JP2005247710A - Method for producing optically active citalopram, intermediate thereof and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an optically active citalopram in higher atom economy than ever. <P>SOLUTION: The method comprises reacting an organometallic reagent(V) on a compound(IV) to form a compound(VI) stereoselectively, which is then derived into the objective optically active citalopram. In the formulas, X is cyano or the like; Y<SP>1</SP>is dimethylamino or the like; R<SP>1</SP>and R<SP>2</SP>are each a (substituted) lower alkyl or the like; M is MgX<SP>1</SP>( X<SP>1</SP>is a halogen atom ) or the like; * denotes an asymmetric carbon atom; and n is an integer of 0 or 1-3. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for producing optically active citalopram useful as an antidepressant, a synthetic intermediate thereof, and a method for producing the same.

  Formula (X ′):

Is useful as an antidepressant, and various production methods have been reported (for example, see Patent Document 1).
However, conventionally, only a method via an optically active intermediate obtained by the optical resolution method is known, and half of the unnecessary enantiomer is discarded, and the atom economy is low, so environmental and cost problems. Therefore, it was not an advantageous production method.
JP-A-2-36177

  An object of the present invention is to provide a method capable of efficiently producing optically active citalopram by developing a novel stereoselective reaction to improve the atom economy.

As a result of diligent research to solve the above problems, the present inventors have found that the formyl group of a novel intermediate represented by the following general formula (II) is converted into an optical activity represented by the following general formula (III). By protecting with a diol, an optically active intermediate represented by the following general formula (IV) is obtained, and when this is used to introduce a side chain moiety by an organometallic method, the asymmetric center of the optically active citalopram is selected. As a result, the present invention has been completed.
That is, the present invention is as follows.
[1] General formula (II):

(Wherein X represents a cyano group or a group that can be converted to a cyano group) (hereinafter also referred to as compound (II)).
[2] General formula (I):

(In the formula, X is as defined above.) A method for producing compound (II), comprising a step of oxidizing a compound represented by the following (hereinafter also referred to as compound (I)).
[3] General formula (IV):

Wherein X is as defined above, R ¹ and R ² are the same or different and each independently represents a lower alkyl group which may have a substituent, and n is 0 or 1-3. A compound represented by the following formula: * represents an asymmetric carbon) (hereinafter also referred to as compound (IV)).
[4] Compound (II) in the presence of an acid is represented by the general formula (III):

(Wherein each symbol has the same meaning as described above) and a step of reacting with an optically active diol compound (hereinafter also referred to as optically active diol compound (III)) IV) Production method.
[5] The production method of the above-mentioned [4], wherein the compound (II) obtained by the method of the above-mentioned [2] is used.
[6] General formula (VI):

(Wherein Y ¹ represents a dimethylamino group or a group that can be converted to a dimethylamino group, and other symbols are as defined above) (hereinafter also referred to as compound (VI)). Or its salt.
[7] Compound (IV) is converted to general formula (V):

(Wherein Y ¹ has the same meaning as described above, M represents Li or MgX ¹ (where X ¹ represents a halogen atom)) (hereinafter referred to as organometallic reagent ( V).) A method for producing compound (VI) or a salt thereof, comprising a step of reacting with V).
[8] The production method of the above-mentioned [7], wherein the compound (IV) obtained by the method of the above-mentioned [4] or [5] is used.
[9] General formula (VII):

(Wherein Y ² is the same as or different from Y ¹ and represents a dimethylamino group or a group that can be converted to a dimethylamino group, and X and * have the same meanings as described above). Compound (VII)) or a salt thereof.
[10] A process for producing compound (VII) or a salt thereof, comprising a step of deprotecting compound (VI) or a salt thereof.
[11] The production method of the above-mentioned [10], wherein the compound (VI) obtained by the method of the above-mentioned [7] or [8] is used.
[12] General formula (VIII), which comprises a step of reducing compound (VII) or a salt thereof:

(Wherein Y ³ is the same as or different from Y ¹ and Y ² and represents a dimethylamino group or a group that can be converted to a dimethylamino group, and X and * are as defined above). (Hereinafter also referred to as compound (VIII)) or a salt thereof.
[13] The production method of the above-mentioned [12], wherein the compound (VII) obtained by the method of the above-mentioned [10] or [11] is used.
[14] A compound represented by the general formula (IX), which comprises a step of cyclizing and reducing the compound (VII) or a salt thereof:

(Wherein Y ⁴ is the same as or different from Y ¹ and Y ² and represents a dimethylamino group or a group that can be converted to a dimethylamino group, and X and * are as defined above). (Hereinafter also referred to as compound (IX)) or a method for producing a salt thereof.
[15] The production method of the above-mentioned [14], wherein the compound (VII) obtained by the method of the above-mentioned [10] or [11] is used.
[16] (i) A step of subjecting compound (VIII) or a salt thereof obtained by the method described in [12] or [13] above to a cyclization reaction to form a phthalane ring, (ii) X is cyano Formula (X), which comprises a step of converting to a cyano group if not a group, and (iii) a step of converting to a dimethylamino group if Y ³ is not a dimethylamino group:

A free base (optically active citalopram) of a compound represented by the formula (hereinafter also referred to as compound (X)) or an acid addition salt thereof.
[17] Compound (IX) or a salt thereof obtained by the method described in [14] or [15] above, (i) when X is not a cyano group, and (ii) Y ⁴ is dimethyl A method for producing a free base (optically active citalopram) of compound (X) or an acid addition salt thereof, comprising a step of converting to a dimethylamino group when it is not an amino group.
[18] Compound (X) comprising at least one method selected from the production methods described in [2], [4], [7], [10], [12] and [14] above Of a free base (optically active citalopram) or an acid addition salt thereof.

  According to the production method of the present invention, the asymmetric center of optically active citalopram can be induced with high selectivity and efficiency, and it is not necessary to discard unnecessary enantiomers as in the optical resolution method. An optically active citalopram can be produced in the atom economy.

Hereinafter, the present invention will be described in detail.
First, the definition of symbols used in the present invention will be described.

  The “group that can be converted into a cyano group” represented by X is not particularly limited as long as it can be converted into a cyano group through one or more steps. For example, a halogen atom (eg, a chlorine atom, a bromine atom, Iodine atom, etc.), protected hydroxyl group, protected hydroxymethyl group, protected amino group, protected formyl group, protected carboxyl group, etc., and avoid reaction with organometallic reagent (V) From the point of needing to be converted and the ease of conversion to a cyano group, a halogen atom, a protected hydroxyl group, and a protected carboxyl group are preferred.

  There are no particular limitations on the protecting group of the “protected hydroxyl group” and “protected hydroxymethyl group”, and examples thereof include 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, 1-ethoxyethyl group, benzyl group, methoxy group. Examples thereof include a methyl group, a benzyloxymethyl group, a tert-butyldimethylsilyl group and the like, and a 2-tetrahydropyranyl group and a 1-ethoxyethyl group are preferable in order to avoid reaction of the reaction with the organometallic reagent (V). .

  The “protected amino group” is not particularly limited, and examples thereof include a benzyloxycarbonylamino group, a tert-butoxycarbonylamino group, an ethoxycarbonylamino group, a methoxycarbonylamino group, and the like, which react with the organometallic reagent (V). In order to avoid this reaction, a benzyloxycarbonylamino group and a tert-butoxycarbonylamino group are preferred.

  The “protected formyl group” is not particularly limited, and examples thereof include a dimethoxymethyl group, a 1,3-dioxolan-2-yl group, a 1,3-dioxane-2-yl group, and a 1,3-dithiolan-2-yl group. Group, 1,3-dithian-2-yl group and the like, and dimethoxymethyl group and 1,3-dioxolan-2-yl group are preferable in order to avoid reaction with organometallic reagent (V). .

  The “protected carboxyl group” is not particularly limited, and examples thereof include a carbamoyl group and an optionally substituted oxazolin-2-yl group (for example, oxazolin-2-yl group, 4,4-dimethyl-oxazoline). -2-yl group, etc.) and the like, and a 4,4-dimethyl-oxazolin-2-yl group is preferred in order to avoid reaction with the organometallic reagent (V).

The “lower alkyl group” of the “lower alkyl group optionally having substituent (s)” represented by R ¹ and R ² is linear or branched having 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl Group, nonyl group, decyl group, undecyl group, dodecyl group and the like, and methyl or ethyl is preferable.

  Examples of the substituent that the lower alkyl group may have include a linear or branched lower alkoxy group having 1 to 8 carbon atoms (eg, methoxy group, ethoxy group, isopropoxy group, butoxy group, isobutoxy group). Group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, hexyloxy group, heptyloxy group, octyloxy group, etc.), straight chain having 2 to 8 carbon atoms or Branched lower alkenyloxy group (eg, vinyloxy group, allyloxy group, 2-propenyloxy group, etc.), aryl group having 6 to 14 carbon atoms (eg, phenyl group, 1 or 2-naphthyl group, 2-3, -Or 4-toluyl group), an aralkyloxy group having 7 to 14 carbon atoms (eg, benzyloxy group, 1 or 2-naphthylmethyloxy group, 4-methoate). Shi benzyloxy group, 4-nitrobenzyl group and the like) and the like, preferably a lower alkoxy group, a lower alkenyloxy group, aralkyloxy group, more preferably a benzyloxy group.

The “lower alkyl group optionally having substituent (s)” represented by R ¹ and R ² is preferably a methyl group, a lower alkoxymethyl group, a lower alkenyloxymethyl group or an aralkyloxy group, more preferably a methyl group. , A benzyloxymethyl group.

Examples of the “halogen atom” represented by X ¹ include a chlorine atom, a bromine atom, and an iodine atom, and a chlorine atom or a bromine atom is preferable.

Y ¹ , Y ² , Y ³ and Y ⁴ are the same or different and each represents a “dimethylamino group or a group convertible to a dimethylamino group”. Alternatively, there is no particular limitation as long as it can be converted into a dimethylamino group through two or more steps. For example, a hydroxyl group (for example, a hydroxyl group, 2-tetrahydropyranyloxy group, 2-tetrahydrofuran which may have a protecting group) may be used. Nyloxy group, 1-ethoxyethoxy group, benzyloxy group, methoxymethoxy group, benzyloxymethoxy group, tert-butyldimethylsilyloxy group, etc.), amino group which may have a protecting group (for example, amino group, benzyl) Oxycarbonylamino group, tert-butoxycarbonylamino group, etc.). The “group that can be converted into a dimethylamino group” represented by Y ¹ is a hydroxyl group having a protecting group that cannot react with the organometallic reagent (for example, 2) because it is necessary to prepare the organometallic reagent (V) stably. -Tetrahydropyranyloxy group, 2-tetrahydrofuranyloxy group, etc.) are preferred.
Y ² , Y ³ and Y ⁴ may be the same as Y ¹ , but as long as it is a group that can be converted to the dimethylamino group listed above, compound (VI) is compound (VII), compound ( Depending on the reaction conditions for conversion to VIII) and compound (IX), it may be converted to a hydroxyl group or an amino group by deprotection or the like.

  Compounds (VI), (VII), (VIII) and (IX) may form a salt if they have a basic dimethylamino group. Such salts include, for example, inorganic acid salts (eg hydrochlorides, sulfates, nitrates, phosphates, hydrobromides, etc.) or organic acid salts (eg acetates, propionates, methanesulfonates). , 4-toluenesulfonate, oxalate, maleate, etc.).

  As the acid addition salt of compound (X), ie, optically active citalopram, a pharmacologically acceptable non-toxic acid addition salt is preferable. For example, maleate, fumarate, benzoate, ascorbate, pamoate , Succinate, oxalate, salicylate, methanesulfonate, ethanedisulfonate, acetate, propionate, tartrate, citrate, gluconate, lactate, malate, mandelate , Cinnamate, citrate, aspartate, stearate, palmitate, itaconate, glycolate, P-aminobenzoate, glutamate, benzenesulfonate, theophylline acetate, 8 -Salts with organic acids such as halotheophylline (eg 8-bromotheophylline) or hydrochloric acid, hydrobromic acid, sulfinic acid, sulfamine , Phosphoric acid, and salts with inorganic acids such as nitric acid.

The optically active diol compound (III), compounds (IV), (VI), (VII), (VIII), (IX) and (X) shown in the structural formula are those in which the attached carbon atom is optically active. A compound having two or more such asymmetric carbons includes any diastereomer or mixture thereof that may be present.
In the present invention, optical activity means that it is not an equimolar mixture (for example, racemate) of isomers having different steric configurations in asymmetric carbon, and one stereoisomer is present in excess (for example, 6 : 4) is defined as optical activity.
The production method of the present invention is shown in the following reaction scheme.

(In the formula, each symbol is as defined above.)
That is, the present invention includes at least one of the following steps (a) to (h): Compound (II), (IV), (VI), (VII), (VIII) and (IX), and compound (X) A method for producing a free base of optically active citalopram or an acid addition salt thereof.
Step (a): Compound (I) is oxidized to obtain Compound (II);
Step (b): Compound (II) is reacted with optically active diol compound (III) in the presence of an acid to obtain compound (IV);
Step (c): Compound (IV) is reacted with organometallic reagent (V) to obtain compound (VI) or a salt thereof;
Step (d): Compound (VI) or a salt thereof is deprotected to obtain compound (VII) or a salt thereof;
Step (e): Compound (VII) or a salt thereof is reduced to obtain Compound (VIII) or a salt thereof;
Step (f): Compound (VII) or a salt thereof is cyclized and reduced to obtain Compound (IX) or a salt thereof;
Step (g): Compound (VIII) or a salt thereof is subjected to the following steps (i) to (iii) to obtain a free base of compound (X) or an acid addition salt thereof;
(I) subject to a cyclization reaction to form a phthalane ring;
(Ii) when X is not a cyano group, it is converted to a cyano group;
(Iii) when Y ³ is not a dimethylamino group, it is converted to a dimethylamino group;
Step (h): Compound (IX) or a salt thereof is converted into a cyano group when (i) X is not a cyano group, and (ii) when Y ⁴ is not a dimethylamino group, converted into a dimethylamino group. A free base of compound (X) or an acid addition salt thereof is obtained.
Hereinafter, steps (a) to (h) will be described in detail.
The introduction or deprotection of protecting groups to hydroxyl groups, amino groups, formyl groups, carboxyl groups, etc. is described in “Protective Groups in Organic Synthesis 3rd edition”, 1999, Theodora Greene et al., John Willy & Sons. (John Wiley & Sons Inc).

1. Step (a)
Step (a) is a method of obtaining compound (II) by oxidizing compound (I).
The oxidation reaction is not particularly limited as long as it is a method capable of oxidizing the hydroxymethyl group of compound (I) to a formyl group, and conventionally known oxidation reactions can be applied without limitation. As such an oxidation reaction, for example, TEMPO oxidation (see Org. Synth., 69, 212 (1990)), swan oxidation (see J. Org. Chem., 43, 2480 (1978)), and a desmartin reagent are used. Methods (see J. Org. Chem., 48, 4156 (1983)), manganese dioxide oxidation (see Synthesis, 1976, 65), TRAP oxidation (see Chem. Soc. Rev., 21, 179 (1992)), etc. From the viewpoint of yield and selectivity, TEMPO oxidation, manganese dioxide oxidation, TRAP oxidation and the like are preferable. Although the TEMPO oxidation which is a preferable aspect is demonstrated below, a process (a) is not limited to the said aspect.

In the TEMPO oxidation in step (a), for example, compound (II) is obtained by oxidizing compound (I) with hypohalite in the presence of TEMPOs in a solvent.
Here, TEMPO means 2,2,6,6-tetramethyl-1-piperidinyloxy (also referred to as TEMPO) and its derivatives. Specifically, TEMPO, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (also called 4-hydroxy-TEMPO), 4-oxo-2,2,6,6-tetramethyl Piperidine-1-oxyl (also referred to as 4-oxo-TEMPO), ester of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (for example, 4- (benzoyloxy) -2,2, 6,6-tetramethylpiperidine-1-oxyl, 4- (methacryloyloxy) -2,2,6,6-tetramethylpiperidine-1-oxyl (also referred to as 4- (methacryloyloxy) -TEMPO), 4- ( Methanesulfonyloxy) -2,2,6,6-tetramethylpiperidine-1-oxyl, etc.), 4-amino-2,2,6,6-tetramethyl Amides or imides of peridine-1-oxyl (eg 4-acetamino-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-maleimido-2,2,6,6-tetramethylpiperidine-1- Oxyl etc.) etc. are mentioned, Preferably it is TEMPO, 4-hydroxy-TEMPO, etc.

  In the TEMPO oxidation, the order of addition of the reagent is not particularly limited, and it is sufficient to add the compound (I) and each reagent simultaneously or sequentially. However, since the operability is good, the compound (I) and the TEMPOs previously charged in the solvent It is preferable to add (preferably drop) a hypohalite solution.

  The amount of TEMPOs used may be a catalytic amount, and is usually 0.005 mol to 0.2 mol, preferably 0.02 mol to 0.1 mol, relative to 1 mol of compound (I). If the amount of TEMPO used is less than this range, the oxidation tends to be slow, and even if it is used beyond this range, the effect on the amount used tends to be small and economically disadvantageous.

  Examples of hypohalite used for TEMPO oxidation include hypochlorite, hypobromite, and hypoiodite. Examples of hypochlorite include sodium hypochlorite, potassium hypochlorite, calcium hypochlorite and the like. Examples of hypobromite include sodium hypobromite, potassium hypobromite, and calcium hypobromite. Examples of hypoiodite include sodium hypoiodite, potassium hypoiodite, calcium hypoiodite and the like. As the hypohalite, a commercially available one may be used as appropriate, or it may be prepared from caustic and halogen. From an economical viewpoint, sodium hypochlorite is particularly preferable.

  The amount of hypohalite used is usually 0.8 mol to 1.5 mol, preferably 1.0 mol to 1.2 mol, per 1 mol of compound (I). If the amount of hypohalite used is less than this range, it becomes difficult to complete the oxidation, and if it is used beyond this range, the oxidation may proceed to the carboxyl group.

  In TEMPO oxidation, a metal bromide (for example, potassium bromide, sodium bromide, etc.) or the like may be added. The amount of the metal bromide to be used is generally 0.01 mol to 0.2 mol, preferably 0.02 mol to 0.1 mol, per 1 mol of compound (I).

  In TEMPO oxidation, it is preferable to adjust the pH during the reaction to pH 3 to 13, and more preferably to pH 7 to 11 in order to promote the reaction. In order to adjust the pH during the reaction, a base such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate sodium hydroxide, potassium hydroxide or the like may be added so that the pH falls within the above range. I) It is used in the range of 0.1 mol to 3 mol with respect to 1 mol.

As a solvent used for TEMPO oxidation, water and a solvent immiscible with water (for example, ethyl acetate, methyl isobutyl ketone, toluene and the like may be used, and these may be used in combination of two or more). A phase solvent may be mentioned, and a two-phase solvent of water and ethyl acetate is preferable. When a two-phase solvent is used, the mixing ratio (v / v) of water and a solvent immiscible with water is not particularly limited, but is preferably in the range of 5: 1 to 1: 5 (v / v).
The usage-amount of a solvent is 1L-20L normally with respect to 1 kg of compounds (I).

  The reaction temperature for TEMPO oxidation is usually from -20 ° C to 50 ° C, but preferably from -10 ° C to 20 ° C. The reaction time is usually 2 to 24 hours.

  The resulting compound (II) decomposes the remaining halite after the oxidation, if necessary, so that a reducing agent (for example, sodium bisulfite, sodium thiosulfate, sodium pyrosulfite, sodium hydrosulfite, sulfide) After treatment with sodium or the like, it can be isolated and purified by a conventional method. For example, the organic layer can be separated, washed with water, dried and then concentrated by concentration, and further purified by silica gel column chromatography, but is not limited thereto. Moreover, it can also use for the next process, without refine | purifying.

  Compound (II) obtained in step (a) is a novel compound and is a useful synthetic intermediate for optically active citalopram.

  Compound (I), which is a raw material of step (a), is a known compound, and can be prepared, for example, by reacting 5-cyanophthalide with 4-fluorophenylmagnesium bromide as in Reference Example 1 described later.

2. Step (b)
Step (b) is a method of obtaining compound (IV) by reacting compound (II) with optically active diol compound (III) in the presence of an acid in a solvent, for example. In the step (b), the addition order of the reagent is not particularly limited, and the compound (II) and each reagent may be added simultaneously or sequentially.

In the optically active diol compound (III) used in the step (b), R ¹ and R ² may be the same or different. The absolute configuration of carbon must be the same, that is, R-form and R-form or S-form and S-form.
The configuration of the two asymmetric carbons of the optically active diol compound (III) may be selected as appropriate from the configuration required for obtaining the compound (IV) having the desired configuration. 4-di-O-benzyl-D-threitol, 1,4-di-O-benzyl-L-threitol, (2R, 4R)-(-)-2,4-pentanediol, (2S, 4S)-( +)-2,4-pentanediol and the like are preferably used.

  The usage-amount of optically active diol compound (III) is 0.9 mol-2 mol normally with respect to 1 mol of compound (II), Preferably it is 1 mol-1.5 mol.

Examples of the acid used in the step (b) include methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfuric acid, trifluoromethanesulfonic acid, zinc chloride, and boron trifluoride, and preferably methanesulfonic acid. P-toluenesulfonic acid.
The amount of the acid to be used is generally 0.001 mol to 0.2 mol, preferably 0.01 mol to 0.1 mol, per 1 mol of compound (II). If the amount of the acid used is less than this range, the reaction tends to be slow, and if it is used beyond this range, the effect on the amount used tends to be small and economically disadvantageous.

The solvent used in the step (b) is not particularly limited as long as it does not inhibit the reaction, and examples thereof include single or mixed solvents such as toluene, xylene, tetrahydrofuran (THF), monochlorobenzene, dichloromethane, chloroform, and the like. Toluene is preferred.
The usage-amount of a solvent is 0.1L-10L normally with respect to 1 kg of compounds (II).

  The reaction temperature in the step (b) is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C., and more preferably carried out with azeotropic dehydration using a Dean-Stark tube. The reaction time is usually 1 to 24 hours.

The resulting compound (IV) can be isolated and purified by a conventional method. For example, the reaction mixture can be washed with water, dried and then concentrated to isolate compound (IV), which can be further purified by silica gel column chromatography, but is not limited thereto. Moreover, it can also use for the next process, without refine | purifying.
Compound (IV) obtained in step (b) is a novel compound and is a useful synthetic intermediate for optically active citalopram.

3. Step (c)
Step (c) is a method in which compound (IV) or a salt thereof is obtained by reacting compound (IV) with organometallic reagent (V) in a solvent, for example. In the step (c), the order of addition of the reagent is not particularly limited, and the compound (IV) and the organometallic reagent (V) may be added simultaneously or sequentially, but in order to improve operability and reaction selectivity, Preferably, a solution of the organometallic reagent (V) is added dropwise to the compound (IV).

The organometallic reagent (V) used in the step (c) is obtained by converting a compound represented by the general formula: X ¹ (CH ₂ ) ₃ Y ¹ into metal lithium and an ether solvent (for example, THF, diethyl ether, methyl tert In butyl ether (MTBE), etc.) at −20 to 60 ° C., or by reacting magnesium with a normal Grignard reagent.

  The amount of the organometallic reagent (V) to be used is generally 0.9 mol to 50 mol, preferably 1.5 mol to 35 mol, per 1 mol of compound (IV). If the amount of the organometallic reagent (V) used is less than this range, the reaction is difficult to complete, and if it is used outside this range, side reactions may proceed.

The solvent used in the step (c) is not particularly limited as long as it does not inhibit the reaction. For example, ether such as THF, methyl tert-butyl ether (MTBE), 1,4-dioxane, 1,2-dimethoxyethane, etc. Aromatic hydrocarbons such as benzene, toluene, xylene, etc .; Aliphatic hydrocarbons such as heptane, hexane, octane, etc., alone or in a mixed solvent, and THF, MTBE, and toluene are preferred.
The amount of the solvent to be used is generally 0.1 L to 10 L with respect to 1 kg of compound (IV).

  The reaction temperature in the step (c) is usually from -20 ° C to 80 ° C, but preferably from 0 ° C to 40 ° C. The reaction time is usually 1 to 24 hours.

The resulting compound (VI) can be isolated and purified by a conventional method. For example, the compound (VI) can be isolated by pouring the reaction mixture into dilute acidic water (eg, aqueous ammonium chloride solution, etc.), washing the organic layer with water, drying and concentrating, and further purifying by silica gel column chromatography. However, the present invention is not limited to this. Moreover, it can also use for the next process, without refine | purifying.
Further, when the compound (VI) is a crystal, it is recrystallized if necessary, or is recrystallized after being converted into a salt with an optically active carboxylic acid such as tartaric acid, di-o-toluoyltartaric acid, mandelic acid or the like by a conventional method. Crystallization can increase the optical purity.
Compound (VI) obtained in step (c) is a novel compound and is a useful synthetic intermediate for optically active citalopram.

4). Step (d)
Step (d) is a method of deprotecting compound (VI) or a salt thereof to obtain compound (VII), and can be usually carried out by hydrolysis in a solvent in the presence of an acid.

Examples of the acid used in the step (d) include hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like, preferably hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluene. Sulfonic acid.
The amount of the acid to be used is generally 0.01 mol to 100 mol with respect to 1 mol of compound (VI). If the amount of the acid used is less than this range, the reaction tends to be slow, and if the amount exceeds this range, the effect on the amount used is reduced, and racemization may proceed.

The solvent used in the step (d) is not particularly limited as long as it does not inhibit the reaction. For example, THF, methanol, ethanol, isopropyl alcohol, water, acetone, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc), dimethylsulfoxide (DMSO) and the like can be used alone or in combination, and THF is preferred.
The usage-amount of a solvent is 1L-50L normally with respect to 1 kg of compounds (VI).

  The reaction temperature in the step (d) is usually 0 ° C to 100 ° C, but preferably 20 ° C to 60 ° C. The reaction time is usually 1 to 20 hours.

  The resulting compound (VII) can be isolated and purified by a conventional method. For example, the reaction mixture can be washed with water, dried and then concentrated to isolate compound (VII), which can be further purified by silica gel column chromatography, but is not limited thereto. Moreover, it can also use for the next process, without refine | purifying. Further, when the compound (VII) is a crystal, it is recrystallized if necessary, or is recrystallized after being converted into a salt with an optically active carboxylic acid such as tartaric acid, di-o-toluoyl tartaric acid, mandelic acid or the like by a conventional method. Crystallization can increase the optical purity.

  Compound (VII) obtained in step (d) is a novel compound and is a useful synthetic intermediate for optically active citalopram. In addition, compound (VII) is represented by the general formula (VII ′):

(Wherein each symbol has the same meaning as described above) and is in equilibrium with a lactol body (hereinafter also referred to as lactol (VII ′)), and compound (VII) includes lactol (VII ′). Is.

5). Step (e)
Step (e) is a method of obtaining compound (VIII) or a salt thereof by reducing compound (VII) or a salt thereof, and can usually be carried out by reacting with a reducing agent in a solvent. The order of reagent addition is not particularly limited, and compound (VII) and the reducing agent may be added simultaneously or sequentially.

The reducing agent used in step (e) is not particularly limited as long as it can reduce the formyl group of compound (VII) to a hydroxymethyl group. Specifically, sodium borohydride, borohydride Examples thereof include lithium, lithium aluminum hydride, diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, and sodium borohydride is preferred.
The amount of the reducing agent to be used is generally 0.25 mol to 2 mol, preferably 0.3 mol to 1.6 mol, per 1 mol of compound (VII).

Examples of the solvent used in the reduction reaction include water, methanol, ethanol, isopropyl alcohol, t-butyl alcohol, THF, MTBE, dimethoxyethane, diglyme, and 1,4-dioxane. Methanol, ethanol, a mixed solvent of methanol and THF, and a mixed solvent of ethanol and THF are preferable.
The amount of the solvent to be used is generally 5 L to 50 L with respect to 1 kg of compound (VII).

  The reaction temperature in the step (e) is usually from -20 ° C to 80 ° C, but preferably from 0 ° C to 50 ° C. The reaction time is usually 1 to 24 hours.

  The resulting compound (VIII) can be isolated and purified by a conventional method. For example, the reaction mixture is poured into dilute acidic water (eg, aqueous ammonium chloride solution), extracted with an organic solvent such as toluene, the organic layer is washed with water, dried and concentrated to isolate compound (VIII), and further silica gel Although it can refine | purify by column chromatography, it is not limited to this. Moreover, it can also use for the next process, without refine | purifying. Further, when the compound (VIII) is a crystal, it is recrystallized if necessary, or recrystallized after being converted to a salt with an optically active carboxylic acid such as tartaric acid, di-o-toluoyltartaric acid, mandelic acid or the like by a conventional method. Crystallization can increase the optical purity.

6). Step (f)
Step (f) is a method in which compound (VII) or a salt thereof is cyclized and reduced to obtain compound (IX) or a salt thereof. Here, the cyclization reduction of compound (VII) means that the hydroxyl group of the phthalane ring of lactol (VII ′), which is a cyclized product of compound (VII), is reduced to a hydrogen atom as shown in the following scheme. To do.

  The cyclization reduction reaction can be performed, for example, by reacting compound (VII) with a reducing agent in a solvent. The order of reagent addition is not particularly limited, and compound (VII) and the reducing agent may be added simultaneously or sequentially. Moreover, it can also carry out by hydrogenation reaction using palladium carbon, palladium hydroxide, etc. as a catalyst.

  Reducing agents used in the cyclization reduction reaction include trialkylsilane (eg, triethylsilane, tributylsilane, etc.), trichlorosilane, trialkoxysilane (eg, triethoxysilane, etc.), diborane, borane / THF complex, hydrogenation A combination of sodium borohydride and Lewis acid (especially boron trifluoride), a combination of sodium borohydride and iodine, and the like, and a combination of triethylsilane, sodium borohydride and boron trifluoride is preferable.

  The amount of the reducing agent to be used is generally 0.25 mol to 2.0 mol, preferably 0.3 mol to 1.5 mol, per 1 mol of compound (VII).

  When using a trialkylsilane or trialkoxysilane, it is preferable to add an acid such as trifluoroacetic acid during the reaction. The amount of the acid used is 0.1 equivalent to 10 equivalents relative to the trialkylsilane. preferable.

  The reaction temperature of the cyclization reduction reaction is usually -20 ° C to 100 ° C, but preferably 0 ° C to 70 ° C. The reaction time is usually 1 to 24 hours.

  When the cyclization reduction reaction is performed by a hydrogenation reaction, the compound (VII) is added in a solvent (eg, ethanol, acetic acid, ethyl acetate, etc.) in the presence of 0.001 to 0.1 equivalent of a catalyst and 1 to 30 atm. In a hydrogen atmosphere, usually at 0 to 80 ° C. for 1 to 24 hours.

  The resulting compound (IX) can be isolated and purified by a conventional method. For example, the organic layer can be separated, washed with water, dried and then concentrated by concentration, and further purified by silica gel column chromatography, but is not limited thereto. Moreover, it can also use for the next process, without refine | purifying. Further, when the compound (IX) is a crystal, it is recrystallized if necessary, or is recrystallized after being converted into a salt with an optically active carboxylic acid such as tartaric acid, di-o-toluoyl tartaric acid, mandelic acid or the like by a conventional method. Crystallization can increase the optical purity.

7). Step (g)
Step (g) is a method in which compound (VIII) or a salt thereof is subjected to the following steps (i) to (iii) to obtain a free base of compound (X) or an acid addition salt thereof. However, when X is a cyano group need not subjected to the following step (ii), Y ³ is not necessary to subject the following step (iii) if a dimethylamino group.
(I) subjecting to a cyclization reaction to form a phthalane ring (hereinafter also referred to as step (g-1));
(Ii) When X is not a cyano group, it is converted to a cyano group (hereinafter also referred to as step (g-2));
(Iii) When Y ³ is not a dimethylamino group, it is converted to a dimethylamino group (hereinafter also referred to as step (g-3)).

  In the step (g), the order of attaching the compound (VIII) to the steps (g-1) to (g-3) is not particularly limited, but in order to suppress by-products, the step (g-1) The order of (g-3) → (g-2) or step (g-3) → (g-1) → (g-2) is preferable.

  Hereinafter, steps (g-1) to (g-3) will be described. In addition, although compound (VIII) attached | subjected to each process may differ with the order of process (g-1)-(g-3), it demonstrates as compound (VIII) for convenience.

7-1. Step (g-1)
The cyclization reaction in the step (g-1) can be performed, for example, by reacting the compound (VIII) with an acid halide in the presence of a base in a solvent. The order of reagent addition is not particularly limited, and compound (VIII) and each reagent may be added simultaneously or sequentially.

Examples of the base used in the step (g-1) include triethylamine, dimethylaniline, pyridine and the like, and triethylamine is preferable.
The amount of the base to be used is generally 0.9 mol to 2 mol, preferably 1 mol to 1.5 mol, per 1 mol of compound (VIII).

The acid halide used in the step (g-1) is preferably one capable of converting the hydroxymethyl group of the compound (VIII) into a detachable ester, such as methanesulfonyl chloride, p-toluenesulfonyl chloride, 10-camphor. Examples include sulfonyl chloride, trifluoroacetyl chloride, trifluoromethanesulfonyl chloride and the like, and methanesulfonyl chloride is preferable.
The amount of the acid halide to be used is generally 0.9 mol to 1.8 mol, preferably 1 mol to 1.4 mol, per 1 mol of compound (VIII).

The solvent used in the step (g-1) is not particularly limited as long as it does not inhibit the reaction, and examples thereof include single or mixed solvents such as toluene, xylene, THF, MTBE, dichloromethane, monochlorobenzene and the like. Or THF is preferable.
The amount of the solvent to be used is generally 1 L to 50 L with respect to 1 kg of compound (VIII).

  The reaction temperature in the step (g-1) is usually from -20 ° C to 50 ° C, but preferably from -10 ° C to 30 ° C. The reaction time is usually 1 to 12 hours.

7-2. Step (g-2)
The process (g-2) differs in the method of converting into a cyano group by the aspect of "group which can be converted into a cyano group" shown by X.
For example, when X is a halogen atom, 0.9 to 2.5 equivalents of cuprous cyanide or palladium catalyst (for example, tetrakis ( (Triphenylphosphine) palladium) in the presence of 0.9 to 2.5 equivalents of metal cyanide (eg, sodium cyanide, potassium cyanide, etc.) at 30 ° C. to 150 ° C. for 1 to 24 hours. Can do.

  When X is a protected hydroxyl group, after deprotection, trifluoromethanesulfonyl chloride or anhydrous trifluoromethane in the presence of a base (eg, triethylamine, pyridine, etc.) in a solvent (eg, dichloromethane, toluene, THF, etc.) The reaction can be carried out by converting a deprotected hydroxyl group into a trifluoromethanesulfonyloxy group by reacting with sulfonyl, and reacting the resulting trifluoromethanesulfonate under the same conditions as described above wherein X is a halogen atom.

When X is a protected amino group, after deprotection, it is deprotected by the so-called Sandmeyer reaction with sodium nitrite and cuprous halide (see Org. Syn., Coll. Vol. 3, 185). The resulting amino group can be converted into a halogen atom and further reacted under the same conditions as described above in which X is a halogen atom.
Alternatively, the deprotected amino group can be converted to a cyano group by a modified Sandmeyer reaction with sodium nitrite and cuprous cyanide (see Org. Syn., Coll. Vol. 1, 514).

  When X is a protected formyl group, it is deprotected and then reacted with hydroxylamine to convert the formyl group into the corresponding oxime, followed by a dehydrating agent (eg, thionyl chloride, phosphorus oxychloride, acetic anhydride, etc. ) To formyl groups can be converted to cyano groups (see Org. Syn., Coll. Vol. 2, 622).

  When X is a protected hydroxymethyl group, after deprotection, for example, after converting the hydroxymethyl group to a formyl group by the same method as in the above step (a), X is a protected formyl group It can carry out by making it react on the conditions similar to the above.

  When X is a protected carboxyl group, after deprotection, the carboxyl group is converted into a carbamoyl group or a 1,3-oxazolin-2-yl group by a conventional method (the same method as that for introducing a protecting group), Further, by reacting with a dehydrating agent (eg, thionyl chloride, phosphorus oxychloride, phosphorus pentoxide, etc.), the formyl group can be converted to a cyano group (Org. Syn., Coll. Vol. 4, 436, 486). reference). In particular, when the protected carboxyl group is a carbamoyl group or an oxazolin-2-yl group, the deprotection can be performed.

7-3. Step (g-3)
Step (g-3), due aspect of the "group convertible to a dimethylamino group" represented by Y ^3, how to convert the dimethylamino group is different.

For example, when Y ³ is a hydroxyl group that may have a protecting group, the deprotection can be performed as necessary, and then the hydroxyl group is converted to a leaving ester and reacted with dimethylamine.

  As a method for converting a hydroxyl group into a leaving ester, 0.9 to 1.5 equivalents of an acid halide (eg, methanesulfonyl chloride, p-toluene) in a solvent (eg, toluene, xylene, THF, MTBE, etc.) Sulfonyl chloride, 10-camphor sulfonyl chloride, trifluoroacetyl chloride, trifluoromethanesulfonyl chloride and the like) and -20 ° C to 80 ° C for 1 to 24 hours.

  Further, in the reaction with dimethylamine, in a solvent (eg, toluene, xylene, THF, MTBE, methanol, ethanol, isopropanol, etc.), 0.9 to 5 equivalents of dimethylamine (preferably an aqueous solution) and 0 ° C to It can carry out by making it react at 80 degreeC for 1 to 24 hours.

As another embodiment of the step (g-3), when Y ³ is an amino group which may have a protecting group, after deprotecting as necessary, a solvent (eg, toluene, xylene, THF, MTBE, etc.) It can be carried out by reacting with 2 to 4 equivalents of a methylating agent (eg, methyl iodide, dimethyl sulfate, etc.) at -20 ° C to 80 ° C for 0.5 to 12 hours.

  Isolation and purification of the compound (X) obtained in the step (g) can be performed by a conventional method, and if necessary, isolation in each step of the step (g-1) to the step (g-3), It may be purified. Furthermore, the optical purity can be increased by subjecting compound (X) to recrystallization as required.

8). Step (h)
In step (h), compound (IX) or a salt thereof is converted to a cyano group when X is not a cyano group (hereinafter also referred to as step (h-1)), and when Y ⁴ is not a dimethylamino group. In this method, the compound (X) is obtained by converting it to a dimethylamino group (hereinafter also referred to as step (h-2)). However, X is not necessary to subject the step (h-1) in the case of a cyano group, Y ⁴ is not necessary to subject the step (h-2) If a dimethylamino group.

  The order in which compound (IX) is subjected to step (h-1) and step (h-2) is not particularly limited, but in order to suppress by-products, step (h-2) → (h-1 ) Is preferred.

  The step (h-1) can be performed under the same conditions as the above step (g-2), and the step (h-2) can be performed under the same conditions as the above step (g-3).

The free base (optically active citalopram) of compound (X) obtained by step (g) or (h) can be converted to an acid addition salt, if necessary.
The acid addition salt can be produced by a conventionally known method. For example, in a solvent miscible with water (eg, acetone, ethanol, methanol, isopropanol, etc.), the free base of compound (X) is converted to an organic acid ( Examples: maleic acid, fumaric acid, benzoic acid, ascorbic acid, pamoic acid, succinic acid, oxalic acid, salicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, citric acid, gluconic acid, lactic acid, malic acid , Mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, theofiloline acetic acid, 8-halotheofylline, etc.) or inorganic acid ( Eg hydrochloric acid, hydrobromic acid, sulfinic acid, sulfamic acid, phosphoric acid, nitric acid etc.) The acid addition salt precipitated by concentration or cooling is isolated by filtration or the like, or reacted in a poor solvent such as ethyl ether, ethyl acetate or dichloromethane, and the acid addition salt precipitated is isolated. Can do. The obtained acid addition salt can be increased in optical purity by subjecting it to recrystallization if necessary.

  Hereinafter, the present invention will be described more specifically with reference to examples. The present invention is not limited by these.

Reference Example 1: Synthesis of 4- (4′-fluorobenzoyl) -3-hydroxymethylbenzonitrile Magnesium (2.8 g, 115 mmol) was dispersed in THF (8 mL) under nitrogen, and iodine (0.01 g) was added. Then, 4-bromofluorobenzene (0.35 g, 2 mmol) was added, and after confirming the temperature rise, THF (40 mL) was introduced. Thereafter, 4-bromofluorobenzene (19 g, 109 mmol) was added dropwise at 45 ° C. or lower and cooled to room temperature. This solution was added dropwise at around −10 ° C. to a solution in which 5-cyanophthalide (16 g, 100 mmol) was dispersed in THF (100 mL), and stirred at the same temperature for 15 hours. The reaction solution was poured into 20% aqueous ammonium chloride solution (150 mL), 1M aqueous citric acid solution (25 mL) was added, the organic phase was separated, washed twice with water (100 mL), and the solvent was distilled off. The title compound (25 g) was obtained.

Example 1: Synthesis of 4- (4'-fluorobenzoyl) -3-formylbenzonitrile 4- (4'-fluorobenzoyl) -3-hydroxymethylbenzonitrile (25 g, 98 mmol) was dissolved in ethyl acetate (100 mL). To the resulting solution was added sodium bicarbonate (4 g, 54 mmol), potassium bromide (0.7 g, 6 mmol), 4-hydroxy-2,2,6,6-tetramethyl-1-piperidin-1-yloxy free radical (HO-TEMPO) (0.6 g, 3.5 mmol) and water (50 mL) were added, and a 13% sodium hypochlorite aqueous solution (31 g, 54 mmol) was added dropwise at 0 to 5 ° C., and HO-TEMPO was further added at the same temperature. (0.4 g, 2.3 mmol) and 13% aqueous sodium hypochlorite solution (31 g, 54 mmol) were added dropwise and stirred overnight. To the reaction mixture was added 2% aqueous sodium sulfite (20 mL) and stirred, and then the organic phase was separated, washed with 20 mL of 10% brine, concentrated under reduced pressure, and purified by silica gel column chromatography to give the title compound (7. 2 g) was obtained.

¹ H-NMR (CDCl ₃ , 400MHz) δ ppm 7.18 (2H, t, J = 9Hz), 7.62 (1H, d, J = 8Hz), 7.81 (2H, dd, J = 9Hz, J = 6Hz), 7.98 (1H, dd, J = 8Hz, J = 2Hz), 8.31 (1H, d, J = 2Hz), 10.00 (1H, s).

Example 2: Synthesis of 3-[(4R, 5R) -4,5-bis (benzyloxymethyl) -1,3-dioxolan-2-yl] -4- (4'-fluorobenzoyl) benzonitrile 4- (4′-Fluorobenzoyl) -3-formylbenzonitrile (0.8 g, 3.2 mmol) was dissolved in toluene (3 mL), methanesulfonic acid (0.01 g, 0.1 mmol) was added, and 1,4 -Di-O-benzyl-D-threitol (1.2 g, 4 mmol) was added and allowed to react overnight. Triethylamine (0.1 g) was added to the reaction solution, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain the title compound (1.2 g).

¹ H-NMR (CDCl ₃ , 400 MHz) δppm 3.45-3.57 (4H, m), 3.98-4.03 (1H, m), 4.13-4.18 (1H, m), 4.46 (4H, s), 7.08 (2H, t , J = 8Hz), 7.2-7.38 (11H, m), 7.70 (1H, dd, J = 8Hz, J = 2Hz), 7.75 (2H, dd, J = 8Hz, J = 4Hz), 8.06 (1H, d , J = 2Hz).

Example 3: 3-[(4R, 5R) -4,5-bis (benzyloxymethyl) -1,3-dioxolan-2-yl] -4- [4-dimethylamino-1- (4′-fluoro Synthesis of optically active form of (phenyl) -1-hydroxy-1-butyl] benzonitrile 3-Dimethylaminopropyl chloride hydrochloride (20 g, 127 mmol) was neutralized with aqueous sodium hydroxide and extracted with toluene (5 mL). The solution was dehydrated with anhydrous potassium carbonate, filtered, washed with THF (5 mL), and the combined solution was added dropwise at room temperature to 65 ° C. in a solution in which magnesium (2.2 g, 90 mmol) was dispersed in THF (3 mL). And react for 3 hours to prepare a 3-dimethylaminopropylmagnesium chloride solution. 3-[(4R, 5R) -4,5-bis (benzyloxymethyl) -1,3-dioxolan-2-yl] -4- (4′-fluorobenzoyl) benzonitrile (0.2 g, 0.4 mmol) ) In THF (2 mL), 3-dimethylaminopropylmagnesium chloride solution (4 g, 12 mmol) prepared above is added dropwise and stirred overnight at room temperature. The reaction solution was poured into a saturated aqueous ammonium chloride solution, and the organic phase was separated. The organic phase is extracted with a 20% aqueous acetic acid solution, neutralized with a 20% aqueous sodium hydroxide solution to a pH of 10 or lower, and the organic phase extracted with toluene is concentrated under reduced pressure to obtain 0.2 g of the title compound. The absolute configuration of the induced asymmetric center has not been determined. The optical purity can be improved by recrystallizing the present compound or recrystallizing a salt with an optically active carboxylic acid such as tartaric acid, di-o-toluoyl tartaric acid or mandelic acid.

Example 4: Synthesis of optically active form of 4- [4-dimethylamino-1- (4′-fluorophenyl) -1-hydroxy-1-butyl] -3-formylbenzonitrile 3-[(4R, 5R) -4,5-bis (benzyloxymethyl) -1,3-dioxolan-2-yl] -4- [4-dimethylamino-1- (4'-fluorophenyl) -1-hydroxy-1-butyl] benzo The optically active substance of nitrile (0.2 g, 0.3 mmol) is dissolved in THF (2 mL), 6N hydrochloric acid (2 mL) is added, and the mixture is stirred at room temperature to 50 ° C. for 3 hours. Toluene (2 mL) is added, and the extracted organic phase is thoroughly washed with water. Then, the solvent is distilled off and the residue is purified by silica gel column chromatography to obtain 0.1 g of the title compound. The optical purity can be improved by recrystallizing the present compound or recrystallizing a salt with an optically active carboxylic acid such as tartaric acid, di-o-toluoyl tartaric acid or mandelic acid.

Example 5: Synthesis of optically active 4- [4-dimethylamino-1- (4′-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) benzonitrile 4- [4- Dimethylamino-1- (4′-fluorophenyl) -1-hydroxy-1-butyl] -3-formylbenzonitrile optically active substance (0.1 g, 0.3 mmol) was dissolved in THF (2 mL) and methanol (2 mL). And sodium borohydride (0.02 g, 0.53 mmol) is added and stirred at room temperature overnight. The reaction solution is poured into water (5 mL), extracted with toluene (3 mL), washed with water, and the residue obtained by distilling off the solvent under reduced pressure is purified by silica gel column chromatography to obtain 0.1 g of the title compound. The optical purity can be improved by recrystallizing the present compound or recrystallizing a salt with an optically active carboxylic acid such as tartaric acid, di-o-toluoyl tartaric acid or mandelic acid.

Example 6 1- (3-Dimethylaminopropyl) -1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile optically active substance (optically active citalopram) and oxalate salt thereof Using the optically active form of 4- [4-dimethylamino-1- (4′-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) benzonitrile obtained in Example 5, The free base of optically active citalopram is obtained by cyclization in the same manner as described in JP-A No. 11-292867, and the title oxalate salt is obtained in the same manner as described in the literature. Optical purity can be improved by recrystallizing the free base or recrystallizing the oxalate.

Example 7: Synthesis of 3-[(4R, 6R) -4,6-dimethyl-1,3-dioxan-2-yl] -4- (4'-fluorobenzoyl) benzonitrile 4- (4'-fluoro Benzoyl) -3-formylbenzonitrile (4.05 g, 16 mmol) was dissolved in toluene (12 mL), methanesulfonic acid (0.01 g, 0.1 mmol) was added, and (2R, 4R)-(-)- 2,4-Pentanediol (2.0 g, 19 mmol) was added and allowed to react overnight. Triethylamine (0.1 g) was added to the reaction solution, and the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography to obtain 4.5 g of the title compound.

¹ H-NMR (CDCl ₃ , 400 MHz) δppm 1.01 (3H, d, J = 6 Hz), 1.24 (3H, d, J = 8 Hz), 1.29-1.33 (1H, m), 1.74-1.82 (1H, m) , 3.91-3.99 (1H, m), 4.23-4.30 (1H, m), 7.13 (2H, t, J = 9Hz), 7.34 (1H, d, J = 8Hz), 7.68 (1H, dd, J = 8Hz , J = 2Hz), 7.81 (2H, dd, J = 9Hz, J = 5Hz), 8.09 (1H, d, J = 2Hz).

Example 8: 1- (3-Dimethylaminopropyl) -1- (4′-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile optically active substance (optically active citalopram) and oxalate salt thereof Synthesis of 3-[(4R, 5R) -4,5-bis (benzyloxymethyl) -1,3-dioxolan-2-yl] -4- (4′-fluorobenzoyl) benzonitrile instead of 3- [ Performed in the same manner as in Examples 3 to 6 except that (4R, 6R) -4,6-dimethyl-1,3-dioxan-2-yl] -4- (4′-fluorobenzoyl) benzonitrile was used. To obtain the optically active citalopram free base and its oxalate salt.

Claims (18)

General formula (II):

(Wherein X represents a cyano group or a group that can be converted to a cyano group). Formula (I):

(Wherein X represents a cyano group or a group that can be converted to a cyano group.), Which comprises a step of oxidizing the compound represented by the general formula (II):

(Wherein X is as defined above). Formula (IV):

(Wherein X represents a cyano group or a group that can be converted to a cyano group, R ¹ and R ² are the same or different and each independently represents a lower alkyl group which may have a substituent, n represents an integer of 0 or 1 to 3, and * represents an asymmetric carbon. General formula (II):

(Wherein X represents a cyano group or a group that can be converted to a cyano group), in the presence of an acid, the compound represented by the general formula (III):

(Wherein R ¹ and R ² are the same or different and each independently represents a lower alkyl group which may have a substituent, n represents an integer of 0 or 1 to 3, and * represents an A compound represented by the general formula (IV), characterized by comprising a step of reacting with an optically active diol compound represented by formula (IV):

(Wherein each symbol has the same meaning as described above).   The manufacturing method of Claim 4 using the compound represented by general formula (II) obtained by the method of Claim 2. General formula (VI):

(Wherein X represents a cyano group or a group that can be converted to a cyano group, Y ¹ represents a dimethylamino group or a group that can be converted to a dimethylamino group, and R ¹ and R ² are the same or different, A lower alkyl group which may have a substituent independently, n represents an integer of 0 or 1 to 3, and * represents an asymmetric carbon) or a salt thereof. Formula (IV):

(Wherein X represents a cyano group or a group that can be converted to a cyano group, R ¹ and R ² are the same or different and each independently represents a lower alkyl group which may have a substituent, n represents an integer of 0 or 1 to 3, and * represents an asymmetric carbon.) A compound represented by the general formula (V):

(Wherein Y ¹ represents a dimethylamino group or a group that can be converted to a dimethylamino group, M represents Li or MgX ¹ (where X ¹ represents a halogen atom)). General formula (VI) characterized in that it comprises a step of reacting with a metal reagent:

(Wherein each symbol is as defined above), or a method for producing a salt thereof.   The manufacturing method of Claim 7 using the compound represented by general formula (IV) obtained by the method of Claim 4 or 5. General formula (VII):

(In the formula, X represents a cyano group or a group that can be converted to a cyano group, Y ² is the same as or different from Y ¹ and represents a dimethylamino group or a group that can be converted to a dimethylamino group, and * represents an asymmetric group. Or a salt thereof. General formula (VI):

(Wherein X represents a cyano group or a group that can be converted to a cyano group, Y ¹ represents a dimethylamino group or a group that can be converted to a dimethylamino group, and R ¹ and R ² are the same or different, A lower alkyl group which may have a substituent independently, n represents 0 or an integer of 1 to 3, and * represents an asymmetric carbon.) Or a salt thereof General formula (VII) characterized in that it comprises a step of:

(Wherein Y ² is the same as or different from Y ¹ and represents a dimethylamino group or a group that can be converted to a dimethylamino group, and X and * are as defined above) or a salt thereof Manufacturing method.   The manufacturing method of Claim 10 using the compound represented by general formula (VI) obtained by the method of Claim 7 or 8. General formula (VII):

(In the formula, X represents a cyano group or a group that can be converted to a cyano group, Y ² is the same as or different from Y ¹ and represents a dimethylamino group or a group that can be converted to a dimethylamino group, and * represents an asymmetric group. A compound represented by formula (VIII): wherein the compound or a salt thereof is reduced.

(Wherein Y ³ is the same as or different from Y ¹ and Y ² and represents a dimethylamino group or a group that can be converted to a dimethylamino group, and X and * are as defined above). Or the manufacturing method of the salt.   The manufacturing method of Claim 12 using the compound represented by general formula (VII) obtained by the method of Claim 10 or 11. General formula (VII):

(In the formula, X represents a cyano group or a group that can be converted to a cyano group, Y ² is the same as or different from Y ¹ and represents a dimethylamino group or a group that can be converted to a dimethylamino group, and * represents an asymmetric group. The compound represented by the general formula (IX):

(Wherein Y ⁴ is the same as or different from Y ¹ and Y ² and represents a dimethylamino group or a group that can be converted to a dimethylamino group, and X and * are as defined above). Or the manufacturing method of the salt.   The manufacturing method of Claim 14 using the compound represented by general formula (VII) obtained by the method of Claim 10 or 11. A compound represented by the general formula (VIII) or a salt thereof obtained by the method according to claim 12 or 13 is subjected to (i) a cyclization reaction to form a phthalane ring, and (ii) X is cyano. Formula (X), which comprises a step of converting to a cyano group if not a group, and (iii) a step of converting to a dimethylamino group if Y ³ is not a dimethylamino group:

The manufacturing method of the free base (optically active citalopram) of the compound represented by these, or its acid addition salt. A compound represented by the general formula (IX) or a salt thereof obtained by the method according to claim 14 or 15, wherein (i) when X is not a cyano group, (ii) Y ⁴ is dimethyl In the case where it is not an amino group, it comprises a step of converting to a dimethylamino group, wherein the formula (X):

The manufacturing method of the free base (optically active citalopram) of the compound represented by these, or its acid addition salt. Formula (X), characterized in that it comprises at least one method selected from the production methods according to claims 2, 4, 7, 10, 12, and 14.

The manufacturing method of the free base (optically active citalopram) of the compound represented by these, or its acid addition salt.