JP6783497B2 - Intermediate of cephalosporin derivative and its production method - Google Patents

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 a cephalosporin derivative having a catechol group represented by (hereinafter referred to as compound (I)) has a broad antibacterial spectrum and exhibits strong antibacterial activity particularly against β-lactamase-producing bacteria, it is used for treatment of infectious diseases and / Or it is described as useful as a prophylactic agent. Further, in Example 12, the following compounds:

(Hereinafter referred to as compound (IA)) is disclosed. Although the specific synthesis method of the compound (IA) is not described, it is synthesized according to the general synthesis method shown below or a specific synthesis method of a similar compound.

Patent Document 1 describes the following scheme as a general method for synthesizing 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 describes compound 9: corresponding to the above compound (IX).

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

And the synthetic method thereof are disclosed, but in each case, the sulfoxide group at the 1-position is described in racemic form, and there is no description regarding the optically active substance.
Further, in Patent Documents 4 and 7, the formula:

Although the S-form compound represented by is disclosed, none of them is a crystal, and there is no description about a crystal. Further, Patent Document 4 describes a method for producing the S-form compound, but does not describe the production method of the present invention. Furthermore, there is no description about 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. 2014/066494

There has been a need to develop an industrially efficient method for producing cephalosporin derivatives such as compound (IA). In addition, it was necessary to develop a useful intermediate and a method for producing the same.

As a result of diligent studies in view of the above problems, the present inventors will study 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 could be improved, the continuous reaction, the reaction near room temperature, and the purification by crystallization 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 independently protecting carboxy groups.)
A compound represented by, 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 the powder X-ray diffraction spectrum, the diffraction angle (2θ): 4.3 ± 0.2 °, 10.9 ± 0.2 °, 14.5 ± 0.2 °, 18.3 ± 0.2 ° and 21. .. Crystal of the methanol sum according to item 2, having at least 3 peaks selected from 2 ± 0.2 °.
(Item 4)
In the powder X-ray diffraction spectrum, the diffraction angles (2θ): 4.8 ± 0.2 °, 14.4 ± 0.2 °, 14.9 ± 0.2 °, 16.0 ± 0.2 ° and 20. .. The solvate crystal of item 2, having at least 3 peaks selected from 5 ± 0.2 °.
(Item 5)
The following steps:
(Second step)
Equation (V):

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

(In the formula, R ¹ , R ² and R ³ have the same meaning as described above)
Step to obtain the compound indicated by (except when the solvent is only dichloromethane)
A method for producing a compound (IV), a pharmaceutically acceptable salt thereof, or a solvate thereof, which comprises the above.
(Item 6)
The production method according to item 5, wherein the peracid is peracetic acid.
(Item 7)
The following steps:
(First step) Equation (VI):

(In the formula, R ³ is a protecting group for the carboxy group)
Compound represented by and formula (VII):

(In the formula, each symbol has the same meaning as above)
The compound represented by is reacted, and the formula (V):

(In the formula, each symbol has the same meaning as above)
The step of obtaining the compound represented by (2nd step).
The step of reacting the compound represented by the formula (V) with a peracid to obtain the compound (IV) is continuously carried out.

(In the formula, each definition has the same meaning as above)
A compound represented by, a pharmaceutically acceptable salt thereof or a solvate thereof, or a method for producing crystals thereof.
(Item 8)
The following steps:
(Third step)
Equation (IV):

(In the formula, each symbol has the same meaning as above)
Compound represented by and formula (X):

(In the formula, R ⁴ and R ⁵ are independent protecting groups for hydroxyl groups.)
Was reacted in the presence of boric acid or boronic acid to formula (III):

(In the formula, X- is a counter ion, and other symbols have the same meaning as above)
The process of obtaining the compound indicated by,
A method for producing a compound (III), a pharmaceutically acceptable salt thereof, or a solvate thereof, which comprises the above.
(Item 9)
The following steps:
(4th step)
Equation (III):

(In the formula, each symbol has the same meaning as above)
The compound represented by is reduced to formula (II):

(In the formula, each symbol has the same meaning as above)
The process of obtaining the compound indicated by,
A method for producing compound (II), a pharmaceutically acceptable salt thereof, or a solvate thereof, which comprises the above.
(Item 10)
The following steps:
(4th step)
Equation (III):

(In the formula, each symbol has the same meaning as above)
The compound represented by the formula (II):

(In the formula, each symbol has the same meaning as above)
Step of obtaining the compound represented by (5th step)
Deprotecting the compound represented by formula (II) to formula (IA):

The step of obtaining the compound represented by (1) is carried out continuously.
A method for producing a compound (IA), a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 11)
The following steps:
(Third step) A step of reacting compound (IV) with compound (X) in the presence of boric acid or boronic acid to obtain compound (III);
(Fourth step) A step of reducing compound (III) to obtain compound (II); and (Fifth step) a step of deprotecting compound (II) to obtain compound (IA);
The method for producing a compound (IA) according to item 10, a pharmaceutically acceptable salt thereof, or a solvate thereof, which comprises the above.
(Item 12)
The following steps:
(Second step) A step of reacting compound (V) with a peracid to obtain compound (IV);
(Third step) A step of reacting compound (IV) with compound (X) in the presence of boric acid or boronic acid to obtain compound (III);
(Fourth step) A step of reducing compound (III) to obtain compound (II); and (Fifth step) a step of deprotecting compound (II) to obtain compound (IA);
10. The method for producing a compound (IA) according to Item 10, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(Item 13)
Equation (III):

(In the formula, each symbol has the same meaning as above)
The compound indicated by.
(Item 14)
Equation (II):

(In the formula, each fixed symbol has the same meaning as above)
The compound indicated by.
(Item 15)
Crystal of the compound according to any one of items 1 to 4, 13 or 14, or a solvate thereof, wherein R ¹ is a t-butoxycarbonyl group.
(Item 16)
The production method according to any one of items 5 to 12, wherein R ¹ is a t-butoxycarbonyl group.
(Item 17)
R ² is t- butyl group, A compound according to any of items 1～4,13 or 14 or crystals of solvate thereof.
(Item 18)
The production method according to any one of items 5 to 12, wherein R ² is a t-butyl group.
(Item 19)
The compound according to any one of items 1 to 4, 13 or 14, or a solvate thereof, wherein R ³ is a p-methoxybenzyl group or a benzhydryl group.
(Item 20)
R ³ is p- methoxybenzyl group or a benzhydryl group, the manufacturing method according to any of items 5-12.
(Item 21)
The compound according to item 13 or 14, wherein R ⁴ and R ⁵ are p-methoxybenzyl groups.
(Item 22)
The production method according to any one of items 8 to 12, wherein R ⁴ and R ⁵ are p-methoxybenzyl groups.

INDUSTRIAL APPLICABILITY The present invention provides synthetic intermediates useful for industrial production of various cephalosporin derivatives and methods for producing the same. Further, by using them, particularly compound (IA) can be produced in good yield, easily, safely and efficiently.

The powder X-ray diffraction spectrum of the methanol-added crystal of the 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 crystal of the 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 carried out "in succession" without isolation. "Continuous steps" includes performing the next step without isolating the compound produced by the reaction of the previous step. For example, two steps can be performed in one pot.

(In the formula, each symbol has the same meaning as above)

(1st step)
Compound (VIII) is obtained by reacting compound (VII) with mesyl chloride in the presence of a base, if desired.
The base is not particularly limited as long as it allows the above steps to proceed efficiently. Inorganic bases such as organic bases or inorganic carbonates 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. It is preferably triethylamine.
The base may be reacted with compound (VII) using about 1-2 molar equivalents.
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, etc.), acetate solvents (eg ethyl acetate, etc.) (Ppropyl acetate, etc.), hydrocarbon solvents (eg, toluene, benzene, hexane, etc.), ether solvents (eg, cyclopentylmethyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxyethane, etc.), nitrile solvents (eg, cyclopentylmethyl ether, tetrahydrofuran, 2-methyltetraethane, etc.) Example: One or more selected from acetonitrile, propionitrile, etc.), halogen-based solvent (eg, dichloromethane, chloroform, etc.), ketone-based solvent (eg, acetone, methylethylketone, etc.), dimethylsulfoxide, etc. can be used. An amide-based solvent is preferable, and N, N-dimethylacetamide is more preferable.
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 mesylate chloride used is preferably about 1-5 molar equivalents, more preferably about 1-1.5 molar equivalents, relative to compound (VII). Mesylate chloride may be added all at once or dropped.
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) in the presence of a base, if desired.
The reaction may be carried out according to the conditions of a normal amidation reaction.
The base is not particularly limited as long as it allows the above steps to proceed efficiently. Inorganic bases such as organic bases or inorganic carbonates 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.
The base may be reacted with compound (VII) using about 1-5 molar equivalents. Preferably, it is about 1-2 molar equivalents.
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, etc.), acetate solvents (eg ethyl acetate, etc.) (Ppropyl acetate, etc.), hydrocarbon solvents (eg, toluene, benzene, hexane, etc.), ether solvents (eg, cyclopentylmethyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.), nitrile-based solvents. One or more selected from a solvent (eg, acetonitrile, propionitrile, etc.), a halogen-based solvent (eg, dichloromethane, chloroform, etc.), a ketone-based solvent (eg, acetone, methylethylketone, etc.), dimethylsulfoxide, 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 are 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) used is preferably about 0.8-5 molar equivalents, more preferably about 0.8-1.5 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-imidazolidi). Non etc.), acetic acid ester solvent (eg ethyl acetate, propyl acetate, etc.), hydrocarbon solvent (eg toluene, benzene, hexane, etc.), ether solvent (eg cyclopentylmethyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran) , 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.), One or more selected from dimethylsulfoxide, water and the like can be used. The solvent can be used as a two-layer solvent with water or a water-containing solvent, if necessary. It is preferably a halogen-based solvent, a nitrile-based solvent, an amide-based solvent, or a mixed solvent of a nitrile-based solvent and an amide-based solvent. More preferably, it 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, the S-form 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 even more preferably about -10 to 0 degrees. The reaction temperature is preferably low from the viewpoint of selectivity of the S-form, but can be set to an industrially controllable temperature (eg, about −10 to 0 ° C.) by selecting a solvent, for example.
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, hydrogen peroxide solution, magnesium monoperoxyphthalate hexahydrate and the like. Peracetic acid is preferred. Further, when adding the peracid, it is preferable to dissolve the peracid in a solvent and drop it if necessary. By dropping, the peracid can be reacted with the compound (V) at the same time as dropping, and the heat of reaction and the like can be safely controlled, so that the risk of explosion during mass production can be avoided.
The ratio of peracid used is preferably about 1 to 2 molar equivalents, more preferably about 1 to 1.2 molar equivalents, relative to compound (V).
Additives other than peracid may be added, if necessary, in order to improve reaction efficiency and yield. 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, 3,5-dihydroxybenzoic acid and the like.
By this reaction, the 1st 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 ratio S-form may be used in the next step without isolation, but is preferably isolated as a salt, a solvate or crystals thereof. If desired, purification by such a method such as crystallization can obtain a very high-purity S-form.

The crystallization method (method of shifting to a supersaturated state) is not particularly limited, and for example, an evaporation method (a method of evaporating a crystallization solvent from a crystallization system) or a cooling method (a crystallization system (or compound (IV) solution)). (Method of cooling), method of adding a poor solvent (method of adding a poor solvent of compound (IV) to the crystallization system), method of adding seed crystals (method of adding seed crystals containing compound (IV) to the crystallization system) Etc. can be exemplified.
For example, an evaporation method (a method of evaporating a crystallization solvent from a crystallization system (or solution) containing a compound (IV) and a crystallization solvent to a hypersaturated state and crystallization from this hypersaturated state) or a cooling method (compound). A seed crystal obtained from a crystallization system (or solution) containing (IV) and a crystallization solvent is cooled to a hypersaturated state and crystallized from this hypersaturated state), and then the compound (IV) is obtained. It can be crystallized by a seed crystal addition method or the like in which seed crystals are added to a solution dissolved in a crystallization solvent and / or an acid to crystallize.
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 of them and water. Depending on the solvent used, crystals of the corresponding solvate can also be obtained. The obtained solvate can also be converted into a non-solvate by air drying, ventilation drying or vacuum drying. 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 the R-form and S-form of 1-sulfoxide have different solubilities in various solvents, the isolation yield of 1-sulfoxide by crystallization or the like is improved in the S-form as compared with the R-form. In addition, since the S-form has higher stability such as storage stability than the R-form, it is possible to stably store it as an intermediate for a longer period of time by increasing the purity of the S-form. .. Further, the S-form crystal has higher stability such as storage stability and coloring stability than the S-form amorphous body, and the formation of decomposition products is suppressed.
Further, in the reaction of the next step, the yield of the compound (III) is preferably improved by about 10% or more by using the S form rather than the 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. Amid 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-methyl tetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.), nitrile solvents (eg Example: One or more selected from acetonitrile, propionitrile, etc.), halogen-based solvent (eg, dichloromethane, chloroform, etc.), ketone-based solvent (eg, acetone, methylethylketone, etc.), dimethylsulfoxide, etc. can be used. An amide solvent or an ether solvent is preferable. Of 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 alkali metal halides (eg, alkali metals iodide (eg, NaI, KI, etc.), alkali metals bromide (eg, NaBr, KBr, etc.), etc.), if necessary. Good. It is preferably an alkali metal iodide. Since the reaction efficiency is improved by adding the alkali metal halide, it is possible to reduce the reaction time and the reagents used and improve the yield.
The ratio of the alkali metal halide used is preferably about 1 to 5 molar equivalents, more preferably about 1 to 3 molar equivalents, relative to compound (IV).
In this reaction, preferably, boric acid or a derivative thereof, boronic acid (: RB (OH) ₂ ); R is a substituent such as an alkyl, a substituted or unsubstituted carbocycle, or a substituted or unsubstituted heterocycle. ) Is performed, the yield is improved by, for example, about 5% or more.
The carbocycle or heterocycle is preferably a 3-10 membered ring, more preferably a 5-6 membered ring. The carbocycle or heterocycle may be a saturated ring or an unsaturated ring. Substituents of the carbocycle or heterocycle 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 alkyl carbamoyl (eg methylcarbamoyl, dimethylcarbamoyl), acyl (eg methylcarbamoyl, dimethylcarbamoyl), acyl : Acetyl, benzoyl) can be exemplified.
The ratio of boric acid or boronic acid used is preferably about 0.1-0.4 molar equivalents, more preferably about 0.1-0.3 molar equivalents, relative to compound (IV).
The obtained compound (III) may be used in the next step without isolation.

(4th step)
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. Amid 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-methyl tetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.), nitrile solvents (eg Example: One or more selected from a halogen-based solvent (eg, dichloromethane, chloroform, etc.), a ketone solvent (eg, acetone, methylethylketone, etc.), etc. can be used. Amide solvents are preferred. Of 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 and iodine, and phosphorus trichloride or phosphorus tribromide is preferable. The reducing agent is preferably dissolved in a solvent and added dropwise, if necessary. By dropping, the peracid can be reacted with the compound (III) at the same time as dropping, and the heat of reaction and the like can be safely controlled, so that the risk of explosion during mass production can be avoided.

(Fifth step)
Removal of each protecting group of compound (II) gives compound (IA), a pharmaceutically acceptable salt thereof, or a solvate thereof.
The reaction may be carried out according to the conditions of each deprotection reaction of an amino group, a hydroxy group or a carboxy group well known to those skilled in the art. Each protecting group may be sequentially deprotected, but preferably one-pot reaction is carried out sequentially without going through an isolation step, 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. Acetate-based solvents (eg, ethyl acetate, propyl acetate, etc.), hydrocarbon-based solvents (eg, toluene, benzene, hexane, etc.), ether-based solvents (eg, cyclopentyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1, 2, -One or more selected from a halogen-based solvent (eg, dichloromethane, chloroform, etc.), a ketone solvent (eg, acetone, methyl ethyl ketone, etc.), etc. can be used. As the solvent, a two-layer solvent with water or a water-containing solvent can be used, if 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. Sulfuric acid is preferred.
Examples of the protecting group (amino protecting group, hydroxy protecting group, carboxy protecting group, etc.) that can be used in the above reaction include Protective Groups in Organic Synthesis, T.I. W. By Greene, John Wiley & Sons Inc. Protecting groups described in (1991) and the like can be mentioned. The introduction and elimination of protecting groups are carried out according to the methods commonly used in synthetic organic chemistry (see, for example, Protective Groups in Organic Synthesis, by T.W. Greene, John Willey & 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 a method well known to those skilled in the art. Preferably, the crude product containing compound (IA) is column treated with a mobile phase (eg, acetonitrile-water and optionally acids such as formic acid, acetic acid, hydrochloric acid and sulfuric acid may be added). An acid addition salt (eg, hydrochloride, sulfate, p-toluenesulfonate, or a mixture thereof) can be concentrated, crystallized, or the like from the eluate containing the obtained compound (IA), if desired. ) May be isolated. The acid addition salt may be a crystal such as a hydrate. Further, the acid addition salt may be converted into an alkali metal salt (eg, sodium salt) by a salt exchange reaction. That is, for example, Na source such as sodium hydroxide aqueous solution or baking soda is added to a solution containing an acid addition salt of compound (IA) or a hydrate thereof, the pH is adjusted to about 5 to 6.5, and concentration under reduced pressure is performed. / Or by lyophilization, a sodium salt of compound (IA) can be obtained.

Pharmaceutically acceptable salts include, for example, acid addition salts or metal salts. The acid of the acid addition salt is selected from, for example, hydrochloric acid, sulfuric acid, nitrate, phosphoric acid, maleic acid, citric acid, tartaric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid or these acids2. Examples include mixed acids of seeds. Examples of the metal salt include sodium salt, potassium salt, calcium salt, magnesium salt and the like.
Examples of the solvate 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 thereof include a benzyloxymethyl group, a benzhydryl group, a 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 and 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) ethoxylymethyl group, Examples thereof include a propenyl group, a phenacyl group, a tetrahydropyranyl group, and a prenyl group. R ⁴ and R ⁵ are independently preferably 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 Alcansulfonyloxy (Lower) Alkyl (eg 2-Mesylethyl), Mono (or Di or Tri) Halo (Lower) Alkyl (Example: 2-iodoethyl, 2,2,2-trichloroethyl), lower alkoxycarbonyloxy (lower) alkyl (eg, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, t-butoxycarbonyloxymethyl, 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), (substitute) aryl (eg, phenyl, p-chlorophenyl, trill, t-butylphenyl, xsilyl) are exemplified. R ² and R ³ are independently preferably a t-butyl group, a p-methoxybenzyl group, and a benzhydryl group, respectively. More preferably, R ² is a t-butyl group, R ³ is a p-methoxybenzyl group or a benzhydryl group, and even more preferably R ³ is a p-methoxybenzyl group.

Furthermore, the present invention provides crystals of compound (IV) in which R ¹ = t-butoxycarbonyl, R ² = t-butyl, R ³ = p-methoxybenzyl. The crystals are preferably a methanol sum, a methanol-hydrate, a hydrate or a solvate. The crystals preferably show 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 ° at least It has 3 peaks.
Preferably, the 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 3 peaks selected from 2 °.
Crystals showing the above pattern are preferably methanol-containing products.
Alternatively, the 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 ° Has at least 3 peaks.
Diffraction angles (2θ): 4.8 ± 0.2 °, 14.4 ± 0.2 °, 14.9 ± 0.2 °, 16.0 ± 0.2 ° and 20.5 ± 0 . At least 3 peaks selected from 2 °.
The crystals showing the above pattern are preferably solvates.

The method for identifying the crystal of the present invention will be described below.
Unless otherwise specified, the numerical values described in the present specification and the scope of claims are approximate values. Numerical fluctuations are due to equipment calibration, equipment errors, material purity, crystal size, sample size, and other factors.

In general, the diffraction angle (2θ) in powder X-ray diffraction may have an error within the range of ± 0.2 °, so the above diffraction angle value is assumed to include a value within the range of about ± 0.2 °. Need to be understood. Therefore, the present invention includes not only crystals in which the diffraction angles of the peaks in powder X-ray diffraction completely match, but also crystals in which the diffraction angles of the peaks match 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 determined by many factors, such as the effect of selective orientation of the crystal on the X-ray beam, the effect of coarse particles, the purity of the material being analyzed or the sample. It is known that it can vary depending on the degree of crystallinity of. The peak position can also be shifted based on fluctuations in sample height. Further, although different shifts are obtained according to Bragg's equation (nλ = 2dsinθ) when measured using different wavelengths, another XRPD pattern obtained by using such different wavelengths is also included in the scope of the present invention.
The characteristic diffraction peak used in the present specification is a peak selected from the observed diffraction patterns. In distinguishing a plurality of crystals, the peaks found in the crystal and not found in the other crystals are the characteristic peaks that are preferable for identifying the crystal, rather than the size of the peak. With such characteristic peaks, one or two peaks can characterize the crystal.

In the present specification, the diffraction peak may be one sharp peak (singlet type) or one gentle peak (broad type), and may be about 2 to 5 multiple peaks (tablet). It may be a multiplet type) such as a shape, a triplet type, a quartet type, or a quintet type), but usually it has one sharp peak in many cases.

The present invention will be described in more detail with reference to the following examples. These do not limit the present invention. Efforts are being made to ensure accuracy with respect to numerical values (eg, quantity, temperature, etc.), but some errors and deviations should be considered. Unless otherwise indicated,% is by weight% of the component and% by weight of the total weight of the composition, and equivalent means 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 carried out 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 carried out under the following measurement conditions according to 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 in which the 2-Theta (2θ) value appears in the vicinity of 38 ° is the peak of aluminum.
(apparatus)
RINT TTR III manufactured by Rigaku
(Method of operation)
Measurement method: Reflection method, Parallel beam method Light source type: Cu tube Wavelength used: CuKα wire tube Current: 300mA
Tube voltage: 50Kv
X-ray incident angle (2θ): 4 ° -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 solution (11-12%) (135 L, 261.1 mol) was added dropwise at −7 ° C. over 2 hours and 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., and the mixture was stirred for 1 hour and 30 minutes, and the precipitated solid was collected by filtration to obtain a undried solid. The undried solid was recrystallized from methanol-water and dried to give compound 10 (46.0 kg, content 57.3%, yield 86.1%).

Step 2: Synthesis of compound 11 Under a nitrogen atmosphere, compound 10 (content conversion 26.0 kg, 139.3 mol) was dissolved in DMA (130 L), pyridine (30.9 kg, 391.2 mol) was added, and the mixture was 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 the mixture was stirred at 53 ° C. for 2 hours. Dilute hydrochloric acid and tetrahydrofuran were added to the reaction mixture for extraction, and the aqueous layer was extracted with tetrahydrofuran. The organic layer was combined and concentrated under reduced pressure. Compound 11 (132.0 kg, content 17.2%, yield 94.4%) was obtained by separating and removing the separated aqueous layer.
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). Suspension of this solution in DMF (47 L) of 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) It was added to the solution at 40 ° C. and stirred at 40 ° C. for 2 hours and 30 minutes. The mixture was cooled to 20 ° C., water and tetrahydrofuran were added for extraction, 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, cooled to 5 ° C., and collected by filtration to give 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 combined with sodium dihydrogen phosphate dihydrate (3.0 kg, 19.3 mol). A 35% hydrogen peroxide solution (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 give compound 13 (32.8 kg, yield 97.6%).
^{1 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. It was dropped and dissolved. This solution was added dropwise to a solution of methanesulfonyl chloride (11.2 kg, 97.8 mol) in tetrahydrofuran at −10 ° C. over 4 hours, and the mixture was stirred for 20 minutes. This reaction solution was added dropwise to a solution of compound 14 (10.2 kg, 89.7 mol) in tetrahydrofuran at −5 ° C. over 2 hours, and the mixture was stirred for 2 hours. Water was added for extraction, acetone (64 L) was added to the organic layer, and then a 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, and then the mixture was stirred 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 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)1st step

Process 1
Compound 2 (254.3 g, 592 mmol) was dissolved in DMA (600 mL) under a nitrogen atmosphere and cooled to −5 ° C. Methanesulfonyl chloride (67.83 g, 592 mmol) was added, triethylamine (59.92 g, 592 mol) was added dropwise at −5 ° C. over 25 minutes, and the mixture was stirred 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), N-methylmorpholine (99.83 g, 987 mmol) was added dropwise at -5 ° C over 20 minutes, and the mixture was added dropwise at -5 ° C over 20 minutes. Was stirred for 60 minutes.
The reaction solution was added to a mixed solution of ethyl acetate and dilute hydrochloric acid, and the mixture was extracted. The organic layer was washed with water, an aqueous sodium hydrogen carbonate solution, and water, and then concentrated under reduced pressure. After adding n-heptane to the obtained residue to precipitate a solid, the mixture was collected by filtration to obtain Compound 6 (373.1 g, yield 97.0%).
^{1 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 <Solvent-free compound seed crystal A synthesis of compound 3>

Step 1: Synthesis of seed crystal A of a solvent-free mixture of Compound 3 Under a nitrogen atmosphere, Compound 6 (120.00 g, 154 mmol) was dissolved in dichloromethane (600 mL) 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 obtained residue to precipitate crystals, which were then cooled to 0 ° C., the crystals were collected by filtration, and air-dried to obtain seed crystals A (92.10 g, yield 75.) of a solvated compound of Compound 3. 2%) was obtained.
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-Consumed Crystal and Solvation-Free Crystal of Compound 3>

Compound 2 (5.83 g, 13.6 mmol) was dissolved in DMA (15 mL) under a nitrogen atmosphere and cooled to −5 ° C. Methanesulfonyl chloride (1.70 g, 14.8 mmol) was added, triethylamine (1.75 g, 17.3 mmol) was added dropwise at −5 ° C. over 90 minutes, and the mixture was stirred at −5 ° C. for 5 minutes. This is added to a suspension of compound 1 (5.00 g, 12.3 mmol) DMA (5 mL) and acetonitrile (22.5 mL) and N-methylmorpholine (2.50 g, 24.7 mmol) at -5 ° C. The mixture was added dropwise over 90 minutes and stirred at −5 ° C. for 30 minutes. Acetonitrile (2.5 mL), 75% refined sulfuric acid (0.81 g), 3,5-dihydroxybenzoic acid (0.50 g), and 39% peracetic acid (2.41 g, 12.4 mmol) 90 at -5 ° C. The mixture was added dropwise over minutes and stirred at −5 ° C. for 30 minutes.
The reaction solution was added to a mixed solution of an aqueous solution of methyl ethyl ketone, sodium bisulfite and sodium chloride, and extracted. The organic layer was washed with a mixed solution of aqueous sodium hydrogen carbonate solution and aqueous ammonia, and then washed with a saline solution. The solvent is concentrated under reduced pressure, methanol is added to the obtained residue, seed crystal A (5.1 mg) is added, crystals are precipitated, methanol-water is added, the mixture is cooled to -10 ° C, and the mixture is collected by filtration. Obtained crystals of the methanol-added product of Compound 3. The crystals were air-dried overnight and dried under reduced pressure at 50 ° C. for 2 hours to obtain crystals of a solvent-free compound of Compound 3 (8.34 g, yield 85%). The water content was measured by volumetric titration by the Karl Fischer method. However, Mitsubishi Chemical's Aquamicron (registered trademark) titrator SS-Z 3 mg was used as the titrator.
^{1 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)
Moisture content (KF method): 0.6131%

The results of powder X-ray diffraction of the obtained methanol-added crystal of Compound 3 are shown in FIGS. 1 and 1.

Diffraction angles 2θ showing characteristic diffraction peaks are 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, it is 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 obtained solvated crystal of Compound 3 are shown in FIGS. 2 and 2.

The 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 °. Preferably, it is 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 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. under a nitrogen atmosphere. Compound 3 (2.00 g, 2.51 mmol) and compound 4 (1.45 g, 2.76 mmol) were added, and the mixture was stirred at 0 ° C. for 6 hours and allowed to stand at 7 ° C. for 17 hours.
It was added to a mixed solution of methyl ethyl ketone and an aqueous sodium hydrogen sulfite solution and extracted. The organic layer was washed twice with a mixed solution of sulfuric acid and 5% saline, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by ODS column chromatography (acetonitrile-sulfuric acid) to obtain Compound 7 (2.60 g, yield 73.2%).
^{1 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 --7.75 (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 WO 2010/050468. Compound (IA) (100 mg) was dissolved in 1.0 mol / L aqueous p-toluenesulfonic acid solution (2 mL) at room temperature using ultrasonic waves, and allowed to stand at 4 ° C. for 4 days. The precipitate was filtered to obtain seed crystal B (73 mg). It was confirmed by a microscope that it was a needle-like crystal.
Step 2: Seed crystal C
Seed crystal 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 Under a nitrogen atmosphere, Compound 2 (35.0 kg, 81.42 mol) was dissolved in DMA (90 L) and cooled to −5 ° C. Methanesulfonyl chloride (10.2 kg, 88.82 mol) was added, triethylamine (10.5 kg, 103.63 mmol) was added dropwise at −5 ° C. over 80 minutes, and the mixture was stirred at −5 ° C. for 30 minutes. This is 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) is added at −5 ° C. for 70 minutes. The mixture was added dropwise, and the mixture was stirred at −5 ° C. for 60 minutes. Acetonitrile (15 L), 75% refined sulfuric acid (4.8 kg), 3,5-dihydroxybenzoic acid (3.00 kg), and peracetic acid (39.8%) (14.14 kg, 74.02 mol) were added at -5 ° C. The mixture was added dropwise over 70 minutes and stirred at −5 ° C. for 140 minutes. The reaction solution was added to a mixed solution of an aqueous solution of methyl ethyl ketone, sodium bisulfite and sodium chloride, and extracted. The organic layer was washed with a mixed solution of aqueous sodium hydrogen carbonate solution and aqueous ammonia, and then washed with a saline solution. 75% refined sulfuric acid was added, the solvent was concentrated under reduced pressure, methanol was added to the obtained residue, seed crystal A (30 g) was added, crystals were precipitated, methanol-water was added, and the mixture was cooled to -10 ° C. The crystals were washed with cold methanol-water and dried under reduced pressure to give 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 raising the temperature to 7 ° C. and stirring for 16 hours, the reaction solution was confirmed to form Compound 7 by HPLC. NMP (18 L) was added to the reaction mixture, cooled to 0 ° C., phosphorus trichloride (4.0 kg, 29.38 mol) was added dropwise at 0 ° C. over 60 minutes, and the mixture was stirred at 0 ° C. for 3 hours before the reaction. The solution was subjected to HPLC to confirm the formation of compound 8.
Anisole (36 L) was added to the reaction solution, and this solution was added to a mixed solution of methyl ethyl ketone and sodium bisulfite aqueous solution for extraction. The organic layer was washed twice with a mixture of sulfuric acid and brine. Anisole (180 L) was added, the mixture was cooled to −5 ° C., 75% refined sulfuric acid (72.0 kg) was added, and the mixture was stirred at 15 ° C. for 90 minutes, and then the reaction solution was confirmed to form compound (IA) by HPLC. 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 chromatographic separation (Diaion ^TM HP20SS). An aqueous solution of 75% refined sulfuric acid (33.3 kg) and p-toluenesulfonic acid monohydrate (16.7 kg) was added to the obtained eluate, and then 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 sulfuric acid water cooled to 5 ° C. to obtain hydrated crystals (16.68 kg, content conversion yield 63.7%) of a mixture of p-toluenesulfonic acid of compound (IA) and sulfuric acid. 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 measurement method was the Japanese Pharmacopoeia General Test Method Moisture (coulometric titration). However, Mitsubishi Chemical's Aquamicron (registered trademark) AX was used as the anode solution, and Aquamicron (registered trademark) CXU was used as the cathode solution. Since the water content measurement by the Karl Fischer method may cause an error within the range of ± 0.3%, it is necessary to understand that the value of the water content includes the value within the 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.
(Method for measuring p-toluenesulfonic acid content)
Step 1: Preparation of sample solution About 40 mg of the sample was precisely weighed and dissolved in a sample diluting solvent to make exactly 25 mL. 2 mL of this solution was accurately weighed, and the sample dilution solvent was added to make exactly 20 mL.
Step 2: Preparation of standard solution
Approximately 25 mg of the standard sodium p-toluenesulfonate product moistened in an environment of 25 ° C./60% RH was precisely weighed and dissolved in a sample dilution solvent to make exactly 100 mL. Weigh accurately 5 mL of this solution and add the sample dilution solvent to make exactly 50 mL.
As the above sample dilution solvent, a 5 mmol / L phosphate buffer solution: an acetonitrile mixture for liquid chromatography (9: 1) was used. Here, as the phosphate buffer solution, water: 0.05 mol / L sodium dihydrogen phosphate test solution: 0.05 mol / L disodium hydrogen phosphate test solution mixed solution = 18: 1: 1 (pH is about 7.1) was used.
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. The dehydrated product conversion is a value calculated assuming that the total amount minus the water content is 100%.
(Test condition)
Column: Unison UK-C18, φ4.6 x 150 mm, 3 μm, made by Imtakt Column temperature: Constant temperature around 35 ° C Flow rate: 1.0 mL / min (holding time of p-toluenesulfonic acid about 7 minutes)
Detector: Ultraviolet absorptiometer (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 formula.
Amount of p-toluenesulfonic acid (%)

M _S: p-weighed amount of toluene sulfonic acid sodium standard (mg)
M _T: weighed amount of sample (mg)
P: Purity (%) of standard sodium p-toluenesulfonate
W _T : Moisture (%) of the sample
_AT : Peak area of p-toluenesulfonic acid obtained from sample solution
_AS : 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

(Sulfuric acid content measurement method)
Step 1: Preparation of standard solution About 50 mg of anhydrous sodium sulfate was precisely weighed and dissolved in the mobile phase to make exactly 25 mL. Weigh accurately 2 mL of this solution and add the mobile phase to make exactly 50 mL. Further, 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 precisely 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 above 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 condition)
Column: Shim-pack IC-A3, φ4.6 × 150 mm, 5 μm, Shimadzu Column temperature: Constant temperature around 40 ° C Flow rate: 1.2 mL / min (sulfate ion retention time approx. 15 minutes)
Detector: Electrical conductivity detector (non-suppressor method)
Mobile phase: Bis-Tris approx. 0.67 g, boric acid approx. 3.09 g, and ground p-hydroxybenzoic acid approx. 1.11 g were precisely 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 x 100 / (100-W _T ) x A _T / A _S x 98.08 / 142.04 x 1/25 x 100

M _S: weighed amount of anhydrous sodium sulfate (mg)
M _T: weighed amount of sample (mg)
W _T : Moisture (%) of the sample
_AS : Peak area of sulfate ion obtained from standard solution
_AT : Peak area of sulfate ion obtained from sample solution
98.08: Molecular weight of sulfuric acid
142.04: Molecular weight of anhydrous sodium sulfate
1/25: Dilution factor (result)
Moisture 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 Under a nitrogen atmosphere, Compound 9 (1.00 g, 0.76 mmol) was dissolved in NMP (4 mL) 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.
It was added to a mixture of ethyl acetate and sodium chloride aqueous solution and extracted. The organic layer was washed twice with 5% salt and 0.75% sulfuric acid water, 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 (10)

The following steps:
(Second step)
Equation (V):

(In the formula, R ¹ is a t-butoxycarbonyl group, R ² is a t-butyl group, and R ³ is a p-methoxybenzyl group.)
The compound represented by (IV) and peracetic acid are reacted in the presence of acetonitrile using the formula (IV):

(In the formula, R ¹ , R ² and R ³ have the same meaning as described above)
In characterized and Turkey give a compound represented, the compound represented by Formula (IV), its pharmaceutically acceptable salt or method of manufacturing a solvate thereof. The following steps:
(Second step)
Equation (V):

(In the formula, R ¹ is a t-butoxycarbonyl group, R ² is a t-butyl group, and R ³ is a p-methoxybenzyl group.)
The compound represented by (1) and peracetic acid are reacted in a mixed solvent of acetonitrile and N, N-dimethylacetamide, and the formula (IV):

(In the formula, R ¹ , R ² and R ³ have the same meaning as described above)
In characterized and Turkey give a compound represented, the compound represented by Formula (IV), its pharmaceutically acceptable salt or method of manufacturing a solvate thereof. The following steps:
(First step) Equation (VI):

(In the formula, R ³ is a p-methoxybenzyl group)
Compound represented by and formula (VIII):

(In the formula, each symbol has the same meaning as claim 1)
The compound represented by is reacted, and the formula (V):

(In the formula, each symbol has the same meaning as claim 1)
The step of obtaining the compound represented by (2nd step).
The step of reacting the compound represented by the formula (V) with peracetic acid in the presence of acetonitrile as a solvent to obtain the compound represented by the formula (IV) is continuously carried out.

(In the formula, each symbol has the same meaning as claim 1)
In the compound represented manufacturing method of a pharmaceutically acceptable salt thereof, or a solvate thereof. The following steps:
(Third step)
Equation (IV):

(In the formula, each symbol has the same meaning as claim 1)
Compound represented by and formula (X):

(In the formula, R ⁴ and R ⁵ are p-methoxybenzyl groups.)
Was reacted in the presence of boric acid or boronic acid to formula (III):

(In the formula, X- is a counter ion, R ⁴ and R ⁵ are p-methoxybenzyl groups, and other symbols have the same meaning as claim 1).
In characterized and Turkey give a compound represented, compounds of formula (III), its pharmaceutically acceptable salt or method of manufacturing a solvate thereof. The following steps:
(4th step)
The manufacturing method of claim 4, wherein (III):

(In the formula, each symbol has the same meaning as claim 4 )
Formula (II):

(In the formula, each symbol has the same meaning as claim 4 )
In characterized and Turkey give a compound represented, the compound represented by Formula (II), a pharmaceutically acceptable salt or method of manufacturing a solvate thereof. The following steps:
(4th step)
The manufacturing method of claim 4, wherein (III):

(In the formula, each symbol has the same meaning as claim 4 )
The compound represented by the above formula (III) was obtained, and the obtained compound represented by the formula (III) was reduced to obtain the compound represented by the formula (II):

(In the formula, each symbol has the same meaning as claim 4 )
Step of obtaining the compound represented by (5th step)
Deprotecting the compound represented by formula (II) to formula (IA):

The step of obtaining the compound represented by (1) is carried out continuously.
A method for producing a compound represented by the formula (IA), a pharmaceutically acceptable salt thereof, or a solvate thereof. The following steps:
(Third step) Equation (IV):

(In the formula, each symbol has the same meaning as claim 1)
Compound represented by and formula (X):

(In the formula, each symbol has the same meaning as claim 4 )
The compound represented by is reacted in the presence of boric acid or boronic acid to formula (III) :

(In the formula, each symbol has the same meaning as claim 4)
Step to obtain the compound indicated by;
(Fourth step) The compound represented by the formula (III) is reduced to the formula (II) :

(In the formula, each symbol has the same meaning as claim 4)
In obtaining a compound represented; and wherein the benzalkonium give the compound of formula (IA) and (Step 5) The compound represented by formula (II) is deprotected, according to claim 6, wherein A method for producing a compound represented by the formula (IA), a pharmaceutically acceptable salt thereof , or a solvate thereof. The following steps:
(Second step) Equation (V):

(In the formula, each symbol has the same meaning as claim 1 )
The compound represented by (IV) is reacted with peracetic acid to formula (IV):

(In the formula, each symbol has the same meaning as claim 1)
Step to obtain the compound indicated by;
(Third step) The compound represented by the formula (IV) and the formula (X):

(In the formula, each symbol has the same meaning as claim 4 )
The compound represented by is reacted in the presence of boric acid or boronic acid to formula (III) :

(In the formula, each symbol has the same meaning as claim 4)
Step to obtain the compound indicated by;
(Fourth step) The compound represented by the formula (III) is reduced to the formula (II) :

(In the formula, each symbol has the same meaning as claim 4)
And (Fifth Step) Formula (II) deprotecting the compound represented by by formula according to claim 6, wherein the benzalkonium give the compound of formula (IA); obtaining a compound represented by in A method for producing a compound represented by (IA), a pharmaceutically acceptable salt thereof , or a solvate thereof. Equation (III):

(In the formula, each symbol has the same meaning as claim 4 )
The compound indicated by. Equation (II):

(In the formula, each symbol has the same meaning as claim 4 )
The compound indicated by.

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