JP2005255630A - Ethyl trans-4-amino-1-cyclohexanecarboxylate salt and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an ethyl trans-4-amino-1-cyclohexanecarboxylate salt, and to provide a method for producing the same. <P>SOLUTION: This method for producing the hydrochloride of a compound represented by formula (I) (Et is ethyl) is characterized by treating the compound represented by formula (I) in ethanol containing dissolved hydrogen chloride, concentrating the treated solution, adding toluene, and crystallizing the hydrogen chloride of the compound. Further, the methanesulfonate, p-toluenesulfonate, sulfate, acetate and formate of the compound (I) are provided. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a salt of trans-4-amino-1-cyclohexanecarboxylic acid ethyl ester (hereinafter, the trans isomer may be referred to as compound (I)) and a method for producing the same.

Trans-4-amino-1-cyclohexanecarboxylic acid or an ester thereof is a useful compound as a raw material for pharmaceutical synthesis or an intermediate.
Patent Document 1 discloses that an NPYY5 receptor is obtained from 4-amino-1-cyclohexanecarboxylic acid (a mixture of a cis isomer and a trans isomer) as a raw material and via a hydrochloride of a methyl ester isomer (a mixture of cis isomer and trans isomer). A method for synthesizing compounds having antagonistic activity is disclosed.
Patent Document 2 discloses NPYY5 receptor antagonism using cis-4-amino-1-cyclohexanecarboxylic acid as a raw material and via cis-methyl ester hydrochloride and trans-methyl ester p-toluenesulfonate. A method for synthesizing compounds having activity is disclosed.
Since all of these methods use a mixture of a cis isomer / trans isomer or a cis isomer as a raw material, a conversion step into a trans isomer is necessary when the target product is a trans isomer. Therefore, there are problems such as an increase in the number of steps, a cis isomer cannot be completely removed even if a step of converting to a trans isomer is performed, and a high temperature reaction is required.
Patent Document 3 and Patent Document 4 disclose dipeptidyl peptidase IV inhibitors, and the hydrochloride of compound (I) is disclosed as an intermediate.
Non-Patent Document 1 discloses a hydrochloride of compound (I) and a method for producing the hydrochloride. In this method, organic solvents such as benzene and diethyl ether are used. However, these solvents have a problem in use as a large-scale method for synthesizing pharmaceuticals in terms of toxicity and safety.
Non-patent document 2, Non-patent document 3, Non-patent document 4 and Non-patent document 5 similarly disclose the hydrochloride of compound (I).
Non-Patent Document 6 discloses a method of obtaining odorous acid salt from 4-amino-1-cyclohexanecarboxylic acid ethyl ester (mixture of cis and trans isomers) using odorous acid and dimethyl ether. .
International Publication No. WO01 / 37826 Pamphlet International Publication No. WO2003 / 076374 Pamphlet International Publication No. WO2002 / 030890 Pamphlet International Publication No. WO2002 / 030890 Pamphlet Journal of Medicinal Chemistry, 1971, Vol. 14, No. 7, pp. 600-614. Chemija, 1997, Volume 1, pp. 74-82. Kangshengsu, 1987, Vol. 12, No. 3, pp. 195-205 Izvestiya Akademii Nauk SSSR, Seriya Khimiceskaya, 1977, Vol. 1, pages 195-7 Journal of Organic Chemistry, 1964, Vol. 29, No. 9, pp. 2585-2587 Ber. 1963, Vol. 96, No. 9, pp. 2377-86

  An object of the present invention is to provide a novel salt of compound (I) useful as a synthetic raw material or intermediate for pharmaceuticals, and a process for producing a salt of compound (I) that can be used industrially.

（式中、Ｅｔはエチル）
で示される化合物を処理することを特徴とする、式（Ｉ）記載の化合物の塩酸塩の製造方法、
（２）塩化水素を溶解させたエタノール中で式（Ｉ）：

（式中、Ｅｔはエチル）
で示される化合物を処理し、濃縮した後にトルエンを添加することを特徴とする、式（Ｉ）記載の化合物の塩酸塩の製造方法、
（３）以下の工程
（工程１）式（Ｉ）：

（式中、Ｅｔはエチル）で示される化合物の塩および式（ＩＩ）：

（式中、Ｒ¹は低級アルキル）で示される化合物を反応させる工程、
（工程２）得られた化合物を酸化する工程、および
（工程３）得られた化合物を加水分解する工程
を含むことを特徴とする、式（Ｖ）

（式中、Ｒ¹は低級アルキル）で示される化合物の製造方法、
（４）式（Ｉ）で示される化合物の塩が塩酸塩である、上記（３）記載の製造方法、
および
（５）式（Ｉ）：

（式中、Ｅｔはエチル）で示される化合物のメタンスルホン酸塩、ｐ−トルエンスルホン酸塩、硫酸塩、酢酸塩またはギ酸塩
を提供する。
また、
（６）上記方法により得られた化合物（Ｖ）に、式（ＶＩ）：
Ｒ２ＮＨ−Ｚ （ＶＩ）
（式中、Ｒ２は水素または低級アルキル；Ｚは置換基を有していてもよい低級アルキル、置換基を有していてもよい低級アルケニル、置換基を有していてもよいアミノ、置換基を有していてもよい低級アルコキシ、置換基を有していてもよい炭化水素環式基または置換基を有していてもよいヘテロ環式基）
で示される化合物を反応させる工程を包含する、式（ＶＩＩ）：

（式中、各記号は前記と同意義）
で示される化合物の製造方法を提供する。 The present invention
(1) Formula (I) in an organic solvent in which hydrogen chloride is dissolved:

(In the formula, Et is ethyl)
A process for producing a hydrochloride salt of the compound of formula (I), characterized in that the compound represented by formula (I) is treated:
(2) Formula (I) in ethanol in which hydrogen chloride is dissolved:

(In the formula, Et is ethyl)
A method for producing a hydrochloride salt of a compound according to formula (I), wherein the compound represented by formula (I) is treated and concentrated, and then toluene is added.
(3) The following steps (Step 1) Formula (I):

(Wherein Et is ethyl) and a salt of the compound represented by formula (II):

A step of reacting a compound represented by the formula (wherein R ¹ is lower alkyl):
(Step 2) comprising the step of oxidizing the obtained compound, and (Step 3) the step of hydrolyzing the obtained compound.

(Wherein R ¹ is lower alkyl),
(4) The production method according to the above (3), wherein the salt of the compound represented by the formula (I) is hydrochloride.
And (5) Formula (I):

A methanesulfonate, p-toluenesulfonate, sulfate, acetate or formate salt of a compound represented by the formula (wherein Et is ethyl) is provided.
Also,
(6) To the compound (V) obtained by the above method, formula (VI):
R2NH-Z (VI)
(In the formula, R2 is hydrogen or lower alkyl; Z is lower alkyl which may have a substituent, lower alkenyl which may have a substituent, amino which may have a substituent, substituent A lower alkoxy optionally having a hydrocarbon, a hydrocarbon cyclic group optionally having a substituent or a heterocyclic group optionally having a substituent)
Comprising the step of reacting a compound of formula (VII):

(Wherein each symbol is as defined above)
The manufacturing method of the compound shown by this is provided.

  As is clear from the test results described below, the salt of the compound (I) of the present invention is a useful compound as a synthetic raw material or an intermediate for pharmaceuticals and the like. Moreover, the new manufacturing method of hydrochloride of compound (I) can be utilized for industrial manufacture as a high yield and safe method. Furthermore, the production method of the compound (V) using the salt of the compound (I) as a raw material is a very useful method because the production rate of by-products is low.

In the present specification, “lower alkyl” includes linear or branched alkyl having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, such as methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl And n-decyl and the like. R ¹ is preferably isopropyl or t-butyl.
Examples of the substituent of “lower alkyl optionally having substituent (s)” in Z include, for example, (1) halogen; (2) cyano; (3) each selected from the substituent group β defined below. (I) hydroxy, (ii) lower alkoxy, (iii) mercapto, (iv) lower alkylthio, (v) acyl, (vi) acyloxy, (vii) carboxy, optionally substituted with the above substitutable groups (Viii) lower alkoxycarbonyl, (ix) imino, (x) carbamoyl, (xi) thiocarbamoyl, (xii) lower alkyl carbamoyl, (xiii) lower alkyl thiocarbamoyl, (xiv) amino, (xv) lower alkyl amino or ( xvi) a group represented by heterocyclic carbonyl and the like.
Substituent group α is (1) halogen; (2) oxo; (3) cyano; (4) nitro; (5) imino optionally substituted with lower alkyl or hydroxy; (6) each substituent group β Optionally substituted with one or more substitutable groups selected from (i) hydroxy, (ii) lower alkyl, (iii) lower alkenyl, (iv) lower alkoxy, (v) carboxy, (vi) lower Alkoxycarbonyl, (vii) acyl, (viii) acyloxy, (ix) imino, (x) mercapto, (xi) lower alkylthio, (xii) carbamoyl, (xiii) lower alkylcarbamoyl, (xiv) cycloalkylcarbamoyl, (xv) ) Thiocarbamoyl, (xvi) lower alkylthiocarbamoyl, (xvii) lower alkylsulfinyl, (Xviii) lower alkylsulfonyl, (xix) sulfamoyl, (xx) lower alkylsulfamoyl and (xxi) cycloalkylsulfamoyl; (7) substituent group β, lower alkyl, lower alkoxy lower alkyl, protected, respectively Optionally substituted with hydroxy lower alkyl, halogeno lower alkyl, lower alkylsulfonyl and / or arylsulfonyl, (i) cycloalkyl, (ii) cycloalkenyl, (iii) cycloalkyloxy, (iv) amino And (v) alkylenedioxy; and (8) (i) phenyl, (ii) naphthyl, (iii) phenoxy, each optionally substituted with substituent group β, lower alkyl, halogeno lower alkyl and / or oxo, (Iv) Phenyl lower a Lucoxy, (v) phenylthio, (vi) phenyl lower alkylthio, (vii) phenylazo, (viii) heterocyclic group, (ix) heterocyclic oxy, (x) heterocyclic thio, (xi) heterocyclic carbonyl and (xii) ) A group consisting of heterocyclic sulfonyl.
Substituent group β is halogen, optionally protected hydroxy, mercapto, lower alkoxy, lower alkenyl, amino, lower alkylamino, lower alkoxycarbonylamino, lower alkylthio, acyl, carboxy, lower alkoxycarbonyl, carbamoyl, cyano, A group consisting of cycloalkyl, phenyl, phenoxy, lower alkylphenyl, lower alkoxyphenyl, halogenophenyl, naphthyl and heterocyclic groups.

“Lower alkenyl” is a straight or branched alkenyl having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, having one or more double bonds at any position. Is included. Specific examples include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl and decenyl.
The substituent of “optionally substituted lower alkenyl” includes halogen, lower alkoxy, lower alkenyl, amino, lower alkylamino, lower alkoxycarbonylamino, lower alkylthio, acyl, carboxy, lower alkoxycarbonyl, carbamoyl. , Cyano, cycloalkyl, phenyl, lower alkylphenyl, lower alkoxyphenyl, naphthyl and / or heterocyclic group.

  As the substituent of “optionally substituted amino”, the substituent group β, the optionally substituted benzoyl and / or the optionally substituted heterocyclic carbonyl ( Examples of the substituent include hydroxy, lower alkyl, lower alkoxy and / or lower alkylthio).

  “Lower alkoxy”, “lower alkylthio”, “lower alkylcarbamoyl”, “lower alkylthiocarbamoyl”, “lower alkylamino”, “lower alkylsulfinyl”, “lower alkylsulfonyl”, “lower alkylsulfamoyl”, “lower” “Alkoxycarbonyl”, “lower alkoxy lower alkyl”, “hydroxy lower alkyl”, “lower alkoxycarbonylamino”, “lower alkylphenyl”, “lower alkoxyphenyl”, “halogenolower alkyl”, “phenyllower alkoxy”, “phenyl” The lower alkyl part of “lower alkylthio” is the same as the above “lower alkyl”.

Examples of the substituent of “lower alkoxy optionally having substituent (s)” include one or more groups selected from the above substituent group β, preferably phenyl, lower alkylphenyl, lower alkoxyphenyl, naphthyl or hetero It is a cyclic group.
“Acyl” means (1) straight or branched alkylcarbonyl or alkenylcarbonyl having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 4 carbon atoms, and (2) carbon number. It includes 4 to 9, preferably 4 to 7 carbon cycloalkylcarbonyl and (3) aryl carbonyl having 7 to 11 carbon atoms. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl and benzoyl.
The acyl part of “acyloxy” is the same as above.
Protecting groups for “optionally protected hydroxy” and “optionally protected hydroxy lower alkyl” include all commonly used hydroxy protecting groups. For example, acyl (acetyl, trichloroacetyl, benzoyl etc.), lower alkoxycarbonyl (t-butoxycarbonyl etc.), lower alkylsulfonyl (methanesulfonyl etc.), lower alkoxy lower alkyl (methoxymethyl etc.), trialkylsilyl (t-butyldimethyl) Silyl etc.).
“Halogen” includes fluorine, chlorine, bromine and iodine. In particular, fluorine and chlorine are preferable.
The halogen part of “halogenophenyl” and “halogeno lower alkyl” is the same as the above “halogen”.
“Lower alkylene” includes a divalent group in which 1 to 6, preferably 2 to 6, and more preferably 3 to 6 methylenes are continuous. Specifically, methylene, ethylene, trimethylene, tetra Examples include methylene, pentamethylene and hexamethylene. Particularly preferred is tetramethylene.
The lower alkylene part of “alkylenedioxy” is the same as the above “lower alkylene”, preferably methylenedioxy or ethylenedioxy.

“Hydrocarbon cyclic group” includes “cycloalkyl”, “cycloalkenyl”, “bicycloalkyl” and “aryl”.
“Cycloalkyl” includes cyclic alkyl having 3 to 8 carbon atoms, preferably 5 or 6 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
“Cycloalkenyl” includes those having one or more double bonds at any position in the ring of the cycloalkyl, specifically, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cyclohexenyl. Sadienyl and the like can be mentioned.
“Bicycloalkyl” includes a group formed by removing one hydrogen from an aliphatic ring having 5 to 8 carbon atoms in which two rings share two or more atoms. Specific examples include bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and bicyclo [3.2.1] octyl.
“Aryl” is a monocyclic or polycyclic aromatic carbocyclic group, and includes phenyl, naphthyl, anthryl, phenanthryl and the like. Also included are aryls fused with other non-aromatic hydrocarbon cyclic groups, and specific examples include indanyl, indenyl, biphenylyl, acenaphthyl, tetrahydronaphthyl and fluorenyl. Particularly preferred is phenyl.
Examples of the substituent of the “hydrocarbon cyclic group which may have a substituent” include one or more groups selected from the above substituent group α and β, and any position is substituted. Also good.

The cycloalkyl part of “cycloalkylcarbamoyl”, “cycloalkylsulfamoyl” and “cycloalkyloxy” is the same as the above “cycloalkyl”.
The aryl part of “arylsulfonyl” is the same as the above “aryl”.

"Heterocyclic group" includes a heterocycle having one or more heteroatoms arbitrarily selected from O, S and N, specifically pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl 5- to 6-membered heteroaryl such as pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and thienyl; indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, Cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazolyl, benzo Sazolyl, benzoxiadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazini Bicyclic fused heterocyclic groups such as quinazolinyl, naphthyridinyl, dihydropyridyl, tetrahydroquinolyl, tetrahydrobenzothienyl; tricyclic such as carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl Fused heterocyclic group; dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl Encompasses pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydro-thiazolyl, non-aromatic heterocyclic group such as tetrahydroisoquinolin thiazolyl.
A condensed heterocyclic group condensed with a ring other than a heterocyclic ring (for example, benzothiazolyl) may have a bond on any ring.
As the heterocyclic group for Z, imidazolyl, benzothiazolyl, isothiazolyl, benzopyranyl, morpholino, pyridyl, quinolyl, pyrimidyl and the like are preferable.
Examples of the substituent of the “heterocyclic group which may have a substituent” are the same as those in the case where the “hydrocarbon cyclic group” is substituted.
The heterocyclic moiety of “heterocyclic oxy”, “heterocyclic thio”, “heterocyclic carbonyl” and “heterocyclic sulfonyl” is the same as the above “heterocyclic group”.

A salt of compound (I) (for example, methanesulfonate, p-toluenesulfonate, sulfate, acetate, formate, or hydrochloride) can be synthesized, for example, by the following method.
First, an organic solvent and an acid corresponding to the target salt are mixed, and compound (I) is added under ice cooling to heating, preferably about 10 ° C. to 50 ° C., more preferably about 20 ° C. to 40 ° C. . You may make it react by adding an acid to the organic solvent in which compound (I) was dissolved.
The amount of the acid to be used is about 1.0 to 2.0 molar equivalents, preferably about 1 molar equivalent, relative to 1 mol of compound (I).
As the organic solvent, for example, toluene, ethyl acetate, acetone, acetonitrile, tetrahydrofuran, chloroform, dimethylformamide, alcohol or the like may be used, and toluene, ethyl acetate or acetone is preferable.
The amount of the solvent used may be any amount that can form a solution or slurry capable of reaction. For example, a solvent having a volume of 1 to 10 times the total volume of the reaction material can be preferably used.
After the addition, if necessary, an appropriate amount of an organic solvent is further added, and the reaction is carried out under ice cooling to room temperature, preferably under ice cooling for about 5 minutes to 10 hours, preferably about 1 hour to 3 hours. The reaction solution thus obtained may be filtered, and the resulting crystals may be washed and dried as necessary.
In the case of producing the hydrochloride of the compound (I), hydrochloric acid can be used, but it is preferable that hydrogen chloride gas is blown into the organic solvent to adjust the organic solvent containing hydrogen chloride and react as described above. . It is also possible to react in the same manner as described above after blowing hydrogen chloride gas into the organic solvent in which the compound (I) is dissolved. A preferred organic solvent is ethyl acetate.
This method does not require a solvent concentration operation, and the target salt can be obtained in a high yield by a very simple operation. Moreover, since the manufacturing method of the said hydrochloride is performed by an anhydrous system, the target salt can be obtained efficiently with little loss.

Alternatively, the hydrochloride can be produced by the following method.
First, compound (I) is added to an organic solvent in which hydrogen chloride gas is dissolved, and the reaction is carried out under ice cooling to heating, preferably at about room temperature for about 10 minutes to 20 hours, preferably about 1 hour to 5 hours. .
The amount of hydrogen chloride gas to be used is about 1.0 to 2.0 molar equivalents, preferably about 1 molar equivalent, relative to 1 mol of compound (I).
As the organic solvent, alcohol, particularly ethanol is preferable. The amount of the solvent used may be any amount that can form a solution or slurry capable of reaction. For example, a solvent having a volume of 1 to 10 times the total volume of the reaction material can be preferably used.
The obtained reaction solution is concentrated by vacuum concentration or the like, a non-aqueous solvent such as toluene, ethyl acetate, acetonitrile, xylene or the like is added, and if necessary, concentrated again. The reaction solution obtained by reacting for about 5 minutes to 20 hours, preferably about 20 minutes to 1 hour under ice cooling to heating, preferably near room temperature, is filtered. The crystals thus obtained may be washed and then dried.

（式中、Ｅｔはエチルであり、Ｒ¹は低級アルキルであり、Ｒ²は水素または低級アルキルであり、Ｚは置換基を有していてもよい低級アルキル、置換基を有していてもよい低級アルケニル、置換基を有していてもよいアミノ、置換基を有していてもよい低級アルコキシ、置換基を有していてもよい炭化水素環式基、または置換基を有していてもよいヘテロ環式基である） Compound (V) can be obtained by sulfinylating the salt of compound (I), followed by oxidation and hydrolysis. Further, compound (VII) can be obtained by reacting compound (V) with compound (VI).

(In the formula, Et is ethyl, R ¹ is lower alkyl, R ² is hydrogen or lower alkyl, Z is optionally substituted lower alkyl, and may be substituted. A lower alkenyl which may have a substituent, an amino which may have a substituent, a lower alkoxy which may have a substituent, a hydrocarbon cyclic group which may have a substituent, or a substituent. A good heterocyclic group)

(First step)
If desired, compound (II) is reacted with a salt of compound (I) in the presence of a base to give compound (III).
Any base can be used as the base. Examples include alkylamine, pyridine, N-methylmorpholine, dimethylaniline and the like, with triethylamine being preferred. The amount of the base to be used is preferably about 2.0 to 3.0 molar equivalents relative to 1 mol of compound (I).
The amount of compound (II) to be used is preferably about 1.0 to 1.5 molar equivalents relative to 1 mol of compound (I).
As the reaction solvent, any solvent that can dissolve or suspend the reaction material to the extent that the reaction is possible and can form a solution or slurry capable of the reaction can be used. Examples thereof include ethyl acetate, tetrahydrofuran, dimethylformamide, toluene and the like, and preferred are toluene, ethyl acetate and dimethylformamide. In particular, when toluene is used, the reaction can proceed without isolating the intermediate.
The solvent can be used in any amount that can form a solution or slurry capable of reaction. For example, a solvent having a volume of 1 to 10 times the total volume of the reaction material can be preferably used. More preferably, the solvent is 3x (ml) when the weight of the reaction material is x (g).
The reaction temperature is not particularly limited, but is usually about −10 to 50 ° C., preferably about 5 to 10 ° C.
The reaction time is not particularly limited, but is usually about 1 hour to 5 days, preferably 1 hour to 2 days, and more preferably about 1 to 3 hours.
The obtained product may be isolated or purified, and may be used as it is in the subsequent step without isolation or purification. If it is used in the next step as it is without isolation or purification, it is advantageous in that the work can be continuously performed until the next step.

(Second step)
Compound (III) is oxidized to give compound (IV).
Any oxidizing agent can be used, but preferably hydrogen peroxide, peracetic acid (ammonium molybdate ammonium tetrahydrate ((NH ₄ ) ₆ Mo ₇ O ₂₄ 4H ₂ O) as a catalyst, Examples thereof include sodium tungstate or a hydrate thereof, and m-chloroperbenzoic acid, but preferably hydrogen peroxide (ammonium molybdate tetrahydrate ((NH ₄ ) ₆ Mo ₇ O ₂₄ 4H as a water catalyst). ₂ O)).
The amount of the catalyst to be used is preferably about 0.01 to 0.05 molar equivalent per 1 mol of compound (III). The amount of the peroxide to be used is preferably about 1.0 to 2.0 molar equivalents relative to 1 mol of compound (III).
As the reaction solvent, any solvent that can dissolve or suspend the reaction material to the extent that the reaction is possible and can form a solution or slurry capable of the reaction can be used. Examples include toluene, dimethylformamide, tetrahydrofuran, dimethylformamide, and ethyl acetate. Preferred are toluene, ethyl acetate, and dimethylformamide.
The solvent can be used in any amount that can form a solution or slurry capable of reaction. For example, a solvent having a volume of 1 to 10 times the total volume of the reaction material can be preferably used. More preferably, the solvent has a volume (ml) of 3 times the total weight (g) of the reaction material.
The reaction temperature is not particularly limited, but is usually about 0 to 100 ° C, preferably about 20 to 80 ° C.
The reaction time is not particularly limited, but is usually about 1 hour to 5 days, preferably 1 hour to 2 days, preferably about 2 to 8 hours.
The obtained product may be isolated or purified, and may be used as it is in the subsequent step without isolation or purification. If it is used in the next step as it is without isolation or purification, it is advantageous in that the work can be continuously performed until the next step.

(Third step)
Compound (IV) is hydrolyzed to obtain compound (V). This step may be performed by a conventional method. For example, compound (IV) may be reacted with a base such as sodium hydroxide or sodium methoxide and water. The amount of the base to be used is preferably about 2.0 to 3.0 molar equivalents relative to 1 mol of compound (IV).
As the reaction solvent, any solvent capable of dissolving or suspending the reaction material to the extent that the reaction can be performed and forming a solution or slurry capable of reacting can be used, and preferably water.
The solvent can be used in any amount that can form a solution or slurry capable of reaction. For example, a solvent having a volume of 1 to 10 times the total volume of the reaction material can be preferably used.
The reaction temperature is preferably 0 to 40 ° C.
The reaction time is preferably about 1 hour to 5 days, more preferably about 2 hours to 24 hours.

(4th process)
Compound (VII) can be obtained by reacting compound (V) with compound (VI). The reaction may be performed in accordance with, for example, the amidation reaction described in Patent Document 1 above.
For example, an activated form such as an acid halide of compound (V) and compound (VI) (for example, using thionyl chloride, oxalyl chloride or phosphorus oxychloride), an acid anhydride, an activated ester, etc. in an appropriate solvent The reaction is carried out at 0 ° C. to 100 ° C. for about 3 minutes to 10 hours. Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, water, and mixed solvents thereof. Can be used, preferably toluene or tetrahydrofuran. If necessary, an activator such as a base (preferably triethylamine or pyridine), thionyl chloride, acid halide (eg thionyl chloride, oxalyl chloride or phosphorus oxychloride), acid anhydride, activated ester or the like is used. Also good.
Alternatively, compound (V) and compound (VI) are combined with a suitable solvent (eg tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, (Heptane, dioxane, acetone, acetonitrile, water and mixed solvents thereof) in the presence of a condensing agent, the target compound can be obtained by reacting at about 0 ° C. to 100 ° C. for about 3 minutes to 10 hours. As the condensing agent, for example, 1,1-carbonyldiimidazole, dicyclohexylcarbodiimide or water-soluble carbodiimide (1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide) can be used.

等が挙げられる。
こうして得られる化合物（ＶＩＩ）は、ＮＰＹＹ５拮抗薬等として有用である。 As the group shown as Z, specifically

Etc.
The compound (VII) thus obtained is useful as an NPYY5 antagonist and the like.

  When the compound (III) is produced using a salt of the compound (I), particularly the hydrochloride, the production of by-products is suppressed as compared with the case of producing the compound (I). Since compound (VII) can be used as a pharmaceutical product, the effect of minimizing the production of by-products and improving the quality has great significance.

  The present invention will be described in more detail with reference to the following examples, but these are not intended to limit the present invention.

Synthesis of Compound (I) hydrochloride (hydrogen chloride / ethanol, toluene solvent substitution)
To a 0.1 M hydrogen chloride / ethanol solution (380 ml, 38 mmol) was added 3.25 g (19.0 mmol) of compound (I), and the mixture was stirred at room temperature for about 2 hours, and then the reaction solution was concentrated under reduced pressure to 17 g. Toluene (49 mL) was added to the concentrate, and the mixture was concentrated under reduced pressure until the concentrate reached 24 g. After stirring at room temperature for 30 minutes, the mixture was filtered, and the crystals were washed with 49 mL of toluene. The obtained crystals were dried under reduced pressure to obtain 3.85 g (yield 97.6%) of Compound (I) hydrochloride.

Synthesis of Compound (I) hydrochloride (4 mol / L hydrogen chloride-containing ethyl acetate, ethyl acetate solvent)
To a solution obtained by mixing 15.3 mL of ethyl acetate containing hydrogen chloride and 15 mL of ethyl acetate dissolved by blowing HCl gas at 4 mol / L, 10.00 g (58.4 mmol) of Compound (I) was stirred at 23 to 39 ° C. The mixture was added dropwise at 9 ° C. over 9 minutes, 20 mL of ethyl acetate was added, and the mixture was further stirred with ice cooling for 1 hour. The mixture was filtered, and the resulting crystals were washed with 20 mL of ethyl acetate and then dried by heating under reduced pressure to obtain 11.82 g (yield 97.4%) of Compound (I) hydrochloride.

Reference Example 1 Synthesis of Compound (I) hydrochloride (hydrogen chloride / ethanol, acetonitrile solvent substitution)
To 36.03 g of a 13% hydrogen chloride / ethanol solution and 150 mL of ethanol were added 20.00 g (116.8 mmol) of Compound (I), and the mixture was stirred at room temperature for 10 minutes to remove insoluble matters. The reaction solution was concentrated under reduced pressure to 86 g. 350 mL of acetonitrile was added to the concentrate, and the mixture was stirred at room temperature for 1.5 hours, filtered, and the crystals were washed with 150 mL of acetonitrile. The obtained crystals were dried under reduced pressure to obtain 16.07 g (yield 66.2%) of Compound (I) hydrochloride.

Reference Example 2 Synthesis of Compound (I) Hydrochloride (35% hydrochloric acid, toluene solvent)
To a solution obtained by mixing 10.00 g (58.4 mmol) of Compound (I) and 30 mL of toluene, 6.39 g of 35% hydrochloric acid was added dropwise at 22 ° C. to 35 ° C. over 11 minutes with stirring, and further stirred at room temperature for 1 hour. did. The mixture was filtered, and the resulting crystals were washed with 20 mL of toluene and then dried under reduced pressure to obtain 7.20 g of Compound (I) hydrochloride (yield 59.4%).

Reference Example 3 Synthesis of Compound (I) Hydrochloride (35% hydrochloric acid, acetone solvent)
To a mixed solution of 10.00 g (58.4 mmol) of Compound (I) and 30 mL of acetone, 6.39 g of 35% hydrochloric acid was added dropwise at 21 ° C. to 32 ° C. over 10 minutes with stirring, and further stirred at room temperature for 1 hour. did. The mixture was filtered, and the resulting crystals were washed with 20 mL of acetone and then dried under reduced pressure to obtain 5.17 g of Compound (I) hydrochloride (yield 42.6%).

Reference Example 4 Synthesis of Compound (I) Hydrochloride (35% hydrochloric acid, ethyl acetate solvent)
To a mixed solution of 10.00 g (58.4 mmol) of Compound (I) and 30 mL of ethyl acetate, 6.39 g of 35% hydrochloric acid was added dropwise at 21 ° C. to 34 ° C. over 10 minutes with stirring, and further at room temperature for 1 hour. Stir. The mixture was filtered, and the obtained crystals were washed with 20 mL of ethyl acetate and then dried under reduced pressure to obtain 6.69 g of Compound (I) hydrochloride (yield 55.2%).

Reference Example 5 Synthesis of Compound (I) Hydrochloride (35% hydrochloric acid, ethyl acetate solvent, concentrated by dehydration)
To a solution obtained by mixing 10.00 g (58.4 mmol) of Compound (I) and 30 mL of ethyl acetate, 6.39 g of 35% hydrochloric acid was added dropwise at 22 ° C. to 39 ° C. over 11 minutes with stirring, and stirred at room temperature for 1 hour. did. After adding 25 mL of ethyl acetate, it concentrated under reduced pressure. After concentration under reduced pressure by adding 40 mL of ethyl acetate three times, the mixture was filtered, and the resulting crystals were washed with 20 mL of ethyl acetate and dried by heating under reduced pressure to obtain 11.59 g of compound (I) hydrochloride (yield). Rate 95.6%).

Reference Example 6 Synthesis of Compound (I) Hydrochloride (35% hydrochloric acid, toluene solvent, dehydration concentration)
To a mixed solution of 10.00 g (58.4 mmol) of Compound (I) and 30 mL of toluene, 6.39 g of 35% hydrochloric acid was added dropwise over 5 minutes at 23 to 36 ° C. with stirring, and the mixture was stirred at room temperature for 1 hour. . After concentration under reduced pressure, 40 mL of toluene was added and concentration under reduced pressure was further performed three times. The mixture was filtered, and the resulting crystals were washed with 20 mL of toluene and then dried under reduced pressure to obtain 9.85 g of Compound (I) hydrochloride (yield 81.2%).

Synthesis of Compound (I) Methanesulfonate Salt A mixture of 5.89 g (58.4 mmol) of methanesulfonic acid and 30 mL of toluene was stirred at 20 ° C. to 37 ° C. over 15 minutes while stirring 10.00 g of Compound (I). After adding 20 mL of toluene, the mixture was further stirred with ice cooling for 1 hour. The mixture was filtered, and the resulting crystals were washed with 20 mL of toluene and dried under reduced pressure to obtain 15.34 g of Compound (I) methanesulfonate (yield 98.3%).

Synthesis of Compound (I) p-Toluenesulfonic Acid Salt A mixture of 11.66 g of p-toluenesulfonic acid monohydrate and 30 mL of toluene was added while stirring 10.00 g (58.4 mmol) of Compound (I) 21 The mixture was added dropwise at 12 to 38 ° C. over 12 minutes, 20 mL of toluene was added, and the mixture was further stirred with ice cooling for 1 hour. The mixture was filtered, and the resulting crystals were washed with 20 mL of toluene and then dried under reduced pressure to obtain 20.01 g of Compound (I) p-toluenesulfonate (yield 99.8%).

Synthesis of Compound (I) Sulfate To a solution obtained by mixing 3.10 g of 97% sulfuric acid and 30 mL of toluene, 10.00 g (58.4 mmol) of Compound (I) was added dropwise at 22 to 38 ° C. over 11 minutes with stirring. After adding 20 mL of toluene, the mixture was further stirred with ice cooling for 1 hour. This mixture was filtered, and the resulting crystals were washed with 20 mL of toluene and dried under reduced pressure to obtain 12.85 g of Compound (I) sulfate (yield 99.9%).

Synthesis of Compound (I) Acetate (Toluene solvent)
To a mixed solution of 3.68 g of acetic acid and 30 mL of toluene, 10.00 g (58.4 mmol) of Compound (I) was added dropwise at 19 ° C. to 39 ° C. over 11 minutes with stirring, and 20 mL of toluene was added and ice was added. Stir cold for 1 hour. The mixture was filtered, and the resulting crystals were washed with 20 mL of toluene and then dried under reduced pressure to obtain 12.96 g of Compound (I) acetate (yield 95.9%).

Synthesis of Compound (I) Acetate (Ethyl acetate solvent)
To a mixed solution of 3.68 g of acetic acid and 50 mL of ethyl acetate, 10.00 g (58.4 mmol) of Compound (I) was added dropwise at 20 ° C. to 39 ° C. over 9 minutes with stirring, and the mixture was stirred for 1 hour with ice cooling. . The mixture was filtered, and the resulting crystals were washed with 20 mL of ethyl acetate and then dried under reduced pressure to obtain 12.71 g of Compound (I) acetate (yield 94.1%).

Synthesis of Compound (I) Acetate (Acetone Solvent)
To a solution obtained by mixing 10.00 g (58.4 mmol) of Compound (I) and 30 mL of acetone, 3.68 g of acetic acid was added dropwise at 20 ° C. to 37 ° C. over 5 minutes with stirring, followed by stirring with ice cooling for 2.5 hours. did. The mixture was filtered, and the resulting crystals were washed with 20 mL of acetone and then dried under reduced pressure to obtain 12.57 g (yield 93.1%) of Compound (I) acetate.

Synthesis of Compound (I) Formate (Toluene solvent)
To a solution obtained by mixing 2.88 g of 98% formic acid and 30 mL of toluene, 10.00 g (58.4 mmol) of Compound (I) was added dropwise at 19 to 36 ° C. over 7 minutes with stirring, and 20 mL of toluene was added. The mixture was further stirred with ice cooling for 1 hour. The mixture was filtered, and the resulting crystals were washed with 20 mL of toluene and dried under reduced pressure to obtain 12.32 g of Compound (I) formate (yield 97.1%).

Synthesis of Compound (I) Formate (Acetone Solvent)
To a solution obtained by mixing 10.00 g (58.4 mmol) of Compound (I) and 30 mL of acetone, 3.68 g of formic acid was added dropwise at 21 ° C. to 39 ° C. over 8 minutes with stirring, followed by stirring with ice cooling for 1 hour. The mixture was filtered, and the obtained crystals were washed with 20 mL of acetone and then dried under reduced pressure to obtain 12.32 g of Compound (I) formate (yield 97.1%).

The physical constants of the salts of the compound (I) obtained in Examples 1 to 10 are shown in the following table. In the table, p-TsOH represents paratoluenesulfonic acid, and AcOH represents acetic acid.

（式中、Ｅｔはエチル）
化合物（Ｉ）の塩酸塩６．００ｇにトルエン１５ｍＬ、化合物（ＩＩ−１）４．４７ｇを加え２℃に冷却した後、トリエチルアミン６．７２ｇを２℃から１０℃の間で１４分かけて滴下した。この混合物を０℃から１０℃で６０分間攪拌し、水道水１２ｍＬを加えた。この混合物に０．５Ｍ 硫酸水１４．６８ｇを１０℃から１８℃で滴下し、ｐＨを５．６とした。４０℃まで昇温し、塩化ナトリウム１．２ｇを加えた後、分液することによって上層２８．１ｇを得た（化合物（ＩＩＩ−１）トルエン溶液）。七モリブデン酸六アンモニウム四水和物１．０７ｇと３５％過酸化水素水４．２１ｇを混合した溶液に上記化合物（ＩＩＩ−１）トルエン溶液を４０℃から５５℃で２６分かけて滴下し、４０℃付近で２１０分間攪拌した。この混合物に８％亜硫酸ナトリウム水４８ｍＬを３４℃から４９℃で９分かけて滴下し、残存過酸化物を除去した後トルエン２４ｍＬを追加し分液して上層４９．４１ｇを得た（化合物（ＩＶ−１）トルエン溶液）。この化合物（ＩＶ−１）トルエン溶液に水５１ｍＬを加えた後、４８％水酸化ナトリウム水溶液６．０２ｇを添加し、５５℃付近で６０分間攪拌した。この混合物を分液し、水層を４０℃まで冷却した後、１０％硫酸水３６．６７ｇを４０℃から４２℃で滴下することによってｐＨを２．５とし、中和晶析させた。この混合物を３℃付近で３０分攪拌した後、反応混合物を濾過し、濾物を４２ｍＬの水道水で洗浄した。未乾晶を取り出し、減圧下加熱（５０℃）乾燥し、６．０１ｇの化合物（Ｖ−１）を得た（収率７９．０％ アミノエチルエステル塩酸塩基準）。得られた化合物（Ｖ−１）は特許文献２に記載の化合物１３と同一物質であった。 Synthesis of Compound (V) Using Compound (I) Hydrochloride as a Raw Material

(In the formula, Et is ethyl)
To 6.00 g of the hydrochloride of compound (I), 15 mL of toluene and 4.47 g of compound (II-1) were added and cooled to 2 ° C., then 6.72 g of triethylamine was added dropwise between 2 ° C. and 10 ° C. over 14 minutes. did. The mixture was stirred at 0 ° C. to 10 ° C. for 60 minutes, and 12 mL of tap water was added. To this mixture, 14.68 g of 0.5 M aqueous sulfuric acid was added dropwise at 10 ° C. to 18 ° C. to adjust the pH to 5.6. The temperature was raised to 40 ° C., and 1.2 g of sodium chloride was added, followed by liquid separation to obtain 28.1 g of an upper layer (compound (III-1) toluene solution). To a solution obtained by mixing 1.07 g of hexamolybdenum hexamolybdate tetrahydrate and 4.21 g of 35% hydrogen peroxide solution, the above compound (III-1) toluene solution was added dropwise at 40 to 55 ° C. over 26 minutes, The mixture was stirred at around 40 ° C for 210 minutes. To this mixture, 48 mL of 8% aqueous sodium sulfite was added dropwise at 34 ° C. to 49 ° C. over 9 minutes, and after removing residual peroxide, 24 mL of toluene was added and liquid-separated to obtain 49.41 g of the upper layer (compound ( IV-1) Toluene solution). After adding 51 mL of water to this compound (IV-1) toluene solution, 6.02 g of 48% aqueous sodium hydroxide solution was added, and the mixture was stirred at around 55 ° C. for 60 minutes. The mixture was separated and the aqueous layer was cooled to 40 ° C., and 36.67 g of 10% sulfuric acid aqueous solution was added dropwise at 40 ° C. to 42 ° C. to adjust the pH to 2.5 for crystallization. After the mixture was stirred at around 3 ° C. for 30 minutes, the reaction mixture was filtered, and the filtrate was washed with 42 mL of tap water. Undried crystals were taken out and dried under reduced pressure (50 ° C.) to obtain 6.01 g of compound (V-1) (yield 79.0% based on aminoethyl ester hydrochloride). The obtained compound (V-1) was the same substance as the compound 13 described in Patent Document 2.

上記副生成物２はLC-MSより下記誘導体であると推定される。

上記より明らかなとおり、塩酸塩を用いて化合物（Ｖ−１）を製造した場合には副生成物の生成がほとんど見られなかった。 Compound (I) or Compound (V-1) prepared from hydrochloride of Compound (I) is dissolved in 20% acetonitrile water, analyzed by HPLC (detector: UV 208 nm), and each by-product is analyzed by area percentage method. The amount was determined.

By-product 2 is estimated to be the following derivative from LC-MS.

As apparent from the above, when the compound (V-1) was produced using the hydrochloride, almost no by-product was observed.

Test Example 1 Stability of Compound (I) Hydrochloride Compound (I) hydrochloride was dissolved in 50% acetonitrile. This was analyzed by HPLC (detector: UV 215 nm), and the amount of each related substance was determined by the area percentage method.
The results are shown below. Compound (I) was contaminated with impurities such as dimers, and an increase in impurities was observed over time. On the other hand, it can be seen that the hydrochloride of the compound (I) is stable with no impurities detected even after storage.

The salt of the compound (I) of the present invention is a compound useful as a synthetic raw material or an intermediate for pharmaceuticals and the like. Moreover, the new manufacturing method of hydrochloride of compound (I) can be utilized for industrial manufacture as a high yield and safe method. Furthermore, the production method of the compound (V) using the salt of the compound (I) as a raw material is a very useful method with a low production rate of by-products.

Claims (5)

Formula (I) in an organic solvent in which hydrogen chloride is dissolved:

(In the formula, Et is ethyl)
A process for producing a hydrochloride of a compound according to formula (I), characterized in that the compound represented by formula (I) is treated. Formula (I) in ethanol in which hydrogen chloride is dissolved:

(In the formula, Et is ethyl)
A method for producing a hydrochloride salt of a compound according to formula (I), wherein the compound represented by formula (I) is treated and concentrated, followed by addition of toluene. The following steps (Step 1) Formula (I):

(Wherein Et is ethyl) and a salt of the compound represented by formula (II):

A step of reacting a compound represented by the formula (wherein R ¹ is lower alkyl):
(Step 2) comprising the step of oxidizing the obtained compound, and (Step 3) the step of hydrolyzing the obtained compound.

(Wherein R ¹ is lower alkyl). The manufacturing method of Claim 3 whose salt of the compound shown by a formula (I) is hydrochloride. Formula (I):

A methanesulfonate, p-toluenesulfonate, sulfate, acetate or formate salt of the compound represented by the formula (Et is ethyl).