JP2006008603A - Process for producing optically active citalopram, its intermediate and process for its production - Google Patents

Abstract

（式中、各記号は本願明細書中に定義の通りである。）
【選択図】 なし
PROBLEM TO BE SOLVED: To provide a method capable of synthesizing a large number of necessary antipodes when synthesizing optically active citalopram in a process excellent in yield and selectivity and with few by-products.
A compound represented by the formula (II) obtained by reacting a compound represented by the formula (I) with an optically active compound having a propane skeleton having an asymmetric center at the central carbon represented by the formula (VI). An optically active citalopram is produced via an optically active intermediate represented by
[Chemical 1]

(In the formula, each symbol is as defined in the present specification.)
[Selection figure] None

Description

  The present invention relates to a method for producing optically active citalopram, a synthetic intermediate, and a method for producing the same.

General formula

Is a compound useful as an antidepressant, and as its production method, various methods including the method described in Patent Document 1 are known. Patent Document 2 discloses the formula (0-A ′)

(In the formula, G ′ represents a group that can be converted to a cyano group.)
In this method, after cyclizing the compound represented by formula (I) to form an isobenzofuran ring, G ′ is changed to a cyano group and further reacted with 3-dimethylaminopropylmagnesium halide. There was room for improvement. Also useful as an antidepressant is the formula (V)

(In the formula, * represents an asymmetric carbon.)
As for the optically active compound represented by the formula, that is, the optically active substance citalopram, various production methods including the method described in Patent Document 3 are known. However, there is no known method based on asymmetric synthesis to obtain the optically active form of citalopram, and so far only the method obtained by the optical resolution method is known, and half of the enantiomer is discarded. From the perspective of the atom economy and cost, it was a problem.
Japanese Examined Patent Publication No. 61-35986 Japanese translation of PCT publication No. 2002-530296 JP-A-2-36177

  An object of the present invention is to provide a method capable of synthesizing a large number of necessary enantiomers in the process of synthesizing optically active citalopram in a process excellent in yield and selectivity, with few by-products.

As a result of diligent research to solve the above problems, the present inventors have an asymmetric center in the compound represented by the following formula (I) and the central carbon represented by the following formula (VI). By producing citalopram via an optically active intermediate represented by the following formula (II) obtained by reacting with an optically active compound having a propane skeleton, the yield and selectivity are excellent. The present inventors have found that it is possible to produce a large number of antipodes of necessary citalopram with few by-products.
That is, the present invention is as follows.
[1] Formula (II)

は、Ｚが水素原子またはヒドロキシル基である場合には単結合を、Ｚが酸素原子である場合には二重結合を示す。）で表される化合物（以下、化合物（II）ともいう。）またはその塩。
〔２〕Ｚが水素原子であり、Ｘが保護基を有していてもよいヒドロキシル基であり、Ｙがジメチルアミノ基またはジメチルアミノ基に変換可能な基である上記〔１〕記載の化合物またはその塩。
〔３〕式（Ｉ） (In the formula, * represents an asymmetric carbon, and R ¹ and R ² are the same or different and are a lower alkyl group, a lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, An aralkyl group which may be substituted, a heteroarylalkyl group which may be substituted or a hydrogen atom, X represents a hydroxyl group which may have a protecting group, Y represents a dimethylamino group or a dimethylamino group Or X and Y may be combined together to form an oxirane ring together with the carbon atoms to which they are bonded, Z represents a hydrogen atom, a hydroxyl group or an oxygen atom,

Represents a single bond when Z is a hydrogen atom or a hydroxyl group, and a double bond when Z is an oxygen atom. ) Or a salt thereof (hereinafter also referred to as compound (II)).
[2] The compound according to the above [1], wherein Z is a hydrogen atom, X is a hydroxyl group which may have a protecting group, and Y is a dimethylamino group or a group convertible to a dimethylamino group Its salt.
[3] Formula (I)

Wherein R ¹ and R ² are the same or different and are a lower alkyl group, a lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted aralkyl group. Represents a heteroarylalkyl group which may be substituted or a hydrogen atom.) (Hereinafter also referred to as compound (I)) is represented by the formula (VI)

[In the formula, * represents an asymmetric carbon, X ′ represents a hydroxyl group which may have a protecting group, Y ′ represents a dimethylamino group or a group convertible to a dimethylamino group, or X ′ 'And Y' together may form an oxirane ring with the carbon atoms to which they are bonded, Q is the formula (VII)

はＡが水素原子である場合には単結合を、Ａが酸素原子である場合には二重結合を示し、Ｊは水素原子またはＬＧ（ＬＧはハロゲン原子またはＲ^３ＳＯ_２Ｏで表される基〔Ｒ^３は低級アルキル基または置換されていてもよいフェニル基を示す。〕を示す。）を示し、但し、Ａ、Ｊが同時に水素原子を示すことはない。｝で表される基を示すか、あるいはＸ’とＡは一緒になってそれぞれ結合する炭素原子と共にオキシラン環を形成してもよい。但し、Ｘ’とＡが一緒になってそれぞれ結合する炭素原子と共にオキシラン環を形成する場合には、

は単結合であり、Ｊは水素原子であり、Ｙ’は前記の定義からオキシラン環と反応する基は除かれる。〕で表される化合物（以下、化合物（VI）ともいう。）と反応させることを特徴とする式（II） {In the formula, A represents a hydrogen atom or an oxygen atom;

Represents a single bond when A is a hydrogen atom, and a double bond when A is an oxygen atom. J represents a hydrogen atom or LG (LG is a halogen atom or R ³ SO ₂ O). Group [wherein R ³ represents a lower alkyl group or an optionally substituted phenyl group.], Provided that A and J do not represent a hydrogen atom at the same time. }, Or X ′ and A together may form an oxirane ring together with the carbon atoms to which they are bonded. However, when X 'and A together form an oxirane ring with the carbon atoms to which they are bonded,

Is a single bond, J is a hydrogen atom, and Y ′ is a group that reacts with the oxirane ring from the above definition. A compound represented by formula (II), which is reacted with a compound represented by the following formula (hereinafter also referred to as compound (VI)):

は、Ｚが水素原子またはヒドロキシル基である場合には単結合を、Ｚが酸素原子である場合には二重結合を示す。）で表される化合物またはその塩の製造方法。
〔４〕式（II）において、Ｚが水素原子であり、Ｘがヒドロキシル基であり、Ｙがジメチルアミノ基に変換可能な基であってオキシラン環とは反応しない基である場合において、化合物（VI）が、式（IX） (In the formula, *, R ¹ and R ² are as defined above, X represents a hydroxyl group which may have a protecting group, and Y represents a dimethylamino group or a group which can be converted to a dimethylamino group. Or X and Y together may form an oxirane ring together with the carbon atoms to which each is bonded, Z represents a hydrogen atom, a hydroxyl group or an oxygen atom;

Represents a single bond when Z is a hydrogen atom or a hydroxyl group, and a double bond when Z is an oxygen atom. ) Or a salt thereof.
[4] In the formula (II), when Z is a hydrogen atom, X is a hydroxyl group, and Y is a group that can be converted into a dimethylamino group and does not react with the oxirane ring, VI) is the formula (IX)

(In the formula, * is as defined above, and Y ″ represents a group that can be converted to a dimethylamino group and does not react with the oxirane ring.)
The production method of the above-mentioned [3], which is a compound represented by the following (hereinafter also referred to as compound (IX)).
[5] Formula (III)

(In the formula, * represents an asymmetric carbon, and R ¹ and R ² are the same or different and are a lower alkyl group, a lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, A compound represented by an aralkyl group which may be substituted, a heteroarylalkyl group which may be substituted or a hydrogen atom (hereinafter also referred to as compound (III)) or a salt thereof.
[6] A method for producing compound (III) or a salt thereof, which comprises subjecting compound (II) or a salt thereof to the following steps (i) to (iv):
(I) when X and Y are combined together to form an oxirane ring together with the carbon atoms to which they are bonded, the step of opening the oxirane ring with an amine compound (ii) when Y is not a dimethylamino group, Step (iii) for converting Y to a dimethylamino group (iv) Step for converting X to a hydrogen atom (iv) When Z is not a hydrogen atom, Step for converting Z to a hydrogen atom [7] Compound (II) The production method of the above-mentioned [6], which is obtained by the method of the above-mentioned [3] or [4].
[8] Formula (V), wherein the compound (III) or a salt thereof is opened with an acid and then cyclized.

(In the formula, * is as defined above.)
A method for producing an optically active compound represented by the following (hereinafter also referred to as compound (V)) or an acid addition salt thereof.
[9] The production method of the above-mentioned [8], wherein the compound (III) is obtained by the method of the above-mentioned [6] or [7].
[10] Compound (II) The compound or a salt thereof is opened with an acid and then cyclized to give a compound of formula (IV)

は前記と同義である。）
で表される化合物（以下、化合物（IV）ともいう。）に変換し、さらに化合物（IV）を以下の工程（ｉ’）〜（iv’）に付することを特徴とする化合物（Ｖ）またはその酸付加塩の製造方法。
（ｉ’）ＸとＹが一緒になってそれぞれ結合する炭素原子と共にオキシラン環を形成している場合は、該オキシラン環をアミン化合物により開環させる工程
（ii’）Ｙがジメチルアミノ基でない場合は、該Ｙをジメチルアミノ基に変換する工程
（iii’）Ｘを水素原子に変換する工程
（iv’）Ｚが水素原子でない場合は、該Ｚを水素原子に変換する工程
〔１１〕化合物（II）が、上記〔３〕または〔４〕記載の方法により得られている上記〔１０〕記載の製造方法。
〔１２〕上記〔３〕、〔４〕、〔６〕、〔８〕および〔１０〕記載の製造方法から選ばれる少なくとも１つの方法を含むことを特徴とする、化合物（Ｖ）またはその酸付加塩の製造方法。 (Where *, X, Y, Z and

Is as defined above. )
The compound (V), wherein the compound (IV) is converted to a compound represented by the formula (hereinafter also referred to as compound (IV)), and the compound (IV) is further subjected to the following steps (i ′) to (iv ′): Or the manufacturing method of the acid addition salt.
(I ′) when X and Y are combined to form an oxirane ring together with the carbon atoms to which they are bonded, the step of opening the oxirane ring with an amine compound (ii ′) when Y is not a dimethylamino group Step (iii ′) for converting Y to a dimethylamino group Step (iv ′) for converting X to a hydrogen atom If Z is not a hydrogen atom, Step (11) for converting Z to a hydrogen atom [11] The production method of the above-mentioned [10], wherein II) is obtained by the method of the above-mentioned [3] or [4].
[12] Compound (V) or acid addition thereof comprising at least one method selected from the production methods described in [3], [4], [6], [8] and [10] above Method for producing salt.

  It is possible to synthesize a large number of necessary enantiomers when synthesizing optically active citalopram in a process with excellent yield and selectivity and few by-products. Further, the intermediate obtained in the course of the production method of the present invention is useful for the synthesis of optically active citalopram.

Hereinafter, the present invention will be described in detail.
First, definitions of symbols and terms used in the present invention will be described.

The “lower alkyl group” represented by R ¹ , R ² and R ³ is a linear or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 2 carbon atoms, such as a methyl group or an ethyl group. Propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group and the like, preferably methyl group and ethyl group.

The “lower alkoxy group” represented by R ¹ and R ² is a linear or branched alkoxy group having 1 to 6 carbon atoms, preferably 1 to 2 carbon atoms, such as a methoxy group, an ethoxy group, or a propoxy group. , Isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, hexyloxy group, etc., preferably methoxy group, ethoxy group It is.

Examples of the “aryl group” in the “optionally substituted aryl group” represented by R ¹ and R ² include aryl groups having 6 to 10 carbon atoms, preferably 6 carbon atoms, such as phenyl group and naphthyl group. Preferably a phenyl group.

The “heteroaryl group” in the “optionally substituted heteroaryl group” represented by R ¹ and R ² is a hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom as an atom constituting the ring. 5- to 6-membered aromatic heterocyclic groups containing 1 to 3 atoms and condensed heterocyclic groups thereof, such as pyridyl group, furanyl group, thienyl group, quinolinyl group, isoquinolinyl group, benzofuranyl group, isobenzofuran Nyl group etc. are mentioned, Preferably it is a pyridyl group.

The “aralkyl group” in the “optionally substituted aralkyl group” represented by R ¹ and R ² is the same as the “aryl group” in the “optionally substituted aryl group” in which the aryl moiety is an alkyl group. Examples thereof include an aralkyl group whose part is a linear or branched alkyl having 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms. Examples include a benzyl group, a 2-phenylethyl group, a 1-phenylethyl group, and the like, preferably a benzyl group.

The “heteroarylalkyl group” in the “optionally substituted heteroarylalkyl group” represented by R ¹ and R ² is the “heteroaryl” in which the heteroaryl moiety is the above “optionally substituted heteroaryl group”. And a heteroarylalkyl group having the same alkyl group as the straight chain or branched alkyl having 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms. Examples include a pyridylmethyl group, a thienylmethyl group, and the like, preferably a pyridylmethyl group.

“Optionally substituted aryl group”, “optionally substituted heteroaryl group”, “optionally substituted aralkyl group” and “optionally substituted hetero group” represented by R ¹ and R ² Examples of the substituent of the “arylalkyl group” include alkyl groups (eg, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group) and the like. Is a methyl group or a tert-butyl group. The substitution position is not limited as long as it is a chemically acceptable position. The number of substituents is preferably 1 to 2, and in the case of 2 or more, they may be the same or different.

  The “protecting group” of the “hydroxyl group optionally having a protecting group” represented by X and X ′ is not particularly limited, and examples thereof include a 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group, 1- An ethoxyethyl group, a benzyl group, a methoxymethyl group, a benzyloxymethyl group, a tert-butyldimethylsilyl group and the like can be mentioned. Among these, a 2-tetrahydropyranyl group, a benzyl group and a tert-butyldimethylsilyl group are preferable.

  The “group that can be converted into a dimethylamino group” represented by Y and Y ′ is not particularly limited as long as it can be converted into a dimethylamino group, and the group can be directly converted into a dimethylamino group. Even a thing which can be indirectly converted into a dimethylamino group may be sufficient. Specific examples include a hydroxyl group which may have a protecting group (for example, hydroxyl group, 2-tetrahydropyranyloxy group, 2-tetrahydrofuranyloxy group, 1-ethoxyethoxy group, benzyloxy group, methoxy group). A methoxy group, a benzyloxymethoxy group, a tert-butyldimethylsilyloxy group, etc.), an amino group optionally having a protecting group (for example, an amino group, a benzyloxycarbonylamino group, a tert-butoxycarbonylamino group, etc.), A halogen atom (for example, a chlorine atom, a bromine atom, an iodine atom, etc.), a methanesulfonyloxy group, a p-toluenesulfonyloxy group, etc. are mentioned, Among these, a hydroxyl group, 2-tetrahydropyranyloxy group, 1-ethoxy. An ethoxy group and a halogen atom are preferred.

  When X 'and A together form an oxirane ring together with the carbon atoms to which they are bonded, examples of the "group that reacts with the oxirane ring" excluded from Y' include an amino group and a dimethylamino group.

  The “group that can be converted to a dimethylamino group and does not react with the oxirane ring” represented by Y ″ is the group listed as the “group that can be converted to a dimethylamino group” represented by Y and Y ′ From which a group reacting with an oxirane ring such as an amino group is removed.

  Examples of the halogen atom represented by LG include a chlorine atom, a bromine atom, and an iodine atom, and among these, a chlorine atom and a bromine atom are preferable.

Examples of the substituent of the “optionally substituted phenyl group” represented by R ³ include an alkyl group (eg, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group). , Tert-butyl group, etc.). The substitution position is not limited as long as it is a chemically acceptable position. The number of substituents is preferably 1 to 2, and in the case of 2 or more, they may be the same or different.

  In the case of having a basic dimethylamino group, the compounds (II) and (IV) and the compound (III) may form a salt. 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.).

  Compound (V), that is, optically active citalopram may be obtained as an acid addition salt, and the acid addition salt is preferably a pharmacologically acceptable non-toxic acid addition salt. For example, maleate, fumarate, benzoic acid Salt, ascorbate, pamoate, succinate, oxalate, salicylate, methanesulfonate, ethanedisulfonate, acetate, propionate, tartrate, citrate, gluconate, lactic acid Salt, malate, mandelate, cinnamate, citrate, aspartate, stearate, palmitate, itaconate, glycolate, p-aminobenzoate, glutamate, benzene Salts with organic acids such as sulfonate, theophylline acetate, 8-halotheophylline (for example, 8-bromotheophylline), hydrochloric acid, hydrobromic acid Sulfinic acid, sulfamic acid, phosphoric acid, and salts with inorganic acids such as nitric acid.

  * Shown in the structural formula indicates that the attached carbon atom is an optically active asymmetric carbon, and the compound (II) and compound (IV) in which two or more of the asymmetric carbon are present are present. Also included are all possible diastereomers or mixtures thereof.

  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 has the same meaning as described above.)
Compound (I) as a starting material can be synthesized according to the following reaction scheme.

(In the formula, R ¹ and R ² are as defined above.)
The compound represented by the formula (0-A) (hereinafter also referred to as the compound (0-A)) is synthesized by a method similar to the method described in WO98 / 19511 and JP2002-530296. Can do.

Process (0-x)
Step (0-x) is a step of acetalizing compound (0-A). This step can be performed by a known method. For example, the compound (0-A) is dissolved in a solvent such as tetrahydrofuran (THF) in the presence of an acid such as pyridinium p-toluenesulfonate (PPTS). It can be carried out by reacting with a compound such as methoxypropene.

  In the step (0-x), the target compound can be isolated and purified by a conventional method. The reaction mixture may be used as it is in the next step.

Step (a)
Step (a) is a step of converting compound (I) to compound (II), and is carried out by reacting compound (I) with compound (VI) in the presence of a base.

  Examples of the base include sodium hydride, lithium diisopropylamide (LDA), lithium dicyclohexylamide, sodium amide and the like, and among these, sodium hydride and LDA are preferable.

  In the step, a solvent is usually used in order to carry out the reaction smoothly. The solvent is not particularly limited as long as it does not inhibit the reaction. Examples of the solvent used include THF, methyl t-butyl ether (MTBE), 1,2-dimethoxyethane, diglyme, 1,3-dioxolane, 1,4-dioxane, toluene, xylene and the like can be mentioned, and these can be used alone or in combination. Among these, THF and toluene are preferable. The amount of the solvent to be used is generally 1 to 50 L, preferably 2 to 20 L, relative to 1 kg of compound (I).

  As a preferred embodiment of the reaction operation, from the viewpoint of preventing side reactions between the compound (VI) and the base, the compound (I) and the base are first reacted. For example, the base is added to a solution in which the compound (I) is dissolved in the solvent under a gas atmosphere inert to the reaction such as nitrogen, and the compound (I) and the base are reacted. When LDA is used, lithium diisopropylamide is first produced by reacting N, N-diisopropylamine with alkyllithium such as butyllithium in the above-described solvent, and then the compound ( I) may be added.

The amount of the base to be used is generally 1 to 1.5 mol, preferably 1 to 1.3 mol, per 1 mol of compound (I). The reaction can be carried out even if the amount of the base used is outside this range, but if it is more than 1.5 mol, the side reaction proceeds remarkably and the yield and quality tend to decrease, and the amount is less than 1 mol. And compound (I) remain, and the yield tends to decrease.
When LDA or the like is used as a base, the reaction temperature is usually −70 to 0 ° C., preferably −60 to −20 ° C., and the reaction time is usually 0.5 to 12 hours, preferably 1 to 6 hours.
When using sodium hydride etc. as a base, reaction temperature is 40-90 degreeC normally, Preferably it is 50-80 degreeC, and reaction time is 1 to 24 hours normally, Preferably it is 3 to 12 hours.

  Compound (VI) is then added to the reaction mixture. At the time of addition, compound (VI) may be dissolved in the above solvent and added as a solution. Specific examples of the compound (VI) include compounds represented by the following formulas.

(In the formula, *, X ′, Y ′, Y ″ and LG have the same meaning as described above, and LG ″ has the same meaning as LG.)
Among these optically active citaloprams, from the viewpoint of high pharmacological effects of escitalopram, those compounds having an absolute configuration capable of synthesizing escitalopram are preferable. Examples of such compounds include (S ) -Epichlorohydrin, (S)-[2- (tert-butyldimethylsilyloxy) -3-chloro-propyl] -dimethylamine.

  Compound (VI) can be used as it is on the market, and can also be obtained by synthesis by a known method.

  When Z is a hydrogen atom in formula (II), a compound represented by formula (VIII) (hereinafter also referred to as compound (VIII)) or compound (IX) is used (compound (VIII) is used). The step in the case where the compound (IX) is used is hereinafter referred to as the step (a'-2)).

  When Z is a hydroxyl group in formula (II), a compound represented by formula (X) (hereinafter also referred to as compound (X)) or a compound represented by formula (XI) (hereinafter referred to as compound (X XI)) is used (the process in this case is hereinafter referred to as process (a'-3)).

  When Z is an oxygen atom in formula (II), a compound represented by formula (XII) (hereinafter also referred to as compound (XII)) or a compound represented by formula (XIII) (hereinafter referred to as compound (X XIII)) is used (the process in this case is hereinafter referred to as process (a'-4)).

Process (a'-1)
The amount of compound (VIII) used is usually 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (I).
The reaction temperature is usually −60 to 100 ° C., preferably −40 to 80 ° C., and the reaction time is usually 1 to 24 hours, preferably 3 to 12 hours.

  In order to make the reaction proceed smoothly, a phase transfer catalyst such as a quaternary ammonium salt may be added. The amount of the phase transfer catalyst used is usually 0.01 to 1 mol with respect to 1 mol of compound (I).

Process (a'-2)
The amount of compound (IX) used is usually 1 to 1.6 mol, preferably 1 to 1.4 mol, per 1 mol of compound (I).
The reaction temperature is usually −60 to 100 ° C., preferably −40 to 80 ° C., and the reaction time is usually 1 to 24 hours, preferably 3 to 12 hours.

  In order to make the reaction proceed smoothly, a phase transfer catalyst such as a quaternary ammonium salt may be added. The amount of the phase transfer catalyst used is usually 0.01 to 1 mol with respect to 1 mol of compound (I).

Process (a'-3)
The amount of compound (X) or (XI) used is usually 1 to 1.5 mol, preferably 1 to 1.3 mol, per 1 mol of compound (I).
The reaction temperature is usually −78 to 30 ° C., preferably −60 to 0 ° C., and the reaction time is usually 0.5 to 12 hours, preferably 1 to 6 hours.

Process (a'-4)
The amount of the compound (XII) or (XIII) used is usually 1 to 1.5 mol, preferably 1 to 1.3 mol, relative to 1 mol of the compound (I).
The reaction temperature is usually −78 to 30 ° C., preferably −60 to 0 ° C., and the reaction time is usually 0.5 to 12 hours, preferably 1 to 6 hours.

  Compound (II) obtained by the step (a) can be isolated and purified by a conventional method. For example, the reaction mixture can be separated by adding water and an organic solvent such as toluene, and the organic layer is washed with water, dried and then concentrated to isolate compound (II), which is further purified by silica gel column chromatography. can do.

  When a racemic form of citalopram is desired, in the method of the present invention, step (a) may be carried out using the racemic form of compound (VI) or compound (VI) wherein X ′ is a hydrogen atom. .

Step (b)
Step (b) is a step of converting compound (II) into compound (III), and includes the following steps (i) to (iv).
(I) when X and Y are combined together to form an oxirane ring together with the carbon atoms to which they are bonded, the step of opening the oxirane ring with an amine compound (ii) when Y is not a dimethylamino group, The step of converting Y to a dimethylamino group (iii) the step of converting X to a hydrogen atom (iv) the step of converting Z to a hydrogen atom when Z is not a hydrogen atom

(I) when X and Y are combined together to form an oxirane ring together with the carbon atoms to which they are bonded, the step of (i) opening the oxirane ring with an amine compound is carried out, for example, in a solvent It can be carried out by reacting (II) with an amine compound. By this reaction, the oxirane ring of compound (II) is cleaved to form a hydroxyl group, and a (dialkyl) amino group and the like are introduced.

  Examples of the solvent include THF, MTBE, toluene, xylene, methanol, ethanol, and the like, and these can be used alone or in combination. Of these, methanol and THF are preferable, and the amount of the solvent used Is usually 1 to 50 L, preferably 2 to 30 L, per 1 kg of compound (II).

  Examples of amine compounds include ammonia compounds such as ammonia, dimethylamine, and methylamine, which are introduced with a dimethylamino group or a group that can be converted to a dimethylamino group by reaction with an oxirane ring. Dimethylamine that can directly introduce a dimethylamino group is preferred. The amount of the amine compound to be used is generally 1 to 500 mol, preferably 3 to 100 mol, per 1 mol of compound (II).

  The reaction temperature is usually 0 to 100 ° C., preferably 20 to 80 ° C., and the reaction time is usually 1 to 72 hours, preferably 3 to 24 hours.

(Ii) When Y is not a dimethylamino group, the step of converting the Y to a dimethylamino group The step of (ii) can be carried out by a known method, and the “convertible to dimethylamino group” represented by Y The method for converting to a dimethylamino group varies depending on the mode of the “group”. For example, when Y is a hydroxyl group which may have a protecting group, if it has a protecting group, it is deprotected and then reacted with an acid halide to remove the hydroxyl group. And can be carried out by reacting 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-) is used in a solvent (eg, toluene, xylene, THF, MTBE, etc.). Toluenesulfonyl chloride, 10-camphor sulfonyl chloride, trifluoroacetyl chloride, trifluoromethanesulfonyl chloride, etc.) 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 (ii), when Y is an amino group which may have a protecting group, if it has a protecting group, after deprotecting, a solvent (eg, toluene, In xylene, THF, MTBE, etc.) 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. be able to.

  In still another embodiment of the step (ii), when Y is a halogen atom, 1 to 500 equivalents of dimethylamine in a solvent (eg, THF, MTBE, toluene, xylene, methanol, ethanol, water, etc.) (Preferably an aqueous solution) and reaction at 0 to 100 ° C. for 1 to 72 hours.

(Iii) Step of converting X into hydrogen atom The step of (iii) can be performed by a known method. Hereinafter, an exemplary embodiment of the step (iii) will be described.

One embodiment of the step (iii) includes the following steps.
(Iii-1) when X is a hydroxyl group having a protecting group, a step of deprotecting (iii-2) a step of converting the hydroxyl group into LG ′ (LG ′ is synonymous with LG) (iii-3) ) A step of treating with a base to remove LG ′ to form an unsaturated bond (iii-4) A step of adding hydrogen to the unsaturated bond

(Iii-1) Step of deprotecting when X is a hydroxyl group having a protecting group This step can be carried out by carrying out a deprotection reaction according to a conventional method.

As (iii-2) step the step of converting the hydroxyl group LG '(LG' is as defined LG), for example, when LG 'is ^{R 3'} is a group represented by SO ₂ O ^{(R 3} 'Is synonymous with R ³ ), in the presence of a base, the hydroxyl group of compound (II) is represented by R ³ ' SO ₂ -Hal (-Hal is a halogen such as a chlorine atom or a bromine atom). Can be carried out by reacting with atoms. LG 'When is a halogen atom, the compound according to the above method the hydroxyl group of (II) R ^3' was converted to a group represented by SO 2 _O, be further reacting the groups with an alkali metal halide Can be implemented. Alternatively, it can be carried out by reacting the hydroxyl group of compound (II) directly with hydrogen halide or phosphorus halide.

An example of specific reaction conditions when LG ′ is a group represented by R ³ ′ SO ₂ O is as follows.

Compound (II) is dissolved in a solvent, a base is added, it is further reacted by adding a compound represented by R ³ 'SO ₂ -Hal.

  Examples of the solvent include THF, MTBE, 1,2-dimethoxyethane, diglyme, 1,3-dioxolane, 1,4-dioxane, toluene, xylene and the like, and these are used alone or in combination. Of these, THF, MTBE, and toluene are preferred. As a usage-amount of a solvent, it is 1-50L normally with respect to 1 kg of compound (II), Preferably it is 2-20L.

  Examples of the base include triethylamine, pyridine, N, N-dimethylaniline, N-methylmorpholine, etc. Among these, triethylamine and pyridine are preferable. The amount of the base used is usually 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (II).

R ³ 'Preferred examples of the compound represented by SO ₂ -Hal are methanesulfonyl chloride, benzenesulfonyl chloride, p- toluenesulfonyl chloride and the like can be exemplified, R ^3' the compound represented by SO ₂ -Hal Is used usually in an amount of 1 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (II).

  The reaction temperature is usually −30 to 70 ° C., preferably −20 to 50 ° C., and the reaction time is usually 0.5 to 12 hours, preferably 1 to 8 hours.

(Iii-3) Step of treating with base to remove LG ′ to form an unsaturated bond In this step, for example, compound (II) into which LG ′ has been introduced is converted to potassium t-butoxide, 1, It can be carried out by reacting with a base such as 8-diazabicyclo [5,4,0] undec-7-ene (DBU).

  An example of specific reaction conditions when the compound (II) having LG 'introduced therein is allowed to act with a base is as follows.

  Compound (II) into which LG ′ has been introduced is dissolved in a solvent, and a base is added.

  Examples of the solvent include xylene, mesitylene, toluene, THF, 1,4-dioxane, diglyme, ethanol, n-butanol, n-hexanol, methyl cellosolve, ethyl cellosolve, and the like. Alternatively, xylene, mesitylene, toluene and diglyme are preferable, and the amount of solvent used is usually 1 to 50 L, preferably 2 with respect to 1 kg of compound (II) into which LG ′ is introduced. ~ 20L.

  Examples of bases include DBU, 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), potassium t-butoxide, sodium methylate, sodium ethylate, potassium hydroxide, sodium hydride, etc. Among these, DBU and potassium t-butoxide are preferable, and the amount of the base used is usually 1 mol to 2 mol with respect to 1 mol of LG ′ of compound (II) into which LG ′ is introduced, Preferably it is 1 mol-1.5 mol.

  The reaction temperature is usually 40 to 200 ° C., preferably 60 to 150 ° C., and the reaction time is usually 1 to 24 hours, preferably 2 to 12 hours.

(Iii-4) Step of adding hydrogen to the unsaturated bond This step is performed, for example, by reacting the compound (II) into which the unsaturated bond is introduced with hydrogen in the presence of a hydrogenation catalyst in a solvent. be able to.

  Examples of the solvent include ethyl acetate, ethanol, acetic acid and the like, and these can be used alone or in combination. Of these, ethyl acetate and ethanol are preferable, and the amount of the solvent used is unsaturated. The amount is usually 1 to 30 L, preferably 2 to 15 L, per 1 kg of the compound (II) into which the bond is introduced.

  Examples of the hydrogenation catalyst include palladium carbon, palladium hydroxide, platinum carbon, platinum oxide, rhodium carbon, etc. Among these, palladium carbon is preferable. Moreover, in order to avoid the reduction | restoration of the nitrile group of compound (II), it is preferable that the hydrogenation catalyst is poisoned with sulfur etc. and the catalyst activity is adjusted.

  The amount of the hydrogenation catalyst to be used is generally 0.1 to 100 g, preferably 0.5 to 50 g, per 1 kg of compound (II) into which an unsaturated bond is introduced.

  The pressure of hydrogen to be used is usually 100 kPa to 1 MPa, preferably 100 kPa to 500 kPa.

  The reaction temperature is usually 0 to 100 ° C., preferably 10 to 70 ° C., and the reaction time is usually 1 to 24 hours, preferably 2 to 12 hours.

Instead of the steps (iii-3) and (iii-4), the compound (II) into which LG ′ has been introduced is converted to N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc), acetone, etc. In the solvent of LG ′, the compound (II) having LG ′ introduced therein is reacted with 1 to 10 equivalents of sodium iodide, potassium iodide and the like to convert to the corresponding iodide, and then in a solvent of toluene, xylene and the like. By reacting the corresponding iodide with a radical generator such as 0.001 to 0.5 equivalent of azobisisobutyronitrile and 1 to 5 equivalent of tributyltin hydride at 30 to 150 ° C. for 1 to 48 hours. It can also be done. This corresponding iodide may be reduced by the method described in Synthesis, 835-849 (2002).

(Iv) When Z is not a hydrogen atom, the step (iv) of converting the Z to a hydrogen atom can be carried out by a known method. Hereinafter, an exemplary embodiment of the step (iv) will be described.

One embodiment of the step (iv) includes the following steps.
(Iv-1) a step of reducing to a hydroxyl group when Z is an oxygen atom (iv-2) a step of converting the hydroxyl group into LG ′ (LG ′ is synonymous with LG) (iv-3) a base (Iv-4) a step of adding hydrogen to the unsaturated bond

(Iv-1) Step of reducing to hydroxyl group when Z is an oxygen atom This step can be performed, for example, by reacting compound (II) with a reducing agent in a solvent.

  Examples of the solvent include methanol, ethanol, 2-propanol, THF, MTBE, toluene and the like, and these can be used alone or in combination. Among these, methanol and THF are preferable, and the solvent Is usually 1 to 50 L, preferably 2 to 30 L, per 1 kg of compound (II).

  Examples of the reducing agent include lithium borohydride, sodium borohydride, lithium aluminum hydride and the like, and among these, sodium borohydride is preferable. The amount of the catalyst to be used is generally 1 mol to 2 mol, preferably 1 mol to 1.5 mol, per 1 mol of compound (II).

  The reaction temperature is usually −20 to 70 ° C., preferably 0 to 50 ° C., and the reaction time is usually 0.5 to 12 hours, preferably 1 to 6 hours.

The steps (iv-2), (iv-3) and (iv-4) can be carried out in the same manner as the steps (iii-2), (iii-3) and (iii-4). When both X and Z are hydroxyl groups, the steps (iii-2) and (iv-2) may be performed simultaneously. In this case, the amount of the base and the compound represented by R ³ 'SO ₂ -Hal is not an amount relative to 1 mol of the compound (II) but an amount relative to 1 mol of the hydroxyl group of the compound (II).

  When both X and Z are converted to LG ′, LG ′ exists in one compound, whereas LG ′ which is eliminated in the step (iii-3) or (iv-3) Is usually one per compound, and therefore, after carrying out steps (iii-3) and (iii-4) ((iv-3) and (iv-4)), (iv-3) and Step (iv-4) ((iii-3) and (iii-4)) is performed again.

  In each step included in step (b), the target product can be isolated and purified by a conventional method. For example, one or more methods can be appropriately selected and isolated and purified from known methods such as concentration, vacuum concentration, solvent extraction, filtration, crystallization, recrystallization, and chromatography. Further, the reaction mixture may be used as it is in the next step.

Step (c)
In step (c), compound (III) is ring-opened with an acid to give a compound of formula (III ′)

(In the formula, * is as defined above.)
In this step, the compound represented by the formula (hereinafter also referred to as compound (III ′)) is obtained and then cyclized. This step can be performed by a known method. Hereinafter, exemplary embodiments of the step (c) will be described.
Ring opening with an acid can be performed by reacting the compound (III) with an acid in a solvent.

  Examples of the solvent include methanol, ethanol, isopropyl alcohol, THF, acetone, water and the like, and these can be used alone or in combination, and among these, methanol, ethanol, THF and the like are preferable. The amount of the solvent used is usually 1 to 50 L, preferably 3 to 30 L, per 1 kg of compound (III).

  Examples of the acid include PPTS and the like, and among these, PPTS is preferable. The amount of the acid used is usually 1 to 50 L, preferably 3 to 30 L, relative to 1 mol of compound (III).

  The reaction temperature is usually −20 to 80 ° C., preferably 0 to 60 ° C., and the reaction time is usually 1 to 24 hours, preferably 2 to 8 hours.

  The desired product can be isolated and purified by a conventional method. For example, one or more methods can be appropriately selected and isolated and purified from known methods such as concentration, vacuum concentration, solvent extraction, filtration, crystallization, recrystallization, and chromatography. Further, the reaction mixture may be used as it is in the next step.

In the ring-closing step, R ³ ″ SO ₂ -Hal ′ (R ³ ″ is synonymous with R ³ , and —Hal ′ is synonymous with —Hal in the presence of a base in a solvent. It can be performed by reacting with a compound represented by:

  Examples of the solvent include THF, MTBE, 1,4-dioxane, 1,3-dioxolane, toluene, xylene, dichloromethane and the like, and these can be used alone or in combination. , THF, toluene and the like are preferable, and the amount of the solvent to be used is generally 1 to 50 L, preferably 3 to 30 L, relative to 1 kg of compound (III ′).

  Examples of the base include triethylamine, pyridine, N-methylmorpholine, N, N-dimethylaniline, N, N-diethylaniline, and among these, triethylamine and pyridine are preferable. The amount of the base to be used is generally 0.9 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (III ′).

Preferable examples of the compound represented by R ³ ″ SO ₂ -Hal ′ include methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride and the like, and are represented by R ³ ″ SO ₂ -Hal ′. The amount of the compound used is usually 0.9 to 2 mol, preferably 1 to 1.5 mol, per 1 mol of compound (III ′).

  The reaction temperature is usually −20 to 100 ° C., preferably 0 to 50 ° C., and the reaction time is usually 1 to 24 hours, preferably 2 to 8 hours.

  When a racemic form of citalopram is desired, the step of ring opening with an acid followed by cyclization may be carried out by treating with a strong acid such as sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid, and the like. The treatment with the strong acid is simple because ring-opening and cyclization can be performed simultaneously. However, since the treatment with the strong acid may cause racemization, the optically active purity (ee) may be lowered when the desired citalopram is an optically active substance.

Step (d)
Step (d) is a step of converting compound (III) into compound (IV), and can be performed in the same manner as in step (c).

Step (e)
Step (e) is a step of converting compound (IV) to compound (V), and can be performed in the same manner as in step (b).

  Compound (V) obtained by the above method can be isolated and purified by a conventional method. For example, one or more methods can be appropriately selected and isolated and purified from known methods such as concentration, vacuum concentration, solvent extraction, filtration, crystallization, recrystallization, and chromatography.

  Compound (V) is obtained as a free base, but 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.) Alternatively, it is reacted with oxalic acid, and the acid addition salt precipitated by concentration or cooling is isolated by filtration or the like, or reacted in a poor solvent such as diethyl ether, ethyl acetate, or dichloromethane, and the precipitated acid addition salt is simply isolated. It can be done by separating. The obtained acid addition salt can be increased in optical purity by subjecting it to recrystallization if necessary.

Hereinafter, although a reference example and an example explain the present invention in detail, the present invention is not limited to these.
Reference Example 1 Synthesis of 5- (4-fluorophenyl) -7,7-dimethyl-5,9-dihydro-6,8-dioxabenzocycloheptene-2-carbonitrile 4-[(4-fluorophenyl) -Hydroxymethyl] -3-hydroxymethyl-benzonitrile (13.43 g, 52.2 mmol) and 2-methoxypropene (11.29 g, 156.6 mmol) were dissolved in THF (50 ml) and cooled to 0-5 <0> C. Thereafter, pyridinium p-toluenesulfonic acid (0.65 g, 2.6 mmol) was added and reacted for 3 hours. Sodium hydrogen carbonate (3.0 g) was added to the reaction solution, stirred for 30 minutes, filtered, and the solvent was concentrated. The obtained residue was dissolved in THF (50 ml), p-toluenesulfonic acid (0.3 g) was added and reacted for 3 hours. After completion of the reaction, toluene (100 ml) and 5% aqueous sodium hydrogen carbonate solution (50 ml) were added for extraction, washed with 5% aqueous sodium hydrogen carbonate solution (50 ml), and dried over magnesium sulfate. After filtering the magnesium sulfate, the residue obtained by concentrating the solvent was recrystallized from diisopropyl ether (25 ml) to obtain the title compound (13.66 g, yield 88.0%).
¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm 1.53 (3H, s), 1.56 (3H, s), 4.62 (1H, d, J = 15 Hz), 5.32 (1H, d, J = 15 Hz), 6.03 ( 1H, s), 6.60 (1H, d, J = 8Hz), 7.10 (2H, t, J = 9Hz), 7.26-7.33 (3H, m), 7.34 (1H, s).

Example 1 Synthesis of optically active 5- (4-fluorophenyl) -7,7-dimethyl-5-oxiranylmethyl-5,9-dihydro-6,8-dioxabenzocycloheptene-2-carbonitrile 2 mol / L lithium diisopropylamide (1.94 ml, 3.88 mmol) was diluted in THF (6 ml), cooled to −55 to −50 ° C., and 5- (4-fluorophenyl) -7,7-dimethyl-5,9. -A solution of -dihydro-6,8-dioxabenzocycloheptene-2-carbonitrile (1.0 g, 3.36 mmol) in THF (6 ml) was added dropwise at -55 to -50 ° C, and the temperature was raised to room temperature over 1 hour. . Then, a solution of (S) -epichlorohydrin (0.36 g, 3.89 mmol) in THF (5 ml) was added dropwise and reacted at room temperature for 5 hours. After completion of the reaction, water (10 ml) and toluene (10 ml) were added for extraction, and the aqueous layer was combined with the solution extracted with toluene (10 ml) again, washed twice with water (10 ml) and dried over magnesium sulfate. After filtration of magnesium sulfate, the solution was concentrated to give the title compound (1.11 g, yield 84.9%) as an orange oil.
¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm 0.69 (1.8 H, s) 0.69 (1.2 H, s) 1.41 (1.2 H, s) 1.44 (1.8 H, s) 2.05 (0.6 H, dd, J = 6.8, 14.2Hz) 2.10 (0.6H, dd, J = 2.4,4.9Hz) 2.32 (0.4H, dd, J = 5.9,14.2Hz) 2.42 (0.6H, dd, J = 4.4,4.4Hz) 2.50 (0.4H, dd, J = 2.4,4.9Hz) 2.66 (0.4H, dd, J = 4.4,4.4Hz) 2.76 (0.4H, dd, J = 4.9,14.2Hz) 2.83-2.87 (0.4H, m) 2.94-2.99 ( 0.6H, m) 3.06 (0.6H, dd, J = 3.9,14.2Hz) 4.48 (0.6H, d, J = 14.2Hz) 4.50 (0.4H, d, J = 14.2Hz) 5.25 (0.4H, d, J = 14.6Hz) 5.29 (0.6H, d, J = 14.6Hz) 6.96-7.01 (2H, m) 7.13-7.32 (3H, m) 7.50-7.56 (2H, m).

Example 2 Optically active 5- (3-dimethylamino-2-hydroxypropyl) -5- (4-fluorophenyl) -7,7-dimethyl-5,9-dihydro-6,8-dioxabenzocycloheptene -2-carbonitrile Optically active 5- (4-fluorophenyl) -7,7-dimethyl-5-oxiranylmethyl-5,9-dihydro-6,8-dioxabenzocycloheptene-2-carbonitrile To a solution of (1.11 g, 2.8 mmol) dissolved in THF (10 ml), 50 wt% dimethylamine (2.52 g, 28.0 mmol) was added at room temperature and stirred overnight. Toluene (10 ml) and water (15 ml) were added to the reaction solution, the organic layer was separated, and the aqueous layer was further extracted with toluene (10 ml). The organic layers were combined, washed twice with water (10 ml), dehydrated with anhydrous sodium sulfate, filtered, and the oil obtained by distilling off the solvent was purified by silica gel chromatography to give the title compound (0.72 g, yield 63%).
¹ H-NMR (CDCl ₃ , 400 MHz) δppm 0.64 (1.8H, s) 0.66 (1.2H, s) 1.39 (1.2H, s) 1.46 (1.8H, s) 2.04 (3.6H, s) 2.07-2.72 ( 4H, m) 2.17 (2.4H, s) 3.36-3.43 (0.6H, m) 3.46-3.55 (0.4H, m) 4.48 (0.6H, d, J = 14.2Hz) 4.50 (0.4H, d, J = 15.1Hz) 5.20 (0.6H, d, J = 14.2Hz) 5.35 (0.4H, d, J = 15.1Hz) 6.93-7.02 (2H, m) 7.11-7.32 (3H, m) 7.46-7.56 (2H, m ).

Example 3 Optically Active 5- [2- (tert-Butyldimethylsilyloxy) -3-dimethylaminopropyl] -5- (4-fluorophenyl) -7,7-dimethyl-5,9-dihydro-6,8 -Synthesis of dioxabenzocycloheptene-2-carbonitrile 5- (4-fluorophenyl) -7,7-dimethyl-5,9-dihydro-6,8-dioxabenzocycloheptene-2-carbonitrile (1.0 g, 3.4 mmol), (S)-[2- (tert-butyldimethylsilyloxy) -3-chloro-propyl] -dimethylamine (1.10 g, 4.4 mmol) and tetrabutylammonium iodide (2.73 g, 7.4 mmol) in DMI (10 ml) was degassed, then 60 wt% sodium hydride (161 mg, 4.0 mmol) was added under a nitrogen atmosphere, and the mixture was heated to 80-85 ° C. and reacted for 5 hours. . After completion of the reaction, 5% aqueous sodium hydrogen carbonate solution (20 ml) and toluene (20 ml) were added for extraction, and the aqueous layer was extracted again with toluene (20 ml). The combined organic layers were combined with 5% aqueous sodium hydrogen carbonate solution (20 ml). The oily substance obtained by washing twice, adding anhydrous sodium sulfate and dehydrating, filtering, and distilling off the solvent was purified by silica gel chromatography to obtain the title compound (0.48 g, yield 28%). .

Example 4 Optically Active 5- (3-Dimethylaminopropyl) -5- (4-fluorophenyl) -7,7-dimethyl-5,9-dihydro-6,8-dioxabenzocycloheptene-2-carbo Synthesis of nitrile Optically active 5- (3-dimethylamino-2-hydroxypropyl) -5- (4-fluorophenyl) -7,7-dimethyl-5,9-dihydro-6,8-dioxabenzocycloheptene 2-carbonitrile (300 mg, 0.77 mmol) was reacted with methanesulfonyl chloride (130 mg, 1.13 mmol) in the presence of triethylamine (400 mg, 3.95 mmol) in THF (3 ml) to give the corresponding methanesulfonyl ester, In ethyl acetate (5 ml) further poisoned with sulfur, reacted with 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (230 mg, 1.51 mmol) in xylene (3 ml). Palladium charcoal Catalyst under by column purification by hydrogenation to give the title compound.
¹ H-NMR (CDCl ₃ , 400 MHz) δppm 0.66 (3H, s) 0.81-0.98 (1H, m) 1.38 (3H, m) 1.60-1.72 (1H, m) 2.00-2.08 (1H, m) 2.11 (6H , s) 2.13-2.25 (2H, m) 2.52-2.60 (1H, m) 4.43 (1H, d, J = 14.6Hz) 5.20 (1H, d, J = 14.2Hz) 6.93-6.97 (2H, m) 7.16 -7.33 (3H, m) 7.45-7.52 (2H, m).

Example 5 Optically Active 5- (3-Dimethylaminopropyl) -5- (4-fluorophenyl) -7,7-dimethyl-5,9-dihydro-6,8-dioxabenzocycloheptene-2-carbo Synthesis of nitrile Optically active 5- (3-dimethylamino-2-hydroxypropyl) -5- (4-fluorophenyl) -7,7-dimethyl-5,9-dihydro-6,8-dioxabenzocycloheptene 2-Carbonitrile was converted to the corresponding iodide by reacting methanesulfonyl chloride with THF in the presence of triethylamine in THF to form the corresponding methanesulfonyl ester and then using sodium iodide with DMF as a solvent. By reacting tributyltin hydride and azobisisobutyronitrile (AIBN) in toluene, the title compound Get.

Example 6 Optically active-1- (4-fluorophenyl) -1- (3-dimethylaminopropyl) -5-phthalancarbonitrile (optically active citalopram)
Optically active 5- (3-dimethylaminopropyl) -5- (4-fluorophenyl) -7,7-dimethyl-5,9-dihydro-6,8-dioxabenzocycloheptene-2-carbonitrile is methanolized The ring is opened by adding a catalytic amount of pyridinium p-toluenesulfonate, and the title compound is obtained by reacting methanesulfonyl chloride in THF in the presence of triethylamine.

Claims (12)

Formula (II)

(In the formula, * represents an asymmetric carbon, and R ¹ and R ² are the same or different and are a lower alkyl group, a lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, An aralkyl group which may be substituted, a heteroarylalkyl group which may be substituted or a hydrogen atom, X represents a hydroxyl group which may have a protecting group, Y represents a dimethylamino group or a dimethylamino group Or X and Y may be combined together to form an oxirane ring together with the carbon atoms to which they are bonded, Z represents a hydrogen atom, a hydroxyl group or an oxygen atom,

Represents a single bond when Z is a hydrogen atom or a hydroxyl group, and a double bond when Z is an oxygen atom. Or a salt thereof.   The compound or a salt thereof according to claim 1, wherein Z is a hydrogen atom, X is a hydroxyl group which may have a protecting group, and Y is a dimethylamino group or a group convertible to a dimethylamino group. Formula (I)

Wherein R ¹ and R ² are the same or different and are a lower alkyl group, a lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted aralkyl group. Represents an optionally substituted heteroarylalkyl group or a hydrogen atom.) A compound represented by formula (VI)

[In the formula, * represents an asymmetric carbon, X ′ represents a hydroxyl group which may have a protecting group, Y ′ represents a dimethylamino group or a group convertible to a dimethylamino group, or X ′ 'And Y' together may form an oxirane ring with the carbon atoms to which they are bonded, Q is the formula (VII)

{In the formula, A represents a hydrogen atom or an oxygen atom;

Represents a single bond when A is a hydrogen atom, and a double bond when A is an oxygen atom. J represents a hydrogen atom or LG (LG is represented by a halogen atom or R ³ SO ₂ O). Wherein R ³ represents a lower alkyl group or an optionally substituted phenyl group.), Provided that A and J do not represent a hydrogen atom at the same time. }, Or X ′ and A together may form an oxirane ring together with the carbon atoms to which they are bonded. However, when X 'and A together form an oxirane ring with the carbon atoms to which they are bonded,

Is a single bond, J is a hydrogen atom, and Y ′ is a group that reacts with the oxirane ring from the above definition. Wherein the compound is reacted with a compound represented by formula (II)

(In the formula, *, R ¹ and R ² are as defined above, X represents a hydroxyl group which may have a protecting group, and Y represents a dimethylamino group or a group which can be converted to a dimethylamino group. Or X and Y together may form an oxirane ring together with the carbon atoms to which each is bonded, Z represents a hydrogen atom, a hydroxyl group or an oxygen atom;

Represents a single bond when Z is a hydrogen atom or a hydroxyl group, and a double bond when Z is an oxygen atom. ) Or a salt thereof. In the formula (II), when Z is a hydrogen atom, X is a hydroxyl group, and Y is a group that can be converted into a dimethylamino group and does not react with the oxirane ring, The compound represented by formula (IX)

(In the formula, * is as defined above, and Y ″ represents a group that can be converted to a dimethylamino group and does not react with the oxirane ring.)
The production method according to claim 3, which is a compound represented by the formula: Formula (III)

(In the formula, * represents an asymmetric carbon, and R ¹ and R ² are the same or different and are a lower alkyl group, a lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, A aralkyl group which may be substituted, a heteroarylalkyl group which may be substituted or a hydrogen atom.) Or a salt thereof. Formula (II)

(In the formula, * represents an asymmetric carbon, and R ¹ and R ² are the same or different and are a lower alkyl group, a lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, An aralkyl group which may be substituted, a heteroarylalkyl group which may be substituted or a hydrogen atom, X represents a hydroxyl group which may have a protecting group, Y represents a dimethylamino group or a dimethylamino group Or X and Y may be combined together to form an oxirane ring together with the carbon atoms to which they are bonded, Z represents a hydrogen atom, a hydroxyl group or an oxygen atom,

Represents a single bond when Z is a hydrogen atom or a hydroxyl group, and a double bond when Z is an oxygen atom. ) Or a salt thereof is subjected to the following steps (i) to (iv):

(Wherein, *, R ¹ and R ² are as defined above), or a method for producing the salt thereof.
(I) when X and Y are combined together to form an oxirane ring together with the carbon atoms to which they are bonded, the step of opening the oxirane ring with an amine compound (ii) when Y is not a dimethylamino group, The step of converting Y to a dimethylamino group (iii) the step of converting X to a hydrogen atom (iv) the step of converting Z to a hydrogen atom when Z is not a hydrogen atom   The production method according to claim 6, wherein the compound represented by formula (II) is obtained by the method according to claim 3 or 4. Formula (III)

(In the formula, * represents an asymmetric carbon, and R ¹ and R ² are the same or different and are a lower alkyl group, a lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, A aralkyl group which may be substituted, a heteroarylalkyl group which may be substituted, or a hydrogen atom.) Or a salt thereof is opened with an acid and then cyclized. Formula (V)

(In the formula, * is as defined above.)
The manufacturing method of the optically active compound represented by these, or its acid addition salt.   The production method according to claim 8, wherein the compound represented by the formula (III) is obtained by the method according to claim 6 or 7. Formula (II)

(In the formula, * represents an asymmetric carbon, and R ¹ and R ² are the same or different and are a lower alkyl group, a lower alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, An aralkyl group which may be substituted, a heteroarylalkyl group which may be substituted or a hydrogen atom, a hydroxyl group which may have an X protecting group, Y represents a dimethylamino group or a dimethylamino group; Represents a convertible group, or X and Y together may form an oxirane ring with the carbon atoms to which they are bonded, Z represents a hydrogen atom, a hydroxyl group or an oxygen atom,

Represents a single bond when Z is a hydrogen atom or a hydroxyl group, and a double bond when Z is an oxygen atom. ) Or a salt thereof is opened with an acid and then cyclized to give a compound of formula (IV)

(Where *, X, Y, Z and

Is as defined above. )
The compound represented by formula (IV) is further subjected to the following steps (i ′) to (iv ′):

(In the formula, * is as defined above.)
The manufacturing method of the optically active compound represented by these, or its acid addition salt.
(I ′) when X and Y are combined to form an oxirane ring together with the carbon atoms to which they are bonded, the step of opening the oxirane ring with an amine compound (ii ′) when Y is not a dimethylamino group Step of converting Y to dimethylamino group (iii ′) Step of converting X to hydrogen atom (iv ′) Step of converting Z to hydrogen atom when Z is not a hydrogen atom   The production method according to claim 10, wherein the compound represented by the formula (II) is obtained by the method according to claim 3 or 4. Formula (V), characterized in that it comprises at least one method selected from the production methods according to claim 3, 4, 6, 8, and 10.

(In the formula, * is as defined above.)
The manufacturing method of the optically active compound represented by these, or its acid addition salt.