HK1100922B - Method for the separation of intermediates which may be used for the preparation of escitalopram - Google Patents

Description

Method for the isolation of an intermediate useful for the preparation of escitalopram

The present invention relates to a novel process for the preparation of an optically active intermediate which is useful in the preparation of escitalopram (escitalopram).

Background

Citalopram (Citalopram) is a well known antidepressant drug which has been marketed for some years.

It is a selective, centrally acting inhibitor of 5-hydroxytryptamine (5-hydroxytryptamine; 5-HT) resorption and therefore has antidepressant activity.

Citalopram was originally disclosed in DE 2,657,013, corresponding to US 4,136,193. This patent publication outlines, inter alia (i.a.) a process for the preparation of citalopram from the corresponding 5-bromo-derivative by reaction with cuprous cyanide in a suitable solvent and by alkylation of 5-bromo-phtalane.

U.S. Pat. No. 4,943,590, which corresponds to EP-B1-347066, describes two processes for the preparation of escitalopram (the S-enantiomer of citalopram). Both methods use racemic diols having the formula

As a raw material. According to a first method, the diol of formula (I) is reacted with an enantiomerically pure acid derivative, such as (+) or (-) - α -methoxy- α -trifluoromethyl-phenylacetyl chloride, to form a diastereomeric ester mixture, which is separated by HPLC or fractional crystallization, whereupon the ester with the correct stereochemistry is enantioselectively converted to escitalopram. According to a second method, the diol of formula (II) is separated into the enantiomers by stereoselective crystallization with an enantiomerically pure acid, such as (+) -di-p-toluoyltartaric acid, whereupon the S-enantiomer of the diol of formula (II) is enantioselectively converted into escitalopram.

Escitalopram has now been developed as an antidepressant. Therefore, there is a need for an improved process for the preparation of escitalopram.

It has now been found that the S-enantiomer of a diol of formula (I) above, as well as acylated derivatives thereof, may be prepared by: the selective enzymatic acylation of the primary hydroxyl group in a racemic diol to obtain an S-diol of formula (I) or an acylated derivative thereof, having a high optical purity, and, in addition, the obtained enantiomer can be efficiently separated by reacting said diol of formula (I) with a compound capable of forming a derivative of said diol of formula (I) comprising a carboxylic acid group. Once the derivative is formed it precipitates and can be easily separated from the reaction mixture.

The invention

An object of the present invention therefore relates to the isolation and purification of a compound having the formula

Wherein R is cyano or a group which can be converted into cyano, the dotted line represents a double or single bond, Hal is halogen, Z is dimethylaminomethyl or Z is a group which can be converted into dimethylaminomethyl, W is O or S and Y is a bond, S or NH, R¹Is C_1-10Alkyl radical, C_2-10-alkenyl or C_2-10-alkynyl, all of which are optionally substituted with one or more substituents selected from the group consisting of: c_1-10-alkoxy, C_1-10Alkylthio, hydroxy, halogen, amino, nitro, cyano, C_1-10Alkylamino, di- (C)_1-10-alkyl) amino, aryl, aryloxy, arylthio and heteroaryl, or R²Is aryl, wherein any one of the aryl and heteroaryl is optionally substituted one or more times with a substituent selected from the group consisting of: c_1-10Alkyl radical, C_2-10-alkenyl, C_2-10-alkynyl, C_1-10-alkoxy, C_1-10Alkylthio, hydroxy, halogen, amino, nitro, cyano, C_1-10Alkylamino, di- (C)_1-10-alkyl) amino, or a salt thereof

And/or a diol of the formula

Wherein R, Z, Hal and the dotted line are as defined above, or a salt thereof, comprising:

a) reacting said mixture comprising a compound of formula (IV) and a diol of formula (II) with a cyclic anhydride or diimide of the formula

Wherein X is- (CHR))_n-, where n is 0 to 2;

and R ', R' and RIndependently selected from hydrogen, C_1-6Alkyl radical, C_1-6Alkoxy, aryloxy, C_1-6Acyloxy, aryl-CO-O, where each aryl group may be substituted by C_1-6-alkyl substitution, or R 'and R' in said anhydride of formula (Ia) together are-O-CR⁴R⁵-O-, wherein R⁴And R⁵Independently is hydrogen or C_1-6-alkyl, or R' and R "in the anhydride of formula (Ib) are close together and form together with the two carbon atoms to which they are attached a phenyl ring;

Q¹and Q²One is nitrogen and the other is carbon, or both are carbon;

a is C_1-6Alkylene, phenylene or naphthylene, where, C_1-6Alkylene, phenylene or naphthylene, optionally with C_1-6-alkyl substitution one or more times;

to form a mixture of a compound of formula (IV) and an ester having the formula

Wherein R, Z and Hal are as defined above and V is-CHR '-X-CR' -COOH, -X-CHR '-CO-NH-A-COOH, -CHR' -X-CO-NH-A-COOH or

Wherein R ', R', X and A are as defined above;

b) isolating the compound of formula (IV) from the ester of formula (V) by a method selected from the group consisting of:

i) allowing the acid of formula (V) or a salt thereof to precipitate from the reaction mixture and separating the precipitate of the compound of formula (V) or a salt thereof from the reaction mixture, optionally followed by separating the compound of formula (IV) or a salt thereof from the reaction mixture;

ii) partitioning between an organic solvent and an aqueous solvent, whereby the compound of formula (IV) is dissolved in the organic phase and the compound of formula (V) is dissolved in the aqueous phase, separating the phases, and optionally separating the compound of formula (IV) or a salt thereof and/or separating the compound of formula (V) or a salt thereof; and

iii) adsorbing the compound of formula (V) on a base resin, separating the solvent containing the compound of formula (IV) from the resin, desorbing the compound of formula (V) from the base resin, and optionally isolating the compound of formula (IV) or a salt thereof and/or isolating the compound of formula (V) or a salt thereof.

A second object of the present invention relates to a process for the production of escitalopram comprising the process as described above.

According to a particular embodiment of the invention, one enantiomer of formula (II) is isolated from the compound of formula (IV) in another enantiomeric form.

According to one embodiment of the invention, the S-enantiomer of the compound of formula (V) or the enantiomeric mixture of the compound of formula (V) comprising more than 50% of the S-enantiomer of the compound of formula (V) is separated from the R-enantiomer of the acyl derivative of formula (IV) or from the enantiomeric mixture of the acyl derivative of formula (IV) comprising more than 50% of the R-enantiomer of the acyl derivative of formula (IV).

According to a particular embodiment of the invention, the S-enantiomer of the compound of formula (V) is isolated from the R-enantiomer of the acyl derivative of formula (IV) or from an enantiomeric mixture of the acyl derivative of formula (IV) comprising more than 50% of the R-enantiomer of the acyl derivative of formula (IV).

According to a more specific embodiment of the invention, the S-enantiomer of the compound of formula (V) is isolated from the R-enantiomer of the acyl derivative of formula (IV).

According to another embodiment of the invention, the S-enantiomer of the acyl derivative of formula (IV) or the enantiomeric mixture of the acyl derivative of formula (IV) comprising more than 50% of the S-enantiomer of the acyl derivative of formula (IV) is separated from the R-enantiomer of the compound of formula (V) or from the enantiomeric mixture of the compound of formula (V) comprising more than 50% of the R-enantiomer of the compound of formula (V).

According to a particular embodiment of the invention, the S-enantiomer of the acyl derivative of formula (IV) is isolated from the R-enantiomer of the compound of formula (V) or from an enantiomeric mixture of the compound of formula (V) comprising more than 50% of the R-enantiomer of the compound of formula (V).

According to a more specific embodiment, the S-enantiomer of the acyl derivative of formula (IV) is isolated from the R-enantiomer of the compound of formula (V).

According to a particular embodiment of the invention, the formulation used is a compound of formula (Ia), suitably succinic anhydride or glutaric anhydride.

According to another embodiment, the formulation used is a compound of formula (Ib), suitably phthalic acid (phtalic acid) anhydride.

According to a third embodiment, the formulation is a diimide of formula (Ic), suitably an N-phenyl-succinimide substituted with a carboxyl group on the phenyl ring.

According to another embodiment of the invention, the R group in the compound of formula (V) obtained in the form of the S-enantiomer is optionally converted into cyano, the Z group in the compound of formula (V) obtained is optionally converted into dimethylaminomethyl, Hal is optionally converted into fluoro and/or the dotted line representing a double bond is optionally converted into a single bond, in any order; the compound of formula (V) is then converted into escitalopram or a derivative thereof having the formula

Wherein R, Z and Hal are as defined above, by treatment with a base, optionally followed in any order by conversion of the R group to a cyano group, conversion of the Z group to a dimethylaminomethyl group, conversion of Hal to a fluoro group, and conversion of the dotted line representing a double bond to a single bond; optionally followed by conversion of escitalopram of formula (VI) or a derivative thereof into its salt.

According to another embodiment of the invention, the R group in the compound of formula (IV) obtained in the form of the S-enantiomer is optionally converted into cyano, the Z group in the compound of formula IV obtained is optionally converted into dimethylaminomethyl, Hal is optionally converted into fluoro and/or the dotted line representing a double bond is optionally converted into a single bond, in any order; the compound of formula (IV) is then converted into escitalopram or a derivative thereof

Wherein R, Z and Hal are as defined above, by treatment with a base, optionally followed in any order by conversion of the R group to a cyano group, conversion of the Z group to a dimethylaminomethyl group, conversion of Hal to a fluoro group, and conversion of the dotted line representing a double bond to a single bond; optionally followed by conversion of escitalopram of formula (VI) or a derivative thereof into its salt.

According to a most preferred embodiment of the invention, wherein R is cyano, the dotted line is a single bond, Z is dimethylaminomethyl, Hal is fluoro, Y is a bond, and R is¹is-CH₂-CH₂-CH₃Of the compounds of the formulae (II) and (IV) and in which X is- (CH)₂)_0-1To form a mixture of the corresponding S-enantiomer of formula (V) and the R-enantiomer of formula (IV). The isolated compound of formula (V) is then treated with NaH to form the compound of formula (VI).

The mixtures of formulae (II) and (IV) used as starting materials are preferably prepared by enzymatic acylation of compounds of formula II, wherein R is cyano, the dotted line is a single bond, Z is dimethylaminomethyl, Hal is fluoro, wherein vinyl butyrate is used as acylating agent, and Candida antartica lipase B.

Detailed Description

The terms "enantiomer", "R-enantiomer", "S-enantiomer", "R-form", "S-form", "R-diol" and "S-diol", when used in combination with compounds of formulae (II), (IV), (V) and (VI), denote the orientation of the group around the carbon atom to which the 4-Hal-phenyl group is attached.

As used herein, the term C_1-10Alkyl denotes branched or unbranched alkyl having 1 to 10 carbon atoms, 1 and 10 also being included, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-2-propyl, 2-methyl-1-propyl, pentyl, hexyl and heptyl. C_1-6Alkyl represents a branched or unbranched alkyl group having 1 to 6 carbon atoms, 1 and 6 also being included, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-2-propyl, 2-methyl-1-propyl, pentyl and hexyl. C_1-4Alkyl represents a branched or unbranched alkyl group having 1 to 4 carbon atoms, 1 and 4 being also included, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl. C_1-3Alkyl represents a branched or unbranched alkyl group having 1 to 3 carbon atoms, 1 and 3 also being included, such as methyl, ethyl, 1-propyl, 2-propyl.

Similarly, C_2-10Alkenyl and C_2-10-alkynyl denotes branched or unbranched alkenyl and alkynyl groups, respectively, having 2-10 carbon atoms, respectively comprising one double bond and one triple bond, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl. C_2-6Alkenyl and C_2-6Alkynyl denotes branched or unbranched alkenyl and alkynyl, respectively, having a total of 2 to 6 carbon atoms, including a double bond and a triple bond, respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl. C_2-4Alkenyl and C_2-4Alkynyl denotes branched or unbranched alkenyl and alkynyl groups, respectively, having 2 to 4 carbon atoms, respectively comprising a double bond and a triple bond, such as ethenyl, propenyl, butenyl, ethenylAlkynyl, propynyl and butynyl. C_2-3Alkenyl and C_2-3Alkynyl denotes branched or unbranched alkenyl and alkynyl groups, respectively, having 2 to 3 carbon atoms, including one double bond and one triple bond, respectively, such as ethenyl, propenyl, ethynyl and propynyl.

Term C_1-10-alkoxy, C_1-10Alkylthio, C_1-10Alkylamino and di- (C)_C1-10-alkyl) amino, etc., represent groups wherein the alkyl is C as defined above_1-10-an alkyl group. Term C_1-6-alkoxy radical, C_1-6Alkylthio, C_1-6Alkylamino and di- (C)_1-6-alkyl) amino, etc., represent groups wherein the alkyl is C as defined above_1-6-an alkyl group. Term C_1-4-alkoxy, C_1-4Alkylthio, C_1-4Alkylamino and di- (C)_1-4-alkyl) amino, etc., represent groups wherein the alkyl is C as defined above_1-4-an alkyl group. Term C_1-3-alkoxy, C_1-3Alkylthio, C_1-3Alkylamino and di- (C)_1-3-alkyl) amino, etc., represent groups wherein the alkyl is C as defined above_1-3-an alkyl group.

Halogen represents fluoro, chloro, bromo or iodo.

As used herein, the term "anti-solvent" means a liquid that, when added to a solvent-solute system, reduces the solubility of the solute.

In a particular embodiment of the invention, the isolation of the compound of formula (IV) from the ester of formula (V) is carried out by allowing the acid of formula (V) to precipitate from the reaction mixture and separating the precipitate of the compound of formula (V) from the reaction mixture, optionally followed by isolating the compound of formula (IV) or a salt thereof from the reaction mixture.

In a particular embodiment of the invention, R' and RIndependently selected from hydrogen and C_1-6-alkyl, and Q¹And Q²Are both carbon.

In a particular embodiment of the invention, the enantiomeric mixture of the compound of formula (V) comprises more than 60% of the S-enantiomer of the compound of formula (V), such as more than 70%, more than 80%, more than 90%, more than 95%, more than 98% or more than 99%.

In another equally specific embodiment of the invention, the enantiomeric mixture of the compound of formula (V) comprises more than 60% of the R-enantiomer of the compound of formula (V), such as more than 70%, more than 80%, more than 90%, more than 95%, more than 98% or more than 99%.

In another equally specific embodiment of the invention, the enantiomeric mixture of the acyl derivative of formula (IV) comprises more than 60% of the S-enantiomer of the compound of formula (V), such as more than 70%, more than 80%, more than 90%, more than 95%, more than 98% or more than 99%.

In another equally specific embodiment of the invention, the enantiomeric mixture of the acyl derivative of formula (IV) comprises more than 60% of the R-enantiomer of the compound of formula (V), such as more than 70%, more than 80%, more than 90%, more than 95%, more than 98% or more than 99%.

In a preferred embodiment of the invention, R is halogen or cyano, most preferably cyano.

In another preferred embodiment of the invention, Hal is fluoro.

In another preferred embodiment of the invention, the dotted lines of formulae (II), (IV) and (V) are single bonds.

In another preferred embodiment, Z is a dimethylaminomethyl group, or a group that can be converted to a dimethylaminomethyl group. In a preferred embodiment, Z is dimethylaminomethyl.

Most preferably, Hal is fluoro, R is cyano, the dotted line is a single bond, and Z is dimethylaminomethyl.

According to one embodiment of the invention, Y in the compound of formula (IV) is O or S.

According to another embodiment of the invention, Y in the compound of formula (IV) is NH.

However, according to a preferred embodiment of the invention, Y in the compound of formula (IV) is a bond.

Suitably, the substituent R in the compound of formula (IV) as defined in any of the embodiments above¹The following were used: r¹Is C_1-6Alkyl radical, C_2-6-alkenyl or C_2-6-alkynyl, all of which are optionally substituted one or more times with substituents selected from the group consisting of: c_1-6-alkoxy, C_1-6Alkylthio, hydroxy, halogen, amino, nitro, cyano, C_1-4Alkylamino and di- (C)_1-6-alkyl) amino, more suitably R¹Is C_1-4Alkyl radical, C_2-4-alkenyl or C_2-4-alkynyl, all of which are optionally substituted one or more times with substituents selected from the group consisting of: c_1-4-alkoxy, C_1-4Alkylthio, hydroxy, halogen, amino, nitro, cyano, C_1-4Alkylamino and di- (C)_1-4-alkyl) amino, preferably R¹Is C_1-3Alkyl radical, C_2-3-alkenyl or C_2-3-alkynyl, all of which are optionally substituted one or more times with: c_1-3-alkoxy, C_1-3Alkylthio, hydroxy, halogen, amino, nitro, cyano, (C)_1-3-alkyl) amino and di- (C)_1-3-alkyl) amino, more preferably R¹Is C_1-3Alkyl radical, C_2-3-alkenyl or C_2-3-alkynyl, and more preferably R¹Is C_1-3Alkyl, especially unbranched C_1-3Alkyl radicals, such as the methyl, ethyl or propyl radical.

The invention is particularly suitable for separating compounds of formula (II) in the form of the S-or R-enantiomer and compounds of formula (IV) in the opposite enantiomeric form, obtained by the enzymatic resolution process described in WO application No. PCT/DK/0300537, publication No. WO 2004/014821.

Thus, according to an embodiment of the invention, the mixture of compounds of formulae (II) and (IV) used in the process is prepared by selective enzymatic acylation or selective enzymatic deacylation.

A particular advantage of the present invention is that after formation, the compound of formula (V) precipitates from the reaction mixture and can subsequently be easily isolated.

Another particular advantage of the present invention is (depending on the particular reagents of formulae (Ia) - (Ic) used) that it leads to the separation and isolation of products which can be directly cyclized by treatment with a base to form escitalopram or a derivative thereof.

The reaction of a mixture of compounds of formula (II) in enantiomeric form with a compound of formula (Ia), (Ib) or (Ic) may be carried out in an inert organic solvent, such as tetrahydrofuran, preferably in a solvent wherein the acid of formula (V) forms a precipitate, and in a certain amount of a specific solvent wherein the acid of formula (V) forms a precipitate. Suitable solvents can be determined by one skilled in the art.

Alternatively, the reaction is carried out in a solvent in which the acid of formula (V) cannot form a precipitate, and an antisolvent is added after the compound of formula (V) is formed, whereby the acid of formula (V) forms a precipitate.

The reaction is suitably carried out at room temperature (25 ℃) or at a temperature close to room temperature.

The compound of formula V is suitably isolated from the compound of formula (IV) by filtration or decantation, or by any other suitable method of isolating a solid form from a liquid.

When the isolated compound of formula V is the S-enantiomer, it may be directly cyclized by treatment with a base in a suitable organic solvent.

The enantioselective ring closure of the S-enantiomer of formula (V) to form escitalopram or other compound of formula (VI) may suitably be carried out by treating the compound of formula (V) with a base, such as KOC (CH)₃)₃Or other alkoxides, NaH or other hydrides, or amines, such as triethylamine, ethyldiisopropylamine or pyridine, at low temperatures in inert organic solvents, such as tetrahydrofuran, toluene, DMSO, DMF, tert-butyl methyl ether, dimethoxyethane, dimethoxymethane, bis (tert-butyl) methyl etherAlkane, acetonitrile or dichloromethane. This process may be carried out similarly to the process described in U.S. Pat. No. 4,943,590.

In the same way, the compound of formula (IV) in the form of the S-enantiomer and isolated from the reaction mixture is cyclized by treatment with a base.

In some cases-CW-Y-R in the compound of formula (IV) is subjected to cyclization¹It may be advantageous to exchange the group or the-CO-V group in the compound of formula (V) for a more labile group. The labile group (leaving group) may typically be a group selected from mesyloxy, p-toluenesulfonyloxy, 10-camphorsulfonyloxy, trifluoroacetyloxy and trifluoromethane-sulfonyloxy groups or a halogen.

Typically, the compound of formula (IV) or (V) is subsequently hydrolysed with an aqueous base, such as NaOH, KOH or LiOH or mixtures thereof dissolved in water or an alcohol, to form a compound of formula (II) which is then reacted with an activated leaving group, such as the group-O-SO₂-A, wherein A is C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl or optionally C_1-6Alkyl-substituted aryl or aryl-C_1-6Alkyl, especially methanesulfonyl chloride or toluenesulfonyl chloride, or trifluoroacetyl chloride, acetyl chloride, or a form of formic acid, e.g. a mixture of formic acid and acetic anhydride, in an organic solvent in the presence ofUnder the condition of organic base.

Preferably, the substituent V in the compound of formula (V) is a substituent which can be directly cyclized by treating the compound of formula V with a base. Most preferably, V is-CH₂-CH₂-COOH or-CH₂-CH₂-CH₂-COOH。

After the ring closure, the optical purity of the escitalopram product has to be improved. Said improvement in optical purity can be obtained by chromatography on a chiral stationary phase or by crystallization of racemic citalopram base or a salt thereof according to the method described in WO 03/000672.

The R-enantiomers of the compounds of formulae (V) and (IV) obtained according to the present invention can be used for the preparation of racemic citalopram and escitalopram by cyclization in an acidic environment, according to the method described in WO 03/000672. Suitable acids for effecting acidic ring closure are mineral acids, carboxylic acids, sulfonic acids or sulfonic acid derivatives, more suitably H₂SO₄Or H₃PO₄。

The starting mixture for the isolation process of the invention may be prepared by enzymatic acylation or deacylation with a hydrolase, such as a lipase, esterase, acyltransferase or protease, as described in WO application No. PCT/DK/0300537, WO 2004/014821.

It has been found that the enzymatic acylation of the present invention can utilize Novozyme from Candida antartica435 LipoZyme derived from Thermomyces lanuginosus^TMTL IM, both of which can be isolated from Novozymes A/S or Pseudomonas lipoprotein lipase (Pseudomonas) species (from Burkholderia Cepacia) and available from Fluka, and particularly good results were obtained when Novozyme 435 from Candida antartica or Pseudomonas lipoprotein lipase species was used.

The "enzyme" or "hydrolase" may be immobilized by known techniques, either as the enzyme itself or as the cell body, and can be used in immobilized form. Immobilization may be performed by methods known to those skilled in the art, including, for example, carrier binding, cross-linking, encapsulation, and the like. Thus, the hydrolase can be used in the form of an immobilized enzyme or a cross-linked enzyme crystal (CLEC) enzyme.

The enzymes described above can also be used in the form of culture products containing the enzymes, such as culture fluids containing cell bodies, or cultured cell bodies, processed products of culture products, and any immobilized forms of these enzymes/culture products.

Mutants, variants or any equivalent of the enzymes specifically mentioned above which are capable of selective acylation or deacylation may also be used. The variant or its equivalent may be isolated from various strains of Pseudomonas, Candida or Thermomyces, or any other source, or may be prepared by mutating the DNA encoding the above enzyme, resulting in a change in the amino acid composition of the enzyme. Suitable mutants or variants of the above-mentioned enzymes are those in which individual amino acids have been removed or replaced by other amino acids, and which have a suitable amino acid sequence which is more than 60%, preferably more than 80%, and most preferably more than 90% identical to the above-mentioned enzyme. The preferred reaction conditions for the enzymatic acylation/deacylation vary depending on the specific enzyme used, whether it is immobilized or not, etc.

Suitable temperatures for the reaction are from 0 to 80 deg.C, more preferably from 20 to 60 deg.C, or more preferably from 30 to 50 deg.C.

The amount of the enzyme to be used is not particularly limited, but is usually 0.01 to 1.0, preferably 0.02 to 0.5, and more preferably 0.02 to 0.3, which is a weight ratio relative to the substrate.

The reaction may be carried out as a batch process, or it may be carried out as a continuous process. The enzyme may be used in multiple batches, either repeatedly or continuously. The reaction time is not particularly limited and depends on the scale and type (batch or continuous) of the enzyme and production method used.

According to WO application No. PCT/DK/0300537, which is disclosed in WO2004/014821, the acylating agent used for the enzymatic acylation can be a preparation of the formula

Or of the formula R¹Isocyanates of the formula-N-C-O or of the formula R¹-isothiocyanates of N ═ C ═ S;

wherein X is O or S; w is O or S; u is O or S, V is halogen;

R⁰is C_1-10Alkyl radical, C_2-10-alkenyl or C_2-10-alkynyl, all of which are optionally substituted one or more times with substituents selected from the group consisting of: c_1-10-alkoxy, C_1-10Alkylthio, hydroxy, halogen, amino, nitro, cyano, C_1-10Alkylamino, di- (C)_1-10-alkyl) amino, aryl, aryloxy, arylthio and heteroaryl, or R⁰Is aryl, wherein any one of the aryl and heteroaryl is optionally substituted one or more times with a substituent selected from the group consisting of: c_1-10Alkyl radical, C_2-10-alkenyl, C_2-10-alkynyl, C_1-10-alkoxy, C_1-10Alkylthio, hydroxy, halogen, amino, nitro, cyano, C_1-10Alkylamino and di- (C)_1-10-alkyl) amino;

R¹definition of (A) and R⁰The same;

R²definition of (A) and R⁰Is the same as, or R²Is a suitable irreversible acyl donor group;

or R⁰And R¹Together form a chain of 3 to 5 carbon atoms;

provided that when X is S, W and U are not S.

Preferably, in the compound of formula (IIIa) U is O.

Preferably, in any of the above acylating agents W is O.

Preferably, in any of the above acylating agents X is O.

Preferably, R is¹And R⁰Is C_1-3Alkyl, in particular unbranched C_1-3Alkyl, such as methyl, ethyl or propyl, and preferably R²Is C_1-3Alkyl, substituted one or more times by halogen, or R²Is C_2-3-alkenyl, and most preferably R²Is C_2-3Alkenyl groups, such as vinyl.

The preferred acylating agent is vinyl butyrate.

Enzymatic deacylation was carried out using a compound of the formula as starting material,

wherein R, Z, W, Y, Hal, the dotted line and R¹Is as defined above in that respect,

among the starting materials for carrying out the enzymatic deacylation, the appropriate R is¹Is C_1-10-alkyl, preferably unbranched C_1-10-alkyl, most preferably R¹Is unbranched C_4-10-an alkyl group.

The selective enzymatic acylation is carried out under conditions which substantially inhibit hydrolysis. Hydrolysis is the reverse reaction of the acylation reaction and occurs if water is present in the reaction system.

Thus, the selective enzymatic acylation is preferably carried out in an anhydrous organic solvent or an almost anhydrous organic solvent (the enzyme usually requires the presence of some water in order to be active). The percentage of water allowed in a particular reaction system can be determined by one skilled in the art.

The organic solvent which can be used for the acylation reaction is not particularly critical as long as it does not inactivate the enzyme used. Suitable solvents include hydrocarbons such as hexane, heptane, benzene and toluene; ethers, e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, 1, 4-bisAlkyl, tert-butyl methyl ether and dimethoxyethane; ketones such as acetone, diethyl ketone, methyl ethyl ketone and methyl ethyl ketone; esters such as methyl acetate, ethyl butyrate, vinyl butyrate, and ethyl benzoate; halogenated hydrocarbons such as dichloromethane, trichloromethane and 1,1, 1-trichloroethane; secondary and tertiary alcohols, such as t-butanol; nitrogen-containing solvents such as dimethylformamide, acetamide (acetoamide), formamide, acetonitrile and propionitrile; and non-acid-base polar solvents such as dimethyl sulfoxide, N-methylpyrrolidone, and hexamethylphosphoramidite (hexamethophorous triamide).

Among them, hydrocarbons such as hexane, heptane, benzene and toluene, ethers such as diethyl ether, diisopropyl ether, 1, 4-di-n-butyl ether, etc. are preferableAlkanes and t-butyl methyl ether, and esters, such as vinyl butyrate. For one enzyme, the most preferred solvents may be ethers and aromatic hydrocarbons, such as benzene or toluene, most preferably toluene, while for another enzyme, the most preferred solvents may be ethers, such as 1, 4-bisAn alkane. The above solvents may be used alone or in combination of two or more solvents.

The concentration of the racemic diol of formula (II) and the acylating agent should not be too high, since a high concentration of the reagent in the solvent may lead to a non-selective acylation of the racemic diol of formula (II). Suitable concentrations of racemic diol of formula (II) and acylating agent are each below 1,0M, more preferably below 0,5M, more preferably below 0,2M, or more preferably below 0, 1M. The person skilled in the art is able to determine the optimum concentration of the racemic diol of formula (II) and of the acylating agent.

The selective enzymatic deacylation is preferably carried out in water or a mixture of water and an organic solvent, preferably in the presence of a buffer. The organic solvent which can be used in the reaction is not particularly important as long as it does not inactivate the enzyme used. Suitable organic solvents are readily water-miscible solvents, such as alcohols, acetonitrile, DMF, DMSO, bisAlkanes, DME and diglyme. Other suitable solvents can be identified by those skilled in the art. The person skilled in the art is able to determine the optimum concentration of the racemic compound of formula (IV) used in the reaction.

The stereoselectivity of the enzyme used can be enhanced by acylation or deacylation in the presence of an organic acid and/or an organic base.

In particular, the enzymatic acylation or enzymatic deacylation is carried out in the presence of an organic acid, preferably an organic carboxylic acid.

Suitably, the organic acid is an aromatic carboxylic acid or an aliphatic carboxylic acid.

Suitable organic acids which can be used in the reaction are alkyl carboxylic acids, cycloalkyl alkyl carboxylic acids, optionally substituted phenyl alkyl carboxylic acids and optionally substituted phenyl carboxylic acids. Suitable aliphatic carboxylic acids are carboxylic acids such as formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, 2-ethylbutyric acid, n-valeric acid, isovaleric acid, pivalic acid, n-hexanoic acid, isocaproic acid, decanoic acid, crotonic acid, palmitic acid, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid, phenyl-C_1-4Alkyl carboxylic acids, such as 3-phenylpropionic acid, 4-phenylbutyric acid, oxalic acid, malonic acid and tartaric acid.Suitable aromatic carboxylic acids include acids such as benzoic acid, p-chlorobenzoic acid, p-nitrobenzoic acid, p-methoxybenzoic acid, p-toluic acid, o-toluic acid, m-toluic acid, naphthoic acid, phthalic and terephthalic acids, salicylic acid, hydrocinnamic acid.

Preferably, the organic acid for improving the stereoselectivity of the enzyme is selected from the group consisting of n-propionic acid, iso-propionic acid, n-butyric acid, iso-valeric acid, 2-ethylbutyric acid, crotonic acid, palmitic acid, cyclohexanecarboxylic acid, pivalic acid, benzoic acid and p-toluic acid, salicylic acid and 3-phenylpropionic acid. The most preferred carboxylic acid used is pivalic acid.

The amount of the organic acid to be used is not particularly limited, but the molar ratio to the substrate is usually 0.1 to 10, preferably 1.0 to 3.0, more preferably 1.0 to 2.0.

Alternatively, the selectivity of the enzyme may be improved with an organic base, either alone or in combination with any of the organic acids mentioned above. Suitable organic bases may be mentioned triethylamine, pyridine and 4-dimethylaminopyridine, and pyridine is preferred. For example, a suitable combination of an organic acid and an organic base is benzoic acid and pyridine.

The amount of the organic base to be used is not particularly limited, but the molar ratio to the substrate is usually 0.5 to 3.0, preferably 0.5 to 2.0.

As indicated above, the R group represents a cyano group or any other group that can be converted to a cyano group.

Groups that can be converted to cyano include halogens such as chloro, bromo, iodo or fluoro, preferably chloro or bromo.

Other groups that can be converted to cyano include CF₃-(CF₂)_n-SO₂-O- (wherein n is 0-8), -OH, -CHO, -CH₂OH、-CH₂NH₂、-CH₂NO₂、-CH₂Cl、-CH₂Br、-CH₃、-NHR⁵、-CHNOH、-COOR⁶、-CONR⁶R⁷Wherein R is⁵Is hydrogen or C_1-6-alkylcarbonyl group, and R⁶And R⁷Selected from hydrogen, optionally substituted C_1-6Alkyl, aryl-C^1-6-alkyl or aryl, and a group of formula

Wherein Z is O or S; r⁸-R⁹Each independently selected from hydrogen and C_1-6-alkyl, or R⁸And R⁹Together form C_2-5-an alkylene chain, thereby forming a spiro ring; r¹⁰Selected from hydrogen and C_1-6-alkyl, R¹¹Selected from hydrogen, C_1-6-alkyl, carboxyl or a precursor group thereof, or R¹⁰And R¹¹Together form C_2-5-an alkylene chain, thereby forming a spiro ring.

When R is halogen, in particular bromo or chloro, the conversion into cyano can be carried out according to the methods described in the following documents: U.S. Pat. No. 4,136,193, WO 00/13648, WO 00/11926 and WO 01/02383.

According to US 4,136,193, the conversion of a bromo group to a cyano group is carried out by reaction with CuCN.

WO 00/13648 and WO 00/11926 describe the conversion of a halogen or triflic acid (triflate) group to a cyano group by cyanation with a cyanide source in the presence of a Pd or Ni catalyst.

Compounds in which the R group is a group of formula (VII) can be converted into the corresponding cyano compounds by methods analogous to those described in WO 00/23431.

Wherein R is OH, -CH₂OH、-CH₂NH₂、-CH₂NO₂、-CH₂Cl、-CH₂Br、-CH₃Or compounds of any of the above groups can be converted into the corresponding cyanation by methods analogous to those described in WO01/68632A compound (I) is provided.

The racemic compound of formula (II) can be prepared by the methods described in the above patents or by the acylation process described in us patent No. 4.136.193 or by the bis-grignard reaction described in EP 171943 or by similar methods. The racemic compound of formula (IV) can be prepared from the racemic compound of formula (II) by non-selective acylation with an anhydride, ester, carbonate, isocyanate or isothiocyanate, such as those of formula (IIIa), (IIIb), (IIIc), R, above¹-N ═ C ═ O and R¹-N ═ C ═ S.

In some cases, the racemic compound of formula (II) can be obtained in the form of an acid addition salt, such as a sulfate, and in such cases, the free base of the compound of formula (II) can be obtained by treating the salt with a base in a mixture of water and an organic solvent to transfer the compound of formula (II) to the organic phase.

Preferably, R is cyano. If R is not cyano, the conversion of the R group to cyano is suitably carried out after ring closure to form the compound of formula (V).

Preferably, Hal is fluoro. If Hal is not fluoro, the conversion of the group Hal to fluoro is suitably carried out after ring closure to form a compound of formula (V). Methods for performing this transformation are described in the following documents: speciality Chemicals Magazine, 4 months 2003, pages 36-38.

The Z group which can be converted into a dimethylaminomethyl group is a group such as-CH₂-L、-CH₂-NO₂-MgHal, cyano, aldehyde, -CH₂-O-Pg、-CH₂-NPg₁Pg₂、-CH₂-NMePg₁、-CH₂NHCH₃、-CH₂-NH₂、-CO-N(CH₃)₂、-CH(A¹R¹²)(A¹R¹³)、-(A¹R¹⁴) (A²R¹⁵) (A³R¹⁶)、-COOR¹⁷、-CH₂-CO-NH₂、-CH＝CH-R¹⁸or-CONHR¹⁹Wherein Pg is a protecting group for an alcohol group, Pg¹And Pg₂Is a protecting group for amino groups, R¹²And R¹³Independently selected from C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl and optionally alkyl-substituted aryl or aralkyl, or R¹²And R¹³Together form a chain of 2 to 4 carbon atoms, R¹⁴-R¹⁸Each of which is independently selected from C_1-6Alkyl radical, C_2-6-alkenyl, C_1-6-alkynyl and optionally C_1-6Alkyl-substituted aryl or aryl-C_1-6-alkyl, R¹⁹Is hydrogen or methyl, and A¹、A²And A³Selected from O and S; l is a leaving group, e.g. halogen or-O-SO₂-A, wherein A is C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl or optionally C_1-6Alkyl-substituted aryl or aryl-C_1-6-an alkyl group.

The alcohol protecting group Pg may be a trialkylsilyl, benzyl or Tetrahydropyranyl (THP).

Suitable radicals Pg₁And Pg₂Is aralkyl or-SO₂-R⁰Wherein R is⁰Is alkyl, aralkyl, aryl or aryl substituted with alkyl (typically methyl), benzyl or tosyl, or Pg₁And Pg₂Together with the N atom to which they are attached form an optionally substituted phthalimide group.

Wherein Z is-CH₂The compound of-O-Pg, wherein Z is dimethylaminomethyl, can be converted into the corresponding compound, as described in WO01/43525, WO 01/51478 or WO01/68631, or by analogous methods.

Wherein Z is-CH₂Compounds of formula-L, wherein L is a leaving group, can be converted to dimethylaminomethyl group in the same manner.

Wherein Z is-CO-N (CH)₃)₂and-CO-NHR¹⁹Wherein R is¹⁹Is hydrogen or methyl, can be converted into the corresponding compound, wherein Z is dimethylaminomethyl, as described in WO01/43525 or WO01/68631 or by analogous methods.

Wherein Z is-CH₂-NMe(Pg₁) or-CH₂Compounds of the formula-N (Pg1) (Pg2) in which Z is dimethylaminomethyl, can be converted into the corresponding compounds, as described in WO01/43525 or WO01/68631 or by analogous methods.

Wherein Z is-CH (A)¹R¹²)(A²R¹³) The compound of (3) can be converted into the corresponding compound wherein Z is dimethylaminomethyl group as described in WO01/43525 or WO01/68631 or by similar methods.

Wherein Z is-C (A)¹R¹⁴)(A²R¹⁵)(A³R¹⁶) Wherein Z is dimethylaminomethyl, as described in WO01/68631 or by analogous methods.

Wherein Z is-COOR¹⁷Can be converted into the corresponding compound, wherein Z is dimethylaminomethyl as described above, starting with a carboxylic ester.

Wherein Z is-CH₂-CONH₂The compound of (b) can be converted into the corresponding compound. Wherein Z is transformed as described in WO01/43525 or WO01/68631 or by similar methods.

Wherein Z is-CH ═ CHR¹⁸The compound of (3) can be converted into the corresponding compound wherein Z is dimethylaminomethyl group as described in WO01/43525 or WO01/68631 or by similar methods.

Wherein Z is cyano or-CH₂-NO₂Wherein Z is dimethylaminomethyl, as described in WO01/68629 or by similar methods.

Compounds wherein Z is-MgHal can be converted into the corresponding compounds wherein Z is dimethylaminomethyl as described in WO01/68629 or by analogous methods.

Preferably, Z is dimethylaminomethyl. If Z is not dimethylaminomethyl, the conversion of Z to dimethylaminomethyl is preferably carried out after the ring closure.

Compounds in which the dotted line represents a double bond can be converted into the corresponding compounds, in which the dotted line is a single bond, by the method described in WO 01/68630 or by a similar method. Preferably, the reduction is carried out after the ring closure.

Experiment of

In the following examples, the% conversion and optical purity were measured and calculated as follows:

HPLC analysis conditions (for conversion rate):

column: lichrospher RP-8 column, 250X 4mm (particle size of 5 μm)

Eluent: buffered MeOH/water, prepared as follows: 1,1ml of Et₃N was added to 150ml water, 10% H₃PO₄(aqueous) was added to pH 7 and water was added to a total volume of 200 ml. The mixture was added to 1,8L MeOH.

Temperature: 35 deg.C

Flow rate: 1 mL/min

Pressure: 16,0MPa

And (3) detection: UV254nm

Injection volume: 10 microliter

Conversion rate (%) > P/(S + P) × 100, (P: product amount, S: residual substrate amount).

And (4) performing supercritical fluid chromatography. Analytical conditions (for optical purity):

column: daicel AD column, size 250X 4,6mm (particle size of 5 μm)

Mobile phase: carbon dioxide

Modifying agent: methanol was reacted with diethylamine (0.5%) and trifluoroacetic acid (0.5%).

Gradient of modifier:

1-2%, 4 minutes

2-4%, 4 min

4-8% for 4 min

8-16% for 4 min

16-32% for 4 min

32-45% for 1,62 minutes

Temperature: ambient temperature

Flow rate: 2 mL/min

Pressure: 20mPa

And (3) detection: UV230nm and 254nm

Injection volume: 10 microliter

Optical purity (% ee) ═ (a-B)/(a + B) × 100, (a and B represent the corresponding stereoisomers, a > B)

E-value ═ ln ((1-c/100) × (1-Es/100))/ln ((1-c/100) × (1+ Es/100)) (c: conversion ratio, Es: optical purity of residual substrate)

Example 1

(S) -1- (3-dimethylamino-propyl) -1- (4-fluorophenyl) -1, 3-dihydro-isobenzo-1 Furan-5-carbonitrile hydrogen oxalate

To a solution of 3,7g of 4- [ (S) -4-dimethylamino-1- (4' -fluorophenyl) -1-hydroxybutyl]-3-hydroxymethylbenzonitrile and 6,3g of butyric acid 5-cyano-2- [ 4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl]To a mixture of benzyl ester (R/S ═ 3: 1) in 50ml of tetrahydrofuran was added 1,2g (1, 1 equivalent) of succinic anhydride. Stirring at room temperatureAnd (4) at night. The precipitated succinic acid mono- { 5-cyano-2- [ (S) -4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl group was filtered off]-benzyl } ester and washed with ice cold tetrahydrofuran to obtain 3,1g of ester with 98% purity. The crystals were dried in an oven and then dissolved in 50ml of anhydrous dimethylformamide. To the solution was added 1, 1g NaH (60% suspension in oil) and stirred at room temperature overnight. The mixture was quenched with water and extracted 3 times with 50ml diethyl ether. The combined organic phases were washed with 50ml of water and Na₂SO₄Dried and evaporated in vacuo. The residual oil was dissolved in 14ml of acetone and 630mg of oxalic acid was added. After stirring at room temperature for 1 hour, the precipitated crystals were filtered off and washed with ice-cold acetone to obtain 2,02g escitalopram hydrogen oxalate (ee-value 95%).

Example 2

(preparation of the mixture for example 1)

(S) -4- [ 4-dimethylamino-1- (4' -fluorophenyl) -1-hydroxybutyl]-3-hydroxymethylbenzonitrile

To racemic 4- [ 4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl]-3-hydroxymethylbenzonitrile (29mmol, 10g) and vinyl butyrate (58mmol, 7,5ml) in anhydrous 1, 4-bisTo a stirred solution of alkane (142,5ml) was added the lipoprotein lipase Pseudomonas species (160U, 250 mg). The reaction was heated to 50 ℃ and subsequently subjected to HPLC. After 192 hours of conversion at 41%, a further 250mg of lipase were added. The reaction was terminated after 504 hours at 63% conversion. The enzyme was filtered off and a small amount of 1, 4-bis was usedAnd (5) washing with alkane. The combined organic phases were evaporated under vacuum and subsequently analyzed on supercritical liquid chromatography. The ee-value obtained ((S-diol)) 95% (S-diol/R-diol 40: 1).

Claims (19)

1. A method for separating and purifying a compound having the formula from a mixture comprising a compound of formula (IV) and a diol of formula (II)

Wherein, R is a cyano group,

the dotted line represents a single bond,

hal is a halogen, and the halogen is,

z is a dimethylaminomethyl group which is a dimethylaminomethyl group,

w is a radical of oxygen, the radical being O,

y is a bond or a salt thereof,

and R is¹Is C_1-10-an alkyl group,

and/or a diol of the formula

Wherein R, Z, Hal and the dotted line are as defined above, or a salt thereof, comprising:

a) reacting the mixture comprising the compound of formula (IV) and the diol of formula (II) with a cyclic anhydride or diimide having the formula

Wherein X is a bond;

and R' are hydrogen;

to form a mixture of a compound of formula (IV) or an ester of the formula

Wherein R, Z and Hal are as defined above and V is-CHR '-X-CR' -COOH wherein R ', R' and X are as defined above;

b) isolating the compound of formula (IV) from the ester of formula (V) by a method selected from the group consisting of:

IV) allowing the acid of formula (V) or a salt thereof to precipitate from the reaction mixture and separating the precipitate of the compound of formula (V) or a salt thereof from the reaction mixture, optionally followed by separating the compound of formula (IV) or a salt thereof from the reaction mixture;

v) partitioning between an organic solvent and an aqueous solvent, whereby the compound of formula (IV) is dissolved in the organic phase and the compound of formula (V) is dissolved in the aqueous phase, separating the phases, and optionally separating the compound of formula (IV) or a salt thereof and/or separating the compound of formula (V) or a salt thereof; and

vi) adsorbing the compound of formula (V) on a base resin, separating the solvent containing the compound of formula (IV) from the resin, desorbing the compound of formula (V) from the base resin, and optionally isolating the compound of formula (IV) or a salt thereof and/or isolating the compound of formula (V) or a salt thereof.

2. The process of claim 1, wherein the isolation of the compound of formula (IV) from the ester of formula (V) is carried out by allowing the acid of formula (V) to precipitate from the reaction mixture and isolating the precipitate of the compound of formula (V) from the reaction mixture, optionally followed by isolation of the compound of formula (IV) or a salt thereof from the reaction mixture.

3. The process of claim 1 or 2, wherein the S-enantiomer of the compound of formula (V) or the enantiomeric mixture of the compound of formula (V) comprising more than 50% of the S-enantiomer of the compound of formula (V) is isolated from the R-enantiomer of the acyl derivative of formula (IV) or from the enantiomeric mixture of the acyl derivative of formula (IV) comprising more than 50% of the R-enantiomer of the acyl derivative of formula (IV).

4. The process of claim 3, wherein the S-enantiomer of the compound of formula (V) is isolated from the R-enantiomer of the acyl derivative of formula (IV) or from a mixture of enantiomers of the acyl derivative of formula (IV) comprising more than 50% of the R-enantiomer of the acyl derivative of formula (IV).

5. The process of claim 4, wherein the S-enantiomer of the compound of formula (V) is isolated from the R-enantiomer of the acyl derivative of formula (IV).

6. The process according to claim 1 or 2, wherein the S-enantiomer of the acyl derivative of formula (IV) or the enantiomeric mixture of the acyl derivative of formula (IV) comprising more than 50% of the S-enantiomer of the acyl derivative of formula (IV) is separated from the R-enantiomer of the compound of formula (V) or from the enantiomeric mixture of the compound of formula (V) comprising more than 50% of the R-enantiomer of the compound of formula (V).

7. The process of claim 6, wherein the S-enantiomer of the acyl derivative of formula (IV) is separated from the R-enantiomer of the compound of formula (V) or from an enantiomeric mixture of the compound of formula (V) comprising more than 50% of the R-enantiomer of the compound of formula (V).

8. The process of claim 7, wherein the S-enantiomer of the acyl derivative of formula (IV) is separated from the R-enantiomer of the compound of formula (V).

9. A process according to claim 3, wherein Hal in the compound of formula (V) is optionally converted to fluoro, and the compound of formula (V) is then converted to escitalopram or a derivative thereof having the formula

Wherein R, Z and Hal are as defined above, by treatment with a base, optionally followed by conversion of Hal to fluoro; optionally followed by conversion of escitalopram of formula (VI) or a derivative thereof into its salt.

10. A process according to claim 6, wherein Hal in the compound of formula (IV) obtained in the form of the S-enantiomer is optionally converted to fluoro, followed by conversion of the compound of formula (IV) to escitalopram or a derivative thereof

Wherein R, Z and Hal are as defined above, by treatment with a base, optionally followed by conversion of Hal to fluoro; optionally followed by conversion of escitalopram of formula (VI) or a derivative thereof into its salt.

11. The process according to any one of claims 9 or 10, wherein the basic cyclization is carried out by treatment with a base.

12. The method of claim 11, wherein the base is KOC (CH)₃)₃Or other alkoxides, NaH or other hydrides, or amines.

13. The process of claim 12 wherein the amine is triethylamine, ethyldiisopropylamine or pyridine.

14. The method of claim 1 or 2, wherein R¹Is C_1-4-an alkyl group.

15. The method of claim 1 or 2, wherein R¹Is C_1-3-an alkyl group.

16. The method of claim 15, wherein R¹Is methyl, ethyl or propyl.

17. The method of claim 16, wherein R¹Is propyl.

18. The process as claimed in claim 1 or 2, wherein the mixture of compounds of the formulae (II) and (IV) is prepared by selective enzymatic acylation or selective enzymatic deacylation.

19. A process for the production of escitalopram comprising the process according to any one of claims 1-18.