and enantioconservative reduction of the resulting levorotatory cyanoacid with a borane.
Description
2116~6~
The present invention relates to a process for the preparation of dextrorotatory 2-(3,4-dichloro-phenyl)-4-hydroxybutylamine of the formula o~ (+) HocH2~H2~H~H2NH2 Cl The compound (I), which is described in the patent applications EP-A-0 428 434, EP-A-0 474 561, EP-A-0 515 240 and EP-A-0 559 538, is a key intermediate in the synthesis of tachykinin antagonists.
According to the above documents, the compound (I) is prepared by resolving the racemate via its D-(-)-tartrate.
It has now been found that treating racemic 3-cyano-3-(3,4-dichlorophenyl)propionic acid with D-(-)-N-methylglucamine effects a second-order asymmetric conversion to give (-)-3-cyano-3-(3,4-dichlorophenyl)-propionic acid, which, on enantioconservative reduction with a borane, gives the compound of formula (I).
It has also been found, surprisingly, that the compound of formula (I) can be obtained from 3,4-dichlorophenylacetonitrile by reaction with an alkalimetal halogenoacetate, preferably sodium chloroacetate, resolution of the 3-cyano-3-(3,4-dichlorophenyl)pro-pionic acid in situ and enantioconservative reduction as indicated above.
Thus, according to one of its features, the present invention relates to a process for the pre-paration of (+)-2-(3,4-dichlorophenyl)-4-hydroxybutyl-amine of formula (I), which comprises (a) treating 3,4-dichlorophenylacetonitrile of formula (II):
-2Il-6464 Cl ~ CH2CN (II) 05 with an alkali metal halogenoacetate in liquid ammonia or in a polar aprotic solvent, in the presence of a strong base, at a temperature of -40~C to +25 C;
(b) treating the resulting racemic 3-cyano-3-t3,4-dichlorophenyl)propionic acid of formula (III):
CN
a~ ~ C ,~CH~H2-COOH (III) with D-(-)-N-methylglucamine in order to crystallize all the acid (III) in the form of the D-(-)-N-methyl-glucamine salt of the levorotatory acid;
(c) treating said salt with a strong acid; and (d) subjecting the freed (-)-3-cyano-3-(3,4-dichloro-phenyl)propionic acid of formula (IV):
CN
(-) a ~ CH-CH2-COOH (IV) to enantioconservative reduction with a borane to give the derivative (I).
More particularly, step (a) is carried out using an alkali metal halogenoacetate such as sodium or potassium chloroacetate or sodium or potassium bromo-acetate, in the presence of a strong base such as sodium amide, sodium tert-butylate or sodium ethylate.
Solvents which can be used are liquid ammonia at low -21164fi4 temperature (-40~C to -30~C) or a polar aprotic solvent which is inert under the reaction conditions, such as dimethyl sulfoxide or N,N-dimethylformamide. The cyanoacid of formula (III) thus obtained after a reac-05 tion time of 4-5 hours is isolated by treatment with water or mixtures of water with an ether, for example isopropyl ether. It can be converted to one of its salts.
Step (b) can be carried out on the isolated cyanoacid (III) or else in situ directly after step (a) in a solvent such as an alcohol, preferably ethanol.
The D-(-)-glucamine salt of (-)-3-cyano-3-(3,4-di-chlorophenyl)propionic acid crystallizes directly and can be isolated.
The levorotatory acid is freed from its salt by treatment with a strong acid, according to step (c), and isolated by extraction with an appropriate solvent such as dichloromethane, dichloroethane or 1,1,1-tri-chloroethane. The acid (IV) can be converted to one of its salts.
In step (d), theenantioconservative reductiOn with a borane such as BH3 or B2H~, optionally in the form of a complex with tetrahydrofuran or dimethyl sulfide, is carried out at room temperature in a solvent of the ether type, such as dioxane or tetra-hydrofuran. After the excess borane has been destroyed and the solvent has been evaporated off, the amino-alcohol (I) is isolated by removal of the by-products using successive treatments with an acid and then with a base, followed by extraction with an appropriate solvent such as dichloromethane, dichloroethane or 1,1,1-trichloroethane.
3-Cyano-3-(3,4-dichlorophenyl)propionic acid (III) is prepared by reacting sodium chloroacetate with 3,4-dichlorophenylacetonitrile (II), for example in 2136g6~
liquid ammonia in the presence of sodium amide accor-ding to the technique of A.G. CHIGAREV and D.V. IOFFE, Zh. Org. Khim. 3, 85-8 (1967), or in the presence of another very strong base such as sodium or potassium 05 tert-butylate in liquid ammonia at -33~C or in anhy-drous dimethyl sulfoxide at room temperature. The yield of 3-cyano-3-(3,4-dichlorophenyl)propionic acid isolated is 74 to 78%, but it is even better if the product is not isolated, because it suffices to react it with D-(-)-N-methylglucamine, an inexpensive indus-trial product obtained from D-glucose and methylamine (KARRER, HERKENRATH - Helv. Chim. Acta, 20, 37 (1937)), in order to crystallize all the racemic cyanoacid (III) in the form of the salt of the levorotatory acid. The yield is excellent, being 190% based on the levorota-tory enantiomer contained in the racemate (III). The crystallization solvent can be methanol, ethanol, Cellosolve~ or any other suitable solvent. The reso-lution temperature is between the boiling point of the solvent and 0~C. The N-methylglucamine must be present in at least the stoichiometric amount. It is pre-ferably used in slight excess.
After the 3-cyano-3-(3,4-dichlorophenyl)pro-pionic acid has been freed from its D-(-)-N-methyl-glucamine salt by reaction with a strong acid such as hydrochloric acid, oxalic acid or an ion exchange resin of the sulfonic acid type, it is reduced in an enantio-conservative manner (enantiomeric purity: 99%) with borane.
The yield of this double reduction is at least 70%.
The borane can be used in the form of its dimer, B2H~, but is preferably used in a more manipula-ble form such as the complex form with tetrahydrofuran or dimethyl sulfide, the latter complex being marketed - ~1646g as BMS.
~ 3 \ S / 3 The second-order asymmetric conversion according to step (b) of the process of the present invention is surprising and constitutes a further subject of the present invention, which thus relates, according to another of its features, to a process for the prepara-tion of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid, which comprises treating racemic 3-cyano-3-(3,4-dichlorophenyl)propionic acid with D-(-)-N-methyl-glucamine and treating the resulting D-(-)-N-methyl-glucamine salt of (-)-3-cyano-3-(3,4-dichlorophenyl)-propionic acid with a strong acid.
3-Cyano-3-(3,4-dichlorophenyl)propionic acid (III) and its salts, and its (-) isomer of formula (IV) and its salts, are novel products and represent a further feature of the present invention.
More particularly, the D-(-)-N-methylglucamine salt of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid constitutes another feature of the present inven-tion.
The compound (I) as obtained by the processaccording to the invention may advantageously be used for the stereoselective synthesis of optically pure arylalkylamines ,which are antagonists of neurokinin receptors.
Particularly, the compound (I) may be used for the preparation of the arylalkylamines described in the patent applications EP-A-0 428 434, EP-A-0 474 561, EP-A-0 515 240 and EP-A-0 559 538 according to the general synthesis scheme illustrated below in Scheme 1, in which the substituents B an~ ~ represent all the substituents of the aminated ring of the arylalkylamines disclosed in the EP patent applications referred above, W, T and Z are as described in said 05 patent applications, and Ar' is a dichlorophenyl group.
OH-(CH2) 2 - * IcH CH2 NH2 Ar' Cl-CO-Z ou W=C=N-Z
OH-(CH2) 2 - * CH-CH2-NH-T - Z
Ar' CH3S02Cl CH3SO2- O - (CH2) 2 ICH CH2 NH T
Ar' ~
B - D NH
B - D Ar' The sign "*" means that the carbon atom identified by this symbol has the defined configuration (+) or (-).
Preferably, the compound (I) as obtained by the process of the invention will be used for the preparation of optically pure arylalkylamines of formula (VI) 21164fi~
A
Y N - (CH2)2*C - CH2 NH-T-Z
Ar' (VI) in which:
05 - Y represents - either a group Cy-N in which . Cy represents a phenyl, unsubstituted or substituted one or more times with one of the substituents selected from:
hydrogen, a halogen atom, a hydroxyl, a C1-C4 alkoxy, a C1-C4 alkyl, a trifluoromethyl, the said substituents being the same or different; a C3-C7 cycloalkyl group; a pyrimidinyl group or a pyridyl group;
X
I
- or a group Ar-(CH2)x-C in which . Ar represents a phenyl, unsubstituted or substituted one or more times with one of the substituents selected from:
hydrogen, a halogen atom, a hydroxyl, a C1-C4 alkoxy, a C1-C4 alkyl, a trifluoromethyl, the said substituents being the same or different; a pyridyl group; a thienyl group;
. x is O or 1;
. X represents a hydroxyl,a C1-C4 alkoxy; a hydroxyalkyl in which the alkyl group is a C1-C3 alkyl group; a C1-C4 acyloxy; a phenacyloxy; a carboxyl, a C1-C4 carbalkoxy; a cyano; an aminoalkylene in which the alkylene is a C1-C3 group;
a group -N-(X1)2 in which the groups X1 independently represent hydrogen, a C1-C4 alkyl; a group -NH-CO-Alk in which Alk represents a C1-C6 alkyl;
a group Alkl-NH-CO-Alk'1 in which Alkl is a Cl-C3 82~6~fi4 alkylene and Alk'1 is a C1-C3 alkyl; a C1-C4 acyl; a group -S-X2 in which X2 represents hydrogen or a C1-C4 alkyl group;
or alternatively, X forms a double bond with the 05 carbon atom to which it is linked and with the adjacent carbon atom in the heterocycle;
- Ar' represents a dichlorophenyl group;
- R represents hydrogen;
- T represents a group selected from ~0~ 1 -C- and -C-NH-W being an oxygen or a sulphur atom, and - Z represents either hydrogen, or M or OM when 01~5 T represents a -C- group, or M when T represents a W
group -C-NH; M represents a C1-C6 alkyl; a phenylalkyl in which the alkyl is a C1-C3 group, optionally substituted on the aromatic ring with a halogen, a trifluoromethyl, a C1-C4 alkyl, a hydroxyl, a C1-C4 alkoxy; a pyridylalkyl in which the alkyl is a C1-C3 group; a naphthylalkyl group, optionally substituted on the naphthyl ring with a halogen, a trifluoromethyl, a C1-C4 alkyl, a hydroxyl, a C1-C4 alkoxy; a pyridylthioalkyl in which the alkyl is a C1-C3 group;a styryl; an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group;
or of one its salts with inorganic or organic acids.
The compounds of formula (VI), which are described in the patent application EP-A-O 474 561, are prepared according to the above Scheme 1, in which B-D<
is represented in formula (VI) by Y.
The compound of formula (I) obtained by the process according to the invention is , particularly suitable for the preparation of - 9 - 21164fi~
the (-)-N-methyl-N-[4-(4-phenyl-4-acetylamino-piperidyl)-2-(3,4-dichlorophenyl)butyl]benzamide hydrochloride or methanesulfonate.
The compound of formula (I) as obtained 05 according to the process of the invention may also be used for the preparation of optically pure quaternary basic amides of formula (VII) Arl Tl CO--N--CH2--*ICH--(CH2)2--Am ~ , A ~ (VII) Ar' in which - Arl is an optionally substituted mono-, di- or tri-cyclic aromatic or heteroaromatic group;
- T1 is a direct bond, a hydroxymethylene group, an alkoxymethylene group in which the alkoxy group is Cl-C4, or a C1-Cs alkylene group;
- Ar' is a dichlorophenyl group;
- R is hydrogen;
- Am ~ is the radical X - N~
in which X1, X2 and X3, together with the nitrogen atom to which they are bonded, form an azabicyclic or azatricyclic system optionally substituted by a phenyl group; and - A ~ is a pharmaceutically acceptable anion.
lo - - 2 ~ ~ ~ 4 6 ~
The compounds of formula (VII) are prepared by a process consisting essentially in:
- reacting a compound of formula (I) as obtained by the process of the invention with a ~v,..~ound of formula Arl-Tl-CO-OH
in which Tl and Arl are as defined above, and - reacting the compound thus obtA~e~ , of formula Ar~ T1 CO NH ~H2 -*ICH-(CH2 ~ OH
in which Ar' is as defined-above, with a ~u...~ound of formula G-Cl, in which G is a leaving group such as mesyl or benzene sulfonyl, then - reacting the resulting cG...~ound, of formula Ar~ Tl CO-NH - CH2- *CIH-(CH2 ~ O - G
with a tertiary amine of formula in which Xl, X2 and X3 are as defined above, in an organic solvent at a temperature between ambient and 120-C, and - isolating the resulting product or else, if a~ro~.iate, exchAnging the methane sulfonate anion of the resulting quaternary salt with another pharmaceutically acceptable anion.
The compound of formula (I) as obtained according to the process of the invention is ~5 particularly suitable for the preparation of the (+)-1-[2-[3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)-acetyl]piperidyn-3-yl]ethyl]-4-phenyl-1-azoniabicyclo-[2.2.2]octane chloride.
The Examples which follow illustrate the invention without however implying a limitation.
(+)-3-Cyano-3-(3,4-dichlorophenyl)propionic acid (III) A mixture of 18.6 g (0.10 mol) of 3,4-dichloro-phenylacetonitrile and 12 g (1.03 mol) of dry sodiumchloroacetate is reacted for 5 hours at room tempera-ture in 150 ml of dry dimethyl sulfoxide, in the pre-sence of 10.5 g (1.05 mol) of sodium tert-butylate.
After the reaction, the reaction mixture is poured into 2~ 1 liter of iced water and acidified to pH < 3 with hydrochloric acid. The cyanoacid is extracted with ethyl acetate, which is washed to pH > 3, dried over magnesium sulfate and concentrated to dryness. Tne residue is solidified in 1,2-dichloroethane to give 16.1 g of the expected compound (III), which is charac-terized by proton NMR.
(+)-3-Cyano-3-(3,4-dichlorophenyl)propionic acid (III) A mixture of 93 g (0.50 mol) of 3,4-dichloro-phenylacetonitrile and 64 g (0.55 mol) of sodium chloroacetate is reacted for 4 hours at -33 C in 500 ml of liquid ammonia, in the presence of 21 g (0.54 mol) of sodium amide. After evaporation of the ammonia, the - 12 - ~ 6 ~
residue is taken up with water and then with isopropyl ether and is acidified to pH < 3 with hydrochloric acid. The organic phase is washed with water to pH ~ 3, separated off by decantation, dried over 05 magnesium sulfate and concentrated to dryness. The residue is solidified in toluene and characterized by proton NMR. M.p. = 106 C.
(+)-3-Cyano-3-(3,4-dichlorophenyl)propionic acid (III) A mixture of 186 g (1.00 mol) of 3,g-dichloro-phenylacetonitrile and 126 g (1.05 mol)ofsodium chloro-nitrile~and 105 g (1.05 mol) of sodium tert-butylate i8 reacted for 4 h~urs at -33 C in 1 liter of liquid ammonia. After the reaction, the ammonia is evaporated off and the residue is taken up with 500 ml of iced water and then with 500 ml of isopropyl ether and is acidified to pH < 3 with hydrochloric acid. The aqueous phase is ~i~c~rded and the organic phase is washed with water to pH ~ 3, separated off by decanta-tion, dried over magnesium sulfate and concentrated under vacuum. The residue is solidified in 250 ml of toluene and the cyanoacid is filtered off and dried at 50 C under a vane pump vacuum to give 190 g (yield:
78%) of the expected (+)-3-cyano-3-(3,4-dichloro-phenyl)propionic acid. M.p. = 104 C.
The product is characterized by proton NMR at 200 MHz in DMS0:
- unresolved signals between 2.85 and 3.1 ppm, 2 protons: -CH~-- complex signal at 4.5 ppm, 1 proton: -CH-- aromatic protons between 7.4 and 7.75 ppm, 3 protons - one acidic proton at 12.8 ppm EXAMPLE 4 211b~6~
(-)-3-Cyano-3-(3,4-dichlorophenyl)propionic acid (IV) A mixture of 186 g (1.00 mol) of 3,4-dichloro-05 phenylacetonitrile, 126 g (1.05 mol) of sodium chloro-acetate and 105 g (1.05 mol) of sodium tert-butylate is reacted for 4 hours at -33 C in 1 liter of liquid ammonla .
After the reaction, the ammonia is evaporated off and the residue is taken up with 500 ml of iced water and then with 500 ml of isopropyl ether and is acidified to pH < 3 with hydrochloric acid. The aqueous phase is discarded and the organic phase is washed with water to pH > 3, separated off by decanta-tion, dried over magnesium sulfate and concentrated under vacuum. The concentrate is redissolved in 2 liters of absolute ethanol, the solution is heated and 292 g of D-(-)-N-methylglucamine are added. After crystallization, the product is filtered off, rinsed with ethanol and dried under vacuum to give 396 g of the N-methylglucamine salt of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid.
[~]D25 = -14.7 (C = 1, CH30H).
The yield is 91% based on the 3,4-dichloro-phenylacetonitrile.
The salt obtained is dissolved in 900 ml of 1 Nhydrochloric acid and extracted with 2 liters of di-chloromethane. The organic phase is washed with water, separated off by decantation, dried over sodium sulfate and concentrated. The product is solidified in 500 ml of cyclohexane to give 187 g of the expected product.
The yield is 76.5% based on the 3,4-dichlorophenyl-acetonitrile. M.p. = 98 C.
[~] 25 = -8.6~ (C = 1, CH30H).
Enantiomeric purity by HPLC: 99%.
Proton NMR at 200 MHz in DMS0: same spectrum as the racemate.
1r ~ 4 6 ~
(+)~2-(3,4-dichlorophenyl)-4-hydroxy-butylamine (I) 350 ml of a l molar solution of BH, in THF are 05 added to a solution of 244 g (1 mol) of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid in 500 ml of THF, cooled to O-C. When the evolution of hydrogen has ceased, 650 ml of the borane solution are added at 20-C, followed by 1000 ml at 40-C. When the reaction is complete, the excess borane is destroyed by the addition of methanol and the reaction mixture is con-centrated to dryness. The concentrate is dissolved in 500 ml of water, acidified with hydrochloric acid and washed twice with 250 ml of toluene. The a~ueous phase ~5 is rendered alkaline with sodium hydroxide and extrac-ted with twice 400 ml of dichloromethane. The organic phase is washed with water, separated off by decanta-tion, dried over magnesium sulfate and concentrated under vacuum to give 159 g (yield: 68%) of the expected product. Chiral purity by HPLC: 99%.
The product is characterized by proton NMR in CDCl3 at 200 MHz:
- unresolved signals at 1.8 ppm, 2H
- one singlet at 2.4 ppm, 3H
- unresolved signals between 2.65 and 2.9 ppm, 3H
- unresolved signals between 3.35 and 3.6 ppm, 2H
- aromatic protons between 6.95 and 7.35 ppm, 3H
[~] 2~ = +9.8- (C = 1, MeOH).
M.p. = 80-81 C.
(+)-2-(3,4-Dichlorophenyl)-4-hydroxybutylamine (I) The pror~ re of EXAMPLE 5 is followed except that borane dimethyl sulfidë is used, dilution is carried out with 750 ml of tetrahydrofuran and the operating temperatures are 20-C and then 50 C. The same product is obtained wi~th the same yield and the same characteristics.
'
The present invention relates to a process for the preparation of dextrorotatory 2-(3,4-dichloro-phenyl)-4-hydroxybutylamine of the formula o~ (+) HocH2~H2~H~H2NH2 Cl The compound (I), which is described in the patent applications EP-A-0 428 434, EP-A-0 474 561, EP-A-0 515 240 and EP-A-0 559 538, is a key intermediate in the synthesis of tachykinin antagonists.
According to the above documents, the compound (I) is prepared by resolving the racemate via its D-(-)-tartrate.
It has now been found that treating racemic 3-cyano-3-(3,4-dichlorophenyl)propionic acid with D-(-)-N-methylglucamine effects a second-order asymmetric conversion to give (-)-3-cyano-3-(3,4-dichlorophenyl)-propionic acid, which, on enantioconservative reduction with a borane, gives the compound of formula (I).
It has also been found, surprisingly, that the compound of formula (I) can be obtained from 3,4-dichlorophenylacetonitrile by reaction with an alkalimetal halogenoacetate, preferably sodium chloroacetate, resolution of the 3-cyano-3-(3,4-dichlorophenyl)pro-pionic acid in situ and enantioconservative reduction as indicated above.
Thus, according to one of its features, the present invention relates to a process for the pre-paration of (+)-2-(3,4-dichlorophenyl)-4-hydroxybutyl-amine of formula (I), which comprises (a) treating 3,4-dichlorophenylacetonitrile of formula (II):
-2Il-6464 Cl ~ CH2CN (II) 05 with an alkali metal halogenoacetate in liquid ammonia or in a polar aprotic solvent, in the presence of a strong base, at a temperature of -40~C to +25 C;
(b) treating the resulting racemic 3-cyano-3-t3,4-dichlorophenyl)propionic acid of formula (III):
CN
a~ ~ C ,~CH~H2-COOH (III) with D-(-)-N-methylglucamine in order to crystallize all the acid (III) in the form of the D-(-)-N-methyl-glucamine salt of the levorotatory acid;
(c) treating said salt with a strong acid; and (d) subjecting the freed (-)-3-cyano-3-(3,4-dichloro-phenyl)propionic acid of formula (IV):
CN
(-) a ~ CH-CH2-COOH (IV) to enantioconservative reduction with a borane to give the derivative (I).
More particularly, step (a) is carried out using an alkali metal halogenoacetate such as sodium or potassium chloroacetate or sodium or potassium bromo-acetate, in the presence of a strong base such as sodium amide, sodium tert-butylate or sodium ethylate.
Solvents which can be used are liquid ammonia at low -21164fi4 temperature (-40~C to -30~C) or a polar aprotic solvent which is inert under the reaction conditions, such as dimethyl sulfoxide or N,N-dimethylformamide. The cyanoacid of formula (III) thus obtained after a reac-05 tion time of 4-5 hours is isolated by treatment with water or mixtures of water with an ether, for example isopropyl ether. It can be converted to one of its salts.
Step (b) can be carried out on the isolated cyanoacid (III) or else in situ directly after step (a) in a solvent such as an alcohol, preferably ethanol.
The D-(-)-glucamine salt of (-)-3-cyano-3-(3,4-di-chlorophenyl)propionic acid crystallizes directly and can be isolated.
The levorotatory acid is freed from its salt by treatment with a strong acid, according to step (c), and isolated by extraction with an appropriate solvent such as dichloromethane, dichloroethane or 1,1,1-tri-chloroethane. The acid (IV) can be converted to one of its salts.
In step (d), theenantioconservative reductiOn with a borane such as BH3 or B2H~, optionally in the form of a complex with tetrahydrofuran or dimethyl sulfide, is carried out at room temperature in a solvent of the ether type, such as dioxane or tetra-hydrofuran. After the excess borane has been destroyed and the solvent has been evaporated off, the amino-alcohol (I) is isolated by removal of the by-products using successive treatments with an acid and then with a base, followed by extraction with an appropriate solvent such as dichloromethane, dichloroethane or 1,1,1-trichloroethane.
3-Cyano-3-(3,4-dichlorophenyl)propionic acid (III) is prepared by reacting sodium chloroacetate with 3,4-dichlorophenylacetonitrile (II), for example in 2136g6~
liquid ammonia in the presence of sodium amide accor-ding to the technique of A.G. CHIGAREV and D.V. IOFFE, Zh. Org. Khim. 3, 85-8 (1967), or in the presence of another very strong base such as sodium or potassium 05 tert-butylate in liquid ammonia at -33~C or in anhy-drous dimethyl sulfoxide at room temperature. The yield of 3-cyano-3-(3,4-dichlorophenyl)propionic acid isolated is 74 to 78%, but it is even better if the product is not isolated, because it suffices to react it with D-(-)-N-methylglucamine, an inexpensive indus-trial product obtained from D-glucose and methylamine (KARRER, HERKENRATH - Helv. Chim. Acta, 20, 37 (1937)), in order to crystallize all the racemic cyanoacid (III) in the form of the salt of the levorotatory acid. The yield is excellent, being 190% based on the levorota-tory enantiomer contained in the racemate (III). The crystallization solvent can be methanol, ethanol, Cellosolve~ or any other suitable solvent. The reso-lution temperature is between the boiling point of the solvent and 0~C. The N-methylglucamine must be present in at least the stoichiometric amount. It is pre-ferably used in slight excess.
After the 3-cyano-3-(3,4-dichlorophenyl)pro-pionic acid has been freed from its D-(-)-N-methyl-glucamine salt by reaction with a strong acid such as hydrochloric acid, oxalic acid or an ion exchange resin of the sulfonic acid type, it is reduced in an enantio-conservative manner (enantiomeric purity: 99%) with borane.
The yield of this double reduction is at least 70%.
The borane can be used in the form of its dimer, B2H~, but is preferably used in a more manipula-ble form such as the complex form with tetrahydrofuran or dimethyl sulfide, the latter complex being marketed - ~1646g as BMS.
~ 3 \ S / 3 The second-order asymmetric conversion according to step (b) of the process of the present invention is surprising and constitutes a further subject of the present invention, which thus relates, according to another of its features, to a process for the prepara-tion of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid, which comprises treating racemic 3-cyano-3-(3,4-dichlorophenyl)propionic acid with D-(-)-N-methyl-glucamine and treating the resulting D-(-)-N-methyl-glucamine salt of (-)-3-cyano-3-(3,4-dichlorophenyl)-propionic acid with a strong acid.
3-Cyano-3-(3,4-dichlorophenyl)propionic acid (III) and its salts, and its (-) isomer of formula (IV) and its salts, are novel products and represent a further feature of the present invention.
More particularly, the D-(-)-N-methylglucamine salt of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid constitutes another feature of the present inven-tion.
The compound (I) as obtained by the processaccording to the invention may advantageously be used for the stereoselective synthesis of optically pure arylalkylamines ,which are antagonists of neurokinin receptors.
Particularly, the compound (I) may be used for the preparation of the arylalkylamines described in the patent applications EP-A-0 428 434, EP-A-0 474 561, EP-A-0 515 240 and EP-A-0 559 538 according to the general synthesis scheme illustrated below in Scheme 1, in which the substituents B an~ ~ represent all the substituents of the aminated ring of the arylalkylamines disclosed in the EP patent applications referred above, W, T and Z are as described in said 05 patent applications, and Ar' is a dichlorophenyl group.
OH-(CH2) 2 - * IcH CH2 NH2 Ar' Cl-CO-Z ou W=C=N-Z
OH-(CH2) 2 - * CH-CH2-NH-T - Z
Ar' CH3S02Cl CH3SO2- O - (CH2) 2 ICH CH2 NH T
Ar' ~
B - D NH
B - D Ar' The sign "*" means that the carbon atom identified by this symbol has the defined configuration (+) or (-).
Preferably, the compound (I) as obtained by the process of the invention will be used for the preparation of optically pure arylalkylamines of formula (VI) 21164fi~
A
Y N - (CH2)2*C - CH2 NH-T-Z
Ar' (VI) in which:
05 - Y represents - either a group Cy-N in which . Cy represents a phenyl, unsubstituted or substituted one or more times with one of the substituents selected from:
hydrogen, a halogen atom, a hydroxyl, a C1-C4 alkoxy, a C1-C4 alkyl, a trifluoromethyl, the said substituents being the same or different; a C3-C7 cycloalkyl group; a pyrimidinyl group or a pyridyl group;
X
I
- or a group Ar-(CH2)x-C in which . Ar represents a phenyl, unsubstituted or substituted one or more times with one of the substituents selected from:
hydrogen, a halogen atom, a hydroxyl, a C1-C4 alkoxy, a C1-C4 alkyl, a trifluoromethyl, the said substituents being the same or different; a pyridyl group; a thienyl group;
. x is O or 1;
. X represents a hydroxyl,a C1-C4 alkoxy; a hydroxyalkyl in which the alkyl group is a C1-C3 alkyl group; a C1-C4 acyloxy; a phenacyloxy; a carboxyl, a C1-C4 carbalkoxy; a cyano; an aminoalkylene in which the alkylene is a C1-C3 group;
a group -N-(X1)2 in which the groups X1 independently represent hydrogen, a C1-C4 alkyl; a group -NH-CO-Alk in which Alk represents a C1-C6 alkyl;
a group Alkl-NH-CO-Alk'1 in which Alkl is a Cl-C3 82~6~fi4 alkylene and Alk'1 is a C1-C3 alkyl; a C1-C4 acyl; a group -S-X2 in which X2 represents hydrogen or a C1-C4 alkyl group;
or alternatively, X forms a double bond with the 05 carbon atom to which it is linked and with the adjacent carbon atom in the heterocycle;
- Ar' represents a dichlorophenyl group;
- R represents hydrogen;
- T represents a group selected from ~0~ 1 -C- and -C-NH-W being an oxygen or a sulphur atom, and - Z represents either hydrogen, or M or OM when 01~5 T represents a -C- group, or M when T represents a W
group -C-NH; M represents a C1-C6 alkyl; a phenylalkyl in which the alkyl is a C1-C3 group, optionally substituted on the aromatic ring with a halogen, a trifluoromethyl, a C1-C4 alkyl, a hydroxyl, a C1-C4 alkoxy; a pyridylalkyl in which the alkyl is a C1-C3 group; a naphthylalkyl group, optionally substituted on the naphthyl ring with a halogen, a trifluoromethyl, a C1-C4 alkyl, a hydroxyl, a C1-C4 alkoxy; a pyridylthioalkyl in which the alkyl is a C1-C3 group;a styryl; an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group;
or of one its salts with inorganic or organic acids.
The compounds of formula (VI), which are described in the patent application EP-A-O 474 561, are prepared according to the above Scheme 1, in which B-D<
is represented in formula (VI) by Y.
The compound of formula (I) obtained by the process according to the invention is , particularly suitable for the preparation of - 9 - 21164fi~
the (-)-N-methyl-N-[4-(4-phenyl-4-acetylamino-piperidyl)-2-(3,4-dichlorophenyl)butyl]benzamide hydrochloride or methanesulfonate.
The compound of formula (I) as obtained 05 according to the process of the invention may also be used for the preparation of optically pure quaternary basic amides of formula (VII) Arl Tl CO--N--CH2--*ICH--(CH2)2--Am ~ , A ~ (VII) Ar' in which - Arl is an optionally substituted mono-, di- or tri-cyclic aromatic or heteroaromatic group;
- T1 is a direct bond, a hydroxymethylene group, an alkoxymethylene group in which the alkoxy group is Cl-C4, or a C1-Cs alkylene group;
- Ar' is a dichlorophenyl group;
- R is hydrogen;
- Am ~ is the radical X - N~
in which X1, X2 and X3, together with the nitrogen atom to which they are bonded, form an azabicyclic or azatricyclic system optionally substituted by a phenyl group; and - A ~ is a pharmaceutically acceptable anion.
lo - - 2 ~ ~ ~ 4 6 ~
The compounds of formula (VII) are prepared by a process consisting essentially in:
- reacting a compound of formula (I) as obtained by the process of the invention with a ~v,..~ound of formula Arl-Tl-CO-OH
in which Tl and Arl are as defined above, and - reacting the compound thus obtA~e~ , of formula Ar~ T1 CO NH ~H2 -*ICH-(CH2 ~ OH
in which Ar' is as defined-above, with a ~u...~ound of formula G-Cl, in which G is a leaving group such as mesyl or benzene sulfonyl, then - reacting the resulting cG...~ound, of formula Ar~ Tl CO-NH - CH2- *CIH-(CH2 ~ O - G
with a tertiary amine of formula in which Xl, X2 and X3 are as defined above, in an organic solvent at a temperature between ambient and 120-C, and - isolating the resulting product or else, if a~ro~.iate, exchAnging the methane sulfonate anion of the resulting quaternary salt with another pharmaceutically acceptable anion.
The compound of formula (I) as obtained according to the process of the invention is ~5 particularly suitable for the preparation of the (+)-1-[2-[3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)-acetyl]piperidyn-3-yl]ethyl]-4-phenyl-1-azoniabicyclo-[2.2.2]octane chloride.
The Examples which follow illustrate the invention without however implying a limitation.
(+)-3-Cyano-3-(3,4-dichlorophenyl)propionic acid (III) A mixture of 18.6 g (0.10 mol) of 3,4-dichloro-phenylacetonitrile and 12 g (1.03 mol) of dry sodiumchloroacetate is reacted for 5 hours at room tempera-ture in 150 ml of dry dimethyl sulfoxide, in the pre-sence of 10.5 g (1.05 mol) of sodium tert-butylate.
After the reaction, the reaction mixture is poured into 2~ 1 liter of iced water and acidified to pH < 3 with hydrochloric acid. The cyanoacid is extracted with ethyl acetate, which is washed to pH > 3, dried over magnesium sulfate and concentrated to dryness. Tne residue is solidified in 1,2-dichloroethane to give 16.1 g of the expected compound (III), which is charac-terized by proton NMR.
(+)-3-Cyano-3-(3,4-dichlorophenyl)propionic acid (III) A mixture of 93 g (0.50 mol) of 3,4-dichloro-phenylacetonitrile and 64 g (0.55 mol) of sodium chloroacetate is reacted for 4 hours at -33 C in 500 ml of liquid ammonia, in the presence of 21 g (0.54 mol) of sodium amide. After evaporation of the ammonia, the - 12 - ~ 6 ~
residue is taken up with water and then with isopropyl ether and is acidified to pH < 3 with hydrochloric acid. The organic phase is washed with water to pH ~ 3, separated off by decantation, dried over 05 magnesium sulfate and concentrated to dryness. The residue is solidified in toluene and characterized by proton NMR. M.p. = 106 C.
(+)-3-Cyano-3-(3,4-dichlorophenyl)propionic acid (III) A mixture of 186 g (1.00 mol) of 3,g-dichloro-phenylacetonitrile and 126 g (1.05 mol)ofsodium chloro-nitrile~and 105 g (1.05 mol) of sodium tert-butylate i8 reacted for 4 h~urs at -33 C in 1 liter of liquid ammonia. After the reaction, the ammonia is evaporated off and the residue is taken up with 500 ml of iced water and then with 500 ml of isopropyl ether and is acidified to pH < 3 with hydrochloric acid. The aqueous phase is ~i~c~rded and the organic phase is washed with water to pH ~ 3, separated off by decanta-tion, dried over magnesium sulfate and concentrated under vacuum. The residue is solidified in 250 ml of toluene and the cyanoacid is filtered off and dried at 50 C under a vane pump vacuum to give 190 g (yield:
78%) of the expected (+)-3-cyano-3-(3,4-dichloro-phenyl)propionic acid. M.p. = 104 C.
The product is characterized by proton NMR at 200 MHz in DMS0:
- unresolved signals between 2.85 and 3.1 ppm, 2 protons: -CH~-- complex signal at 4.5 ppm, 1 proton: -CH-- aromatic protons between 7.4 and 7.75 ppm, 3 protons - one acidic proton at 12.8 ppm EXAMPLE 4 211b~6~
(-)-3-Cyano-3-(3,4-dichlorophenyl)propionic acid (IV) A mixture of 186 g (1.00 mol) of 3,4-dichloro-05 phenylacetonitrile, 126 g (1.05 mol) of sodium chloro-acetate and 105 g (1.05 mol) of sodium tert-butylate is reacted for 4 hours at -33 C in 1 liter of liquid ammonla .
After the reaction, the ammonia is evaporated off and the residue is taken up with 500 ml of iced water and then with 500 ml of isopropyl ether and is acidified to pH < 3 with hydrochloric acid. The aqueous phase is discarded and the organic phase is washed with water to pH > 3, separated off by decanta-tion, dried over magnesium sulfate and concentrated under vacuum. The concentrate is redissolved in 2 liters of absolute ethanol, the solution is heated and 292 g of D-(-)-N-methylglucamine are added. After crystallization, the product is filtered off, rinsed with ethanol and dried under vacuum to give 396 g of the N-methylglucamine salt of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid.
[~]D25 = -14.7 (C = 1, CH30H).
The yield is 91% based on the 3,4-dichloro-phenylacetonitrile.
The salt obtained is dissolved in 900 ml of 1 Nhydrochloric acid and extracted with 2 liters of di-chloromethane. The organic phase is washed with water, separated off by decantation, dried over sodium sulfate and concentrated. The product is solidified in 500 ml of cyclohexane to give 187 g of the expected product.
The yield is 76.5% based on the 3,4-dichlorophenyl-acetonitrile. M.p. = 98 C.
[~] 25 = -8.6~ (C = 1, CH30H).
Enantiomeric purity by HPLC: 99%.
Proton NMR at 200 MHz in DMS0: same spectrum as the racemate.
1r ~ 4 6 ~
(+)~2-(3,4-dichlorophenyl)-4-hydroxy-butylamine (I) 350 ml of a l molar solution of BH, in THF are 05 added to a solution of 244 g (1 mol) of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid in 500 ml of THF, cooled to O-C. When the evolution of hydrogen has ceased, 650 ml of the borane solution are added at 20-C, followed by 1000 ml at 40-C. When the reaction is complete, the excess borane is destroyed by the addition of methanol and the reaction mixture is con-centrated to dryness. The concentrate is dissolved in 500 ml of water, acidified with hydrochloric acid and washed twice with 250 ml of toluene. The a~ueous phase ~5 is rendered alkaline with sodium hydroxide and extrac-ted with twice 400 ml of dichloromethane. The organic phase is washed with water, separated off by decanta-tion, dried over magnesium sulfate and concentrated under vacuum to give 159 g (yield: 68%) of the expected product. Chiral purity by HPLC: 99%.
The product is characterized by proton NMR in CDCl3 at 200 MHz:
- unresolved signals at 1.8 ppm, 2H
- one singlet at 2.4 ppm, 3H
- unresolved signals between 2.65 and 2.9 ppm, 3H
- unresolved signals between 3.35 and 3.6 ppm, 2H
- aromatic protons between 6.95 and 7.35 ppm, 3H
[~] 2~ = +9.8- (C = 1, MeOH).
M.p. = 80-81 C.
(+)-2-(3,4-Dichlorophenyl)-4-hydroxybutylamine (I) The pror~ re of EXAMPLE 5 is followed except that borane dimethyl sulfidë is used, dilution is carried out with 750 ml of tetrahydrofuran and the operating temperatures are 20-C and then 50 C. The same product is obtained wi~th the same yield and the same characteristics.
'
Claims (9)
1. A process for the preparation of (+)-2-(3,4-dichlorophenyl)-4-hydroxybutylamine of formula (I):
(+) HOCH2-CH2-CH-CH2NH2 (I) which comprises (a) treating 3,4-dichlorophenylacetonitrile of formula (II):
(II) with an alkali metal halogenoacetate in liquid ammonia or in a polar aprotic solvent, in the presence of a strong base, at a temperature of -40°C to +25°C;
(b) treating the resulting racemic 3-cyano-3-(3,4-dichlorophenyl)propionic acid of formula (III):
(III) with D-(-)-N-methylglucamine in order to crystallize all the acid (III) in the form of the D-(-)-N-methyl-glucamine salt of the levorotatory acid;
(c) treating said salt with a strong acid; and (d) subjecting the freed (-)-3-cyano-3-(3,4-dichloro-phenyl)propionic acid of formula (IV):
(-) (IV) to enantioconservative reduction with a borane.
(+) HOCH2-CH2-CH-CH2NH2 (I) which comprises (a) treating 3,4-dichlorophenylacetonitrile of formula (II):
(II) with an alkali metal halogenoacetate in liquid ammonia or in a polar aprotic solvent, in the presence of a strong base, at a temperature of -40°C to +25°C;
(b) treating the resulting racemic 3-cyano-3-(3,4-dichlorophenyl)propionic acid of formula (III):
(III) with D-(-)-N-methylglucamine in order to crystallize all the acid (III) in the form of the D-(-)-N-methyl-glucamine salt of the levorotatory acid;
(c) treating said salt with a strong acid; and (d) subjecting the freed (-)-3-cyano-3-(3,4-dichloro-phenyl)propionic acid of formula (IV):
(-) (IV) to enantioconservative reduction with a borane.
2. A process according to claim 1 wherein step (a) is carried out in liquid ammonia at a temperature of -40 to -30°C.
3. A process according to claim 2 wherein step (a) is carried out in the presence of sodium amide or sodium tert-butylate.
4. A process according to claim 1 wherein step (a) is carried out in a polar aprotic solvent which is inert under the reaction conditions.
5. A process according to any one of claims 1 to 4 wherein sodium chloroacetate is used as the alkali metal halogenoacetate.
6. A process for the preparation of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid, which comprises treating racemic 3-cyano-3-(3,4-dichlorophenyl)propionic acid with D-(-)-N-methylglucamine and treating the resulting D-(-)-N-methylglucamine salt of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid with a strong acid.
7. 3-Cyano-3-(3,4-dichlorophenyl)propionic acid of the formula and its salts.
8. (-)-3-Cyano-3-(3,4-dichlorophenyl)propionic acid and its salts.
9. The D-(-)-N-methylglucamine salt of (-)-3-cyano-3-(3,4-dichlorophenyl)propionic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9302262 | 1993-02-26 | ||
| FR9302262A FR2701946B1 (en) | 1993-02-26 | 1993-02-26 | Process for the preparation of an optically pure amino alcohol. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2116464A1 CA2116464A1 (en) | 1994-08-27 |
| CA2116464C true CA2116464C (en) | 1997-10-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002116464A Expired - Fee Related CA2116464C (en) | 1993-02-26 | 1994-02-25 | Process for the preparation of an optically pure aminoalcohol |
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| Country | Link |
|---|---|
| EP (1) | EP0612716B1 (en) |
| JP (1) | JP2546624B2 (en) |
| CN (2) | CN1053655C (en) |
| AT (1) | ATE137736T1 (en) |
| CA (1) | CA2116464C (en) |
| DE (1) | DE69400170T2 (en) |
| DK (1) | DK0612716T3 (en) |
| ES (1) | ES2089889T3 (en) |
| FR (1) | FR2701946B1 (en) |
| GR (1) | GR3020346T3 (en) |
| HU (1) | HU213260B (en) |
| TW (1) | TW240216B (en) |
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| WO2017009753A1 (en) * | 2015-07-13 | 2017-01-19 | Piramal Enterprises Limited | An improved process for the preparation of baclofen and its intermediate |
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| US5512680A (en) * | 1993-02-26 | 1996-04-30 | Sanofi | Process for the preparation of an optically pure aminoalcohol |
| WO2007136323A1 (en) * | 2006-05-18 | 2007-11-29 | Albireo Ab | A novel process suitable for large-scale production of phenyl propan derivatives of formula i |
| DE202008001786U1 (en) | 2007-03-12 | 2008-12-24 | Inventio Ag | Elevator installation, suspension element for an elevator installation and device for producing a suspension element |
| CZ2009385A3 (en) * | 2009-06-16 | 2010-07-28 | Zentiva, K. S. | Process for preparing (S)-4-methylamino-3-(3,4-dichlorophenyl)butan-1-ole |
| CN107445864B (en) * | 2017-08-09 | 2020-01-17 | 无锡殷达尼龙有限公司 | Method for purifying long-carbon-chain cyano acid product |
| CN107311911B (en) * | 2017-08-21 | 2020-09-08 | 钟桂发 | Preparation method of chiral intermediate of nilapanib |
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| FI97540C (en) * | 1989-11-06 | 1997-01-10 | Sanofi Sa | Process for the preparation of therapeutically useful aromatically substituted piperidine and piperazine derivatives |
-
1993
- 1993-02-26 FR FR9302262A patent/FR2701946B1/en not_active Expired - Fee Related
-
1994
- 1994-02-19 TW TW083101427A patent/TW240216B/zh not_active IP Right Cessation
- 1994-02-25 EP EP94400409A patent/EP0612716B1/en not_active Expired - Lifetime
- 1994-02-25 DK DK94400409.2T patent/DK0612716T3/en active
- 1994-02-25 HU HU9400562A patent/HU213260B/en not_active IP Right Cessation
- 1994-02-25 AT AT94400409T patent/ATE137736T1/en active
- 1994-02-25 DE DE69400170T patent/DE69400170T2/en not_active Expired - Lifetime
- 1994-02-25 ES ES94400409T patent/ES2089889T3/en not_active Expired - Lifetime
- 1994-02-25 CA CA002116464A patent/CA2116464C/en not_active Expired - Fee Related
- 1994-02-26 CN CN94101933.0A patent/CN1053655C/en not_active Expired - Fee Related
- 1994-02-28 JP JP6030491A patent/JP2546624B2/en not_active Expired - Fee Related
-
1996
- 1996-06-27 GR GR960401715T patent/GR3020346T3/en unknown
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017009753A1 (en) * | 2015-07-13 | 2017-01-19 | Piramal Enterprises Limited | An improved process for the preparation of baclofen and its intermediate |
| EP3322691A4 (en) * | 2015-07-13 | 2019-03-27 | Piramal Enterprises Limited | An improved process for the preparation of baclofen and its intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1053655C (en) | 2000-06-21 |
| CN1100410A (en) | 1995-03-22 |
| JPH06340595A (en) | 1994-12-13 |
| ATE137736T1 (en) | 1996-05-15 |
| HU9400562D0 (en) | 1994-05-30 |
| EP0612716A1 (en) | 1994-08-31 |
| DE69400170D1 (en) | 1996-06-13 |
| HU213260B (en) | 1997-04-28 |
| TW240216B (en) | 1995-02-11 |
| DK0612716T3 (en) | 1996-08-19 |
| DE69400170T2 (en) | 1996-10-02 |
| CA2116464A1 (en) | 1994-08-27 |
| GR3020346T3 (en) | 1996-09-30 |
| CN1242358A (en) | 2000-01-26 |
| HUT66401A (en) | 1994-11-28 |
| EP0612716B1 (en) | 1996-05-08 |
| ES2089889T3 (en) | 1996-10-01 |
| FR2701946B1 (en) | 1995-05-24 |
| CN1122660C (en) | 2003-10-01 |
| FR2701946A1 (en) | 1994-09-02 |
| JP2546624B2 (en) | 1996-10-23 |
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