JPWO2016035847A1 - Intermediate of cephalosporin derivative and method for producing the same - Google Patents

Abstract

According to the present invention, a compound of formula (IV): (wherein R1 is an amino-protecting group; R2 and R3 are each independently a carboxy-protecting group), and a pharmaceutically acceptable salt thereof Or a solvate thereof, or a crystal thereof, a production method thereof, and a novel production method of a useful cephem compound using the formula (IV).

Description

  The present invention relates to an intermediate of a cephalosporin derivative and a method for producing the same.

で表されるカテコール基を有するセファロスポリン誘導体（以下、化合物（Ｉ）という）が広範な抗菌スペクトルを有し、特にβ−ラクタマーゼ産生菌に対し強い抗菌活性を示すため、感染症の治療および／または予防剤として有用であることが記載されている。またその実施例１２には、以下の化合物：

（以下、化合物（ＩＡ）という）が開示されている。化合物（ＩＡ）については、その具体的な合成法は記載されていないが、以下に示す一般的合成法または類似化合物の具体的な合成法に準じて合成されている。In Patent Document 1, the following formula:

Since the cephalosporin derivative (hereinafter referred to as Compound (I)) having a catechol group represented by the formula has a broad antibacterial spectrum and exhibits a strong antibacterial activity particularly against β-lactamase producing bacteria, It is described that it is useful as a preventive agent. Also included in Example 12 are the following compounds:

(Hereinafter referred to as Compound (IA)). The compound (IA) is synthesized according to a general synthesis method shown below or a specific synthesis method of an analogous compound, although a specific synthesis method thereof is not described.

Patent Document 1 describes the following scheme as a general synthesis method of compound (I).

が開示されているが、セフェム母核１位のスルホキシド基はラセミ形で記載されており、Ｒ体またはＳ体の光学活性体に関する記載はない。また、特許文献２〜４、および６には、化合物：

およびその合成法が開示されているが、いずれも１位のスルホキシド基はラセミ形で記載されており、光学活性体に関する記載はない。
さらに、特許文献４および７には、式：

で示されるＳ体の化合物が開示されているが、いずれも結晶ではなく、さらに結晶に関する記載はない。また、特許文献４には上記Ｓ体の化合物の製造方法の記載はあるが、本願発明の製法は記載されていない。さらに、Ｓ体やその利点に関する記載はない。Patent Document 1 discloses Compound 9 corresponding to Compound (IX) above:

However, the sulfoxide group at the 1-position of the cephem nucleus is described in a racemic form, and there is no description regarding the optically active form of R-form or S-form. Patent Documents 2 to 4 and 6 include compounds:

In addition, the sulfoxide group at the 1-position is described in a racemic form, and there is no description regarding the optically active substance.
Further, Patent Documents 4 and 7 include the formula:

Are disclosed, but none of them are crystals, and there is no description about crystals. Further, Patent Document 4 describes a method for producing the above S-form compound, but does not describe the production method of the present invention. Furthermore, there is no description regarding the S body and its advantages.

International Publication No. 2010/050468 International Publication No. 2011-125966 International Publication No. 2011/125967 International Publication No. 2013/052568 European Patent Publication No. 416410 European Patent Publication No. 409164 International Publication No. 2014/069649

  Development of an industrially efficient production method of cephalosporin derivatives such as compound (IA) has been demanded. In addition, it was necessary to develop a useful intermediate and a production method thereof.

  As a result of intensive studies in view of the above problems, the present inventors have examined various reaction conditions, particularly in the production method of the 1-position sulfoxide S form of the cephem mother nucleus, the formation of the 3-position side chain, and the reduction of the sulfoxide S form. As a result, it was found that the selectivity and yield of the reaction, the continuous reaction, the reaction near room temperature, the purification by crystallization and the like could be achieved, and the following inventions were found.

（式中、Ｒ^１はアミノ基の保護基；Ｒ^２およびＲ^３はそれぞれ独立してカルボキシ基の保護基である。）
で示される化合物、その製薬上許容される塩、またはそれらの溶媒和物。
（項目２）
Ｒ^１がｔ−ブトキシカルボニル基であり、Ｒ^２がｔ−ブチル基であり、Ｒ^３がｐ−メトキシベンジル基である、項目１記載の結晶。
（項目３）
粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：４．３±０．２°、１０．９±０．２°、１４．５±０．２°、１８．３±０．２°および２１．２±０．２°から選択される少なくとも３本のピークを有する、項目２記載のメタノール和物の結晶。
（項目４）
粉末Ｘ線回折スペクトルにおいて、回折角度（２θ）：４．８±０．２°、１４．４±０．２°、１４．９±０．２°、１６．０±０．２°および２０．５±０．２°から選択される少なくとも３本のピークを有する、項目２記載の無溶媒和物の結晶。
（項目５）
以下の工程：
（第２工程）
式（Ｖ）：

（式中、Ｒ^１はアミノ基の保護基；Ｒ^２およびＲ^３はそれぞれ独立してカルボキシ基の保護基である。）
で示される化合物と過酸を溶媒中で反応させ式（ＩＶ）：

（式中、Ｒ^１，Ｒ^２およびＲ^３は、前記と同意義）
で示される化合物を得る工程（ただし、溶媒がジクロロメタンのみである場合を除く）
を包含することを特徴とする、化合物（ＩＶ）、その製薬上許容される塩、またはそれらの溶媒和物の製造方法。
（項目６）
該過酸が過酢酸である、項目５記載の製造方法。
（項目７）
以下の工程：
（第１工程）式（ＶＩ）：

（式中、Ｒ^３はカルボキシ基の保護基である）
で示される化合物と式（ＶＩＩ）：

（式中、各記号は前記と同意義）
で示される化合物を反応させ、式（Ｖ）：

（式中、各記号は前記と同意義）
で示される化合物を得る工程、および
（第２工程）
式（Ｖ）で示される化合物を過酸と反応させ化合物（ＩＶ）を得る工程を、連続して行うことを特徴とする、式（ＩＶ）：

（式中、各定義は前記と同意義）
で示される化合物、その製薬上許容される塩またはそれらの溶媒和物、もしくはそれらの結晶の製造方法。
（項目８）
以下の工程：
（第３工程）
式（ＩＶ）：

（式中、各記号は前記と同意義）
で示される化合物と式（Ｘ）：

（式中、Ｒ^４およびＲ^５はそれぞれ独立して水酸基の保護基である。）
を、ホウ酸またはボロン酸存在下で反応させ式（ＩＩＩ）：

（式中、X-はカウンターイオン、その他の記号は前記と同意義）
で示される化合物を得る工程、
を包含することを特徴とする、化合物（ＩＩＩ）、その製薬上許容される塩、またはそれらの溶媒和物の製造方法。
（項目９）
以下の工程：
（第４工程）
式（ＩＩＩ）：

（式中、各記号は前記と同意義）
で示される化合物を還元して式（ＩＩ）：

（式中、各記号は前記と同意義）
で示される化合物を得る工程、
を包含することを特徴とする、化合物（ＩＩ）、その製薬上許容される塩、またはそれらの溶媒和物の製造方法。
（項目１０）
以下の工程：
（第４工程）
式（ＩＩＩ）：

（式中、各記号は前記と同意義）
で示される化合物を還元し、式（ＩＩ）：

（式中、各記号は前記と同意義）
で示される化合物を得る工程、および
（第５工程）
式（ＩＩ）で示される化合物を脱保護して式（ＩＡ）：

で示される化合物を得る工程、を連続して行うことを特徴とする、
化合物（ＩＡ）、その製薬上許容される塩、またはそれらの溶媒和物の製造方法。
（項目１１）
以下の工程：
（第３工程）化合物（ＩＶ）と化合物（Ｘ）をホウ酸またはボロン酸存在下で反応させ化合物（ＩＩＩ）を得る工程；
（第４工程）化合物（ＩＩＩ）を還元し化合物（ＩＩ）を得る工程；および
（第５工程）化合物（ＩＩ）を脱保護して化合物（ＩＡ）を得る工程；
を包含することを特徴とする、項目１０記載の化合物（ＩＡ）、その製薬上許容される塩またはそれらの溶媒和物の製造方法。
（項目１２）
以下の工程：
（第２工程）化合物（Ｖ）と過酸を反応させ化合物（ＩＶ）を得る工程；
（第３工程）化合物（ＩＶ）と化合物（Ｘ）をホウ酸またはボロン酸存在下で反応させ化合物（ＩＩＩ）を得る工程；
（第４工程）化合物（ＩＩＩ）を還元し化合物（ＩＩ）を得る工程；および
（第５工程）化合物（ＩＩ）を脱保護して化合物（ＩＡ）を得る工程；
を包含することを特徴とする項目１０記載の化合物（ＩＡ）、その製薬上許容される塩またはそれらの溶媒和物の製造方法。
（項目１３）
式（ＩＩＩ）：

（式中、各記号は前記と同意義）
で示される化合物。
（項目１４）
式（ＩＩ）：

（式中、各定記号は前記と同意義）
で示される化合物。
（項目１５）
Ｒ^１はｔ−ブトキシカルボニル基である、項目１〜４、１３または１４のいずれかに記載の化合物またはその溶媒和物の結晶。
（項目１６）
Ｒ^１はｔ−ブトキシカルボニル基である、項目５〜１２のいずれかに記載の製造方法。
（項目１７）
Ｒ^２はｔ−ブチル基である、項目１〜４、１３または１４のいずれかに記載の化合物またはその溶媒和物の結晶。
（項目１８）
Ｒ^２はｔ−ブチル基である、項目５〜１２のいずれかに記載の製造方法。
（項目１９）
Ｒ^３はｐ−メトキシベンジル基またはベンズヒドリル基である、項目１〜４、１３または１４のいずれかに記載の化合物またはその溶媒和物。
（項目２０）
Ｒ^３はｐ−メトキシベンジル基またはベンズヒドリル基である、項目５〜１２のいずれかに記載の製造方法。
（項目２１）
Ｒ^４およびＲ^５はｐ−メトキシベンジル基である、項目１３または１４記載の化合物。
（項目２２）
Ｒ^４およびＲ^５はｐ−メトキシベンジル基である、項目８〜１２のいずれかに記載の製造方法。(Item 1)
Crystalline, formula (IV):

(In the formula, R ¹ is an amino-protecting group; R ² and R ³ are each independently a carboxy-protecting group.)
Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 2)
The crystal according to item 1, wherein R ¹ is a t-butoxycarbonyl group, R ² is a t-butyl group, and R ³ is a p-methoxybenzyl group.
(Item 3)
In powder X-ray diffraction spectrum, diffraction angle (2θ): 4.3 ± 0.2 °, 10.9 ± 0.2 °, 14.5 ± 0.2 °, 18.3 ± 0.2 ° and 21 3. Crystal of methanol solvate according to item 2, having at least 3 peaks selected from 2 ± 0.2 °.
(Item 4)
In powder X-ray diffraction spectrum, diffraction angles (2θ): 4.8 ± 0.2 °, 14.4 ± 0.2 °, 14.9 ± 0.2 °, 16.0 ± 0.2 ° and 20 3. Solvate-free crystals according to item 2, having at least three peaks selected from 5 ± 0.2 °.
(Item 5)
The following steps:
(Second step)
Formula (V):

(In the formula, R ¹ is an amino-protecting group; R ² and R ³ are each independently a carboxy-protecting group.)
A compound represented by formula (IV) is reacted with a peracid in a solvent:

(Wherein R ¹ , R ² and R ³ are as defined above)
Step for obtaining the compound represented by (except when the solvent is only dichloromethane)
A process for producing compound (IV), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 6)
Item 6. The method according to Item 5, wherein the peracid is peracetic acid.
(Item 7)
The following steps:
(First Step) Formula (VI):

(Wherein R ³ is a protecting group for a carboxy group)
And a compound of formula (VII):

(Wherein each symbol is as defined above)
And a compound of formula (V):

(Wherein each symbol is as defined above)
And (second step) to obtain a compound represented by
The step of obtaining a compound (IV) by reacting a compound represented by the formula (V) with a peracid is continuously carried out:

(Wherein each definition is as defined above)
Or a pharmaceutically acceptable salt thereof, a solvate thereof, or a crystal thereof.
(Item 8)
The following steps:
(Third step)
Formula (IV):

(Wherein each symbol is as defined above)
And a compound of formula (X):

(In the formula, R ⁴ and R ⁵ are each independently a hydroxyl-protecting group.)
Is reacted in the presence of boric acid or boronic acid to give the formula (III):

(In the formula, X- is a counter ion, and other symbols are as defined above.)
Obtaining a compound represented by:
A process for producing compound (III), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 9)
The following steps:
(4th process)
Formula (III):

(Wherein each symbol is as defined above)
To reduce the compound of formula (II):

(Wherein each symbol is as defined above)
Obtaining a compound represented by:
A process for producing compound (II), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 10)
The following steps:
(4th process)
Formula (III):

(Wherein each symbol is as defined above)
The compound represented by formula (II):

(Wherein each symbol is as defined above)
A step of obtaining a compound represented by formula (5)
The compound of formula (II) is deprotected to give formula (IA):

A step of obtaining a compound represented by:
A method for producing compound (IA), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 11)
The following steps:
(Step 3) A step of reacting compound (IV) with compound (X) in the presence of boric acid or boronic acid to obtain compound (III);
(Step 4) Step of reducing Compound (III) to obtain Compound (II); and (Step 5) Step of deprotecting Compound (II) to obtain Compound (IA);
The manufacturing method of the compound (IA) of item 10, pharmaceutically acceptable salt, or those solvates characterized by including these.
(Item 12)
The following steps:
(Second Step) A step of reacting compound (V) with peracid to obtain compound (IV);
(Step 3) A step of reacting compound (IV) with compound (X) in the presence of boric acid or boronic acid to obtain compound (III);
(Step 4) Step of reducing Compound (III) to obtain Compound (II); and (Step 5) Step of deprotecting Compound (II) to obtain Compound (IA);
Item 10. A method for producing a compound (IA) according to Item 10, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 13)
Formula (III):

(Wherein each symbol is as defined above)
A compound represented by
(Item 14)
Formula (II):

(Wherein the constant symbols are as defined above)
A compound represented by
(Item 15)
The crystal | crystallization of the compound or its solvate in any one of the items 1-4, 13 or 14 whose R < ¹ > is t-butoxycarbonyl group.
(Item 16)
13. The production method according to any one of items 5 to 12, wherein R ¹ is a t-butoxycarbonyl group.
(Item 17)
The crystal | crystallization of the compound or its solvate in any one of the items 1-4, 13 or 14 whose R < ² > is t-butyl group.
(Item 18)
The production method according to any one of Items 5 to 12, wherein R ² is a t-butyl group.
(Item 19)
R ³ is p- methoxybenzyl group or a benzhydryl group, the compound or a solvate thereof according to any of items 1～4,13 or 14.
(Item 20)
The production method according to any one of Items 5 to 12, wherein R ³ is a p-methoxybenzyl group or a benzhydryl group.
(Item 21)
R ⁴ and ^{R 5} are p- methoxybenzyl group, item 13 or 14 compound as described.
(Item 22)
The production method according to any one of Items 8 to 12, wherein R ⁴ and R ⁵ are p-methoxybenzyl groups.

The present invention provides a synthetic intermediate useful for industrial production of various cephalosporin derivatives and a method for producing the same. Moreover, by using them, especially a compound (IA) can be manufactured with sufficient yield, simply, safely, and efficiently.

The powder X-ray-diffraction spectrum of the methanol solvate crystal | crystallization of compound (IV) obtained in Example 3 is shown. The horizontal axis represents the diffraction angle 2θ (°), and the vertical axis represents the intensity (Count). The powder X-ray-diffraction spectrum of the solvate-free crystal | crystallization of compound (IV) obtained in Example 3 is shown.

（式中、各記号は前記と同意義）The production method of the present invention is shown in the following scheme.
In the present specification, reacting a compound with a compound includes reacting a salt thereof or a solvate thereof. In addition, the following reaction may be performed “continuously in the process” without isolation. Performing “steps continuously” includes performing the next step without isolating the compound produced by the reaction of the previous step. For example, performing two processes by one pot is mentioned.

(Wherein each symbol is as defined above)

(First step)
Compound (VIII) is obtained by reacting compound (VII) with mesyl chloride, optionally in the presence of a base.
The base is not particularly limited as long as it allows the above process to proceed efficiently. An inorganic base such as an organic base or an inorganic carbonate can be used. Preferably, an organic base can be used. For example, triethylamine, pyridine, dimethylaminopyridine, diazabicycloundecene, 1,8-bis (dimethylamino) naphthalene, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Triethylamine is preferred.
What is necessary is just to make a base react using about 1-2 molar equivalent with respect to compound (VII).
The reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently. For example, amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone), acetate solvents (eg, ethyl acetate, Propyl acetate, etc.), hydrocarbon solvents (eg, toluene, benzene, hexane, etc.), ether solvents (eg, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, etc.), nitrile solvents ( Examples: One or more selected from acetonitrile, propionitrile, etc., halogen solvents (eg, dichloromethane, chloroform, etc.), ketone solvents (eg, acetone, methyl ethyl ketone, etc.), dimethyl sulfoxide, etc. can be used. An amide solvent is preferred, and N, N-dimethylacetamide is more preferred.
The reaction temperature is not particularly limited, but is usually about -20 to 100 degrees, preferably about -10 to 0 degrees.
The reaction time is not particularly limited, but is usually 0.5 to 20 hours, preferably about 0.5 to 2 hours.
The ratio of mesyl chloride used is preferably about 1 to 5 molar equivalents, more preferably about 1 to 1.5 molar equivalents, relative to compound (VII). Mesyl chloride may be added all at once or dropwise.
The obtained compound (VIII) may be used in the next step without isolation.

(First step)
Compound (V) is obtained by reacting compound (VI) with compound (VIII), optionally in the presence of a base.
What is necessary is just to perform the said reaction according to the conditions of normal amidation reaction.
The base is not particularly limited as long as it allows the above process to proceed efficiently. An inorganic base such as an organic base or an inorganic carbonate can be used. Preferably, an organic base can be used. For example, triethylamine, pyridine, dimethylaminopyridine, diazabicycloundecene, 1,8-bis (dimethylamino) naphthalene, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. N-methylmorpholine is preferred.
What is necessary is just to make a base react using about 1-5 molar equivalent with respect to compound (VII). Preferably, it is about 1-2 molar equivalent.
The reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently. For example, amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone), acetate solvents (eg, ethyl acetate, Propyl acetate, etc.), hydrocarbon solvents (eg, toluene, benzene, hexane, etc.), ether solvents (eg: cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.), nitriles One or more selected from a solvent (eg, acetonitrile, propionitrile, etc.), a halogen solvent (eg, dichloromethane, chloroform, etc.), a ketone solvent (eg, acetone, methyl ethyl ketone, etc.), dimethyl sulfoxide, etc. can be used. An amide solvent, an acetate ester solvent or a nitrile solvent is preferable, and N, N-dimethylacetamide, ethyl acetate or acetonitrile is particularly preferable. More preferably, it is a mixed solvent of N, N-dimethylacetamide and acetonitrile.
The reaction temperature is not particularly limited, but is usually about -20 to 100 degrees, preferably about -10 to 0 degrees.
The reaction time is not particularly limited, but is usually 0.5 to 20 hours, preferably about 0.5 to 2 hours.
The ratio of compound (VIII) to be used is preferably about 0.8 to 5 molar equivalents, more preferably about 0.8 to 1.5 molar equivalents, relative to compound (VI).
The obtained compound (V) may be used in the next step without isolation.

(Second step)
By reacting compound (V) with a peracid, compound (IV) which is the S form of 1-sulfoxide is obtained.
The reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently. For example, alcohol solvents (eg, methanol, ethanol, isopropanol, etc.), amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolide Non-acetate), acetate solvents (eg, ethyl acetate, propyl acetate, etc.), hydrocarbon solvents (eg, toluene, benzene, hexane, etc.), ether solvents (eg: cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran) , 1,2-dimethoxyethane, anisole, etc.), nitrile solvents (eg, acetonitrile, propionitrile, etc.), halogen solvents (eg, dichloromethane, chloroform, etc.), ketone solvents (eg, acetone, methyl ethyl ketone, etc.), Select from dimethyl sulfoxide, water, etc. It can be used at least one element. The solvent can be used as a two-layer solvent with water or a water-containing solvent as necessary. A halogen solvent, a nitrile solvent, an amide solvent or a mixed solvent of a nitrile solvent and an amide solvent is preferable. More preferred is dichloromethane, acetonitrile, N-methylpyrrolidone or N, N-dimethylacetamide. More preferably, it is acetonitrile or a mixed solvent of acetonitrile and N, N-dimethylacetamide or N-methylpyrrolidone. The ratio of the mixed solvent (acetonitrile: N, N-dimethylacetamide or N-methylpyrrolidone) is preferably 5: 1 to 5: 5, more preferably 5: 4 to 5: 5. When acetonitrile is used as the solvent, S-isomer selectivity can be improved.
The reaction temperature is not particularly limited, but is preferably about -80 to 10 degrees, more preferably about -40 to 0 degrees, and still more preferably about -10 to 0 degrees. The reaction temperature is preferably lower from the viewpoint of the selectivity of the S form, but can be set to an industrially controllable temperature (for example, about −10 to 0 degrees), for example, by selecting a solvent.
The reaction time is not particularly limited, but is preferably about 0.5 to 10 hours, more preferably about 1 to 3 hours.

Examples of the peracid include metachloroperbenzoic acid (mCPBA), perbenzoic acid, peracetic acid, aqueous hydrogen peroxide, magnesium monoperoxyphthalate hexahydrate, and the like. Peracetic acid is preferred. Moreover, when adding a peracid, it is preferable to melt | dissolve a peracid in a solvent as needed and to drop. By dropping, the peracid can be reacted with the compound (V) at the same time as dropping, and the reaction heat can be controlled safely, so that dangers such as explosion during mass production can be avoided.
The use ratio of the peracid is preferably about 1 to 2 molar equivalents, more preferably about 1 to 1.2 molar equivalents, relative to compound (V).
In order to improve reaction efficiency and yield, additives other than peracid may be added as necessary. Examples of the additive include nitric acid, sulfuric acid, 3,5-dihydroxybenzoic acid, 2-methyl-2-butene, resorcinol, sulfamic acid and the like. Preferred additives include sulfuric acid and 3,5-dihydroxybenzoic acid.
By this reaction, the 1-position of the cephem skeleton is selectively converted to S-form sulfoxide. The conversion rate of the S form is preferably about 80% or more, more preferably 85% or more, still more preferably about 90% or more, and particularly preferably about 93% or more. The compound (IV) obtained as a high proportion of S form may be used in the next step without isolation, but is preferably isolated as a salt, solvate or crystal thereof. If desired, an extremely high purity S form can be obtained by purification by such a method as crystallization.

The crystallization method (method for transitioning to a supersaturated state) is not particularly limited, and for example, an evaporation method (a method for evaporating a crystallization solvent from a crystallization system), a cooling method (a crystallization system (or compound (IV) solution) Cooling method), poor solvent addition method (method of adding poor solvent of compound (IV) to crystallization system), seed crystal addition method (method of adding seed crystal containing compound (IV) to crystallization system) Etc. can be exemplified.
For example, an evaporation method (a crystallization system (or solution) containing a compound (IV) and a crystallization solvent is used to evaporate the crystallization solvent to a supersaturated state and crystallize from this supersaturated state) or a cooling method (compound) After cooling the crystallization system (or solution) containing (IV) and the crystallization solvent to a supersaturated state and crystallizing from this supersaturated state), a seed crystal obtained from the compound (IV) is obtained. It can be crystallized by a seed crystal addition method in which a seed crystal is added to a solution dissolved in a crystallization solvent and / or an acid for crystallization.
As the crystallization solvent, an alcohol solvent (eg, methanol, ethanol, isopropanol, etc.) or a mixed solvent of an alcohol solvent and water can be used. Preferably, it is methanol, ethanol, or a mixed solvent thereof with water. Depending on the solvent used, the corresponding solvate crystals can also be obtained. The obtained solvate can also be converted into a solvate by natural drying, ventilation drying or drying under reduced pressure. The drying temperature may be, for example, room temperature to warming, preferably 20 to 60 degrees. The drying time may be, for example, about 0.5 to 48 hours, preferably about 0.5 to 24 hours (for example, 2 to 18 hours). Since R-form and S-form of 1-sulfoxide have a difference in solubility in various solvents, the S-form has an improved isolation yield of 1-sulfoxide by crystallization or the like compared to the R-form. In addition, since the S-form has higher stability such as storage stability than the R-form, it can be stably stored as an intermediate for a long period of time by increasing the purity of the S-form. . In addition, S-form crystals have higher stability such as storage stability and coloring stability than S-form amorphous bodies, and the generation of decomposition products is also suppressed.
Further, in the reaction of the next step, the yield of compound (III) is preferably improved by about 10% or more by using S form rather than R form of 1-sulfoxide.
Therefore, the crystal of compound (IV) which is the S form of 1-sulfoxide of the present invention is very useful as an industrial intermediate.

(Third step)
Compound (III) is obtained by reacting compound (IV) with compound (X). Compound (III) is also an S form of 1-sulfoxide.
The reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently. Amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, etc.), acetate solvents (eg, ethyl acetate, propyl acetate) Etc.), hydrocarbon solvents (eg, toluene, benzene, hexane, etc.), ether solvents (eg: cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.), nitrile solvents ( Examples: One or more selected from acetonitrile, propionitrile, etc., halogen solvents (eg, dichloromethane, chloroform, etc.), ketone solvents (eg, acetone, methyl ethyl ketone, etc.), dimethyl sulfoxide, etc. can be used. Amide solvents or ether solvents are preferred. Among these, N, N-dimethylacetamide, N-methylpyrrolidone or tetrahydrofuran is preferable, and N-methylpyrrolidone is more preferable.
The reaction temperature is not particularly limited, but is usually about 0 to 100 degrees, preferably about -5 to 15 degrees.
The reaction time is not particularly limited, but is usually about 0.5 to 36 hours, preferably about 3 to 24 hours.

This reaction may be carried out in the presence of an alkali metal halide (for example, an alkali metal iodide (eg, NaI, KI, etc.), an alkali metal bromide (eg, NaBr, KBr, etc.), if necessary. Good. Preferred is an alkali metal iodide. Since the reaction efficiency is improved by adding an alkali metal halide, the reaction time, the reagent used, and the yield can be improved.
The use ratio of the alkali metal halide is preferably about 1 to 5 molar equivalents, more preferably about 1 to 3 molar equivalents, relative to compound (IV).
This reaction is preferably a boronic acid (: R—B (OH) ₂ ) which is boric acid or a derivative thereof; R is a substituent such as alkyl, substituted or unsubstituted carbocycle, substituted or unsubstituted heterocycle ), The yield is improved by, for example, about 5% or more.
The carbocycle or heterocycle is preferably a 3- to 10-membered ring, more preferably a 5- to 6-membered ring. The carbocyclic or heterocyclic ring may be a saturated ring or an unsaturated ring. Examples of the substituent of the carbocycle or heterocyclic ring include lower alkyl (eg, methyl, ethyl, isopropyl, t-butyl), halo lower alkyl (eg, trifluoromethyl, chloromethyl), halogen (eg, fluorine, chlorine) , Hydroxy, carboxy, amino, lower alkoxy (eg, methoxy, ethoxy, t-butoxy), cyano, nitro, sulfamoyl, imino, hydroxyimino, carbamoyl, lower alkylcarbamoyl (eg, methylcarbamoyl, dimethylcarbamoyl), acyl (eg, : Acetyl, benzoyl).
The ratio of boric acid or boronic acid to be used is preferably about 0.1 to 0.4 molar equivalent, more preferably about 0.1 to 0.3 molar equivalent, relative to compound (IV).
The obtained compound (III) may be used in the next step without isolation.

(4th process)
Compound (II) is obtained by reducing compound (III).
The reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently. Amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, etc.), acetate solvents (eg, ethyl acetate, propyl acetate) Etc.), hydrocarbon solvents (eg, toluene, benzene, hexane, etc.), ether solvents (eg: cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.), nitrile solvents ( Examples: One or more selected from acetonitrile, propionitrile, etc., halogen solvents (eg, dichloromethane, chloroform, etc.), ketone solvents (eg, acetone, methyl ethyl ketone, etc.) and the like can be used. Amide solvents are preferred. Among these, N, N-dimethylacetamide or N-methylpyrrolidone is preferable, and N-methylpyrrolidone is more preferable.
The reaction temperature is not particularly limited, but is usually about −40 ° C. to about 30 ° C., preferably about −10 to 10 ° C.
The reaction time is not particularly limited, but is usually about 1 to 10 hours, preferably about 1 to 5 hours.
Examples of the reducing agent include phosphorus trichloride, phosphorus tribromide, acetyl chloride and sodium iodide, sodium borohydride, iodine and the like, preferably phosphorus trichloride or phosphorus tribromide. The reducing agent is preferably dissolved in a solvent and added dropwise as necessary. By dropping, peracid can be reacted with compound (III) at the same time as dropping, and the reaction heat can be controlled safely, so that dangers such as explosion during mass production can be avoided.

(5th process)
By removing each protecting group of compound (II), compound (IA), a pharmaceutically acceptable salt thereof, or a solvate thereof can be obtained.
The reaction may be performed according to conditions for each deprotection reaction of amino group, hydroxy group or carboxy group well known to those skilled in the art. Each protecting group may be sequentially deprotected. However, it is preferable that deprotection is sequentially performed without going through an isolation step in a one-pot reaction, or all protecting groups may be removed in one reaction.
The reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently. Acetic ester solvents (eg, ethyl acetate, propyl acetate, etc.), hydrocarbon solvents (eg, toluene, benzene, hexane, etc.), ether solvents (eg, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2 -Dimethoxyethane, anisole, etc.), halogen solvents (eg, dichloromethane, chloroform, etc.), ketone solvents (eg, acetone, methyl ethyl ketone, etc.) and the like can be used. As the solvent, a two-layer solvent with water or a water-containing solvent can be used as necessary. Ketone solvents and / or ether solvents are preferred. Of these, anisole and methyl ethyl ketone are preferable, and a mixed solvent of anisole and methyl ethyl ketone is more preferable.
The reaction temperature is not particularly limited, but is usually about -10 to 30 degrees, preferably about 10 to 20 degrees.
The reaction time is not particularly limited, but is usually about 0.5 to 5 hours, preferably about 0.5 to 2 hours.

Examples of the deprotecting reagent include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like. Preferably, it is sulfuric acid.
Examples of protecting groups (amino protecting group, hydroxy protecting group, carboxy protecting group and the like) that can be used in the above reaction include Protective Groups in Organic Synthesis, T. et al. W. By Greene, John Wiley & Sons Inc. (1991) and the like. The introduction and removal of protecting groups are carried out in accordance with methods commonly used in organic synthetic chemistry (for example, see Protective Groups in Organic Synthesis, TW Greene, John Wiley & Sons Inc. (1991)) and the like. It can be carried out.
The reaction solution containing the obtained compound (IA) may be post-treated or purified according to methods well known to those skilled in the art. Preferably, the crude product containing the compound (IA) is subjected to column treatment with a mobile phase (for example, acetonitrile-water or the like, and optionally an acid such as formic acid, acetic acid, hydrochloric acid, sulfuric acid, etc. may be added). The eluate containing the resulting compound (IA) is optionally concentrated, crystallized, etc. to give an acid addition salt (eg, hydrochloride, sulfate, p-toluenesulfonate, or a mixed salt thereof) ) May be isolated. The acid addition salt may be a crystal such as a hydrate. The acid addition salt may be converted to an alkali metal salt (eg, sodium salt) by a salt exchange reaction. That is, for example, a sodium source such as an aqueous sodium hydroxide solution or sodium bicarbonate is added to a solution containing the acid addition salt of compound (IA) or a hydrate thereof, the pH is adjusted to about 5 to 6.5, concentrated under reduced pressure, and The sodium salt of compound (IA) can be obtained by lyophilization.

Examples of the pharmaceutically acceptable salt include acid addition salts and metal salts. The acid of the acid addition salt is selected from, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, citric acid, tartaric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, or these acids. Examples include mixed acid of seeds. Examples of the metal salt include sodium salt, potassium salt, calcium salt, magnesium salt and the like.
Examples of solvates include hydrates and acetonitrile solvates.

As the amino protecting group, various amino protecting groups that can be generally used in the field of β-lactam antibacterial agents can be used. Specific examples thereof include t-butyldimethylsilyl group, benzyloxycarbonyl group, t-butoxycarbonyl group, allyl group, 9-fluorenylmethyloxycarbonyl group, benzyl group, p-methoxybenzyl group, methoxymethyl group, Examples include benzyloxymethyl group, benzhydryl group, trityl group and the like. R ¹ is preferably a t-butoxycarbonyl group or a benzyloxycarbonyl group, more preferably a t-butoxycarbonyl group.

As the hydroxy protecting group, various hydroxy protecting groups that can be generally used in the field of β-lactam antibacterial agents can be used. Specific examples thereof include benzyl group, p-methoxyphenylbenzyl group, p-methoxybenzyl group, acetyl group, formyl group, benzoyl group, chloroacetyl group, pivaloyl group, methyl carbonate group, isobutyl carbonate group, benzyl carbonate group, Vinyl carbonate group, phenyl carbonate group, mesyl group, tosyl group, trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, methoxymethyl group, benzyloxymethyl group, methoxyethoxymethyl group, 2- (trimethylsilyl) ethoxymethyl group, Examples include propenyl group, phenacyl group, tetrahydropyranyl group, prenyl group and the like. R ⁴ and R ⁵ are preferably each independently a p-methoxybenzyl group or a prenyl group, and more preferably a p-methoxybenzyl group.

As the carboxy protecting group, various carboxy protecting groups that can be generally used in the field of β-lactam antibacterial agents can be used. Specific examples thereof include lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl), lower alkanoyloxy (lower) alkyl, (eg, acetoxymethyl, propionyloxymethyl, Butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, hexanoyloxymethyl), lower alkanesulfonyloxy (lower) alkyl (eg 2-mesylethyl), mono (or di or tri) halo (lower) alkyl (Example: 2-iodoethyl, 2,2,2-trichloroethyl), lower alkoxycarbonyloxy (lower) alkyl (Example: methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, t-butoxycarbonyloxy) Methyl, 1- (or 2-) methoxycarbonyloxyethyl), lower alkenyl (eg vinyl, allyl), lower alkynyl (eg ethynyl, propynyl), (substituted) aryl (lower) alkyl (eg benzyl, p- Methoxybenzyl, p-nitrobenzyl, phenethyl, trityl, benzhydryl, bis (methoxyphenyl) methyl, 3,4-dimethoxybenzyl, 4-hydroxy-3,5-dit-butylbenzyl), (substituted) aryl (example: Phenyl, p-chlorophenyl, tolyl, t-butylphenyl, xylyl). R ² and R ³ are preferably each independently a t-butyl group, a p-methoxybenzyl group, or a benzhydryl group. More preferably, R ² is a t-butyl group, R ³ is a p-methoxybenzyl group or a benzhydryl group, and more preferably, R ³ is a p-methoxybenzyl group.

Furthermore, the present invention provides a crystal of compound (IV) wherein R ¹ = t-butoxycarbonyl, R ² = t-butyl, R ³ = p-methoxybenzyl. The crystals are preferably methanol solvate, methanol-hydrate, hydrate or solvate-free. The crystals preferably exhibit the powder X-ray pattern shown below.
Diffraction angle (2θ): 4.3 ± 0.2 °, 10.9 ± 0.2 °, 12.7 ± 0.2 °, 14.5 ± 0.2 °, 16.2 ± 0.2 ° , 18.0 ± 0.2 °, 18.3 ± 0.2 °, 21.2 ± 0.2 °, 25.6 ± 0.2 ° and 26.5 ± 0.2 ° It has 3 peaks.
Preferably, diffraction angle (2θ): 4.3 ± 0.2 °, 10.9 ± 0.2 °, 14.5 ± 0.2 °, 18.3 ± 0.2 ° and 21.2 ± 0 . At least three peaks selected from 2 °.
The crystal showing the pattern is preferably a methanol solvate.
Or diffraction angle (2θ): 4.8 ± 0.2 °, 14.1 ± 0.2 °, 14.4 ± 0.2 °, 14.9 ± 0.2 °, 16.0 ± 0. Selected from 2 °, 17.1 ± 0.2 °, 17.6 ± 0.2 °, 20.5 ± 0.2 °, 25.2 ± 0.2 ° and 33.1 ± 0.2 ° At least three peaks.
Preferably, diffraction angle (2θ): 4.8 ± 0.2 °, 14.4 ± 0.2 °, 14.9 ± 0.2 °, 16.0 ± 0.2 ° and 20.5 ± 0 . At least three peaks selected from 2 °.
The crystal showing the above pattern is preferably a solvate.

The method for specifying the crystal of the present invention will be described below.
Unless otherwise stated, the numerical values described in the specification and claims are approximate values. Numerical fluctuations are due to instrument calibration, instrument error, substance purity, crystal size, sample size, and other factors.

  In general, since the diffraction angle (2θ) in powder X-ray diffraction may cause an error within a range of ± 0.2 °, the above diffraction angle value includes a numerical value within a range of about ± 0.2 °. Need to be understood. Therefore, the present invention includes not only a crystal in which the diffraction angle of the peak in powder X-ray diffraction completely matches but also a crystal in which the diffraction angle of the peak matches with an error of about ± 0.2 °.

In general, the absolute and relative intensities of the peaks shown in the tables and figures below are a number of factors, such as the effect of selective orientation of the crystal on the x-ray beam, the influence of coarse particles, the purity of the substance being analyzed or the sample. It is known that it can vary depending on the degree of crystallinity. The peak position can also be shifted based on the variation in sample height. Furthermore, although different shifts are obtained according to the Bragg equation (nλ = 2dsin θ) when measured using different wavelengths, other XRPD patterns obtained by using such different wavelengths are also within the scope of the present invention.
A characteristic diffraction peak as used herein is a peak selected from the observed diffraction pattern. In distinguishing a plurality of crystals, a peak that is seen in the crystal and not seen in other crystals is a preferable characteristic peak for specifying the crystal, rather than the size of the peak. With such characteristic peaks, even one or two peaks can characterize the crystal.

  In the present specification, the diffraction peak may be one sharp peak (singlet shape), one gentle peak (broad shape), or about 2 to 5 multiple peaks (tablet). Shape, triplet shape, quartet shape, quintet shape), etc., but usually one sharp peak in many cases.

The invention is further illustrated by the following examples. These do not limit the invention. Efforts are being made to ensure accuracy with respect to numbers (eg, amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless otherwise indicated,% is the weight percent of the component and the weight percent of the total weight of the composition, and equivalent means the molar equivalent of the component. The pressure is at or near atmospheric pressure. Other abbreviations used herein are defined as follows:
(Abbreviation):
Boc: t-butoxycarbonyl DMA: N, N-dimethylacetamide DMF: N, N-dimethylformamide DMSO: dimethyl sulfoxide NMP: N-methylpyrrolidone PMB: p-methoxybenzyl

The NMR analysis obtained in the examples was performed at 300 MHz or 400 MHz and measured using DMSO-d ₆ , CDCl ₃ or the like.

(Measurement of powder X-ray diffraction pattern)
The powder X-ray diffraction measurement of the crystals obtained in each Example was performed under the following measurement conditions in accordance with the powder X-ray diffraction measurement method described in the general test method of the Japanese Pharmacopoeia. An aluminum plate is used as the sample folder. The peak where the 2-Theta (2θ) value appears in the vicinity of 38 ° is an aluminum peak.
(apparatus)
RINT TTR III manufactured by Rigaku
(Method of operation)
Measurement method: reflection method, parallel beam method Light source type: Cu tube Wavelength: CuKα tube current: 300 mA
Tube voltage: 50Kv
X-ray incident angle (2θ): 4 ° to 40 °
Sampling width: 0.02 °
Scan speed: 5 ° / min

工程１：化合物１０の合成
窒素雰囲気下、化合物９（２５．０ｋｇ、１６４．３ｍｏｌ）をメタノール（１２５Ｌ）に溶解し、−７℃に冷却した。次亜塩素酸ナトリウム水溶液（１１〜１２％）（１３５L、２６１．１ｍｏｌ）を−7℃で２時間３０分かけて滴下し、−7℃で３時間撹拌した。反応液を硫酸水とメタノールの混合液に４０℃で加え、１時間３０分撹拌し、析出した固体をろ取することにより未乾の固体を得た。未乾の固体をメタノール−水で再結晶し、乾燥することで化合物１０（４６．０kg、含量５７．３％、収率８６．１％）を得た。<Synthesis of Compound 4>

Step 1: Synthesis of Compound 10 Under a nitrogen atmosphere, Compound 9 (25.0 kg, 164.3 mol) was dissolved in methanol (125 L) and cooled to −7 ° C. Aqueous sodium hypochlorite (11-12%) (135 L, 261.1 mol) was added dropwise at −7 ° C. over 2 hours 30 minutes, and the mixture was stirred at −7 ° C. for 3 hours. The reaction solution was added to a mixed solution of sulfuric acid water and methanol at 40 ° C., stirred for 1 hour and 30 minutes, and the precipitated solid was collected by filtration to obtain an undried solid. The undried solid was recrystallized from methanol-water and dried to obtain Compound 10 (46.0 kg, content 57.3%, yield 86.1%).

Step 2: Synthesis of Compound 11 Under a nitrogen atmosphere, compound 10 (26.0 kg in terms of content), 139.3 mol) is dissolved in DMA (130 L), pyridine (30.9 kg, 391.2 mol) is added, and the mixture is heated to 50 ° C. did. A solution of aluminum chloride (26.0 kg, 195.0 mol) in anisole (78 L) was added dropwise at 53 ° C. over 2 hours and stirred at 53 ° C. for 2 hours. The reaction mixture was extracted with dilute hydrochloric acid and tetrahydrofuran, and the aqueous layer was extracted with tetrahydrofuran. The organic layers were combined and concentrated under reduced pressure. The separated aqueous layer was separated and removed to obtain Compound 11 (132.0 kg, content: 17.2%, yield: 94.4%).
Step 3: Synthesis of Compound 12 Under a nitrogen atmosphere, p-methoxybenzyl chloride (23.0 kg, 147.1 mol) was added to Compound 11 (content conversion: 12.0 kg, 69.5 mol). This solution was suspended in potassium carbonate (22.1 kg, 159.8 mol), sodium iodide (0.516 kg, 3.4 mol), p-methoxybenzyl chloride (1.1 kg, 6.8 mol) in DMF (47 L). It added at 40 degreeC to the liquid, and stirred at 40 degreeC for 2 hours and 30 minutes. The mixture was cooled to 20 ° C., extracted by adding water and tetrahydrofuran, and the aqueous layer was extracted with tetrahydrofuran. The organic layers were combined, washed twice with brine, and concentrated under reduced pressure. Isopropyl alcohol was added and the mixture was concentrated under reduced pressure to precipitate a solid, then cooled to 5 ° C. and collected by filtration to obtain Compound 12 (25.0 kg, yield 86.9%).

Step 4: Synthesis of Compound 13 Under a nitrogen atmosphere, Compound 12 (32.0 kg, 77.5 mol) was dissolved in DMF (320 L), and sodium dihydrogen phosphate dihydrate (3.0 kg, 19.3 mol) was dissolved. 35% aqueous hydrogen peroxide (9.1 kg, 93.9 mol) was added at 27 ° C. The mixture was cooled to 20 ° C., an aqueous solution of sodium hypochlorite (10.5 kg, 116.4 mol) was added dropwise at 20 ° C. over 1 hour and 45 minutes, and the mixture was stirred for 2 hours and 25 minutes. The temperature was raised to 30 ° C., water and dilute hydrochloric acid were added, and the mixture was stirred at 30 ° C. for 1 hour and 25 minutes. The precipitated solid was collected by filtration to obtain Compound 13 (32.8 kg, yield 97.6%).
¹ H NMR (DMSO-d ₆ ) δ: 3.74 (s, 3 H) 3.78 (s, 3 H) 4.88 (s, 2 H) 5.17 (s, 2 H) 6.86 (d, J = 8.59 Hz, 2 H ) 6.99 (m, J = 8.59 Hz, 2 H) 7.21-7.34 (m, 3 H) 7.44 (m, J = 8.59 Hz, 2 H) 7.61 (d, J = 8.59 Hz, 1 H) 13.00 (br. s., 1 H)

Step 5: Synthesis of Compound 4 Under a nitrogen atmosphere, Compound 13 (32.0 kg, 74.6 mol) was suspended in tetrahydrofuran (160 L), and triethylamine (12.2 kg, 120.2 mol) was added at 27 ° C. over 30 minutes. Dropped and dissolved. This solution was added dropwise to a tetrahydrofuran solution of methanesulfonyl chloride (11.2 kg, 97.8 mol) at −10 ° C. over 4 hours and stirred for 20 minutes. This reaction solution was added dropwise to a tetrahydrofuran solution of compound 14 (10.2 kg, 89.7 mol) at −5 ° C. over 2 hours and stirred for 2 hours. Water was added for extraction, acetone (64 L) was added to the organic layer, and then 10% aqueous sodium hydroxide solution (5.92 kg) was added to adjust the pH to 10.0. Water was added at 30 ° C. to precipitate a solid, followed by stirring at 30 ° C. for 75 minutes. After cooling to 5 ° C. and stirring for 30 minutes, the precipitated solid was collected by filtration to obtain Compound 4 (35.2 kg, yield 89.9%).
¹ H NMR (CDCl ₃ ) δ: 1.76 (br. S., 4 H) 2.54 (br. S., 4 H) 2.69 (t, J = 6.06 Hz, 2 H) 3.54 (q, J = 5.81 Hz, 2 H) 3.79 (s, 3 H) 3.82 (s, 3 H) 4.95 (s, 2 H) 5.07 (s, 2 H) 6.83 (d, J = 7.83 Hz, 2 H) 6.92 (dd, J = 8.46 , 4.67 Hz, 4 H) 7.34 (d, J = 7.33 Hz, 4 H) 7.42 (d, J = 8.59 Hz, 1 H)

工程１
窒素雰囲気下、化合物２（２５４．３ｇ、５９２ｍｍｏｌ）をＤＭＡ（６００ｍＬ）に溶解し、−５℃に冷却した。塩化メタンスルホニル（６７．８３ｇ、５９２ｍｍｏｌ）を加え、トリエチルアミン（５９．９２ｇ、５９２ｍｏｌ）を−５℃で２５分かけて滴下し、−５℃で６０分撹拌した。これを化合物１（２００．０ｇ、４９３ｍｍｏｌ）の酢酸エチル（１Ｌ）の懸濁液に加え、Ｎ−メチルモルホリン（９９．８３ｇ、９８７ｍｍｏｌ）を−５℃で２０分かけて滴下し、−５℃で６０分撹拌した。
反応液を酢酸エチルと希塩酸の混合液に加え、抽出した。有機層を水、炭酸水素ナトリウム水溶液、水で洗浄した後、減圧濃縮した。得られた残渣にｎ−ヘプタンを加え固体を析出させた後、ろ取することにより化合物６（３７３．１ｇ、収率９７．０％）を得た。
¹H-NMR（CDCl₃）δ： 1.41 (s, 9 H) 1.53 (s, 9 H) 1.59 (s, 3 H) 1.62 (s, 3 H) 3.47 (d, J=18.19 Hz, 1 H) 3.64 (d, J=18.19 Hz, 1 H) 3.81 (s, 3 H) 4.45 (d, J=11.87 Hz, 1 H) 4.54 (d, J=11.87 Hz, 1 H) 5.05 (d, J=5.05 Hz, 1 H) 5.17 - 5.29 (m, 2 H) 6.00 (dd, J=8.84, 5.05 Hz, 1 H) 6.90 (d, J=7.93 Hz, 2 H) 7.26 - 7.37 (m, 3 H) 8.21 (d, J=8.84 Hz, 1 H)First step

Process 1
Under a nitrogen atmosphere, compound 2 (254.3 g, 592 mmol) was dissolved in DMA (600 mL) and cooled to −5 ° C. Methanesulfonyl chloride (67.83 g, 592 mmol) was added, and triethylamine (59.92 g, 592 mol) was added dropwise at −5 ° C. over 25 minutes, followed by stirring at −5 ° C. for 60 minutes. This was added to a suspension of Compound 1 (200.0 g, 493 mmol) in ethyl acetate (1 L), and N-methylmorpholine (99.83 g, 987 mmol) was added dropwise at −5 ° C. over 20 minutes. For 60 minutes.
The reaction solution was added to a mixture of ethyl acetate and dilute hydrochloric acid and extracted. The organic layer was washed with water, an aqueous sodium bicarbonate solution, and water, and then concentrated under reduced pressure. N-Heptane was added to the resulting residue to precipitate a solid, which was then collected by filtration to obtain Compound 6 (373.1 g, yield 97.0%).
¹ H-NMR (CDCl ₃ ) δ: 1.41 (s, 9 H) 1.53 (s, 9 H) 1.59 (s, 3 H) 1.62 (s, 3 H) 3.47 (d, J = 18.19 Hz, 1 H) 3.64 (d, J = 18.19 Hz, 1 H) 3.81 (s, 3 H) 4.45 (d, J = 11.87 Hz, 1 H) 4.54 (d, J = 11.87 Hz, 1 H) 5.05 (d, J = 5.05 Hz, 1 H) 5.17-5.29 (m, 2 H) 6.00 (dd, J = 8.84, 5.05 Hz, 1 H) 6.90 (d, J = 7.93 Hz, 2 H) 7.26-7.37 (m, 3 H) 8.21 (d, J = 8.84 Hz, 1 H)

工程１：化合物３の無溶媒和物の種晶Ａ合成
窒素雰囲気下、化合物６（１２０．００ｇ、１５４ｍｍｏｌ）をジクロロメタン（６００ｍＬ）に溶解し、−２０℃に冷却した。３９％過酢酸（２９．９９ｇ、１５４ｍｍｏｌ）を５０分かけて滴下し、−２０℃で３０分撹拌した。反応液を亜硫酸水素ナトリウム水溶液に加え、抽出した。有機層を水で洗浄した後、減圧濃縮した。得られた残渣にエタノールを加え結晶を析出させた後０℃に冷却し、結晶をろ取し、風乾することにより化合物３の無溶媒和物の種晶Ａ（９２．１０ｇ、収率７５．２％）を得た。
¹H-NMR（CDCl₃）δ：1.41 (s, 9 H) 1.52 (s, 9 H) 1.58 (d, J=6.06 Hz, 6 H) 3.42 (d, J=18.69 Hz, 1 H) 3.78 - 3.86 (m, 4 H) 4.23 (d, J=12.63 Hz, 1 H) 4.58 (d, J=3.79 Hz, 1 H) 5.01 (d, J=12.38 Hz, 1 H) 5.21 - 5.32 (m, 2 H) 6.20 (dd, J=9.85, 4.80 Hz, 1 H) 6.91 (d, J=8.59 Hz, 2 H) 7.25 - 7.30 (m, 1 H) 7.36 (d, J=8.59 Hz, 2 H) 7.88 (d, J=9.85 Hz, 1 H) 8.23 - 8.66 (m, 1 H)Second Step <Synthesis of Seed Crystal A of Solvate of Compound 3>

Step 1: Synthesis of Seed Crystal A of Solvate of Compound 3 Compound 6 (120.00 g, 154 mmol) was dissolved in dichloromethane (600 mL) under a nitrogen atmosphere and cooled to −20 ° C. 39% peracetic acid (29.99 g, 154 mmol) was added dropwise over 50 minutes, and the mixture was stirred at −20 ° C. for 30 minutes. The reaction solution was added to an aqueous sodium hydrogen sulfite solution and extracted. The organic layer was washed with water and then concentrated under reduced pressure. Ethanol was added to the resulting residue to precipitate crystals, which were then cooled to 0 ° C., and the crystals were collected by filtration and air-dried to give seed crystal A (92.10 g, yield 75.75) of compound 3. 2%).
¹ H-NMR (CDCl ₃ ) δ: 1.41 (s, 9 H) 1.52 (s, 9 H) 1.58 (d, J = 6.06 Hz, 6 H) 3.42 (d, J = 18.69 Hz, 1 H) 3.78- 3.86 (m, 4 H) 4.23 (d, J = 12.63 Hz, 1 H) 4.58 (d, J = 3.79 Hz, 1 H) 5.01 (d, J = 12.38 Hz, 1 H) 5.21-5.32 (m, 2 H) 6.20 (dd, J = 9.85, 4.80 Hz, 1 H) 6.91 (d, J = 8.59 Hz, 2 H) 7.25-7.30 (m, 1 H) 7.36 (d, J = 8.59 Hz, 2 H) 7.88 (d, J = 9.85 Hz, 1 H) 8.23-8.66 (m, 1 H)

窒素雰囲気下、化合物２（５．８３ｇ、１３．６ｍｍｏｌ）をＤＭＡ（１５ｍＬ）に溶解し、−５℃に冷却した。塩化メタンスルホニル（１．７０ｇ、１４．８ｍｍｏｌ）を加え、トリエチルアミン（１．７５ｇ、１７．３ｍｍｏｌ）を−５℃で９０分かけて滴下し、−５℃で５分撹拌した。これを化合物１（５．００ｇ、１２．３ｍｍｏｌ）のＤＭＡ（５ｍＬ）とアセトニトリル（２２．５ｍＬ）の懸濁液に加え、Ｎ−メチルモルホリン（２．５０ｇ、２４．７ｍｍｏｌ）を−５℃で９０分かけて滴下し、−５℃で３０分撹拌した。アセトニトリル（２．５ｍＬ）、７５％精硫酸（０．８１ｇ）、３，５−ジヒドロキシ安息香酸（０．５０ｇ）加え、３９％過酢酸（２．４１ｇ、１２．４ｍｍｏｌ）を−５℃で９０分かけて滴下し、−５℃で３０分撹拌した。
反応液をメチルエチルケトンと亜硫酸水素ナトリウムおよび食塩の水溶液の混合液に加え、抽出した。有機層を炭酸水素ナトリウム水溶液とアンモニア水の混合液で洗浄した後、食塩水で洗浄した。溶媒を減圧濃縮し、得られた残渣にメタノールを加え、種晶Ａ（５．１ｍｇ）を加え、結晶を析出させた後、メタノール−水を加え、−１０℃に冷却し、ろ取することにより化合物３のメタノール和物の結晶を得た。この結晶を終夜で風乾し，５０℃で２時間減圧乾燥することにより化合物３の無溶媒和物の結晶（８．３４ｇ、収率８５％）を得た。水分量は、カール・フィッシャー法の容量滴定より測定を行った。ただし，滴定剤として三菱化学製アクアミクロン（登録商標）滴定剤SS-Z3mgを用いた。
¹H NMR (CDCl₃) δ : 1.36 - 1.48 (m, 9 H) 1.48 - 1.62 (m, 15 H) 3.42 (d, J=18.45 Hz, 1 H) 3.78 - 3.87 (m, 4 H) 4.23 (d, J=12.42 Hz, 1 H) 4.59 (d, J=4.77 Hz, 1 H) 5.01 (d, J=12.42 Hz, 1 H) 5.18 - 5.36 (m, 2 H) 6.20 (dd, J=9.72, 4.83 Hz, 1 H) 6.91 (m, J=8.28 Hz, 2 H) 7.26 - 7.31 (m, 1 H) 7.36 (m, J=8.41 Hz, 2 H) 7.90 (d, J=9.79 Hz, 1 H) 8.47 (br. s., 1 H)
水分量（ＫＦ法）：0.6131%First Step and Second Step <Synthesis of Methanol Solvate Crystal and Solvate-Free Crystal of Compound 3>

Under a nitrogen atmosphere, Compound 2 (5.83 g, 13.6 mmol) was dissolved in DMA (15 mL) and cooled to −5 ° C. Methanesulfonyl chloride (1.70 g, 14.8 mmol) was added, and triethylamine (1.75 g, 17.3 mmol) was added dropwise at −5 ° C. over 90 minutes, followed by stirring at −5 ° C. for 5 minutes. This was added to a suspension of compound 1 (5.00 g, 12.3 mmol) in DMA (5 mL) and acetonitrile (22.5 mL) and N-methylmorpholine (2.50 g, 24.7 mmol) was added at −5 ° C. The solution was added dropwise over 90 minutes and stirred at -5 ° C for 30 minutes. Acetonitrile (2.5 mL), 75% concentrated sulfuric acid (0.81 g), 3,5-dihydroxybenzoic acid (0.50 g) were added, and 39% peracetic acid (2.41 g, 12.4 mmol) was added at −5 ° C. at 90 ° C. The solution was added dropwise over a period of time and stirred at -5 ° C for 30 minutes.
The reaction solution was added to a mixed solution of methyl ethyl ketone, sodium bisulfite and sodium chloride aqueous solution and extracted. The organic layer was washed with a mixed solution of aqueous sodium hydrogen carbonate solution and aqueous ammonia, and then washed with brine. Concentrate the solvent under reduced pressure, add methanol to the resulting residue, add seed crystal A (5.1 mg), precipitate crystals, add methanol-water, cool to −10 ° C., and filter. As a result, crystals of methanol solvate of Compound 3 were obtained. The crystals were air-dried overnight and dried under reduced pressure at 50 ° C. for 2 hours to obtain solvate-free crystals of compound 3 (8.34 g, yield 85%). The amount of water was measured by volumetric titration by the Karl Fischer method. However, as a titrant, Aquachemical (registered trademark) titrant SS-Z 3 mg manufactured by Mitsubishi Chemical was used.
¹ H NMR (CDCl ₃ ) δ: 1.36-1.48 (m, 9 H) 1.48-1.62 (m, 15 H) 3.42 (d, J = 18.45 Hz, 1 H) 3.78-3.87 (m, 4 H) 4.23 ( d, J = 12.42 Hz, 1 H) 4.59 (d, J = 4.77 Hz, 1 H) 5.01 (d, J = 12.42 Hz, 1 H) 5.18-5.36 (m, 2 H) 6.20 (dd, J = 9.72 , 4.83 Hz, 1 H) 6.91 (m, J = 8.28 Hz, 2 H) 7.26-7.31 (m, 1 H) 7.36 (m, J = 8.41 Hz, 2 H) 7.90 (d, J = 9.79 Hz, 1 H) 8.47 (br. S., 1 H)
Water content (KF method): 0.6131%

The results of powder X-ray diffraction analysis of the methanol solvate crystals of Compound 3 are shown in FIG.

The diffraction angle 2θ showing a characteristic diffraction peak is 4.3 ± 0.2 °, 10.9 ± 0.2 °, 12.7 ± 0.2 °, 14.5 ± 0.2 °, 16. 2 ± 0.2 °, 18.0 ± 0.2 °, 18.3 ± 0.2 °, 21.2 ± 0.2 °, 25.6 ± 0.2 ° and 26.5 ± 0.2 °. Preferably, they are 4.3 ± 0.2 °, 10.9 ± 0.2 °, 14.5 ± 0.2 °, 18.3 ± 0.2 ° and 21.2 ± 0.2 °.

The results of powder X-ray diffraction of the crystals of the resulting solvate-free compound 3 are shown in FIG.

  Diffraction angles 2θ showing characteristic diffraction peaks are 4.8 ± 0.2 °, 14.1 ± 0.2 °, 14.4 ± 0.2 °, 14.9 ± 0.2 °, 16. 0 ± 0.2 °, 17.1 ± 0.2 °, 17.6 ± 0.2 °, 20.5 ± 0.2 °, 25.2 ± 0.2 ° and 33.1 ± 0.2 °. Preferred are 4.8 ± 0.2 °, 14.4 ± 0.2 °, 14.9 ± 0.2 °, 16.0 ± 0.2 °, and 20.5 ± 0.2 °.

工程１ 化合物７の合成
窒素雰囲気下、ホウ酸（４６．０ ｍｇ、０．７５ｍｍｏｌ）、ヨウ化ナトリウム（１．１３ｇ、７．５３ｍｍｏｌ）をＮＭＰ（６ｍＬ）に溶解し、０℃に冷却した。化合物３（２．００ｇ、２．５１ｍｍｏｌ）、化合物４（１．４５ｇ、２．７６ｍｍｏｌ）を加え、０℃で６時間撹拌、７℃で１７時間静置した。
メチルエチルケトンと亜硫酸水素ナトリウム水溶液の混合液に加え、抽出した。有機層を硫酸と５％食塩水の混合液で２回洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた残渣をＯＤＳカラムクロマトグラフィー（アセトニトリル−硫酸）で精製して化合物７（２．６０ｇ、収率７３．２％）を得た。
¹H NMR (DMSO-D₆) δ： 1.38(s, 9 H) 1.47(s, 9 H) 1.48(s, 3 H) 1.49(s, 3 H) 1.91 - 2.07 (m, 4 H) 3.40 - 3.67 (m, 8 H) 3.75 (s, 3 H) 3.76 (s, 3 H) 3.77 (s, 3 H) 4.13 (d, J=20.01 Hz, 1 H) 4.33 (d, J=20.01 Hz, 1 H) 4.34 (d, J=12.00 Hz, 1 H) 4.71 (d, J=12.00 Hz, 1 H) 4.90 (s, 2 H) 5.17 (s, 2 H) 5.23 (d, J=4.00 Hz, 1 H) 5.28 (d, J=12.00 Hz, 1 H) 5.39 (d, J=12.00 Hz, 1 H) 6.16 (dd, J=8.00, 4.00 Hz, 1 H) 6.86 - 6.99 (m, 6 H) 7.23 - 7.45 (m, 9 H) 8.65 (d, J=8.00 Hz, 1 H) 8.75 (t, J=4.00 Hz, 1 H) 11.81 (br. s., 1 H)Third step

Step 1 Synthesis of Compound 7 Under a nitrogen atmosphere, boric acid (46.0 mg, 0.75 mmol) and sodium iodide (1.13 g, 7.53 mmol) were dissolved in NMP (6 mL) and cooled to 0 ° C. Compound 3 (2.00 g, 2.51 mmol) and compound 4 (1.45 g, 2.76 mmol) were added, stirred at 0 ° C. for 6 hours, and allowed to stand at 7 ° C. for 17 hours.
The mixture was extracted with a mixture of methyl ethyl ketone and aqueous sodium hydrogen sulfite solution. The organic layer was washed twice with a mixture of sulfuric acid and 5% brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by ODS column chromatography (acetonitrile-sulfuric acid) to obtain Compound 7 (2.60 g, yield 73.2%).
¹ H NMR (DMSO-D ₆ ) δ: 1.38 (s, 9 H) 1.47 (s, 9 H) 1.48 (s, 3 H) 1.49 (s, 3 H) 1.91-2.07 (m, 4 H) 3.40- 3.67 (m, 8 H) 3.75 (s, 3 H) 3.76 (s, 3 H) 3.77 (s, 3 H) 4.13 (d, J = 20.01 Hz, 1 H) 4.33 (d, J = 20.01 Hz, 1 H) 4.34 (d, J = 12.00 Hz, 1 H) 4.71 (d, J = 12.00 Hz, 1 H) 4.90 (s, 2 H) 5.17 (s, 2 H) 5.23 (d, J = 4.00 Hz, 1 H) 5.28 (d, J = 12.00 Hz, 1 H) 5.39 (d, J = 12.00 Hz, 1 H) 6.16 (dd, J = 8.00, 4.00 Hz, 1 H) 6.86-6.99 (m, 6 H) 7.23 -7.45 (m, 9 H) 8.65 (d, J = 8.00 Hz, 1 H) 8.75 (t, J = 4.00 Hz, 1 H) 11.81 (br. S., 1 H)

Step 1: Synthesis of seed crystal B
Compound (IA) was prepared according to the method described in WO2010 / 050468. Compound (IA) (100 mg) was dissolved in 1.0 mol / L p-toluenesulfonic acid aqueous solution (2 mL) at room temperature using ultrasound, and allowed to stand at 4 ° C. for 4 days. The precipitate was filtered to obtain seed crystal B (73 mg). It was confirmed to be a needle-like crystal by a microscope.
Process 2: Seed crystal C
Seed B (50 mg) is dissolved in 6 mol / L H ₂ SO ₄ (3 mL) at room temperature on an ultrasonic bath and allowed to stand at 4 ° C. for 2 days. The precipitated crystalline solid was filtered and washed with ice-cold water to obtain seed crystal C (23 mg).

工程３：化合物３の合成
窒素雰囲気下、化合物２（３５．０ｋｇ、８１．４２ｍｏｌ）をＤＭＡ（９０Ｌ）に溶解し、−５℃に冷却した。塩化メタンスルホニル（１０．２ｋｇ、８８．８２ｍｏｌ）を加え、トリエチルアミン（１０．５ｋｇ、１０３．６３ｍｍｏｌ）を−５℃で８０分かけて滴下し、−５℃で３０分撹拌した。これを化合物１（３０．００ｋｇ、７４．０２ｍｏｌ）のアセトニトリル（１２０Ｌ）とＤＭＡ（３０Ｌ）の懸濁液に加え、Ｎ−メチルモルホリン（１５．０ｋｇ、１４８．０４ｍｍｏｌ）を−５℃で７０分かけて滴下し、−５℃で６０分撹拌した。アセトニトリル（１５Ｌ）、７５％精硫酸（４．８ｋｇ）、３，５−ジヒドロキシ安息香酸（３．００ｋｇ）加え、過酢酸（３９．８％）（１４．１４ｋｇ、７４．０２ｍｏｌ）を−５℃で７０分かけて滴下し、−５℃で１４０分撹拌した。 反応液をメチルエチルケトンと亜硫酸水素ナトリウムおよび食塩の水溶液の混合液に加え、抽出した。有機層を炭酸水素ナトリウム水溶液とアンモニア水の混合液で洗浄した後、食塩水で洗浄した。７５％精硫酸を加え、溶媒を減圧濃縮し、得られた残渣にメタノールを加え、種晶Ａ（３０ｇ）を加え、結晶を析出させた後、メタノール−水を加え、−１０℃に冷却し、ろ過、冷メタノール−水で結晶を洗浄、減圧乾燥することにより化合物３（収量５３．３２ｋｇ、収率９０．５％）を得た（（Ｒ）：（Ｓ）=１．３０：９５．７３）。<Synthesis of Compound (IA)>

Step 3: Synthesis of Compound 3 Compound 2 (35.0 kg, 81.42 mol) was dissolved in DMA (90 L) under a nitrogen atmosphere and cooled to −5 ° C. Methanesulfonyl chloride (10.2 kg, 88.82 mol) was added, and triethylamine (10.5 kg, 103.63 mmol) was added dropwise at −5 ° C. over 80 minutes, followed by stirring at −5 ° C. for 30 minutes. This was added to a suspension of Compound 1 (30.00 kg, 74.02 mol) in acetonitrile (120 L) and DMA (30 L), and N-methylmorpholine (15.0 kg, 148.04 mmol) was added at −5 ° C. for 70 minutes. The mixture was added dropwise and stirred at -5 ° C for 60 minutes. Acetonitrile (15 L), 75% concentrated sulfuric acid (4.8 kg), 3,5-dihydroxybenzoic acid (3.00 kg) were added, and peracetic acid (39.8%) (14.14 kg, 74.02 mol) was added at -5 ° C. The solution was added dropwise over 70 minutes and stirred at -5 ° C for 140 minutes. The reaction solution was added to a mixed solution of methyl ethyl ketone, sodium bisulfite and sodium chloride aqueous solution and extracted. The organic layer was washed with a mixed solution of aqueous sodium hydrogen carbonate solution and aqueous ammonia, and then washed with brine. 75% concentrated sulfuric acid was added, the solvent was concentrated under reduced pressure, methanol was added to the resulting residue, seed crystal A (30 g) was added, and crystals were precipitated, then methanol-water was added, and the mixture was cooled to -10 ° C. , Filtration, washing of the crystals with cold methanol-water and drying under reduced pressure gave compound 3 (yield 53.32 kg, yield 90.5%) ((R) :( S) = 1.30: 95.). 73).

Step 4: Synthesis of Compound (IA) Boric acid (0.4 kg, 6.78 mol) was dissolved in NMP (50 L) under a nitrogen atmosphere, sodium iodide (10.2 kg, 67.80 mol) was added, and the temperature was 0 ° C. Cooled to. Compound 3 (18.0 kg, 22.60 mol) and compound 4 (13.1 kg, 24.86 mol) were added, and the mixture was stirred at 0 ° C. for 6 hours. After heating up to 7 degreeC and stirring for 16 hours, the production | generation of the compound 7 was confirmed for the reaction liquid by HPLC. After adding NMP (18 L) to the reaction solution and cooling to 0 ° C., phosphorus trichloride (4.0 kg, 29.38 mol) was added dropwise at 0 ° C. over 60 minutes, followed by stirring at 0 ° C. for 3 hours. Formation of compound 8 was confirmed by HPLC of the liquid.
Anisole (36 L) was added to the reaction solution, and this solution was added to a mixed solution of methyl ethyl ketone and aqueous sodium hydrogen sulfite and extracted. The organic layer was washed twice with a mixture of sulfuric acid and brine. Anisole (180 L) was added, and the mixture was cooled to −5 ° C., 75% concentrated sulfuric acid (72.0 kg) was added, and the mixture was stirred at 15 ° C. for 90 minutes. Water (90 L) and methyl ethyl ketone (54 L) were added and extracted. The aqueous layer was washed with methyl isobutyl ketone and then purified by reverse layer column chromatography (acetonitrile-sulfuric acid aqueous solution) using a small particle size synthetic adsorbent for chromatography separation (Diaion ^™ HP20SS). After adding an aqueous solution of 75% concentrated sulfuric acid (33.3 kg) and p-toluenesulfonic acid monohydrate (16.7 kg) to the obtained eluate, seed crystal C (180 g) was added to precipitate crystals. It was. The mixture was cooled to 5 ° C., stirred at 5 ° C. for 10 hours, and the precipitated crystals were filtered. The crystals were washed with aqueous sulfuric acid cooled to 5 ° C. to obtain hydrate crystals of a mixed salt of compound (IA), p-toluenesulfonic acid and sulfuric acid (16.68 kg, content conversion yield 63.7%). Obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 1.48 (d, J = 6.02 Hz, 6 H) 1.80-2.20 (m, 5 H) 2.29 (s, 4 H) 3.21-3.85 (m, 9 H) 3.99 (d, J = 17.07 Hz, 1 H) 4.29 (d, J = 14.18 Hz, 1 H) 4.65 (d, J = 14.18 Hz, 1 H) 5.32 (d, J = 5.14 Hz, 1 H) 5.96 (dd , J = 8.22, 5.08 Hz, 1 H) 6.74-6.83 (m, 3 H) 7.11 (m, J = 7.91 Hz, 2 H) 7.48 (m, J = 8.03 Hz, 2 H) 8.47 (t, J = 5.40 Hz, 1 H) 9.59 (d, J = 8.28 Hz, 1 H) 10.12 (Br s, 1 H)
The water content was measured by the Karl Fischer method. The measuring method was tested from the Japanese Pharmacopoeia General Test Method Moisture (coulometric titration). However, Aquamicron (registered trademark) AX manufactured by Mitsubishi Chemical was used as the anolyte, and Aquamicron (registered trademark) CXU was used as the catholyte. Since the water measurement by the Karl Fischer method may cause an error within a range of ± 0.3%, the value of the water content needs to be understood as including a numerical value within a range of about ± 0.3%.

以下の計算式を用いて、試料中のp-トルエンスルホン酸の含有量を求めた。
p-トルエンスルホン酸の量 (%)

M_S：ｐ−トルエンスルホン酸ナトリウム標準品の秤取量 (mg)
M_T：試料の秤取量 (mg)
P：ｐ−トルエンスルホン酸ナトリウム標準品の純度 (%)
W_T：試料の水分 (%)
A_T：試料溶液から得られるp-トルエンスルホン酸のピーク面積
A_S：標準溶液から得られるp-トルエンスルホン酸のピーク面積
172.20：p-トルエンスルホン酸の分子量
194.18：p-トルエンスルホン酸ナトリウムの分子量

The contents of p-toluenesulfonic acid and sulfuric acid in the obtained crystals were quantified by the following method.
(Measurement method of p-toluenesulfonic acid content)
Step 1: Preparation of sample solution About 40 mg of a sample was accurately weighed and dissolved in a sample dilution solvent to make exactly 25 mL. 2 mL of this solution was accurately weighed and a sample dilution solvent was added to make exactly 20 mL.
Step 2: Preparation of standard solution
About 25 mg of standard p-toluenesulfonate standardized in a 25 ° C./60% RH environment was accurately weighed and dissolved in the sample dilution solvent to make exactly 100 mL. 5 mL of this solution was accurately weighed and a sample dilution solvent was added to make exactly 50 mL.
As the sample dilution solvent, a 5 mmol / L phosphate buffer solution: acetonitrile mixture for liquid chromatography (9: 1) was used. The phosphate buffer used here was water: 0.05 mol / L sodium dihydrogen phosphate sample solution: 0.05 mol / L disodium hydrogen phosphate sample solution = 18: 1: 1 (pH is about 7.1).
Step 3: Measurement and Quantification The above sample solution and standard solution were measured by liquid chromatography under the following test conditions, and the peak area of p-toluenesulfonic acid was measured by an automatic integration method. In addition, dehydrated equivalent is a value calculated by subtracting the water content from the total amount as 100%.
(Test conditions)
Column: Unison UK-C18, φ4.6 × 150 mm, 3 μm, Immtak Column temperature: Constant temperature around 35 ° C Flow rate: 1.0 mL / min (p-toluenesulfonic acid retention time approx. 7 minutes)
Detector: UV spectrophotometer (measurement wavelength: 218 nm)
Mobile phase A: 0.1% trifluoroacetic acid solution
Mobile phase B: Acetonitrile gradient program for liquid chromatography

The content of p-toluenesulfonic acid in the sample was determined using the following calculation formula.
Amount of p-toluenesulfonic acid (%)

M _S : Weighed amount of standard sodium p-toluenesulfonate (mg)
M _T : Weighed sample (mg)
P: Purity of standard sodium p-toluenesulfonate (%)
W _T : Sample moisture (%)
A _T : Peak area of p-toluenesulfonic acid obtained from the sample solution
A _S : Peak area of p-toluenesulfonic acid obtained from standard solution
172.20: Molecular weight of p-toluenesulfonic acid
194.18: Molecular weight of sodium p-toluenesulfonate

(Method for measuring sulfuric acid content)
Step 1: Preparation of standard solution About 50 mg of anhydrous sodium sulfate was accurately weighed and dissolved in the mobile phase to make exactly 25 mL. 2 mL of this solution was accurately weighed, and the mobile phase was added to make exactly 50 mL. Furthermore, 2 mL of this solution was accurately weighed and the mobile phase was added to make exactly 20 mL.
Step 2: Preparation of sample solution About 30 mg of the sample was accurately weighed and dissolved in the mobile phase to make exactly 25 mL. 2 mL of this solution was accurately weighed and the mobile phase was added to make exactly 20 mL.
Step 3: Measurement and Quantification The sample solution and standard solution were measured by liquid chromatography (ion chromatography) under the following test conditions, and the peak area of sulfate ions was measured by an automatic integration method. (Test conditions)
Column: Shim-pack IC-A3, φ4.6 × 150 mm, 5 μm, Shimadzu Corporation Column temperature: Constant temperature around 40 ° C Flow rate: 1.2 mL per minute (sulfate ion retention time approx. 15 minutes)
Detector: Electrical conductivity detector (Non-suppressor system)
Mobile phase: Bis-Tris about 0.67 g, boric acid about 3.09 g, and ground p-hydroxybenzoic acid about 1.11 g accurately weighed and dissolved in water to make exactly 1000 mL. The content of sulfuric acid in the sample was determined.
Amount of sulfuric acid (%) = M _S / M _T × 100 / (100-W _T ) × A _T / A _S × 98.08 / 142.04 × 1/25 × 100

M _S : Weighed amount of anhydrous sodium sulfate (mg)
M _T : Weighed sample (mg)
W _T : Sample moisture (%)
A _S : Peak area of sulfate ion obtained from standard solution
A _T : Peak area of sulfate ion obtained from the sample solution
98.08: Molecular weight of sulfuric acid
142.04: Molecular weight of anhydrous sodium sulfate
1/25: Dilution factor (result)
Water content (KF method): 13.3%
p-Toluenesulfonic acid: 21.5 ± 0.2% (dehydrated equivalent)
Sulfuric acid: 4.9 ± 0.1% (dehydrated equivalent)

工程１ 化合物10の合成
窒素雰囲気下、化合物９（１．００ｇ、０．７６ｍｍｏｌ）をＮＭＰ（４ｍＬ）に溶解し、０℃に冷却した。三塩化リン（０．１４ｇ、１．０２ｍｏｌ）を1時間かけて滴下し、０℃で２時間撹拌した。
酢酸エチルと塩化ナトリウム水溶液の混合液に加え、抽出した。有機層を５％食塩，０．７５％硫酸水で２回洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去して化合物１０（０．９７ｇ、収率９８．２％）を得た。
¹H NMR (400 MHz, CHLOROFORM-d) δ ： 1.38 - 1.42 (m, 9 H) 1.51 (s, 9 H) 1.57 (s, 3 H) 1.60 (s, 3 H) 1.92 - 2.04 (m, 4 H) 2.33 - 2.43 (m, 2 H) 2.84 (s, 2 H) 3.35 - 3.47 (m, 3 H) 3.76 - 3.80 (m, 7 H) 3.82 (s, 3 H) 3.87 (d, J=5.90 Hz, 2 H) 3.99 (d, J=17.94 Hz, 1 H) 4.61 (d, J=13.68 Hz, 1 H) 4.91 (s, 2 H) 4.95 (d, J=13.55 Hz, 1 H) 5.03 (s, 2 H) 5.14 - 5.21 (m, 1 H) 5.22 - 5.30 (m, 2 H) 5.95 (dd, J=8.60, 5.21 Hz, 1 H) 6.81 (d, J=7.79 Hz, 2 H) 6.86 - 6.94 (m, 5 H) 7.27 - 7.38 (m, 8 H) 8.29 (d, J=8.66 Hz, 1 H) 8.70 (s, 1 H)Fourth step

Step 1 Synthesis of Compound 10 Compound 9 (1.00 g, 0.76 mmol) was dissolved in NMP (4 mL) under a nitrogen atmosphere and cooled to 0 ° C. Phosphorus trichloride (0.14 g, 1.02 mol) was added dropwise over 1 hour, and the mixture was stirred at 0 ° C. for 2 hours.
The mixture was extracted with a mixture of ethyl acetate and aqueous sodium chloride solution. The organic layer was washed twice with 5% sodium chloride and 0.75% aqueous sulfuric acid and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 10 (0.97 g, yield 98.2%).
¹ H NMR (400 MHz, CHLOROFORM-d) δ: 1.38-1.42 (m, 9 H) 1.51 (s, 9 H) 1.57 (s, 3 H) 1.60 (s, 3 H) 1.92-2.04 (m, 4 H) 2.33-2.43 (m, 2 H) 2.84 (s, 2 H) 3.35-3.47 (m, 3 H) 3.76-3.80 (m, 7 H) 3.82 (s, 3 H) 3.87 (d, J = 5.90 (Hz, 2 H) 3.99 (d, J = 17.94 Hz, 1 H) 4.61 (d, J = 13.68 Hz, 1 H) 4.91 (s, 2 H) 4.95 (d, J = 13.55 Hz, 1 H) 5.03 ( s, 2 H) 5.14-5.21 (m, 1 H) 5.22-5.30 (m, 2 H) 5.95 (dd, J = 8.60, 5.21 Hz, 1 H) 6.81 (d, J = 7.79 Hz, 2 H) 6.86 -6.94 (m, 5 H) 7.27-7.38 (m, 8 H) 8.29 (d, J = 8.66 Hz, 1 H) 8.70 (s, 1 H)

Claims (22)

Crystalline, formula (IV):

(In the formula, R ¹ is an amino-protecting group; R ² and R ³ are each independently a carboxy-protecting group.)
Or a pharmaceutically acceptable salt thereof, or a solvate thereof. The crystal according to claim 1, wherein R ¹ is a t-butoxycarbonyl group, R ² is a t-butyl group, and R ³ is a p-methoxybenzyl group.   In powder X-ray diffraction spectrum, diffraction angle (2θ): 4.3 ± 0.2 °, 10.9 ± 0.2 °, 14.5 ± 0.2 °, 18.3 ± 0.2 ° and 21 3. The crystal of claim 2, having at least 3 peaks selected from 2 ± 0.2 °.   In powder X-ray diffraction spectrum, diffraction angles (2θ): 4.8 ± 0.2 °, 14.4 ± 0.2 °, 14.9 ± 0.2 °, 16.0 ± 0.2 ° and 20 The crystal according to claim 2, having at least three peaks selected from 5 ± 0.2 °. The following steps:
(Second step)
Formula (V):

(In the formula, R ¹ is an amino-protecting group; R ² and R ³ are each independently a carboxy-protecting group.)
A compound represented by formula (IV) is reacted with a peracid in a solvent:

(Wherein R ¹ , R ² and R ³ are as defined above)
Step for obtaining the compound represented by (except when the solvent is only dichloromethane)
A process for producing compound (IV), a pharmaceutically acceptable salt thereof, or a solvate thereof. The production method according to claim 5, wherein the peracid is peracetic acid. The following steps:
(First Step) Formula (VI):

(Wherein R ³ is a protecting group for a carboxy group)
And a compound of formula (VII):

(Wherein each symbol is as defined above)
And a compound of formula (V):

(Wherein each symbol is as defined above)
And (second step) to obtain a compound represented by
The step of obtaining a compound (IV) by reacting a compound represented by the formula (V) with a peracid is continuously carried out:

(Wherein each definition is as defined above)
Or a pharmaceutically acceptable salt thereof, a solvate thereof, or a crystal thereof. The following steps:
(Third step)
Formula (IV):

(Wherein each symbol is as defined above)
And a compound of formula (X):

(In the formula, R ⁴ and R ⁵ are each independently a hydroxyl-protecting group.)
Is reacted in the presence of boric acid or boronic acid to give the formula (III):

(In the formula, X- is a counter ion, and other symbols are as defined above.)
Obtaining a compound represented by:
A process for producing compound (III), a pharmaceutically acceptable salt thereof, or a solvate thereof. The following steps:
(4th process)
Formula (III):

(Wherein each symbol is as defined above)
To reduce the compound of formula (II):

(Wherein each symbol is as defined above)
Obtaining a compound represented by:
A process for producing compound (II), a pharmaceutically acceptable salt thereof, or a solvate thereof. The following steps:
(4th process)
Formula (III):

(Wherein each symbol is as defined above)
The compound represented by formula (II):

(Wherein each symbol is as defined above)
A step of obtaining a compound represented by formula (5)
The compound of formula (II) is deprotected to give formula (IA):

A step of obtaining a compound represented by:
A method for producing compound (IA), a pharmaceutically acceptable salt thereof, or a solvate thereof. The following steps:
(Step 3) A step of reacting compound (IV) with compound (X) in the presence of boric acid or boronic acid to obtain compound (III);
(Step 4) Step of reducing Compound (III) to obtain Compound (II); and (Step 5) Step of deprotecting Compound (II) to obtain Compound (IA);
A process for producing a compound (IA) according to claim 10, a pharmaceutically acceptable salt thereof or a solvate thereof. The following steps:
(Second Step) A step of reacting compound (V) with peracid to obtain compound (IV);
(Step 3) A step of reacting compound (IV) with compound (X) in the presence of boric acid or boronic acid to obtain compound (III);
(Step 4) Step of reducing Compound (III) to obtain Compound (II); and (Step 5) Step of deprotecting Compound (II) to obtain Compound (IA);
A process for producing a compound (IA) according to claim 10, a pharmaceutically acceptable salt thereof or a solvate thereof. Formula (III):

(Wherein each symbol is as defined above)
A compound represented by Formula (II):

(Wherein the constant symbols are as defined above)
A compound represented by R ¹ is a t- butoxycarbonyl group, crystals of the compound or a solvate of any one of claims 1～4,13 or 14. The production method according to any one of claims 5 to 12, wherein R ¹ is a t-butoxycarbonyl group. The crystal | crystallization of the compound or its solvate in any one of Claims 1-4, 13 or 14 whose R < ² > is t-butyl group. R ² is t- butyl group, The process according to any one of claims 5-12. The compound or solvate thereof according to any one of claims 1 to 4, 13 or 14, wherein R ³ is a p-methoxybenzyl group or a benzhydryl group. R ³ is p- methoxybenzyl group or a benzhydryl group, The process according to any one of claims 5-12. The compound according to claim 13 or 14, wherein R ⁴ and R ⁵ are p-methoxybenzyl groups. The production method according to any one of claims 8 to 12, wherein R ⁴ and R ⁵ are p-methoxybenzyl groups.

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