JP2005220079A - Synthesis of pyrrolidine compound and crystal therefor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a pyrrolidine compound having cPLA<SB>2</SB>(cytoplasma type PLA<SB>2</SB>)-inhibiting activities; and to provide a method for producing an intermediate thereof and a crystal thereof. <P>SOLUTION: The method for producing the compound represented by formula (II) (wherein, R<SP>1</SP>is phenyl, a 1-6C alkyl, or the like; R<SP>2</SP>is a 1-6C alkyl, or the like; and Pro is a t-butyloxycarbonyl group, or the like), a solvate thereof or a salt thereof involves subjecting a compound represented by formula (I) (wherein, R<SP>1</SP>, R<SP>2</SP>and Pro have the same meanings as the above), a solvate thereof or a salt thereof to hydrogenation reaction in the presence of a catalyst. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to a method for producing a pyrrolidine compound having cPLA ₂ inhibitory activity, a method for producing an intermediate thereof, and a crystal thereof.

しかしながら、詳細な実験条件は開示されておらず、中間体としては爆発性の高いアジド基を有するピロリジン環化合物を経由おり、環境に有害な塩化スズを用いて還元する工程が含まれるなど、安全性および環境の面でも問題があり、工業的にふさわしい工程とはいえない。
国際公開第９７／０５１３５号パンフレット 国際公開第９８／３３７９７号パンフレット 国際公開第０１／３０３８７号パンフレット 瀬野薫ら、ジャーナル オブ メディシナル ケミストリー (J. Med. Chem.) 2000年、第43巻、第6号、p.1042-1044 瀬野薫ら、アメリカ化学会 ジャーナル オブ メディシナル ケミストリー (American Chemical Society, J. Med. Chem.) jm9905155, Supporting Info Page 1-12 [online]［平成16年2月4日検索］インターネット<URL:http://pubs.acs.org/subscribe/journals/jmcmar/suppinfo/43/i06/jm9905155/jm9905155#s.pdf> Phospholipase A ₂ (PLA ₂ ) is a generic term for enzymes that hydrolyze the ester bond at the 2-position of phospholipids. It is involved in the formation and metabolism of biological membrane phospholipids and the arachidonic acid cascade leading to the production of lipid mediators such as prostanoids. Functions as a starting enzyme. At present, the existence of various PLA ₂ has been clarified in mammals. Based on its localization, molecular weight, substrate specificity, etc., secreted PLA ₂ (sPLA ₂ ), Ca ²⁺ -independent PLA ₂ (IPLA ₂ ) and cytoplasmic PLA ₂ (cPLA ₂ ) are classified into families.
Among these PLA ₂ , pyrrolidine compounds having thiazolidinedione at the 2-position side chain, which selectively inhibits cPLA ₂ , are described in Patent Documents 1, 2, and 3, and Non-Patent Document 1. Yes. Furthermore, the production method of the compound is described as Supporting Information on the Web page related to Non-Patent Document 1 as follows (Non-Patent Document 2).

However, detailed experimental conditions are not disclosed, and the intermediate includes a pyrrolidine ring compound having a highly explosive azide group, and includes a step of reduction using tin chloride harmful to the environment. There are also problems in terms of properties and environment, and it cannot be said that this is an industrially suitable process.
International Publication No. 97/05135 Pamphlet International Publication No. 98/33797 Pamphlet International Publication No. 01/30387 Pamphlet Seno, et al., Journal of Medicinal Chemistry (2000), Volume 43, Number 6, p.1042-1044 Seno, et al., American Chemical Society, Journal of Medicinal Chemistry (American Chemical Society, J. Med. Chem.) Jm9905155, Supporting Info Page 1-12 [online] [searched February 4, 2004] Internet <URL: http: //pubs.acs.org/subscribe/journals/jmcmar/suppinfo/43/i06/jm9905155/jm9905155#s.pdf>

In order to provide a pyrrolidine compound having cPLA ₂ inhibitory activity as a pharmaceutical product, an efficient industrial production method of the compound has been desired.

  In view of the above points, the present inventors have conducted extensive studies, and as a result, completed the following invention characterized in that a pyrrolidine compound having a nitrile group is reduced to an amino group by a hydrogenation reaction in the presence of a catalyst. .

（式中、Ｒ¹はアラルキル；
Ｒ²は水素原子またはＣ１−Ｃ６アルキル；および
Ｐｒｏは保護基）
で表わされる化合物、その溶媒和物、またはそれらの塩を、ニッケル、パラジウム、白金から選ばれる少なくとも一つの触媒存在下で水素添加反応に付することを特徴とする、一般式（ＩＩ）：

（式中、Ｒ¹、Ｒ²、およびＰｒｏは前記と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩の製造方法、に関する。 That is, the present invention relates to 1) general formula (I):

Wherein R ¹ is aralkyl;
R ² is a hydrogen atom or C1-C6 alkyl; and Pro is a protecting group)
Or a solvate thereof, or a salt thereof is subjected to a hydrogenation reaction in the presence of at least one catalyst selected from nickel, palladium, and platinum, represented by the general formula (II):

(Wherein R ¹ , R ² and Pro are as defined above)
Or a solvate thereof, or a method for producing a salt thereof.

（式中、Ｒ¹、Ｒ²、およびＰｒｏは１）と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩を、脱水剤存在下で脱水反応に付し、一般式（Ｉ）：

（式中、Ｒ¹、Ｒ²、およびＰｒｏは１）と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩を得る工程、
（ｂ）一般式（Ｉ）：

（式中、Ｒ¹、Ｒ²、およびＰｒｏは１）と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩を、ニッケル、パラジウム、白金から選ばれる少なくとも一つの触媒存在下で水素添加反応に付する工程
を包含することを特徴とする、一般式（ＩＩ）：

（式中、Ｒ¹、Ｒ²、およびＰｒｏは１）と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩の製造方法。 More specifically, it relates to the following 2) to 24).
2) The following steps:
(A) General formula (III):

(Wherein R ¹ , R ² and Pro are the same as 1))
Or a solvate thereof, or a salt thereof is subjected to a dehydration reaction in the presence of a dehydrating agent, and is represented by the general formula (I):

(Wherein R ¹ , R ² and Pro are the same as 1))
A compound represented by the formula: solvates thereof, or salts thereof;
(B) General formula (I):

(Wherein R ¹ , R ² and Pro are the same as 1))
And a solvate thereof, or a salt thereof, which is subjected to a hydrogenation reaction in the presence of at least one catalyst selected from nickel, palladium and platinum. II):

(Wherein R ¹ , R ² and Pro are the same as 1))
Or a solvate thereof, or a salt thereof.

（式中、Ｒ¹、Ｒ²、およびＰｒｏは１）と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩を、脱水剤存在下で脱水反応に付し、一般式（Ｉ）：

（式中、Ｒ¹、Ｒ²、およびＰｒｏは１）と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩を得る工程、
（ｂ）一般式（Ｉ）：

（式中、Ｒ¹、Ｒ²、およびＰｒｏは１）と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩を、ニッケル、パラジウム、白金から選ばれる少なくとも一つの触媒存在下で水素添加反応に付し、一般式（ＩＩ）：

（式中、Ｒ¹、Ｒ²、およびＰｒｏは１）と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩を得る工程、
（ｃ）一般式（ＩＩ）：

（式中、Ｒ¹、Ｒ²、およびＰｒｏは１）と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩と、一般式（ＩＶ）：

（式中、Ｘはハロゲンまたはヒドロキシ）
で表わされる化合物、その溶媒和物、またはそれらの塩をアミド結合生成反応に付し、一般式（Ｖ）：

（式中、Ｒ¹、Ｒ²、およびＰｒｏは１）と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩を得る工程、
（ｄ）一般式（Ｖ）：

（式中、Ｒ¹、Ｒ²、およびＰｒｏは１）と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩を脱保護反応に付し、一般式（ＶＩ）：

（式中、Ｒ¹およびＲ²は１）と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩を得る工程、
（ｅ）一般式（ＶＩ）：

（式中、Ｒ¹およびＲ²は１）と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩と一般式（ＶＩＩ）：

（式中、Ｙはハロゲンまたはヒドロキシ）
で表わされる化合物、その溶媒和物、またはそれらの塩をアミド結合生成反応に付する工程を包含することを特徴とする、一般式（ＶＩＩＩ）：

（式中、Ｒ¹およびＲ²は１）と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩の製造方法。 3) The following steps:
(A) General formula (III):

(Wherein R ¹ , R ² and Pro are the same as 1))
Or a solvate thereof, or a salt thereof is subjected to a dehydration reaction in the presence of a dehydrating agent, and is represented by the general formula (I):

(Wherein R ¹ , R ² and Pro are the same as 1))
A compound represented by the formula: solvates thereof, or salts thereof;
(B) General formula (I):

(Wherein R ¹ , R ² and Pro are the same as 1))
Or a solvate thereof, or a salt thereof is subjected to a hydrogenation reaction in the presence of at least one catalyst selected from nickel, palladium, and platinum, and is represented by the general formula (II):

(Wherein R ¹ , R ² and Pro are the same as 1))
A compound represented by the formula: solvates thereof, or salts thereof;
(C) General formula (II):

(Wherein R ¹ , R ² and Pro are the same as 1))
And a solvate thereof, or a salt thereof, and a general formula (IV):

(Where X is halogen or hydroxy)
Or a solvate thereof, or a salt thereof, is subjected to an amide bond formation reaction, and is represented by the general formula (V):

(Wherein R ¹ , R ² and Pro are the same as 1))
A compound represented by the formula: solvates thereof, or salts thereof;
(D) General formula (V):

(Wherein R ¹ , R ² and Pro are the same as 1))
Or a solvate thereof, or a salt thereof, is subjected to a deprotection reaction to give a general formula (VI):

(Wherein R ¹ and R ² have the same meanings as 1))
A compound represented by the formula: solvates thereof, or salts thereof;
(E) General formula (VI):

(Wherein R ¹ and R ² have the same meanings as 1))
Or a solvate thereof, or a salt thereof and the general formula (VII):

(Where Y is halogen or hydroxy)
The compound represented by general formula (VIII) characterized by including the process of attaching | subjecting the compound represented by these, its solvate, or those salts to amide bond production | generation reaction:

(Wherein R ¹ and R ² have the same meanings as 1))
Or a solvate thereof, or a salt thereof.

4) The production method according to any one of 1) to 3), wherein R ¹ is phenyl C1-C6 alkyl, biphenyl C1-C6 alkyl, diphenyl C1-C6 alkyl, or triphenyl C1-C6 alkyl.
5) The production method according to 4), wherein R ¹ is biphenylmethyl or diphenylmethyl.
6) The production method according to any one of 1) to 5), wherein R ² is C4 alkyl.
7) The production method according to any one of 1) to 6), wherein R ¹ is 2-biphenylmethyl and R ² is isobutyl.
8) The production method according to any one of 1) to 7), wherein the catalyst is Raney nickel or nickel chloride.
9) The production method according to 8), wherein the catalyst is Raney nickel.
10) The protecting group is a t-butyloxycarbonyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, an allyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, or a p-nitrobenzyloxycarbonyl group. The production method according to any one of 1) to 9).
11) The production method according to 10), wherein the protecting group is a t-butyloxycarbonyl group.
12) The production method according to any one of 2) to 11), wherein the dehydrating agent is trichloroacetyl chloride, phosphorus oxychloride, oxalyl chloride, trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, or thionyl chloride.
13) The production method according to 12), wherein the dehydrating agent is trichloroacetyl chloride or phosphorus oxychloride.
14) To obtain a compound represented by the general formula (VIII) wherein R ¹ is 2-biphenylmethyl and R ² is isobutyl, a solvate thereof, a p-toluenesulfonate, a sulfate thereof, or a hydrochloride thereof The production method according to any one of 3) to 13).

（式中、Ｂｏｃはｔ−ブチルオキシカルボニル）
で表わされる化合物のベンゼンスルホン酸塩、またはその溶媒和物。
１６）式（ＩＸ）：

（式中、Ｂｏｃはｔ−ブチルオキシカルボニル）
で表わされる化合物のベンゼンスルホン酸塩、またはその溶媒和物の、結晶。
１７）粉末Ｘ線回折パターンにおいて、回折角（２θ）が19.3、20.2、20.7、および27.0（単位：°）に主なるピークを示す、１６）記載の結晶。
１８）式（Ｘ）：

で表わされる化合物、またはその溶媒和物の、結晶。
１９）粉末Ｘ線回折パターンにおいて、回折角（２θ）が5.8、13.0、18.5、および26.4（単位：°）に主なるピークを示す、１８）記載の結晶。
２０）式（ＸＩ）：

（式中、Ｂｏｃはｔ−ブチルオキシカルボニル）
で表わされる化合物、その溶媒和物、またはそれらの塩。
２１）一般式（ＩＩＩ）：

（式中、Ｒ¹はアラルキル；
Ｒ²は水素原子またはＣ１−Ｃ６アルキル；および
Ｐｒｏは保護基）
で表わされる化合物、その溶媒和物、またはそれらの塩を、水素化ホウ素ナトリウム、水素化リチウムアルミニウム、およびジボランから選ばれる少なくとも一つの試薬と反応させることを特徴とする、一般式（ＩＩ）：

（式中、Ｒ¹、Ｒ²、およびＰｒｏは１）と同意義）
で表わされる化合物、その溶媒和物、またはそれらの塩の製造方法。
２２）水素化ホウ素ナトリウムと反応させることを特徴とする２１）記載の製造方法。
２３）酢酸の存在下で反応させることを特徴とする２２）記載の製造方法。
２４）Ｒ¹が２−ビフェニルメチル、Ｒ²がイソブチル、および保護基がｔ−ブチルオキシカルボニルである２１）〜２３）のいずれかに記載の製造方法。 15) Formula (IX):

(Where Boc is t-butyloxycarbonyl)
Or a solvate thereof.
16) Formula (IX):

(Where Boc is t-butyloxycarbonyl)
A crystal of a benzenesulfonate salt of a compound represented by the formula:
17) The crystal according to 16), wherein in the powder X-ray diffraction pattern, diffraction angles (2θ) show main peaks at 19.3, 20.2, 20.7, and 27.0 (unit: °).
18) Formula (X):

Or a solvate thereof.
19) The crystal according to 18), wherein in the powder X-ray diffraction pattern, diffraction angles (2θ) show main peaks at 5.8, 13.0, 18.5, and 26.4 (unit: °).
20) Formula (XI):

(Where Boc is t-butyloxycarbonyl)
Or a solvate thereof, or a salt thereof.
21) General formula (III):

Wherein R ¹ is aralkyl;
R ² is a hydrogen atom or C1-C6 alkyl; and Pro is a protecting group)
Or a solvate thereof, or a salt thereof, is reacted with at least one reagent selected from sodium borohydride, lithium aluminum hydride, and diborane, represented by the general formula (II):

(Wherein R ¹ , R ² and Pro are the same as 1))
Or a solvate thereof, or a salt thereof.
22) The production method according to 21), which is reacted with sodium borohydride.
23) The production method according to 22), wherein the reaction is carried out in the presence of acetic acid.
24) The production method according to any one of 21) to 23), wherein R ¹ is 2-biphenylmethyl, R ² is isobutyl, and the protecting group is t-butyloxycarbonyl.

The compounds of formula (IX), formula (X) and formula (XI) are intended to encompass all possible optical isomers and mixtures of optical isomers including racemates.
In the present specification, the “solvate” includes, for example, solvates with organic solvents, hydrates and the like. When forming a hydrate, it may be coordinated with any number of water molecules.
As salts of the compounds used in this specification, inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, etc.) and organic acids (acetic acid, oxalic acid, citric acid, maleic acid, fumaric acid, benzene) A salt with sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid, or the like, or an alkali metal (lithium, sodium, potassium, etc.), an alkaline earth metal (magnesium, calcium, etc.), ammonium, an organic base, and an amino acid. Of the salt. These salts can be formed by a commonly performed method.

In the present specification, the “hydrogenation reaction” means a reaction in which hydrogen is added to the position of multiple bonds in an organic compound. In particular, a reaction in which a cyano group (—C≡N) is reduced to an aminomethyl group (—CH ₂ NH ₂ ) is preferable.
In the present specification, “dehydration reaction” means a reaction in which hydrogen and oxygen are desorbed from an organic compound as water. In particular, a reaction for converting an amide group (—CONH ₂ ) into a cyano group (—C≡N) is preferable.
In this specification, the term “deprotection reaction” refers to a reaction in which a protective group introduced to protect a highly reactive functional group or a functional group that is difficult to react is removed and returned to the original functional group. means. Although the reaction conditions differ depending on the protecting group, the method described in Protective Groups in Organic Synthesis, 3rd ed., (Theodora W. Greene and Peter GM Wuts, New York, John Wiley, 1999) and the like can be mentioned. Examples of the reaction include acid hydrolysis reaction, alkali hydrolysis reaction, oxidation reaction, hydrogenation reaction, reduction reaction with hydride, electrode reaction, and photoreaction.
When the protecting group is a t-butyloxycarbonyl group, hydrochloric acid, sulfuric acid, trifluoroacetic acid, nitric acid, formic acid, or a mixture of these acids, as well as Lewis acids (eg, AlCl ₃ , TiCl ₄ , ZnCl ₂ , BF ₃ ) And a condition of a mixture of aniline and anisole.
When the protecting group is a benzyloxycarbonyl group, a hydrogenation reaction with a palladium-carbon catalyst, a deprotection reaction with an acid such as Lewis acid of aluminum chloride or boron tribromide, hydrobromic acid, acetic acid, trifluoroacetic acid, etc. It is done.
When the protecting group is a p-methoxybenzyloxycarbonyl group, a deprotection reaction with an acid such as p-toluenesulfonic acid or trifluoroacetic acid can be mentioned.
When the protecting group is an allyloxycarbonyl group, a deprotection reaction by a palladium catalyst-formic acid system can be mentioned.
When the protecting group is a 9-fluorenylmethyloxycarbonyl group, deprotection with a base such as piperidine can be mentioned.
When the protecting group is a p-nitrobenzyloxycarbonyl group, a hydrogenation reaction using a palladium-carbon catalyst, an electrode reaction, and deprotection with an acid such as hydrobromic acid-acetic acid can be used. Deprotection is mentioned.
In the present specification, the “amide bond formation reaction” means a reaction between a carboxylic acid (—COOH) or a carboxylic acid halide (—COHal; Hal is halogen) and an amino group (—NH ² ) to form an amide bond ( -CONH-).

As used herein, the term “alkyl” used alone or in combination with other terms includes straight or branched monovalent hydrocarbon groups. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, etc. Is mentioned. Preferably, C1-C6 alkyl is mentioned. More preferably, C1-C4 alkyl is mentioned.
Examples of the alkyl in R ² include C1-C6 alkyl. Preferably, C1-C4 alkyl is mentioned. More preferably, C4 alkyl is mentioned. Particularly preferred is an isobutyl group (—CH ₂ CH (CH ₃ ) ₂ ).
In the present specification, “aryl” used alone or in combination with other terms means a monocyclic, condensed cyclic aromatic hydrocarbon, or a fragrance in which 2 to 3 fragrances are continuously connected. Including group hydrocarbons. For example, phenyl, naphthyl (1-naphthyl, 2-naphthyl), anthryl, biphenyl (2-biphenyl, 3-biphenyl, 4-biphenyl) and the like can be mentioned.
In the present specification, “aralkyl” is a compound in which the above “alkyl” is substituted with one or more of the above “aryl”, and includes phenyl C1-C6 alkyl, biphenyl C1-C6 alkyl, diphenyl C1-C6 alkyl, Examples include triphenyl C1-C6 alkyl, naphthyl C1-C6 alkyl, anthryl C1-C6 alkyl, and the like. For example, benzyl, phenylethyl (such as 2-phenylethyl), phenylpropyl (such as 3-phenylpropyl), biphenylmethyl (such as 2-biphenylmethyl, 3-biphenylmethyl, 4-biphenylmethyl), Examples include diphenylmethyl, triphenylmethyl, naphthylmethyl (for example, 1-naphthylmethyl, 2-naphthylmethyl, and the like), anthrylmethyl (for example, 9-anthrylmethyl and the like), and the like.
Examples of aralkyl in R ¹ include phenyl C1-C6 alkyl, biphenyl C1-C6 alkyl, diphenyl C1-C6 alkyl, and triphenyl C1-C6 alkyl. Preferred are biphenylmethyl and diphenylmethyl. Furthermore, Preferably, 2-biphenylmethyl is mentioned.

In the present specification, the “catalyst” means a compound containing at least one metal selected from nickel, palladium and platinum and catalyzing a hydrogenation reaction. Raney nickel, nickel chloride, nickel oxide, nickel (II) acetylacetonate, nickel catalyst such as nickel cyclooctadiene, Pd-C, Lindlar catalyst, tetrakistriphenylphosphine palladium, palladium acetate, palladium chloride, dichlorobis (triphenylphosphine) Examples thereof include palladium catalysts such as palladium, platinum catalysts such as chloroplatinic acid and platinum oxide. Nickel compounds that catalyze the hydrogenation reaction are preferred. Preferably, Raney nickel or nickel chloride is used. Particularly preferred is Raney nickel.
In the present specification, the “protecting group” means an atomic group used for the purpose of temporarily protecting a reactive characteristic group. Examples of the protecting group for the nitrogen atom of the pyrrolidine ring include t-butyloxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, p-nitro. A benzyloxycarbonyl group etc. are mentioned. In particular, a t-butyloxycarbonyl group is preferable.
In the present specification, the “dehydrating agent” means a reagent that accelerates the dehydration reaction. Trichloroacetyl chloride, phosphorus oxychloride, oxalyl chloride, trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, thionyl chloride, trichloroacetic anhydride, p-toluenesulfonic acid, phosgene, dicyclohexylcarbodiimide, 1- (3-dimethylamino Propyl) -3-ethylcarbodiimide hydrochloride, diphosphorus pentoxide, ethoxyacetylene, cyanuric chloride and the like. Preferable examples include trichloroacetyl chloride, phosphorus oxychloride, oxalyl chloride, trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, thionyl chloride, and the like. Particularly preferred are trichloroacetyl, phosphorus oxychloride and the like.

In the reaction of converting the pyrrolidine compound (21) having a cyano group shown in Reference Example 13 to an amino group by subjecting it to a hydrogenation reaction in the presence of Raney nickel, the fluorine atom of the substituent at the 1-position of one molecule is Another problem is a side reaction of reacting with the amino group at the 2-position of one molecule to form a dimer. In particular, this side reaction tends to occur in the case of mass synthesis, and removal of the generated by-product is not easy. Therefore, this problem could be avoided by using a compound protected with a protecting group such as t-butyloxycarbonyl.
When compound 15 is synthesized from compound 6, the method of Reference Example 6 → 7 → 8 → 11 → 12 → 13 → 14 → 15 and Examples 1 → 2 → 3 → 4 → 6 → 7 of the present invention. When comparing yields by the method of → 8, the former is 36% and the latter is 48%. Despite the multistage reaction, the yield can be improved by as much as 12%, and it can be said that the present invention is suitable for the industrial production method of the compound (15).

An efficient production method for industrially producing a pyrrolidine compound having cPLA ₂ inhibitory activity was found by reducing a pyrrolidine compound having a nitrile group to an amino group by hydrogenation reaction in the presence of a catalyst.

（式中、Ｒ²およびＰｒｏは前記と同意義、Ｍｓはメタンスルホニル）
本工程は、4位側鎖をＲ²ＮＨ基に変換する工程である。
一般式（ＸＩＩ）で表される化合物をＲ²ＮＨ₂と反応させて、一般式（ＸＩＩＩ）で表される化合物を得ることができる。
Ｒ²ＮＨ₂のＲ²としてはＣ１−Ｃ６アルキル、好ましくは、Ｃ１−Ｃ４アルキル、さらに好ましくは、Ｃ４アルキル、最も好ましくは、イソブチル基が挙げられる。
溶媒としては、水、ジメチルスルホキシド、クロロホルム、アセトニトリル、メタノール、ジメチルホルムアミド等の溶媒が挙げられる。特に、水が好ましい。
反応温度としては、0℃〜150℃が、好ましくは30℃〜120℃が、さらに好ましくは50℃〜100℃が挙げられる。
反応時間としては、1.0時間〜24時間、好ましくは3.0時間〜18時間、さらに好ましく5.0時間〜15時間が挙げられる。 1st process

(Wherein R ² and Pro are as defined above, Ms is methanesulfonyl)
This step is a step of converting the 4-position side chain into an R ² NH group.
A compound represented by the general formula (XII) can be reacted with R ² NH ₂ to obtain a compound represented by the general formula (XIII).
C1-C6 alkyl as R ² in R ² NH _2, preferably, C1-C4 alkyl, more preferably, C4 alkyl, most preferably isobutyl group.
Examples of the solvent include water, dimethyl sulfoxide, chloroform, acetonitrile, methanol, dimethylformamide and the like. In particular, water is preferable.
The reaction temperature is 0 ° C to 150 ° C, preferably 30 ° C to 120 ° C, more preferably 50 ° C to 100 ° C.
The reaction time is 1.0 hour to 24 hours, preferably 3.0 hours to 18 hours, more preferably 5.0 hours to 15 hours.

（式中、Ｒ¹、Ｒ²およびＰｒｏは前記と同意義）
本工程は、4位側鎖にＲ¹基を導入する工程である。
一般式（ＸＩＩＩ）で表される化合物を溶媒中、Ｒ¹−Ｈａｌ（式中、Ｈａｌはハロゲン）もしくはＲ¹−Ｏ−ＳＯ₂−Ｒ^a（式中、Ｒ^aはハロゲンで置換されていてもよいメチル）、および塩基と反応させ、一般式（ＩＩＩ）で表される化合物を得る。
溶媒としては、アセトニトリル、ジメチルホルムアミド、ジメチルスルホキシド、テトラヒドロフラン、エタノール、プロパノール、イソプロパノール、トルエン、酢酸エチル、酢酸プロピル、酢酸イソプロピル、ジメチルホルムアミド、ジメチルアセトアミド等が挙げられる。アセトニトリル、酢酸イソプロピル、ジメチルホルムアミド、酢酸イソプロピル−ジメチルホルムアミド、酢酸イソプロピル−アセトニトリル混合溶媒が好ましい。
Ｒ¹−ＨａｌのＨａｌとしては、塩素原子、臭素原子、ヨウ素原子等が挙げられる。臭素原子が好ましい。
Ｒ¹−Ｏ−ＳＯ₂−Ｒ^aのＲ^aとしては、メチル、トリフルオロメチル等が挙げられる。メチルが好ましい。
Ｒ¹−ＨａｌのＲ¹としては、フェニルＣ１−Ｃ６アルキル、ビフェニルＣ１−Ｃ６アルキル、ジフェニルＣ１−Ｃ６アルキル、およびトリフェニルＣ１−Ｃ６アルキル等のアラルキルがあげられる。好ましくは、フェニルＣ１−Ｃ３アルキル、ビフェニルＣ１−Ｃ３アルキル、ジフェニルＣ１−Ｃ３アルキル等が挙げられる。さらに好ましくは、ベンジル、ビフェニルメチル、ジフェニルメチル（ベンズヒドリル）等が挙げられる。特に好ましくは、２―ビフェニルメチルが挙げられる。
塩基としては、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、ジイソプロピルアミン等があげられる。炭酸ナトリウムが好ましい。
反応温度としては、20℃〜120℃、好ましくは40℃〜100℃、特に好ましくは60℃〜90℃が挙げられる。
反応時間としては、5.0時間〜24時間、好ましくは7.0時間〜12時間が挙げられる。 Second step

(Wherein R ¹ , R ² and Pro are as defined above)
This step is a step of introducing an R ¹ group into the 4-position side chain.
A compound represented by the general formula (XIII) in a solvent, R ¹ -Hal (where Hal is a halogen) or R ¹ -O—SO ₂ -R ^a (wherein R ^a is substituted with ^a halogen) And a compound represented by the general formula (III).
Examples of the solvent include acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethanol, propanol, isopropanol, toluene, ethyl acetate, propyl acetate, isopropyl acetate, dimethylformamide, dimethylacetamide and the like. Acetonitrile, isopropyl acetate, dimethylformamide, isopropyl acetate-dimethylformamide, and isopropyl acetate-acetonitrile mixed solvent are preferred.
As Hal of R < ¹ > -Hal, a chlorine atom, a bromine atom, an iodine atom, etc. are mentioned. A bromine atom is preferred.
Examples of R ^{a in} R ¹ —O—SO ₂ —R ^a include methyl and trifluoromethyl. Methyl is preferred.
The R ¹ in R ¹ -Hal, phenyl C1-C6 alkyl, biphenyl C1-C6 alkyl, diphenyl C1-C6 alkyl, and aralkyl such as triphenyl C1-C6 alkyl like. Preferably, phenyl C1-C3 alkyl, biphenyl C1-C3 alkyl, diphenyl C1-C3 alkyl, etc. are mentioned. More preferred are benzyl, biphenylmethyl, diphenylmethyl (benzhydryl) and the like. Particularly preferred is 2-biphenylmethyl.
Examples of the base include sodium carbonate, sodium hydrogen carbonate, potassium carbonate, diisopropylamine and the like. Sodium carbonate is preferred.
The reaction temperature is 20 ° C to 120 ° C, preferably 40 ° C to 100 ° C, particularly preferably 60 ° C to 90 ° C.
The reaction time is 5.0 hours to 24 hours, preferably 7.0 hours to 12 hours.

（式中、Ｒ¹、Ｒ²およびＰｒｏは前記と同意義、ＨＡは酸を表わす）
本工程は、一般式（ＩＩＩ）で表される化合物を塩とすることにより、精製する工程である。
一般式（ＩＩＩ）で表される化合物を溶媒に溶解し、酸（ＨＡ）を加えることにより、一般式（ＸＩＶ）で表される塩を得ることができる。
酸（ＨＡ）としては、ベンゼンスルホン酸、ｐ−トルエンスルホン酸、塩酸、硫酸、硝酸、ぎ酸、シュウ酸等が挙げられる。ベンゼンスルホン酸が好ましい。
酢酸エチル、酢酸イソプロピル、メタノール、アセトン、エタノール、テトラヒドロフラン、アセトニトリル、メチルエチルケトン、塩化メチレン、エチルエーテル、水またはそれらの混合溶液等の溶媒が挙げられる。酢酸エチル、酢酸イソプロピル、水、酢酸エチル−水、酢酸イソプロピル−水の混合溶液が好ましい。特に、酢酸イソプロピルが好ましい。
反応温度としては、-20℃〜60℃、好ましくは-10℃〜40℃が挙げられる。
反応時間としては、5.0時間〜48時間、好ましくは7.0時間〜24時間が挙げられる。 Third step

(Wherein R ¹ , R ² and Pro are as defined above, and HA represents an acid)
This step is a step of purification by converting the compound represented by the general formula (III) into a salt.
A salt represented by the general formula (XIV) can be obtained by dissolving the compound represented by the general formula (III) in a solvent and adding an acid (HA).
Examples of the acid (HA) include benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, formic acid, oxalic acid and the like. Benzenesulfonic acid is preferred.
Examples thereof include solvents such as ethyl acetate, isopropyl acetate, methanol, acetone, ethanol, tetrahydrofuran, acetonitrile, methyl ethyl ketone, methylene chloride, ethyl ether, water, or a mixed solution thereof. A mixed solution of ethyl acetate, isopropyl acetate, water, ethyl acetate-water, and isopropyl acetate-water is preferable. In particular, isopropyl acetate is preferred.
As reaction temperature, -20 degreeC-60 degreeC, Preferably -10 degreeC-40 degreeC is mentioned.
The reaction time is 5.0 hours to 48 hours, preferably 7.0 hours to 24 hours.

（式中、Ｒ¹、Ｒ²およびＰｒｏは前記と同意義、ＨＡは酸を表わす）
本工程は一般式（ＸＩＶ）で表される塩を脱塩反応に付し、一般式（ＩＩＩ）で表される化合物を得る工程である。
一般式（ＸＩＶ）で表される塩に溶媒を加えた後、アルカリ水溶液またはアルカリを加え、攪拌して、一般式（ＶＩＩＩ）で表される化合物を得ることができる。
溶媒としては、酢酸エチル、メタノール、エタノール、アセトン、アセトニトリル、ジメチルスルホキシド、水、またはその混合溶媒等の溶媒が挙げられる。酢酸エチル、水、酢酸エチル−水の混合溶媒が好ましい。特に、酢酸エチル−水の混合溶媒が好ましい。
アルカリ水溶液またはアルカリとしては、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム等があげられる。炭酸水素ナトリウム、水酸化ナトリウムが好ましい。特に、水酸化ナトリウム水溶液と炭酸水素ナトリウムが好ましい。
反応温度としては、0℃〜50℃が挙げられるが、0℃〜35℃が好ましい。
反応時間としては、5分〜3.0時間が挙げられるが、10分〜1.5時間が好ましい。 Fourth step

(Wherein R ¹ , R ² and Pro are as defined above, and HA represents an acid)
This step is a step of obtaining a compound represented by the general formula (III) by subjecting the salt represented by the general formula (XIV) to a desalting reaction.
After adding a solvent to the salt represented by the general formula (XIV), an aqueous alkali solution or an alkali is added and stirred to obtain the compound represented by the general formula (VIII).
Examples of the solvent include solvents such as ethyl acetate, methanol, ethanol, acetone, acetonitrile, dimethyl sulfoxide, water, or a mixed solvent thereof. A mixed solvent of ethyl acetate, water, and ethyl acetate-water is preferable. In particular, a mixed solvent of ethyl acetate and water is preferable.
Examples of the alkaline aqueous solution or alkali include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like. Sodium bicarbonate and sodium hydroxide are preferred. In particular, an aqueous sodium hydroxide solution and sodium bicarbonate are preferable.
Examples of the reaction temperature include 0 ° C to 50 ° C, preferably 0 ° C to 35 ° C.
The reaction time includes 5 minutes to 3.0 hours, preferably 10 minutes to 1.5 hours.

（式中、Ｒ¹、Ｒ²、およびＰｒｏは前記と同意義）
本工程は2位側鎖のアミド基をシアノ基に変換する工程である。
一般式（ＩＩＩ）で表される化合物を溶媒に溶解し、塩基および脱水剤の溶液を加え、攪拌後、一般式（Ｉ）で表される化合物を得ることができる。
溶媒としては、テトラヒドロフラン、塩化メチレン、クロロホルム、ジオキサン、ジメチルスルホキシド、ジメチルホルムアミド、アセトニトリル等が挙げられる。テトラヒドロフラン、酢酸エチルが好ましい。
塩基としては、トリエチルアミン、ピリジン、Ｎ−メチルモルホリン等が挙げられる。トリエチルアミンが好ましい。
脱水剤としては、塩化トリクロロアセチル、オキシ塩化リン、塩化オキザリル、トリフルオロ酢酸無水物、トリフルオロメタンスルホン酸無水物、および塩化チオニル等が挙げられる。塩化トリクロロアセチル、オキシ塩化リンが好ましい。
反応温度としては、-10℃〜50℃が挙げられる。-5℃〜35℃が好ましい。
反応時間としては、0.1時間〜5.0時間が挙げられる。0.2時間〜2.0時間が好ましい。 5th process

(Wherein R ¹ , R ² and Pro are as defined above)
This step is a step of converting the amide group at the 2-position side chain into a cyano group.
The compound represented by general formula (III) can be obtained by dissolving the compound represented by general formula (III) in a solvent, adding a solution of a base and a dehydrating agent, and stirring.
Examples of the solvent include tetrahydrofuran, methylene chloride, chloroform, dioxane, dimethyl sulfoxide, dimethylformamide, acetonitrile and the like. Tetrahydrofuran and ethyl acetate are preferred.
Examples of the base include triethylamine, pyridine, N-methylmorpholine and the like. Triethylamine is preferred.
Examples of the dehydrating agent include trichloroacetyl chloride, phosphorus oxychloride, oxalyl chloride, trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, and thionyl chloride. Trichloroacetyl chloride and phosphorus oxychloride are preferred.
Examples of the reaction temperature include -10 ° C to 50 ° C. -5 ° C to 35 ° C is preferred.
Examples of the reaction time include 0.1 hour to 5.0 hours. 0.2 hours to 2.0 hours are preferred.

（式中、Ｒ¹、Ｒ²、およびＰｒｏは前記と同意義）
本工程は2位側鎖であるシアノ基を還元してアミノ基に変換する工程である。
一般式（Ｉ）で表される化合物を溶媒に溶解し、アンモニア溶液、および触媒を加え、水素添加した後、触媒をろ別し、一般式（ＩＩ）で表される化合物を得ることができる。
一般式（ＩＩ）で表される化合物を溶解する溶媒およびアンモニア溶液の溶媒としては、エタノール、メタノール、イソプロパノール、水、テトラヒドロフラン、酢酸エチル等の溶液が挙げられる。エタノールが好ましい。
触媒としては、ラネーニッケル、塩化ニッケル等のニッケル触媒、Ｐｄ−Ｃ、リンドラー触媒等のパラジウム触媒、酸化白金等の白金触媒がが挙げられる。好ましくは、ラネーニッケル、塩化ニッケル等のニッケル触媒が挙げられる。特に、好ましくは、ラネーニッケル等が挙げられる。ニッケル触媒に代えて、パラジウム触媒や白金触媒を用いた場合では、Ｒ¹−Ｎの部分のベンジル結合が切断されてしまい、目的物の収率が低下することがある。
反応温度としては、0℃〜50℃が挙げられる。5℃〜40℃が好ましい。
反応時間としては、1.0時間〜12時間が挙げられる。2.0時間〜8.0時間が好ましい。 6th process

(Wherein R ¹ , R ² and Pro are as defined above)
This step is a step of reducing the cyano group that is the 2-position side chain to convert it to an amino group.
The compound represented by the general formula (I) can be obtained by dissolving the compound represented by the general formula (I) in a solvent, adding an ammonia solution and a catalyst, hydrogenating, and then filtering off the catalyst. .
Examples of the solvent for dissolving the compound represented by the general formula (II) and the solvent for the ammonia solution include ethanol, methanol, isopropanol, water, tetrahydrofuran, ethyl acetate and the like. Ethanol is preferred.
Examples of the catalyst include nickel catalysts such as Raney nickel and nickel chloride, palladium catalysts such as Pd-C and Lindlar catalyst, and platinum catalysts such as platinum oxide. Preferably, nickel catalysts such as Raney nickel and nickel chloride are used. In particular, Raney nickel and the like are preferable. When a palladium catalyst or a platinum catalyst is used in place of the nickel catalyst, the benzyl bond at the R ¹ —N portion is cleaved, and the yield of the target product may be reduced.
As reaction temperature, 0 degreeC-50 degreeC is mentioned. 5 to 40 degreeC is preferable.
Examples of the reaction time include 1.0 hour to 12 hours. 2.0 to 8.0 hours are preferred.

（式中、Ｘはハロゲンまたはヒドロキシ；Ｒ¹、Ｒ²、およびＰｒｏは前記と同意義）
本工程は、一般式（ＩＩ）で表される化合物またはその塩の２位に側鎖を導入する工程である。
一般式（ＩＩ）で表される化合物またはその塩を溶媒に溶解し、２位側鎖の酸または一般式（ＩＶ）で表される化合物を加え、攪拌後、化合物（Ｖ）を得ることができる。
出発物質としては、一般式（ＩＩ）で表される化合物が好ましい。
一般式（ＩＶ）で表される化合物としては、酸ハロゲン化物が好ましい。特に、酸クロリドが好ましい。
溶媒としては、アセトニトリル、テトラヒドロフラン、ベンゼン、塩化メチレン、クロロホルム、ジオキサン、ジグライム、酢酸エチル等が挙げられる。好ましくは、ジグライム、酢酸エチル、アセトニトリル、ジグライム−酢酸エチルの混合溶媒が挙げられる。特に好ましくは、ジグライム−酢酸エチルの混合溶媒が好ましい。
反応温度としては、-20℃〜30℃が挙げられる。-20℃〜15℃が好ましい。
反応時間としては、0.5時間〜5.0時間が挙げられる。1.0時間〜4.0時間が好ましい。 7th process

(Wherein X is halogen or hydroxy; R ¹ , R ² and Pro are as defined above)
This step is a step of introducing a side chain at the 2-position of the compound represented by the general formula (II) or a salt thereof.
A compound represented by the general formula (II) or a salt thereof is dissolved in a solvent, a 2-position side chain acid or a compound represented by the general formula (IV) is added, and the compound (V) is obtained after stirring. it can.
As the starting material, a compound represented by the general formula (II) is preferable.
As the compound represented by the general formula (IV), an acid halide is preferable. In particular, acid chloride is preferred.
Examples of the solvent include acetonitrile, tetrahydrofuran, benzene, methylene chloride, chloroform, dioxane, diglyme, ethyl acetate and the like. Preferably, a mixed solvent of diglyme, ethyl acetate, acetonitrile, diglyme-ethyl acetate is used. Particularly preferred is a mixed solvent of diglyme-ethyl acetate.
Examples of the reaction temperature include -20 ° C to 30 ° C. -20 ° C to 15 ° C is preferred.
As reaction time, 0.5 hour-5.0 hours are mentioned. 1.0 to 4.0 hours are preferred.

（式中、Ｒ¹、Ｒ²、およびＰｒｏは前記と同意義）
本工程は、一般式（Ｖ）で表される化合物の１位の保護基を脱保護する反応である。脱保護反応は、保護基によって変わるが、Protective Groups in Organic Synthesis, 3rd ed.,(Theodora W. Greene and Peter G. M. Wuts, New York, John Wiley, 1999年)等に記載の方法による。
保護基がｔ−ブチルオキシカルボニルの場合は、塩酸、硫酸、トリフルオロ酢酸、硝酸、ぎ酸、またはこれらの酸の混合物、並びにLewis酸（たとえばAlCl₃, TiCl₄, ZnCl₂, BF₃）とアニソールとの混合物による条件による脱保護が好ましい。塩酸が特に好ましい。
溶媒としては、メタノール、エタノール、酢酸エチル、ジグライム等が好ましい。特に、メタノールが好ましい。
反応温度としては、0℃〜100℃が挙げられる。20℃〜80℃が好ましい。
反応時間としては、0.5時間〜48時間が挙げられる。3時間〜15時間が好ましい。
保護基がベンジルオキシカルボニル基の場合は、パラジウム−炭素触媒を用いた水素添加反応、塩化アルミニウムや三臭化ホウ素のルイス酸、臭化水素酸、酢酸、トリフルオロ酢酸等の酸による脱保護反応が挙げられる。
保護基がｐ−メトキシベンジルオキシカルボニル基の場合は、ｐ−トルエンスルホン酸、トリフルオロ酢酸等の酸による脱保護反応が挙げられる。
保護基がアリルオキシカルボニル基の場合は、パラジウム触媒−ギ酸の系による脱保護反応が挙げられる。
保護基が９−フルオレニルメチルオキシカルボニル基の場合は、ピペリジン等の塩基による脱保護が挙げられる。
保護基がｐ−ニトロベンジルオキシカルボニル基の場合は、パラジウム−炭素触媒よる水素添加反応、臭化水素酸−酢酸、電極反応等による脱保護が挙げられる。 8th step

(Wherein R ¹ , R ² and Pro are as defined above)
This step is a reaction for deprotecting the protecting group at the 1-position of the compound represented by the general formula (V). The deprotection reaction varies depending on the protecting group, but is based on the method described in Protective Groups in Organic Synthesis, 3rd ed., (Theodora W. Greene and Peter GM Wuts, New York, John Wiley, 1999).
When the protecting group is t-butyloxycarbonyl, hydrochloric acid, sulfuric acid, trifluoroacetic acid, nitric acid, formic acid, or a mixture of these acids, as well as Lewis acids (eg, AlCl ₃ , TiCl ₄ , ZnCl ₂ , BF ₃ ) Deprotection by conditions with a mixture with anisole is preferred. Hydrochloric acid is particularly preferred.
As the solvent, methanol, ethanol, ethyl acetate, diglyme and the like are preferable. In particular, methanol is preferable.
Examples of the reaction temperature include 0 ° C to 100 ° C. 20 ° C to 80 ° C is preferred.
As reaction time, 0.5 hour-48 hours are mentioned. 3 hours to 15 hours are preferred.
When the protecting group is a benzyloxycarbonyl group, a hydrogenation reaction using a palladium-carbon catalyst, a deprotection reaction with an acid such as Lewis acid of aluminum chloride or boron tribromide, hydrobromic acid, acetic acid or trifluoroacetic acid Is mentioned.
When the protecting group is a p-methoxybenzyloxycarbonyl group, a deprotection reaction with an acid such as p-toluenesulfonic acid or trifluoroacetic acid can be mentioned.
When the protecting group is an allyloxycarbonyl group, a deprotection reaction by a palladium catalyst-formic acid system can be mentioned.
When the protecting group is a 9-fluorenylmethyloxycarbonyl group, deprotection with a base such as piperidine can be mentioned.
When the protecting group is a p-nitrobenzyloxycarbonyl group, deprotection by a hydrogenation reaction with a palladium-carbon catalyst, hydrobromic acid-acetic acid, an electrode reaction or the like can be mentioned.

（式中、Ｙはハロゲンまたはヒドロキシ；ＨＢは酸；Ｒ¹、Ｒ²、およびＰｒｏは前記と同意義）
本工程は1位に、置換されたベンゾイル基を導入する工程である。
1位側鎖に対応する一般式（ＶＩＩ）で表される化合物を溶媒に溶解し、少量のジメチルホルムアミドとハロゲン化剤を加え、攪拌後、１位側鎖に対応する酸ハロゲン化物を得る。酸ハロゲン化物を合成する際の溶媒としては、アセトニトリル、塩化メチレン、テトラヒドロフラン、酢酸エチル等が挙げられる。アセトニトリル、酢酸エチルが好ましい。
一般式（ＶＩ）で表される化合物の溶媒中、塩基および上記の酸ハロゲン化物の溶液を加え、攪拌後、一般式（ＶＩＩＩ）で表される化合物を得ることができる。
酸ハロゲン化物と一般式（ＶＩ）で表される化合物との反応溶媒としては、ジメチルホルムアミド、ジメチルアセトアミド、テトラヒドロフラン、アセトニトリル、ベンゼン、塩化メチレン、クロロホルム、ジオキサン、酢酸エチル等が挙げられる。好ましくは、テトラヒドロフラン、ジメチルアセトアミド、酢酸エチル、ジメチルアセトアミド−酢酸エチル混合溶媒が挙げられる。特に好ましくは、ジメチルアセトアミド−酢酸エチル混合溶媒が挙げられる。
塩基としては、トリエチルアミン、トリブチルアミン、ピリジン、Ｎ−メチルモルホリン等が挙げられる。トリエチルアミンが好ましい。
また、一般式（ＶＩ）で表される化合物の溶媒中、縮合剤および一般式（ＶＩＩ）で表される化合物を直接反応させることにより、一般式（ＶＩＩＩ）で表される化合物を得ることもできる。
溶媒としては、テトラヒドロフラン、ジメチルアセトアミド、酢酸エチル、ジメチルアセトアミド−酢酸エチル混合溶媒が挙げられる。特に好ましくは、ジメチルアセトアミド−酢酸エチル混合溶媒が挙げられる。
縮合剤としては、ジシクロヘキシルカルボジイミド（ＤＣＣ）、カルボニルイミダゾール（ＣＤＩ）、１−エチル−３―（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（ＷＳＣ）が挙げられる。
反応温度としては、0℃〜100℃が挙げられる。0℃〜70℃が好ましい。
反応時間としては、0.5時間〜24時間が挙げられる。0.5時間〜20時間が好ましい。
一般式（ＶＩＩＩ）で表される化合物は、反応後単離した後、または粗生成物のまま、一般式（ＸＶ）で表される塩に誘導することができる。
一般式（ＶＩＩＩ）で表される化合物を溶媒に溶かし、酸（ＨＢ）を加え、攪拌、ろ過後、一般式（ＸＶ）で表される塩を得ることができる。
酸（ＨＢ）としては、塩酸、硫酸、硝酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸、ぎ酸、シュウ酸が挙げられる。好ましくは、塩酸、硫酸、ｐ−トルエンスルホン酸が挙げられる。とくに、このましくは、ｐ−トルエンスルホン酸が挙げられる。
塩の反応溶媒（結晶溶媒）としては、酢酸エチル、メタノール、アセトン、エタノール、テトラヒドロフラン、アセトニトリル、メチルエチルケトン、塩化メチレン、エチルエーテル、またはそれらの混合溶液等の溶媒が挙げられる。酢酸エチルとメタノールの混合溶媒が好ましい。
反応温度としては、0℃〜50℃が挙げられる。5℃〜35℃が好ましい。
反応時間としては、0.5時間〜24時間が挙げられる。0.5時間〜12時間が好ましい。 9th process

(Where Y is halogen or hydroxy; HB is acid; R ¹ , R ² , and Pro are as defined above)
This step is a step of introducing a substituted benzoyl group at the 1-position.
A compound represented by the general formula (VII) corresponding to the 1-position side chain is dissolved in a solvent, a small amount of dimethylformamide and a halogenating agent are added, and after stirring, an acid halide corresponding to the 1-position side chain is obtained. Examples of the solvent for synthesizing the acid halide include acetonitrile, methylene chloride, tetrahydrofuran, and ethyl acetate. Acetonitrile and ethyl acetate are preferred.
In a solvent of the compound represented by the general formula (VI), a base and a solution of the above acid halide are added, and after stirring, the compound represented by the general formula (VIII) can be obtained.
Examples of the reaction solvent for the acid halide and the compound represented by the general formula (VI) include dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, benzene, methylene chloride, chloroform, dioxane, ethyl acetate and the like. Preferably, tetrahydrofuran, dimethylacetamide, ethyl acetate, dimethylacetamide-ethyl acetate mixed solvent is used. Particularly preferred is a dimethylacetamide-ethyl acetate mixed solvent.
Examples of the base include triethylamine, tributylamine, pyridine, N-methylmorpholine and the like. Triethylamine is preferred.
Moreover, the compound represented by general formula (VIII) can be obtained by directly reacting the condensing agent and the compound represented by general formula (VII) in the solvent of the compound represented by general formula (VI). it can.
Examples of the solvent include tetrahydrofuran, dimethylacetamide, ethyl acetate, and a mixed solvent of dimethylacetamide-ethyl acetate. Particularly preferred is a dimethylacetamide-ethyl acetate mixed solvent.
Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), carbonylimidazole (CDI), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC).
Examples of the reaction temperature include 0 ° C to 100 ° C. 0 ° C to 70 ° C is preferred.
As reaction time, 0.5 hour-24 hours are mentioned. 0.5 hours to 20 hours are preferred.
The compound represented by the general formula (VIII) can be derived into a salt represented by the general formula (XV) after isolation after the reaction or as a crude product.
The compound represented by general formula (VIII) can be dissolved in a solvent, acid (HB) can be added, and the salt represented by general formula (XV) can be obtained after stirring and filtration.
Examples of the acid (HB) include hydrochloric acid, sulfuric acid, nitric acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, and oxalic acid. Preferably, hydrochloric acid, sulfuric acid, and p-toluenesulfonic acid are used. Particularly preferred is p-toluenesulfonic acid.
Examples of the salt reaction solvent (crystal solvent) include solvents such as ethyl acetate, methanol, acetone, ethanol, tetrahydrofuran, acetonitrile, methyl ethyl ketone, methylene chloride, ethyl ether, or a mixed solution thereof. A mixed solvent of ethyl acetate and methanol is preferred.
As reaction temperature, 0 degreeC-50 degreeC is mentioned. 5 to 35 degreeC is preferable.
As reaction time, 0.5 hour-24 hours are mentioned. 0.5 hours to 12 hours are preferred.

（式中、Ｒ¹およびＲ²は前記と同意義、ＨＢは酸）
本工程は、一般式（ＸＶ）で表される塩を脱塩反応に付し、一般式（ＶＩＩＩ）で表される化合物を得る工程である。
一般式（ＸＶ）で表される化合物に溶媒を加えた後、アルカリ水溶液を加え、攪拌して、一般式（ＶＩＩＩ）で表される化合物を得ることができる。
溶媒としては、酢酸エチル、メタノール、エタノール、アセトン、アセトニトリル、ジメチルスルホキシド等の溶媒が挙げられるが、酢酸エチルが好ましい。
アルカリ水溶液としては、炭酸水素ナトリウム水溶液、炭酸ナトリウム水溶液、水酸化ナトリウム水溶液、水酸化カリウム水溶液等があげられるが、炭酸水素ナトリウム水溶液が好ましい。
反応温度としては、0℃〜50℃が挙げられるが、0℃〜35℃が好ましい。
反応時間としては、5分〜3.0時間が挙げられるが、10分〜1.5時間が好ましい。
一般式（ＶＩＩＩ）で表される化合物は、上記の方法にて固体にすることができる。 10th step

(Wherein R ¹ and R ² are as defined above, HB is an acid)
This step is a step of obtaining a compound represented by the general formula (VIII) by subjecting the salt represented by the general formula (XV) to a desalting reaction.
After adding a solvent to the compound represented by the general formula (XV), an alkaline aqueous solution is added and stirred to obtain the compound represented by the general formula (VIII).
Examples of the solvent include solvents such as ethyl acetate, methanol, ethanol, acetone, acetonitrile, and dimethyl sulfoxide, and ethyl acetate is preferable.
Examples of the alkaline aqueous solution include a sodium hydrogen carbonate aqueous solution, a sodium carbonate aqueous solution, a sodium hydroxide aqueous solution, and a potassium hydroxide aqueous solution, and a sodium hydrogen carbonate aqueous solution is preferable.
Examples of the reaction temperature include 0 ° C to 50 ° C, preferably 0 ° C to 35 ° C.
The reaction time includes 5 minutes to 3.0 hours, preferably 10 minutes to 1.5 hours.
The compound represented by the general formula (VIII) can be made solid by the above method.

（式中、Ｒ¹、Ｒ²、およびＰｒｏは前記と同意義）
本工程は、一般式（ＩＩＩ）で表される化合物を還元反応に付し、一般式（ＩＩ）で表される化合物を得る工程である。
水素化ホウ素ナトリウムと酢酸を溶媒に溶かした後、一般式（ＩＩＩ）で表される化合物の溶液を加えて、還元を行ない、一般式（ＩＩ）を得ることができる。
水素化リチウムアルミニウム、およびボラン等を用いても同様に還元することができる。
溶媒としては、ジグライム、テトラヒロドフラン、エタノール、メタノール、水、エーテル等の溶媒が挙げられるが、ジグライムが好ましい。
反応温度としては、-20℃〜150℃が挙げられるが、-10℃〜100℃が好ましい。
反応時間としては、1時間〜24時間が挙げられるが、3時間〜10時間が好ましい。 11th step

(Wherein R ¹ , R ² and Pro are as defined above)
This step is a step of obtaining a compound represented by the general formula (II) by subjecting the compound represented by the general formula (III) to a reduction reaction.
After dissolving sodium borohydride and acetic acid in a solvent, a solution of the compound represented by the general formula (III) is added and reduction is performed to obtain the general formula (II).
The same reduction can be achieved using lithium aluminum hydride and borane.
Examples of the solvent include solvents such as diglyme, tetrahydrofuran, ethanol, methanol, water, and ether, but diglyme is preferred.
Examples of the reaction temperature include -20 ° C to 150 ° C, but -10 ° C to 100 ° C is preferable.
Examples of the reaction time include 1 hour to 24 hours, but 3 hours to 10 hours are preferable.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. Details of each step will be described in Reference Examples 1 to 20 and Examples 1 to 10.
The following abbreviations are used in the examples.
Boc: t-butyloxycarbonyl Ms: methanesulfonyl Ph: phenyl Ts: p-toluenesulfonyl

トランス-4-ヒドロキシ-L-プロリン (1) 1000 g (7.63 mol)のメタノール 3.6 L懸濁液に、水酸化ナトリウム 317.8 g (96%, 7.63 mol)を水 1.5 Lに溶解した溶液を5〜8℃で加えた。この溶液にジ-tert-ブチルジカーボネート 1831 g (8.39 mol)のテトラヒドロフラン 150 mL溶液を3〜9℃にて1時間10分間で滴下し、室温で3時間攪拌した。反応液を減圧濃縮し、得られた残留液 3.44 kgを酢酸エチルで2回洗浄し、有機層は水で抽出した。水層は合併し、濃塩酸でpH 2.0に調整し、食塩を加え塩析して酢酸エチルで3回抽出した。有機層は飽和食塩水で洗浄後減圧濃縮した。得られた残留液に酢酸エチルを加え、減圧濃縮する操作を3回繰り返し（水分が基質の1%以下になるまで）、ヒドロキシ体 (2)の酢酸エチル溶液 3.50 kgを得た。この溶液を次工程に使用した。 Reference example 1

Trans-4-hydroxy-L-proline (1) A solution of sodium hydroxide 317.8 g (96%, 7.63 mol) dissolved in 1.5 L of water in a suspension of 1000 g (7.63 mol) of methanol in 3.6 L Added at 8 ° C. To this solution, a solution of 1831 g (8.39 mol) of di-tert-butyl dicarbonate in 150 mL of tetrahydrofuran was added dropwise at 3-9 ° C. over 1 hour and 10 minutes, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and 3.44 kg of the resulting residual solution was washed twice with ethyl acetate, and the organic layer was extracted with water. The aqueous layers were combined, adjusted to pH 2.0 with concentrated hydrochloric acid, salted out with salt and extracted three times with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The operation of adding ethyl acetate to the obtained residual liquid and concentrating under reduced pressure was repeated three times (until the water content became 1% or less of the substrate) to obtain 3.50 kg of an ethyl acetate solution of the hydroxy form (2). This solution was used in the next step.

ヒドロキシ体 (2)の酢酸エチル溶液 3.50 kg (7.63 mol相当) に酢酸エチル 15.7 Lを加え、次いでトリエチルアミン 2551 mL (d 0.726, 18.3 mol) を-3〜-7℃で加えた。この混合物にメタンスルホニルクロリド 1299 mL (d 1.48, 16.8 mol) を-5〜-9℃にて1時間55分間で滴下し、-5〜-8℃で1時間30分間攪拌した。次いで、水 4.5 Lと無水炭酸ナトリウム 1617 g (15.3 mol) を水4.5 Lに溶解した溶液を加え、15〜24℃で2時間20分間攪拌した。反応液を濃塩酸でpH 2.0に調整し、分液した。水層は酢酸エチルで抽出し、有機層は飽和食塩水で2回洗浄後減圧濃縮した。得られた残留液に酢酸エチルを加え、減圧濃縮し（水分を基質の1%以下にした）、メシレート体 (3) の酢酸エチル溶液 3.50 kgを得た。この溶液を次工程に使用した。 Reference example 2

15.7 L of ethyl acetate was added to 3.50 kg (equivalent to 7.63 mol) of the ethyl acetate solution of the hydroxy compound (2), and then 2551 mL (d 0.726, 18.3 mol) of triethylamine was added at -3 to -7 ° C. To this mixture, 1299 mL (d 1.48, 16.8 mol) of methanesulfonyl chloride was added dropwise at -5 to -9 ° C over 1 hour and 55 minutes, and the mixture was stirred at -5 to -8 ° C for 1 hour and 30 minutes. Subsequently, a solution of 4.5 L of water and 1617 g (15.3 mol) of anhydrous sodium carbonate dissolved in 4.5 L of water was added, and the mixture was stirred at 15 to 24 ° C. for 2 hours and 20 minutes. The reaction solution was adjusted to pH 2.0 with concentrated hydrochloric acid and separated. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed twice with saturated brine and concentrated under reduced pressure. Ethyl acetate was added to the obtained residual liquid and concentrated under reduced pressure (water was adjusted to 1% or less of the substrate) to obtain 3.50 kg of an ethyl acetate solution of the mesylate body (3). This solution was used in the next step.

メシレート体 (3)の酢酸エチル溶液 3.50 kg (7.63 mol相当) に酢酸エチル 1.0 L、ジメチルホルムアミド 4.7 Lおよび無水炭酸ナトリウム 970 g (9.15 mol) を加え、80〜86℃で1時間18分間攪拌した。反応液は冷却後酢酸 524 mL (d 1.049, 9.15 mol) の氷水 14.1 kgの溶液に加え、酢酸エチルで2回抽出した。有機層は水で3回洗浄後減圧濃縮し、ラクトン体 (4) の酢酸エチル溶液5.06 kgを得た。この溶液を次工程に使用した。 Reference example 3

Ethyl acetate 1.0 L, dimethylformamide 4.7 L and anhydrous sodium carbonate 970 g (9.15 mol) were added to 3.50 kg (equivalent to 7.63 mol) of mesylate body (3) in ethyl acetate, and the mixture was stirred at 80 to 86 ° C. for 1 hour and 18 minutes. . The reaction mixture was cooled, added to a solution of acetic acid (524 mL, d 1.049, 9.15 mol) in ice water (14.1 kg), and extracted twice with ethyl acetate. The organic layer was washed three times with water and concentrated under reduced pressure to obtain 5.06 kg of an ethyl acetate solution of the lactone form (4). This solution was used in the next step.

ラクトン体 (4) の酢酸エチル溶液5.06 kg (7.63 mol相当)に酢酸エチル 3.5 Lを加え、28%アンモニア水 650 mL (d 0.995, 10.6 mol) を10〜17℃にて32分間で滴下し、16〜20℃で1時間20分間攪拌した。反応液を減圧濃縮し、得られた残査に酢酸エチルを加え、再度減圧濃縮した。得られた結晶性残査を酢酸エチル／トルエン (1/1) で洗浄してアミド体 (5) を1442 g (4工程通算収率82.1%) 無色結晶（融点164〜166℃）として得た。
Anal. Calcd for C₁₀H₁₈N₂O₄. C, 52.16; H, 7.88; N, 12.17. Found C, 52.13; H, 7.87; N, 12.31; H₂O, 0.31.
[α]_D −3.1±0.4°, [α]₃₆₅ −19.8±0.6°(MeOH, c 1.004, 25℃) Reference example 4

To 5.06 kg (equivalent to 7.63 mol) of an ethyl acetate solution of the lactone (4), 3.5 L of ethyl acetate is added, and 650 mL (d 0.995, 10.6 mol) of 28% aqueous ammonia is added dropwise at 10-17 ° C. for 32 minutes. The mixture was stirred at 16 to 20 ° C. for 1 hour and 20 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and the mixture was concentrated again under reduced pressure. The obtained crystalline residue was washed with ethyl acetate / toluene (1/1) to obtain 1442 g of amide compound (5) (total yield of 4 steps: 82.1%) as colorless crystals (melting point: 164 to 166 ° C.). .
Anal. Calcd for C ₁₀ H ₁₈ N ₂ O _4. C, 52.16; H, 7.88; N, 12.17. Found C, 52.13; H, 7.87; N, 12.31; H ₂ O, 0.31.
[α] _D −3.1 ± 0.4 °, [α] ₃₆₅ −19.8 ± 0.6 ° (MeOH, c 1.004, 25 ° C)

アミド体 (5) 1300 g (5.65 mol) のテトラヒドロフラン 15.6 L懸濁液に、ジイソプロピルアミン 959 mL (d 0.715, 6.78 mol) を-3〜-3.5℃で加え、次いでメタンスルホニルクロリド 481 mL (d 1.48, 6.21 mol) を-5〜2℃にて45分間で滴下し、1〜-2℃で1時間攪拌した。反応液に1 mol/L HCl 1.2 Lの氷水 8.8 kgの溶液及び食塩 (1.9 kg) を加え、酢酸エチルで3回抽出した。有機層は飽和食塩水で2回洗浄後減圧濃縮した。得られた残査を酢酸エチル／トルエンより結晶化し、メシレート体 (6)を1670 g (収率95.9%) 無色結晶（融点112〜114℃）として得た。
Anal. Calcd for C₁₁H₂₀N₂O₆S. C, 42.85; H, 6.54; N, 9.08; S, 10.40. Found C, 42.55; H, 6.45; N, 9.22; S, 10.34; H₂O, 0.31.
[α]_D −24.9±0.7°(MeOH, c 1.000, 25℃) Reference Example 5

Amide (5) To a suspension of 1300 g (5.65 mol) in 15.6 L of tetrahydrofuran was added 959 mL (d 0.715, 6.78 mol) of diisopropylamine at -3 to -3.5 ° C, and then 481 mL (d 1.48 of methanesulfonyl chloride). , 6.21 mol) was added dropwise at -5 to 2 ° C over 45 minutes and stirred at 1 to -2 ° C for 1 hour. A 1 mol / L HCl 1.2 L ice water solution (8.8 kg) and sodium chloride (1.9 kg) were added, and the mixture was extracted three times with ethyl acetate. The organic layer was washed twice with saturated brine and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate / toluene to obtain 1670 g (yield 95.9%) of mesylate (6) as colorless crystals (melting point 112-114 ° C.).
Anal. Calcd for C ₁₁ H ₂₀ N ₂ O ₆ S. C, 42.85; H, 6.54; N, 9.08; S, 10.40. Found C, 42.55; H, 6.45; N, 9.22; S, 10.34; H ₂ O , 0.31.
[α] _D −24.9 ± 0.7 ° (MeOH, c 1.000, 25 ° C)

化合物 (6) (123.3 g, 0.4 mol) を水 (62 mL)、イソブチルアミン (159 mL, 4 eq) に溶解、65-87℃で９時間、80-89℃で２時間攪拌した。酢酸イソプロピル(1.2 L)、10% 食塩水 (0.25 L) を加え抽出した。水槽は更に酢酸イソプロピル(0.4 L)にて抽出した。各々の有機層は10% 食塩水 (0.25 L) で洗浄した。有機層を合わせ減圧下、溶媒を濃縮した。残渣に酢酸イソプロピル(0.5 L, 0.2 L)を加え再度濃縮して、化合物 (7) (249.5 g, purity 74%, H₂O: 0.10%) を得た。同化合物を(16) (98.9 g, 1.0 eq) の酢酸イソプロピル (147 mL) 溶液、酢酸イソプロピル (68 mL)、DMF (370 mL)、炭酸ナトリウム (84.8 g, 2 eq) を加え75-80℃で８時間攪拌した。水 (1 L) を加え、酢酸イソプロピル (0.5L × 2) にて抽出した。各々の有機層は水 (1 L × 2) で洗浄した。有機層を合わせ減圧下濃縮して、化合物 (8) (460.5 g, 304 mmol 相当, 含水量0.185%) を得た。 Example 1

Compound (6) (123.3 g, 0.4 mol) was dissolved in water (62 mL) and isobutylamine (159 mL, 4 eq) and stirred at 65-87 ° C. for 9 hours and at 80-89 ° C. for 2 hours. Isopropyl acetate (1.2 L) and 10% brine (0.25 L) were added for extraction. The water bath was further extracted with isopropyl acetate (0.4 L). Each organic layer was washed with 10% saline (0.25 L). The organic layers were combined and the solvent was concentrated under reduced pressure. Isopropyl acetate (0.5 L, 0.2 L) was added to the residue and the mixture was concentrated again to obtain compound (7) (249.5 g, purity 74%, H ₂ O: 0.10%). Add (16) (98.9 g, 1.0 eq) in isopropyl acetate (147 mL), isopropyl acetate (68 mL), DMF (370 mL), sodium carbonate (84.8 g, 2 eq) For 8 hours. Water (1 L) was added, and the mixture was extracted with isopropyl acetate (0.5 L × 2). Each organic layer was washed with water (1 L × 2). The organic layers were combined and concentrated under reduced pressure to obtain Compound (8) (460.5 g, equivalent to 304 mmol, water content 0.185%).

上記の (8) に酢酸イソプロピル0.94 Lを加え、氷冷下ベンゼンスルホン酸の一水和物56.2 g (1.05 eq) の酢酸イソプロピル0.36 L溶液を4-5℃にて20分で加えた。水8.2 mL を加えシードして室温で１６時間静置した。析出晶を濾過、酢酸イソプロピルで洗浄した。乾燥後、塩 (9) (180 g, 71.7% from 6) を得た。
分解点：１０９℃
Anal. Calcd for C₃₃H₄₅N₃O₇S・1.2 H₂O・0.1AcOⁱPr: C,62.25; H, 7.24; N, 6.50; S, 4.96; H₂O, 3.15. Found: C, 62.15; H, 7.18; N, 6.60; S, 5.05; H₂O, 3.15. Example 2

To the above (8), 0.94 L of isopropyl acetate was added, and a solution of 0.36 L of isopropyl acetate in 56.2 g (1.05 eq) of benzenesulfonic acid monohydrate was added at 4-5 ° C. over 20 minutes under ice cooling. 8.2 mL of water was added, seeded, and allowed to stand at room temperature for 16 hours. The precipitated crystals were filtered and washed with isopropyl acetate. After drying, salt (9) (180 g, 71.7% from 6) was obtained.
Decomposition point: 109 ° C
Anal.Calcd for C ₃₃ H ₄₅ N ₃ O ₇ S ・ 1.2 H ₂ O ・ 0.1AcO ⁱ Pr: C, 62.25; H, 7.24; N, 6.50; S, 4.96; H ₂ O, 3.15. Found: C, 62.15; H, 7.18; N, 6.60; S, 5.05; H ₂ O, 3.15.

塩 (9) (50 g, 79.65 mol) を水（250 mL）と酢酸エチル (300 mL) に溶解させ、氷冷下 1 mol/L 水酸化ナトリウム水溶液 (101.6 mL) を滴下（pH 6.22になった）、次いで重曹 (1.62 g) を加え20分攪拌した。(pH 8.1となった）分液後有機層を5%重曹水 (0.2 L)、水 (0.15 L) で洗浄し、減圧下溶媒を留去して化合物 (8) (41.01 g) を得た。
¹H NMR (CDCl₃):δ 0.79 (d, 6H, J = 6.6 Hz), 1.44 (s, 9H), 1.62 (s, 2H), 2.12 (d, 2H, J = 6.9 Hz), 2.89-3.47 (m, 3H), 4.24 (br, 1H), 5.30 (br, 1H), 5.90 (br, 1H), 6.76 (br, 1H), 7.15-7.7 (m, 11H) Example 3

Salt (9) (50 g, 79.65 mol) was dissolved in water (250 mL) and ethyl acetate (300 mL), and 1 mol / L aqueous sodium hydroxide solution (101.6 mL) was added dropwise with ice cooling (to pH 6.22). Then, sodium bicarbonate (1.62 g) was added and stirred for 20 minutes. After separation, the organic layer was washed with 5% aqueous sodium bicarbonate (0.2 L) and water (0.15 L), and the solvent was distilled off under reduced pressure to obtain compound (8) (41.01 g). .
¹ H NMR (CDCl ₃ ): δ 0.79 (d, 6H, J = 6.6 Hz), 1.44 (s, 9H), 1.62 (s, 2H), 2.12 (d, 2H, J = 6.9 Hz), 2.89-3.47 (m, 3H), 4.24 (br, 1H), 5.30 (br, 1H), 5.90 (br, 1H), 6.76 (br, 1H), 7.15-7.7 (m, 11H)

上記化合物 (8) を酢酸エチル (293 mL) に溶解させ、氷冷下、トリエチルアミン （28.9 mL, 2.6 eq）を加え、塩化トリクロロアセチル (11.6 mL, 1.3 eq) を3.5-9.2℃で14分にて滴下した。更に2 ℃にて0.5時間攪拌した。反応液を1 mol/L 塩酸 (193 mL) 中へ注ぎ込み、抽出した。水槽は酢酸エチル（138 mL）にて再度抽出した。各々の有機層は、5% 炭酸ナトリウム水溶液(193 mL × 2), 水（193 mL）にて洗浄し、減圧下濃縮して化合物 (10) (37.01 g, 酢酸エチル：4.8%) を得た。 Example 4

Dissolve the above compound (8) in ethyl acetate (293 mL), add triethylamine (28.9 mL, 2.6 eq) under ice-cooling, and add trichloroacetyl chloride (11.6 mL, 1.3 eq) at 3.5-9.2 ° C for 14 minutes. And dripped. The mixture was further stirred at 2 ° C for 0.5 hour. The reaction solution was poured into 1 mol / L hydrochloric acid (193 mL) and extracted. The water bath was extracted again with ethyl acetate (138 mL). Each organic layer was washed with 5% aqueous sodium carbonate solution (193 mL × 2), water (193 mL), and concentrated under reduced pressure to obtain compound (10) (37.01 g, ethyl acetate: 4.8%). .

化合物 (8) (100.71 g, 223.0 mmol) に酢酸エチル (700 mL)、トリエチルアミン(112.83 g, 1115.0 mmol) を加えた溶液を約0 ℃まで冷却し、オキシ塩化リン (51.35 g, 334.9 mmol) を約30分間かけて滴下した。滴下終了後、約30分間かけて25 ℃まで昇温し、反応を完結させた。得られた反応液を再び約0 ℃まで冷却し、水道水420 mLを加え、2 mol/L 塩酸で約pH 3に調整した。分液後、水層に酢酸エチル420 mL を加え再び分液し、引き続き有機層を5 %炭酸ナトリウム水溶液448 mL、水道水420 mLで2回洗浄した。それぞれの有機層を合併後、約560 mL まで減圧濃縮を行い、褐色の化合物 (10) の濃縮液 (HPLC 定量値99%)を得た。
¹H NMR (CDCl₃):δ 0.80 (d, 6H, J = 6.3 Hz), 1.47 (s, 9H), 1.52-1.70 (m, 1H), 1.80-1.96 (m, 2H), 2.21 (d, 2H, J = 6.9 Hz), 2.86-3.63 (m, 3H), 4.28-4.52 (m, 1H), 7.17-7.63 (m, 11H) Example 5

A solution obtained by adding ethyl acetate (700 mL) and triethylamine (112.83 g, 1115.0 mmol) to compound (8) (100.71 g, 223.0 mmol) was cooled to about 0 ° C., and phosphorus oxychloride (51.35 g, 334.9 mmol) was added. The solution was added dropwise over about 30 minutes. After completion of the dropping, the temperature was raised to 25 ° C. over about 30 minutes to complete the reaction. The obtained reaction solution was again cooled to about 0 ° C., 420 mL of tap water was added, and the pH was adjusted to about 3 with 2 mol / L hydrochloric acid. After separation, 420 mL of ethyl acetate was added to the aqueous layer, and the mixture was separated again. Subsequently, the organic layer was washed twice with 448 mL of 5% aqueous sodium carbonate and 420 mL of tap water. After merging the organic layers, the mixture was concentrated under reduced pressure to about 560 mL to obtain a brown compound (10) concentrate (HPLC quantitative value 99%).
¹ H NMR (CDCl ₃ ): δ 0.80 (d, 6H, J = 6.3 Hz), 1.47 (s, 9H), 1.52-1.70 (m, 1H), 1.80-1.96 (m, 2H), 2.21 (d, 2H, J = 6.9 Hz), 2.86-3.63 (m, 3H), 4.28-4.52 (m, 1H), 7.17-7.63 (m, 11H)

実施例４で得られた 化合物 (10) を2 mol/L アンモニア／エタノール (173 mL, 79.65 mmol × 5V) に溶解、ラネーニッケル (78 mL) を加え室温にて水添した。反応終了後、触媒を濾別し、エタノール洗浄した。減圧下濃縮して残渣を酢酸エチル (350 mL) に溶解、水（175 mL）を加え抽出した。水槽は酢酸エチル (175 mL) にて更に抽出した。各々の有機層は食塩水(175 mL × 2)洗浄した。有機層を合わせ減圧下、濃縮し、酢酸エチル (50 mL)を加え再濃縮して、化合物 (11) (32.32 g, 92.7%) を得た。
¹H NMR (CDCl₃):δ 0.80 (d, 6H, J = 6.6 Hz), 1.43 (s, 9H), 1.49-1.60 (m, 2H), 1.63-1.78 (m, 1H), 2.09 (d, 2H, J = 6.8 Hz), 2.42-2.51 (m, 1H), 2.65-2.77 (m, 1H), 2.95-3.07 (m, 1H), 3.11-3.32 (m, 2H), 3.53 (s, 2H), 3.60-3.73 (m, 1H), 7.17-7.63 (m, 11H) Example 6

The compound (10) obtained in Example 4 was dissolved in 2 mol / L ammonia / ethanol (173 mL, 79.65 mmol × 5V), Raney nickel (78 mL) was added and hydrogenated at room temperature. After completion of the reaction, the catalyst was filtered off and washed with ethanol. The residue was dissolved in ethyl acetate (350 mL) and extracted by adding water (175 mL). The water bath was further extracted with ethyl acetate (175 mL). Each organic layer was washed with brine (175 mL × 2). The organic layers were combined and concentrated under reduced pressure, ethyl acetate (50 mL) was added, and the mixture was concentrated again to obtain compound (11) (32.32 g, 92.7%).
¹ H NMR (CDCl ₃ ): δ 0.80 (d, 6H, J = 6.6 Hz), 1.43 (s, 9H), 1.49-1.60 (m, 2H), 1.63-1.78 (m, 1H), 2.09 (d, 2H, J = 6.8 Hz), 2.42-2.51 (m, 1H), 2.65-2.77 (m, 1H), 2.95-3.07 (m, 1H), 3.11-3.32 (m, 2H), 3.53 (s, 2H) , 3.60-3.73 (m, 1H), 7.17-7.63 (m, 11H)

上記化合物 (11)の1.05 g (3.72 mmol) をジグライム (4.9 mL)、酢酸エチル (3 mL) に溶解して、氷冷攪拌下、酸クロライド (17) (1.05 g, 3.54 mmol) を2.7-9.8℃にて加えた。同温度にて２時間攪拌後、メタノール (16.3 mL)、濃塩酸 (1.5 mL) を加え60℃で9.5時間攪拌した。4 mol/L 水酸化ナトリウム水溶液 (3.7 mL) を加え、均質な結晶が析出するまで攪拌した。冷却後濾別、乾燥して化合物 (13) (1.72 g, 81.5%) を得た。
Mp 205.7 ℃.
¹H NMR (d₆-DMSO, 300 MHz): 0.74 (6H, dd), 1.42-1.62 (2H, m), 1.74-1.86 (1H, m), 2.90 (2H, dd), 2.78 (ddd, 1H), 3.07 (ddd, 1H), 3.36 (m, 1H), 3.45 (m, 1H), 3.49 (s, 2H), 3.58-3.68 (m, 2H), 6.61 (d, 1H), 7.17 (1H, d), 7.24-7.60 (14H, m).
Anal. Calcd for C₃₅H₃₈N₄O₃S・0.6 H₂O: C,69.42; H, 6.52; N, 9.25; S, 5.25; H₂O, 1.78. Found: C, 69.52; H, 6.54; N, 9.32; S, 5.32; H₂O, 1.48. Example 7

1.05 g (3.72 mmol) of the above compound (11) was dissolved in diglyme (4.9 mL) and ethyl acetate (3 mL), and acid chloride (17) (1.05 g, 3.54 mmol) was dissolved in 2.7- under stirring with ice cooling. Added at 9.8 ° C. After stirring at the same temperature for 2 hours, methanol (16.3 mL) and concentrated hydrochloric acid (1.5 mL) were added, and the mixture was stirred at 60 ° C. for 9.5 hours. A 4 mol / L aqueous sodium hydroxide solution (3.7 mL) was added, and the mixture was stirred until homogeneous crystals were precipitated. After cooling, it was filtered and dried to obtain compound (13) (1.72 g, 81.5%).
Mp 205.7 ° C.
¹ H NMR (d ₆ -DMSO, 300 MHz): 0.74 (6H, dd), 1.42-1.62 (2H, m), 1.74-1.86 (1H, m), 2.90 (2H, dd), 2.78 (ddd, 1H ), 3.07 (ddd, 1H), 3.36 (m, 1H), 3.45 (m, 1H), 3.49 (s, 2H), 3.58-3.68 (m, 2H), 6.61 (d, 1H), 7.17 (1H, d), 7.24-7.60 (14H, m).
Anal.Calcd for C ₃₅ H ₃₈ N ₄ O ₃ S ・ 0.6 H ₂ O: C, 69.42; H, 6.52; N, 9.25; S, 5.25; H ₂ O, 1.78. Found: C, 69.52; H, 6.54 ; N, 9.32; S, 5.32; H ₂ O, 1.48.

上記の (13) (1.5 g, 2.52 mmol) をジメチルアセトアミド (13.5 mL) に懸濁させ、トリエチルアミン (1. 5 mL, 3 eq) を氷冷下加えた後、化合物 (18) の酸クロライド(1.0 eq) の酢酸エチル溶液を加えた。38-48℃で1.5時間攪拌後、希塩酸水に注ぎ込酢酸エチルで抽出した。有機層は5%重曹水、水で順じ洗浄した。溶媒を留去後、残渣 (14)を酢酸エチルで溶解しｐ−トルエンスルホン酸一水和物 (479 mg)のメタノール(5.1 mL)溶液を加えた。析出した結晶を濾過、乾燥してｐ−トルエンスルホン酸塩 (15) (2.30 g, 90.2%) を得た。
Mp 118℃,
Anal. Calcd. for C₅₆H₅₂F₂N₄O₈S₂・1.6 H₂O: C, 64.67; H, 5.35; F, 3.65; N, 5.39; S, 6.17, Found: C, 64.73; H, 5.43; F, 3.46; N, 5.34; S, 5.92; H₂O, 1.95, Ash<0.1. Example 8

The above (13) (1.5 g, 2.52 mmol) was suspended in dimethylacetamide (13.5 mL), triethylamine (1.5 mL, 3 eq) was added under ice-cooling, and then the acid chloride of compound (18) ( 1.0 eq) of ethyl acetate solution was added. After stirring at 38-48 ° C for 1.5 hours, the mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed sequentially with 5% aqueous sodium bicarbonate and water. After the solvent was distilled off, the residue (14) was dissolved in ethyl acetate, and a solution of p-toluenesulfonic acid monohydrate (479 mg) in methanol (5.1 mL) was added. The precipitated crystals were filtered and dried to obtain p-toluenesulfonate (15) (2.30 g, 90.2%).
Mp 118 ℃,
Anal.Calcd.for C ₅₆ H ₅₂ F ₂ N ₄ O ₈ S ₂・ 1.6 H ₂ O: C, 64.67; H, 5.35; F, 3.65; N, 5.39; S, 6.17, Found: C, 64.73; H , 5.43; F, 3.46; N, 5.34; S, 5.92; H ₂ O, 1.95, Ash <0.1.

ｐ−トルエンスルホン酸塩 (15) (9.07 g) の酢酸 (90 mL) けん濁液に5% 重曹水 (90 mL) を加え、室温にて17 分攪拌した。分液した水層は酢酸エチル (32 mL) で抽出した。各々酢酸エチル層は、食塩水(32 mL×2) で洗浄した。硫酸ナトリウムで乾燥後、減圧下濃縮して化合物 (14) 残渣 (7.88 g) を得た。
Anal. Calcd. for C₄₉H₄₄F₂N₄O₅S・0.5 H₂O.: C, 69.40; H, 6.53; F, 4.48; N, 6.61; S, 3.78; H₂O, 0.26. Found: C, 69.45; H, 5.35; F, 4.47; N, 6.64; S, 3.85; H₂O, 1.83, Na<0.1, Cl<0.1%.
¹H NMR (CDCl₃) δ 0.72 (d, 3H, J = 6.3 Hz), 0.78 (d, 3H, J = 6.6 Hz), 1.47-1.56 (m, 1 H), 1.68-1.75 (m, 1 H), 1.94-2.17 (m, 4 H), 2.95-3.01 (m, 1 H), 3.13-3.19 (m, 1H), 3.39-3.71 (m, 5 H), 4.41-4.57 (m, 1 H), 6.52 (d, 1 H, J = 15.9 Hz), 6.84-7.00 (m, 2 H), 7.12-7.75 (m, 21 H). Example 9

To a suspension of p-toluenesulfonate (15) (9.07 g) in acetic acid (90 mL) was added 5% aqueous sodium bicarbonate (90 mL), and the mixture was stirred at room temperature for 17 minutes. The separated aqueous layer was extracted with ethyl acetate (32 mL). Each ethyl acetate layer was washed with brine (32 mL × 2). The extract was dried over sodium sulfate and concentrated under reduced pressure to give a residue of compound (14) (7.88 g).
Anal.Calcd.for C ₄₉ H ₄₄ F ₂ N ₄ O ₅ S ・ 0.5 H ₂ O .: C, 69.40; H, 6.53; F, 4.48; N, 6.61; S, 3.78; H ₂ O, 0.26. Found : C, 69.45; H, 5.35; F, 4.47; N, 6.64; S, 3.85; H ₂ O, 1.83, Na <0.1, Cl <0.1%.
¹ H NMR (CDCl ₃ ) δ 0.72 (d, 3H, J = 6.3 Hz), 0.78 (d, 3H, J = 6.6 Hz), 1.47-1.56 (m, 1 H), 1.68-1.75 (m, 1 H ), 1.94-2.17 (m, 4 H), 2.95-3.01 (m, 1 H), 3.13-3.19 (m, 1H), 3.39-3.71 (m, 5 H), 4.41-4.57 (m, 1 H) , 6.52 (d, 1 H, J = 15.9 Hz), 6.84-7.00 (m, 2 H), 7.12-7.75 (m, 21 H).

水素化ホウ素ナトリウム (5.67 g, 150 mmol) のジグライム溶液 (110 mL) に酢酸 (8.6 mL, 150 mmol)のジグライム溶液 (20 mL) を、氷冷下で1〜2℃に保ちながら、55分かけて滴下した。同温度で10分間攪拌した後、化合物 (8) (13.70 g, 30.3 mmol) のジグライム溶液 (50 mL) を、氷冷下で1〜2℃に保ちながら10分かけて滴下した。滴下終了後、60-66℃で6.5時間加熱攪拌を行なった。冷却後、反応液を、冷却した1 mol/L 塩酸 (300mL) に滴下し、酢酸エチル 120mL を加えた後、氷冷下で1時間攪拌した。さらに、酢酸エチル120mLを加えて分液後、水層は酢酸エチル 80mL で洗浄し、有機層は冷却した 1 mol/L 塩酸 (50 mL) で2回洗浄した。水層を合わせた後、4 mol/L 水酸化ナトリウム水溶液 (約105 mL) て、pHを約10に調節した後、酢酸エチル (120mL×1、100mL×1)で抽出した。有機層をそれぞれ10% 塩化ナトリウム水溶液 (80 mL×2) で洗浄後、有機層を合わせ、硫酸ナトリウムで乾燥後減圧下濃縮して、目的物 (12.36 g, 含有溶媒と液クロにより純度換算した収率76.1%) を得た。 A method for directly obtaining the amine body 11 from the amide body 8 with sodium borohydride-acetic acid will be described.
Example 10

A diglyme solution (20 mL) of acetic acid (8.6 mL, 150 mmol) in a diglyme solution (110 mL) of sodium borohydride (5.67 g, 150 mmol) was maintained at 1-2 ° C. under ice cooling for 55 minutes. It was dripped over. After stirring at the same temperature for 10 minutes, a diglyme solution (50 mL) of compound (8) (13.70 g, 30.3 mmol) was added dropwise over 10 minutes while maintaining at 1 to 2 ° C. under ice cooling. After completion of the dropwise addition, the mixture was heated and stirred at 60 to 66 ° C. for 6.5 hours. After cooling, the reaction solution was added dropwise to cooled 1 mol / L hydrochloric acid (300 mL), 120 mL of ethyl acetate was added, and the mixture was stirred for 1 hour under ice cooling. Further, 120 mL of ethyl acetate was added for liquid separation, the aqueous layer was washed with 80 mL of ethyl acetate, and the organic layer was washed twice with cooled 1 mol / L hydrochloric acid (50 mL). After combining the aqueous layers, the pH was adjusted to about 10 with a 4 mol / L aqueous sodium hydroxide solution (about 105 mL), and the mixture was extracted with ethyl acetate (120 mL × 1, 100 mL × 1). After washing each organic layer with 10% aqueous sodium chloride solution (80 mL × 2), the organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure, and the target product (12.36 g, containing solvent and liquid chromatography was used to convert the purity. Yield 76.1%) was obtained.

For reference, the protecting group at position 1 is first deprotected and a 2- (2,4-difluorobenzoyl) benzoyl group is introduced, then the amide group at position 2 is dehydrated and reduced, and the necessary side chain The route to introduce is shown below.

メシレート体 (6) 1500 g (4.87 mol) をイソブチルアミン2417 mL (d 0.736, 24.3 mol) および水 495 mLに溶解し、10時間30分間還流攪拌した。反応液は減圧濃縮して得られた油状残査に酢酸エチルを加え、減圧濃縮する操作を2回繰り返した。得られた油状残査に酢酸エチル、氷水および20%炭酸ナトリウム水溶液を加え、抽出した。水層は酢酸エチルで抽出し、有機層を10%食塩水で洗浄後減圧濃縮した。得られた油状残査をアセトニトリルに溶解し、再度減圧濃縮し、イソブチルアミノ体 (7) 1.50 kgを油状物として得た。
¹H NMR (CDCl₃):δ 0.89 (d, 6H, J = 6.6 Hz), 1.47 (s, 9H), 1.62-1.75 (m, 2H), 2.35-2.41 (m, 2H), 2.56 (br, 1H), 3.12 (br, 1H), 3.39 (br, 1H), 3.58 (br, 1H), 4.39 (br, 1H), 5.45 (br, 1H), 6.01 (br, 1H), 6.90 (br, 1H) Reference Example 6

1500 g (4.87 mol) of the mesylate form (6) was dissolved in 2417 mL (d 0.736, 24.3 mol) of isobutylamine and 495 mL of water, and stirred at reflux for 10 hours and 30 minutes. The reaction solution was concentrated twice under reduced pressure, and ethyl acetate was added to the oily residue obtained by concentration under reduced pressure. Ethyl acetate, ice water and 20% aqueous sodium carbonate solution were added to the resulting oily residue for extraction. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with 10% brine and concentrated under reduced pressure. The obtained oily residue was dissolved in acetonitrile and concentrated again under reduced pressure to obtain 1.50 kg of isobutylamino compound (7) as an oily substance.
¹ H NMR (CDCl ₃ ): δ 0.89 (d, 6H, J = 6.6 Hz), 1.47 (s, 9H), 1.62-1.75 (m, 2H), 2.35-2.41 (m, 2H), 2.56 (br, 1H), 3.12 (br, 1H), 3.39 (br, 1H), 3.58 (br, 1H), 4.39 (br, 1H), 5.45 (br, 1H), 6.01 (br, 1H), 6.90 (br, 1H )

イソブチルアミノ体 (7)1.56 kg(4.83 mol分) のアセト二トリル 9 L 溶液に2-フエニル-ベンジルブロミド(16) 1260 g (純度補正1202 g; 1 eq) と炭酸ナトリウム 774 g (1.5 eq)を加え45〜46℃で8.5時間攪拌した。一夜放置後ろ紙粉末で濾過し減圧濃縮して目的物 (8) の油状残渣 2.50 kg（理論量 2183 g）を得た。 Reference Example 7

Isobutylamino compound (7) 2-phenyl-benzyl bromide (16) 1260 g (purity correction 1202 g; 1 eq) and sodium carbonate 774 g (1.5 eq) in a 9 L solution of 1.56 kg (4.83 mol) of acetonitrile And stirred at 45-46 ° C. for 8.5 hours. The mixture was filtered overnight with back paper powder and concentrated under reduced pressure to obtain 2.50 kg (theoretical amount: 2183 g) of the oily residue of the desired product (8).

ベンジルアミノ体 (8) 2.47 kg (4.77 mol分)の酢酸エチル 4.3 L、メタノール1.1 L 溶液に4 mol/L 塩酸/酢酸エチル溶液 5.96 L (5 eq) を11〜19℃で滴下した。25〜28℃で1時間25分攪拌後氷水を加え分液した。水層を酢酸エチル 4.3 Lで洗浄、酢酸エチル層は水 4.3 Lで抽出した。水層に氷を加え15〜19℃で冷4 mol/L水酸化ナトリウム水溶液 (6 L) を滴下しpH 9.5に調整後酢酸エチル 7.5L、4.3 Lで順次抽出した。酢酸エチル層を10% 食塩水 7.5 L×2で順次洗浄後減圧濃縮して目的物 (19) の油状残渣 1.52 kg（90.6%, 理論量 1677 g）を得た。 Reference Example 8

Benzylamino compound (8) 5.96 L (5 eq) of 4 mol / L hydrochloric acid / ethyl acetate solution was added dropwise at 11 to 19 ° C. to a solution of 4.3 L of 2.47 kg (4.77 mol) of ethyl acetate and 1.1 L of methanol. After stirring at 25-28 ° C. for 1 hour and 25 minutes, ice water was added to separate the layers. The aqueous layer was washed with 4.3 L of ethyl acetate, and the ethyl acetate layer was extracted with 4.3 L of water. Ice was added to the aqueous layer, and a cold 4 mol / L aqueous sodium hydroxide solution (6 L) was added dropwise at 15 to 19 ° C. to adjust to pH 9.5, followed by sequential extraction with 7.5 L and 4.3 L of ethyl acetate. The ethyl acetate layer was washed successively with 7.5% × 2 of 10% brine and concentrated under reduced pressure to obtain 1.52 kg (90.6%, theoretical amount 1677 g) of the oily residue of the target product (19).

化合物(19) 1457 gの酢酸n-ブチルエステル 19.28 Lと酢酸エチル5.86 Lの溶液にｐ−トルエンスルホン酸一水和物 1392 g (1.6 eq)／酢酸エチル 7 L溶液を40℃で加えた。40℃で2時間攪拌後さらに室温で2時間攪拌して結晶化した。結晶を濾過し酢酸n-ブチルエステル／酢酸エチル = 2/1 3.2 Lと酢酸n-ブチルエステル／酢酸エチル = 5/1 3.2 Lで順次洗浄、加温減圧乾燥して白色のp-トルエンスルホン酸塩 (23) 2238 g(69% from 6)を得た。
Anal. Calcd. for C₂₂H₂₉N₃O・2.0 C₂H₂O₄・0.1 H₂O: C, 61.97; H, 6.53; N, 6.02; S, 9.19; H₂O, 0.26. Found: C, 61.43; H, 6.49; N, 6.10; S, 9.38; H₂O, 0.19 Reference Example 9

Compound (19) To a solution of 1457 g of acetic acid n-butyl ester 19.28 L and ethyl acetate 5.86 L, p-toluenesulfonic acid monohydrate 1392 g (1.6 eq) / ethyl acetate 7 L solution was added at 40 ° C. After stirring at 40 ° C. for 2 hours, the mixture was further stirred at room temperature for 2 hours to crystallize. The crystals were filtered, washed successively with acetic acid n-butyl ester / ethyl acetate = 2/1 3.2 L and acetic acid n-butyl ester / ethyl acetate = 5/1 3.2 L, heated to dryness under reduced pressure, and then washed with white p-toluenesulfonic acid. The salt (23) 2238 g (69% from 6) was obtained.
Anal.Calcd.for C ₂₂ H ₂₉ N ₃ O ・ 2.0 C ₂ H ₂ O ₄・ 0.1 H ₂ O: C, 61.97; H, 6.53; N, 6.02; S, 9.19; H ₂ O, 0.26. Found: C, 61.43; H, 6.49; N, 6.10; S, 9.38; H ₂ O, 0.19

化合物 (8) 2341 gの酢酸エチル13.4 Lの溶液にp-トルエンスルホン酸一水和物 2266 g (2.5 eq)を加えた。40℃で３時間攪拌後、酢酸n-ブチルエステル20.1 Lを加え40℃から室温さらに氷冷で攪拌して結晶化した。結晶を濾過し酢酸n-ブチルエステル/酢酸エチル = 2/1 3.35 Lと酢酸n-ブチルエステル/酢酸エチル = 5/1 3.35 Lで順次洗浄、加温減圧乾燥して白色のp-トルエンスルホン酸塩 (23) 2135g (63.7%)を得た。 Reference Example 10

Compound (8) To a solution of 2341 g of 13.4 L of ethyl acetate was added 2266 g (2.5 eq) of p-toluenesulfonic acid monohydrate. After stirring at 40 ° C. for 3 hours, 20.1 L of acetic acid n-butyl ester was added, and the mixture was crystallized from 40 ° C. by stirring at room temperature and further with ice cooling. The crystals were filtered, washed sequentially with acetic acid n-butyl ester / ethyl acetate = 2/1 3.35 L and acetic acid n-butyl ester / ethyl acetate = 5/1 3.35 L, heated to dryness under reduced pressure, and washed with white p-toluenesulfonic acid. Obtained 2135 g (63.7%) of salt (23).

1−位側鎖カルボン酸 (18) （320 g, 1.22 mol）のアセトニトリル (2.56 L) 溶液にジメチルホルムアミド (3 mL)、塩化チオニル (107 mL, 1.464 mol) を室温で加え、同温度で2時間攪拌した。減圧濃縮して油状物質 385 gをえた。化合物（19）（フリー体、440 g, 1.25 mol）のテトラヒドロフラン (2.4 L) 溶液に、トリエチルアミン (510 mL, 3.66 mol)、上記の油状物質のテトラヒドロフラン (2 L) 溶液を10℃以下で加えた。3-9℃で0.5時間攪拌後、室温で17.5時間攪拌した。希塩酸(5 L) 中に反応液を注ぎこみ、酢酸エチル (3 L×2) で抽出した。各々有機層は5%炭酸ナトリウム水溶液 (3 L×2)、 水 (3 L×2)、食塩水 (3 L) で洗浄した。溶媒を留去して、目的物質 (20) (740 g, 99%) を得た。 Reference Example 11

To a solution of 1-position side chain carboxylic acid (18) (320 g, 1.22 mol) in acetonitrile (2.56 L), dimethylformamide (3 mL) and thionyl chloride (107 mL, 1.464 mol) are added at room temperature. Stir for hours. Concentration under reduced pressure gave 385 g of an oily substance. To a solution of compound (19) (free form, 440 g, 1.25 mol) in tetrahydrofuran (2.4 L) was added triethylamine (510 mL, 3.66 mol) and a solution of the above oily substance in tetrahydrofuran (2 L) at 10 ° C or less. . After stirring at 3-9 ° C for 0.5 hour, the mixture was stirred at room temperature for 17.5 hours. The reaction mixture was poured into dilute hydrochloric acid (5 L) and extracted with ethyl acetate (3 L × 2). Each organic layer was washed with 5% aqueous sodium carbonate solution (3 L × 2), water (3 L × 2), and brine (3 L). The solvent was distilled off to obtain the target substance (20) (740 g, 99%).

化合物 (20) (280 g, 0.432 mol) のテトラヒドロフラン (1.12 L) 溶液に、トリエチルアミン (180 mL, 1.296 mol), 塩化トリクロロアセチル (72.4 mL, 0.648) のテトラヒドロフラン (280 mL) 溶液を10℃以下で加えた。2-10℃で1時間攪拌後希塩酸 (1．5 L) 中に反応液を注ぎこみ、酢酸エチル (1 L×2)で抽出した。各々有機層は5%炭酸ナトリウム水溶液 (1 L×2)、水(1 L×2)、食塩水(1 L) で洗浄した。溶媒を留去して、目的物質 (21) (262 g, 98%) を得た。 Reference Example 12

Add a solution of compound (20) (280 g, 0.432 mol) in tetrahydrofuran (1.12 L) to a solution of triethylamine (180 mL, 1.296 mol), trichloroacetyl chloride (72.4 mL, 0.648) in tetrahydrofuran (280 mL) at 10 ° C or less. added. After stirring at 2-10 ° C for 1 hour, the reaction mixture was poured into dilute hydrochloric acid (1.5 L) and extracted with ethyl acetate (1 L × 2). Each organic layer was washed with 5% aqueous sodium carbonate solution (1 L × 2), water (1 L × 2), and brine (1 L). The solvent was distilled off to obtain the target substance (21) (262 g, 98%).

化合物 (21) （188 g, 0.3 mol）のエタノール (300 mL) 溶液に、4 mol/L アンモニアのエタノール(300 mL, 1.2 mol) 溶液、ラネーニッケル (376 mL) を加え、室温にて6時間水添した。触媒をろ別し、酢酸エチル(900 mL)で洗浄した。酢酸エチル溶液は水 （600 mL×2）、食塩水 (300 mL) で洗浄した。各水層は、酢酸エチル (300 mL) で抽出した。酢酸エチル層は合併し、硫酸ナトリウムで乾燥後、4 mol/L 塩酸の酢酸エチル (240 mL) を加え室温で16時間攪拌した。析出晶をろ過、酢酸エチル (500 mL) で洗浄した。減圧乾燥して、目的物 (22) (120 g, 61%) を得た。 Reference Example 13

To a solution of compound (21) (188 g, 0.3 mol) in ethanol (300 mL), add 4 mol / L ammonia in ethanol (300 mL, 1.2 mol) and Raney nickel (376 mL), and water at room temperature for 6 hours. Added. The catalyst was filtered off and washed with ethyl acetate (900 mL). The ethyl acetate solution was washed with water (600 mL × 2) and brine (300 mL). Each aqueous layer was extracted with ethyl acetate (300 mL). The ethyl acetate layers were combined, dried over sodium sulfate, 4 mol / L hydrochloric acid ethyl acetate (240 mL) was added, and the mixture was stirred at room temperature for 16 hr. The precipitated crystals were filtered and washed with ethyl acetate (500 mL). The product was dried under reduced pressure to obtain the desired product (22) (120 g, 61%).

化合物 (22) (10 g, 15.3 mol)のアセトニトリル(200mL)溶液に、n-トリブチルアミン (12.7 mL)を3℃で加えた。次いで、2-位側鎖の酸クロリド (17) (4.49 g, 15.3 mol) を、-11〜-14℃で加え、更に同温度にて3.5時間攪拌後、水 (150 mL) に反応液を注ぎこみ、酢酸エチル (150 mL, 100 mL) で抽出した。各々有機層は１ mol/L 塩酸(150 mL)、5%炭酸ナトリウム水溶液 (150 mL)、水 (1 L×2)、食塩水 (150 mL) で洗浄した。溶媒を留去して、目的物質 (17.5 g) を得た。別ロットを合わせ (total 60 g) エタノール：アセトン(9:1) (300 mL)の溶液を5%食塩水に室温にて滴下し、同温で2時間攪拌後ろ過した。水 (200 mL×3) で洗浄した後乾燥し、化合物 (14) (53.35 g, 88.95%)を得た。
Anal. Calcd. for C₄₉H₄₄F₂N₄O₅S・0.5 H₂O.: C, 69.40; H, 6.53; F, 4.48; N, 6.61; S, 3.78; H₂O, 0.26. Found: C, 69.45; H, 5.35; F, 4.47; N, 6.64; S, 3.85; H₂O, 1.83, Na<0.1, Cl<0.1%.
¹H NMR (CDCl₃) δ 0.72 (d, 3H, J = 6.3 Hz), 0.78 (d, 3H, J = 6.6 Hz), 1.47-1.56 (m, 1 H), 1.68-1.75 (m, 1 H), 1.94-2.17 (m, 4 H), 2.95-3.01 (m, 1 H), 3.13-3.19 (m, 1H), 3.39-3.71 (m, 5 H), 4.41-4.57 (m, 1 H), 6.52 (d, 1 H, J = 15.9 Hz), 6.84-7.00 (m, 2 H), 7.12-7.75 (m, 21 H). Reference Example 14

N-Tributylamine (12.7 mL) was added to a solution of compound (22) (10 g, 15.3 mol) in acetonitrile (200 mL) at 3 ° C. Next, 2-position side chain acid chloride (17) (4.49 g, 15.3 mol) was added at -11 to -14 ° C, and the mixture was further stirred at the same temperature for 3.5 hours. Poured and extracted with ethyl acetate (150 mL, 100 mL). Each organic layer was washed with 1 mol / L hydrochloric acid (150 mL), 5% aqueous sodium carbonate solution (150 mL), water (1 L × 2), and brine (150 mL). The solvent was distilled off to obtain the target substance (17.5 g). Separate lots were combined (total 60 g). A solution of ethanol: acetone (9: 1) (300 mL) was added dropwise to 5% brine at room temperature, and the mixture was stirred at the same temperature for 2 hours and filtered. The extract was washed with water (200 mL × 3) and dried to obtain compound (14) (53.35 g, 88.95%).
Anal.Calcd.for C ₄₉ H ₄₄ F ₂ N ₄ O ₅ S ・ 0.5 H ₂ O .: C, 69.40; H, 6.53; F, 4.48; N, 6.61; S, 3.78; H ₂ O, 0.26. Found : C, 69.45; H, 5.35; F, 4.47; N, 6.64; S, 3.85; H ₂ O, 1.83, Na <0.1, Cl <0.1%.
¹ H NMR (CDCl ₃ ) δ 0.72 (d, 3H, J = 6.3 Hz), 0.78 (d, 3H, J = 6.6 Hz), 1.47-1.56 (m, 1 H), 1.68-1.75 (m, 1 H ), 1.94-2.17 (m, 4 H), 2.95-3.01 (m, 1 H), 3.13-3.19 (m, 1H), 3.39-3.71 (m, 5 H), 4.41-4.57 (m, 1 H) , 6.52 (d, 1 H, J = 15.9 Hz), 6.84-7.00 (m, 2 H), 7.12-7.75 (m, 21 H).

化合物 (14) (8.96 g) を酢酸エチル (25.2 mL) とメタノール (8.4 mL) に溶解し、p-トルエンスルホン酸 (1.9 g, 1.0 eq) の酢酸エチル (5.2 mL) 溶液を加え、室温3時間攪拌した。析出晶をろ過し、酢酸エチル(50 mL)で洗浄した。減圧乾燥し、p-トルエンスルホン酸塩 (15) (9.07 g, 88.1%) を得た。
Mp 118℃,
Anal. Calcd. for C₅₆H₅₂F₂N₄O₈S₂・1.6 H₂O: C, 64.67; H, 5.35; F, 3.65; N, 5.39; S, 6.17, Found: C, 64.73; H, 5.43; F, 3.46; N, 5.34; S, 5.92; H₂O, 1.95, Ash<0.1. Reference Example 15

Dissolve compound (14) (8.96 g) in ethyl acetate (25.2 mL) and methanol (8.4 mL), add a solution of p-toluenesulfonic acid (1.9 g, 1.0 eq) in ethyl acetate (5.2 mL), and add room temperature 3 Stir for hours. The precipitated crystals were filtered and washed with ethyl acetate (50 mL). The residue was dried under reduced pressure to obtain p-toluenesulfonate (15) (9.07 g, 88.1%).
Mp 118 ℃,
Anal.Calcd.for C ₅₆ H ₅₂ F ₂ N ₄ O ₈ S ₂・ 1.6 H ₂ O: C, 64.67; H, 5.35; F, 3.65; N, 5.39; S, 6.17, Found: C, 64.73; H , 5.43; F, 3.46; N, 5.34; S, 5.92; H ₂ O, 1.95, Ash <0.1.

2-フェニル−ベンジルアルコール (23) (13.6 g, 65 mmol, 11.6% 酢酸エチル含有)の酢酸エチル(60 mL)溶液にトリエチルアミン(10.9 mL, 1.2 eq)を加え、メシルクロライド(5.55 mL, 1.1 eq)を-3〜3.3℃で加えた。その後、室温にて45分攪拌した。希塩酸中に注ぎ込、酢酸エチルで抽出した。有機層は食塩水で洗浄後、濃縮してメシレート (24) (17.7 g, 4.7%酢酸エチル含有、99.1%)
を得た。 Another synthesis method of compound (9) from compound (7) using mesylate (24) is shown.
Reference Example 16

Triethylamine (10.9 mL, 1.2 eq) is added to a solution of 2-phenyl-benzyl alcohol (23) (13.6 g, 65 mmol, containing 11.6% ethyl acetate) in ethyl acetate (60 mL), and mesyl chloride (5.55 mL, 1.1 eq) is added. ) Was added at -3 to 3.3 ° C. Then, it stirred at room temperature for 45 minutes. The mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and concentrated to mesylate (24) (17.7 g, containing 4.7% ethyl acetate, 99.1%)
Got.

原料 (7) (10.8 g, 16.22 mmol, 酢酸イソプロピル含有)と酢酸イソプロピル(9 mL)とアセトニトリル(15 mL)の混合液に上記メシレート (24) (4.85 g, 1.0 eq)と炭酸ソーダ(2.58 g, 1.5 eq)を加え、70℃にて9時間攪拌した。反応液を水に注ぎ込、酢酸イソプロピル(35 mL, 25 mL)で2回抽出した。有機層は、水洗2回、食塩水で洗浄後濃縮した。残渣 (8) 8.38 g (純度換算収率 53%)にベンゼンスルホン酸(1.66 g, 1.1 eq)の酢酸イソプロピル(20 mL)と水(0.31 mL)を加え、結晶化して目的物 (9) (2.07 g, 20.3%)を得た。 Reference Example 17

Raw material (7) (10.8 g, 16.22 mmol, containing isopropyl acetate), isopropyl acetate (9 mL) and acetonitrile (15 mL) were mixed in the above mesylate (24) (4.85 g, 1.0 eq) and sodium carbonate (2.58 g , 1.5 eq) and stirred at 70 ° C. for 9 hours. The reaction mixture was poured into water and extracted twice with isopropyl acetate (35 mL, 25 mL). The organic layer was washed twice with water, washed with brine and concentrated. Add benzenesulfonic acid (1.66 g, 1.1 eq) isopropyl acetate (20 mL) and water (0.31 mL) to 8.38 g (purity conversion yield 53%) of the residue (8), and crystallize the desired product (9) ( 2.07 g, 20.3%) was obtained.

テレフタルアルデヒド (25) (22.0g, 164 mmol)、マロン酸 (26) (23.9g, 230 mmol)にアセトニトリル (154 mL) を加えた懸濁液にピリジン (6.6 mL, 82 mmol) を加え、約70℃まで加熱して8時間反応熟成を行った。20 ℃まで冷却後、アセトニトリル (66 mL)を加え、濾過して得られる未乾結晶をアセトニトリル (110 mL)で洗浄して白色の未乾ホルミルケイ皮酸 (27) (37.8g) を得た。 A method for synthesizing the 2-position side chain 17 is shown below.
Reference Example 18

Add pyridine (6.6 mL, 82 mmol) to a suspension of terephthalaldehyde (25) (22.0 g, 164 mmol), malonic acid (26) (23.9 g, 230 mmol) and acetonitrile (154 mL), The reaction was aged for 8 hours by heating to 70 ° C. After cooling to 20 ° C., acetonitrile (66 mL) was added, and the undried crystals obtained by filtration were washed with acetonitrile (110 mL) to obtain white undried formylcinnamic acid (27) (37.8 g).

得られた未乾結晶 (27) (37.8 g)、チアゾリジンジオン (28) (25.0g, 213mmol)に２−プロパノール (220 mL) を加えた懸濁液に、ピペリジン （16.3 mL, 164 mmol) を加え、約75℃まで加熱して8時間反応熟成を行った。20℃まで冷却後、アセトニトリル 110m L、酢酸 (18.8 mL, 328 mmol)を加え、濾過して得られる未乾結晶をアセトニトリル (110 mL)で洗浄して黄色の未乾結晶 29 (87.7g) を得た。減圧乾燥後、黄色の結晶 29 (31.9g, 71%) を得た。 Reference Example 19

Piperidine (16.3 mL, 164 mmol) was added to the suspension obtained by adding 2-propanol (220 mL) to the obtained undried crystals (27) (37.8 g), thiazolidinedione (28) (25.0 g, 213 mmol). In addition, the reaction was aged for 8 hours by heating to about 75 ° C. After cooling to 20 ° C, 110 mL of acetonitrile and acetic acid (18.8 mL, 328 mmol) were added, and the undried crystals obtained by filtration were washed with acetonitrile (110 mL) to obtain yellow undried crystals 29 (87.7 g). Obtained. After drying under reduced pressure, yellow crystals 29 (31.9 g, 71%) were obtained.

上記で得られた結晶 29 (20.0g, 72.7mmol) のN-メチルピロリドン (200 mL) 溶液を約50℃まで加熱した後、塩化チオニル (9.5g, 80mmol)を約30分間かけて滴下し、約50℃で30分間反応熟成を行った。氷冷後、濾過して得られた未乾結晶をトルエン (150mL)で洗浄し、黄色の未乾結晶 (30) (34.1g)を得た。減圧乾燥後、黄色の結晶 (30) (34.4g, 85%)を得た。 Reference Example 20

After heating a solution of the crystal 29 (20.0 g, 72.7 mmol) obtained above in N-methylpyrrolidone (200 mL) to about 50 ° C., thionyl chloride (9.5 g, 80 mmol) was added dropwise over about 30 minutes, Reaction aging was performed at about 50 ° C. for 30 minutes. After cooling with ice, the undried crystals obtained by filtration were washed with toluene (150 mL) to obtain yellow undried crystals (30) (34.1 g). After drying under reduced pressure, yellow crystals (30) (34.4 g, 85%) were obtained.

Provided is a production method useful as an industrial production method of a pyrrolidine compound having cPLA ₂ inhibitory activity.

4 is a result of powder X-ray measurement of crystals of compound 9 obtained in Example 2. Diffraction angle (2θ) shows main peaks at 19.3, 20.2, 20.7, and 27.0 (unit: °) 3 is a result of powder X-ray measurement of a crystal of compound 13 obtained in Example 7. FIG. Main peaks at diffraction angles (2θ) of 5.8, 13.0, 18.5, and 26.4 (unit: °)

Claims (16)

Formula (I):

Wherein R ¹ is aralkyl;
R ² is a hydrogen atom or C1-C6 alkyl; and Pro is a protecting group)
Or a solvate thereof, or a salt thereof is subjected to a hydrogenation reaction in the presence of at least one catalyst selected from nickel, palladium, and platinum, represented by the general formula (II):

(Wherein R ¹ , R ² and Pro are as defined above)
Or a solvate thereof, or a salt thereof. The following steps:
(1) General formula (III):

(Wherein R ¹ , R ² and Pro are as defined in claim 1)
Or a solvate thereof, or a salt thereof is subjected to a dehydration reaction in the presence of a dehydrating agent, and is represented by the general formula (I):

(Wherein R ¹ , R ² and Pro are as defined in claim 1)
A compound represented by the formula: solvates thereof, or salts thereof;
(2) General formula (I):

(Wherein R ¹ , R ² and Pro are as defined in claim 1)
And a solvate thereof, or a salt thereof, which is subjected to a hydrogenation reaction in the presence of at least one catalyst selected from nickel, palladium and platinum. II):

(Wherein R ¹ , R ² and Pro are as defined in claim 1)
Or a solvate thereof, or a salt thereof. The following steps:
(1) General formula (III):

(Wherein R ¹ , R ² and Pro are as defined in claim 1)
Or a solvate thereof, or a salt thereof is subjected to a dehydration reaction in the presence of a dehydrating agent, and is represented by the general formula (I):

(Wherein R ¹ , R ² and Pro are as defined in claim 1)
A compound represented by the formula: solvates thereof, or salts thereof;
(2) General formula (I):

(Wherein R ¹ , R ² and Pro are as defined in claim 1)
Or a solvate thereof, or a salt thereof is subjected to a hydrogenation reaction in the presence of at least one catalyst selected from nickel, palladium, and platinum, and is represented by the general formula (II):

(Wherein R ¹ , R ² and Pro are as defined in claim 1)
A compound represented by the formula: solvates thereof, or salts thereof;
(3) General formula (II):

(Wherein R ¹ , R ² , and Pro are as defined in claim 1)
And a solvate thereof, or a salt thereof, and a general formula (IV):

(Where X is halogen or hydroxy)
Or a solvate thereof, or a salt thereof, is subjected to an amide bond formation reaction, and is represented by the general formula (V):

(Wherein R ¹ , R ² and Pro are as defined in claim 1)
A compound represented by the formula: solvates thereof, or salts thereof;
(4) General formula (V):

(Wherein R ¹ , R ² and Pro are as defined in claim 1)
Or a solvate thereof, or a salt thereof, is subjected to a deprotection reaction to give a general formula (VI):

(Wherein R ¹ and R ² are as defined in claim 1)
A compound represented by the formula: solvates thereof, or salts thereof;
(5) General formula (VI):

(Wherein R ¹ and R ² are as defined in claim 1)
Or a solvate thereof, or a salt thereof and the general formula (VII):

(Where Y is halogen or hydroxy)
A compound represented by the formula:

(Wherein R ¹ and R ² are as defined in claim 1)
Or a solvate thereof, or a salt thereof. The production method according to claim 1, wherein R ¹ is 2-biphenylmethyl and R ² is isobutyl. The production method according to claim 1, wherein the catalyst is Raney nickel. The production method according to claim 1, wherein the protective group is a t-butyloxycarbonyl group. The production method according to any one of claims 2 to 6, wherein the dehydrating agent is trichloroacetyl chloride or phosphorus oxychloride. Claims for obtaining a compound represented by the general formula (VIII) wherein R ¹ is 2-biphenylmethyl and R ² is isobutyl, a solvate thereof, a p-toluenesulfonate, a sulfate thereof, or a hydrochloride thereof The manufacturing method in any one of 3-7. Formula (IX):

(Where Boc is t-butyloxycarbonyl)
Or a solvate thereof. Formula (IX):

(Where Boc is t-butyloxycarbonyl)
A crystal of a benzenesulfonate salt of a compound represented by the formula: The crystal according to claim 10, wherein in the powder X-ray diffraction pattern, diffraction peaks (2θ) show main peaks at 19.3, 20.2, 20.7, and 27.0 (unit: °). Formula (X):

Or a solvate thereof. The crystal according to claim 12, which shows main peaks at diffraction angles (2θ) of 5.8, 13.0, 18.5, and 26.4 (unit: °) in a powder X-ray diffraction pattern. Formula (XI):

(Where Boc is t-butyloxycarbonyl)
Or a solvate thereof, or a salt thereof. Formula (III):

Wherein R ¹ is aralkyl;
R ² is a hydrogen atom or C1-C6 alkyl; and Pro is a protecting group)
Or a solvate thereof, or a salt thereof, is reacted with sodium borohydride and acetic acid, represented by the general formula (II):

(Wherein R ¹ , R ² and Pro are as defined above)
Or a solvate thereof, or a salt thereof. The production method according to claim 15, wherein R ¹ is 2-biphenylmethyl, R ² is isobutyl, and the protecting group is t-butyloxycarbonyl.

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