WO2010073706A1

WO2010073706A1 - Improved process for producing intermediate for side chain of carbapenem

Info

Publication number: WO2010073706A1
Application number: PCT/JP2009/007261
Authority: WO
Inventors: 揚野貴文; 岡島基範; 古賀照義
Original assignee: 株式会社カネカ
Priority date: 2008-12-25
Filing date: 2009-12-25
Publication date: 2010-07-01
Also published as: CN102264744A

Abstract

Disclosed is a process for producing a pyrrolidine derivative usable as an intermediate for the production of a side chain of a carbapenem compound in a simple manner and in high yield, which utilizes a readily applicable and relatively inexpensive reagent and is not required to isolate a thiocarboxylic acid (an intermediate). Specifically, a reaction is carried out by adding an aqueous metal sulfide solution to a compound represented by formula (2) at an agitation power consumption per unit volume of 0.2 kW/m³ or more while adjusting the value calculated by dividing the amount of the aqueous metal sulfide solution added per second by the total amount of the aqueous metal sulfide solution added to 0.003 to 0.2.

Description

Improved process for the preparation of carbapenem side chain intermediates

The present invention relates to a method for producing a carbapenem side chain. Specifically, the present invention relates to a method for producing an intermediate of a carbapenem side chain containing a pyrrolidino group.

The following formula (1):

(Wherein P represents an amino-protecting group) (in this specification, it may be referred to as “compound (1)”. The same applies to other compounds). It is used when constructing the 2-position side chain portion of a carbapenem compound having excellent antibacterial activity.

Conventionally, as a method for producing compound (1), for example, the following methods are known.

1) The following formula (4):

(Wherein P is the same as described above) is reacted with isopropyl chlorocarbonate in the presence of triethylamine in methylene chloride to give the following formula (3a):

(Wherein P is the same as above, R represents an isopropyl group). Thereafter, the compound (3a) is reacted with methanesulfonyl chloride in the presence of triethylamine to give the following formula (2a):

(Wherein P and R are the same as above; R 'represents a methyl group). Further, a thiocarboxylic acid compound obtained by excessively reacting compound (2a) with hydrogen sulfide gas in the presence of triethylamine is isolated, and then refluxed in the presence of triethylamine in methylene chloride to synthesize compound (1). (Patent Document 1, Non-Patent Document 1).

2) The compound (4) is reacted with diphenylphosphine chloride in the presence of diisopropylethylamine in THF to obtain a compound corresponding to the above compound (3a). Thereafter, the compound is reacted with methanesulfonyl chloride in the presence of pyridine to obtain a compound corresponding to the compound (2a). Furthermore, the said compound is made to react with sodium sulfide aqueous solution, and a compound (1) is synthesize | combined (patent document 2, nonpatent literature 2).

JP-A-5-186476 WO97 / 06154

In the methods described in Patent Document 1 and Non-Patent Document 1, anhydrous hydrogen sulfide gas, which is highly toxic, is used. Further, it is necessary to once isolate the intermediate thiocarboxylic acid. For this reason, there is a problem in manufacturing on an industrial scale from the viewpoint of safety and operability.

In the methods described in Patent Document 2 and Non-Patent Document 2, diisopropylethylamine and diphenylphosphine acid chloride are used as reagents for preparing a compound corresponding to compound (3a). Moreover, the compound (1) is synthesized with good results by using pyridine and methanesulfonyl chloride as reagents for methanesulfonylation of hydroxyl groups and using an aqueous sodium sulfide solution as a sulfide source. In this method, in order to improve the stability of the mixed acid anhydride corresponding to the compound (2a) to water, a special reagent diphenylphosphinic acid chloride is used. However, diphenylphosphine acid chloride is not readily available and expensive. Furthermore, THF used as a solvent, diisopropylethylamine and pyridine used as a base are also relatively expensive. Therefore, it is not satisfactory from the viewpoint of raw material availability and economy.

Furthermore, in the method described in Non-Patent Document 2, it is suggested that isobutyl chlorocarbonate can be used in place of diphenylphosphine acid chloride, but relatively expensive pyridine is used for methanesulfonylation of a hydroxyl group. However, it was not satisfactory from the viewpoint of economy.

In view of the above problems, the present inventors have intensively studied a method for producing Compound (1) with a simple operation and using a readily available raw material with high yield, and have completed the present invention.

That is, the present invention has the following formula (2):

(In the formula, P represents an amino-protecting group. R ¹ is an optionally substituted alkyl group having 1 to 7 carbon atoms, an optionally substituted alkenyl group having 3 to 6 carbon atoms, or a substituted group.) Represents an optionally substituted aryl group having 6 to 12 carbon atoms, and R ² represents an optionally substituted alkyl group or an optionally substituted aryl group. The required stirring power per hit is 0.2 kW / m ³ or more, and the following formula (I):
(Amount of metal sulfide aqueous solution added per second) / (total amount of metal sulfide aqueous solution added) (I)
The metal sulfide aqueous solution is added while controlling so that the value of is 0.003 to 0.2, the following formula (1):

(Wherein P is the same as defined above).

The present invention also provides the compound (1) obtained as described above and the following formula (6):
NHR ³ R ⁴ (6)
(Wherein R ³ and R ⁴ are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted alkenyl group having 2 to 6 carbon atoms, substituted) Represents any of an optionally substituted aryl group having 6 to 12 carbon atoms and an optionally substituted heteroaryl group having 4 to 12 carbon atoms, and R ³ and R ⁴ are each bonded to A 4- to 8-membered optionally substituted cyclic amine compound may be formed together with the nitrogen atom, and the amine compound represented by the following formula (7): ):

(Wherein P, R ³ and R ⁴ are the same as defined above), and a method for producing a 4-mercaptopyrrolidine derivative.

Furthermore, the present invention provides the following formula (8) by deprotecting the protecting group P of the compound (7) obtained as described above with a deprotecting agent:

(Wherein R ³ and R ⁴ are the same as defined above) and a method for producing a 4-mercaptopyrrolidine derivative or a mineral acid salt thereof.

According to the method of the present invention, the compound (1) can be obtained in a high yield by a simple operation using an easily available and relatively inexpensive reagent and without isolating the intermediate thiocarboxylic acid. Can be manufactured.

Hereinafter, the present invention will be described in detail for each step.

Step (A)
In this step, the following formula (4):

And a compound represented by the following formula (5):
ClCOOR ¹ (5)
Is reacted in the presence of a trialkylamine in a poorly water-soluble organic solvent to obtain the following formula (3):

Is synthesized.

P represents an amino-protecting group. Specifically, it is described in Protective Groups in Organic Synthesis 4th Edition (PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 4th. Ed.), JOHN WILEY & SONS Publication (2006) Protecting groups can be used.

Examples of P include an optionally substituted alkoxycarbonyl group having 1 to 6 carbon atoms, an optionally substituted alkenyloxycarbonyl group having 2 to 6 carbon atoms, an optionally substituted benzyloxycarbonyl group, and a substituted group. An optionally substituted benzyl group, an optionally substituted trialkylsilyl group having 3 to 9 carbon atoms, an optionally substituted dialkylarylsilyl group having 8 to 12 carbon atoms, and an optionally substituted carbon number Examples thereof include 13 to 16 alkyldiarylsilyl groups or triarylsilyl groups.

4-nitrobenzyloxycarbonyl group, t-butyloxycarbonyl group, benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, allyloxycarbonyl group, more preferably 4-nitrobenzyloxycarbonyl group, t A -butyloxycarbonyl group, most preferably a t-butyloxycarbonyl group.

Preferred examples of the compound represented by compound (4) include optically active trans-4-hydroxy-L-proline in which an amino group is protected.

In the present invention, the compound (4) used as a raw material can be synthesized by a known method. When P is a 4-nitrobenzyloxycarbonyl group, for example, according to the method described in JP-A-4-217661, trans-4-hydroxy-L-proline is converted to 4-nitrobenzyl chlorocarbonate in the presence of a base. It can be prepared by reacting with.

R ¹ is an optionally substituted alkyl group having 1 to 7 carbon atoms, an optionally substituted alkenyl group having 3 to 6 carbon atoms, and an optionally substituted aryl group having 6 to 12 carbon atoms. .

Examples of the optionally substituted alkyl group having 1 to 7 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, t-butyl group, isobutyl group, n -Pentyl group, 3-pentyl group, neopentyl group, cyclopentyl group, n-hexyl group, cyclohexyl group, 2-chloroethyl group, 2-cyanoethyl group, 2-methoxyethyl group, 2-nitroethyl group, benzyl group, 4-nitro Examples include benzyl group, 4-methoxybenzyl group, 4-chlorobenzyl group and the like.

Examples of the optionally substituted alkenyl group having 3 to 6 carbon atoms include allyl group and 2-butenyl group.

Examples of the optionally substituted aryl group having 6 to 12 carbon atoms include a phenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, a 4-nitrophenyl group, and a 4-chlorophenyl group.

The amount of the chlorocarbonate (5) used is usually 1.0 mol or more, preferably 1.05 mol or more, relative to 1 mol of the compound (4). Although an upper limit is not specifically limited, Usually, it is 2.0 mol or less, Preferably it is 1.5 mol or less.

Examples of the trialkylamine include triethylamine, trimethylamine, tributylamine, diisopropylethylamine and the like. The trialkylamine is preferably triethylamine and / or trimethylamine.

The amount of trialkylamine used is usually 1.0 mol or more, preferably 1.05 mol or more, relative to 1 mol of the compound (4). Although an upper limit is not specifically limited, Usually, it is 2.5 mol or less, Preferably it is 2.0 mol or less. However, it is preferable to use 1.0 mol or more and 1.5 mol or less with respect to 1 mol of chlorocarbonic acid ester from the viewpoint of economical aspect and suppression of impurity generation.

As the reaction solvent, a poorly water-soluble organic solvent is used. Here, the poorly water-soluble organic solvent means a solvent having a saturated solubility of water of 1 wt% or less with respect to the solvent at room temperature.

Examples of the poorly water-soluble organic solvent include halogenated hydrocarbon solvents such as methylene chloride, chloroform and 1,2-dichloroethane, aromatic hydrocarbon solvents such as benzene, toluene, xylene, chlorobenzene and nitrobenzene, and n-hexane. And hydrocarbon solvents such as cyclohexane, and two or more of them may be used as necessary. Among these, halogenated hydrocarbon solvents and aromatic hydrocarbon solvents are preferable, and methylene chloride, chloroform, 1,2-dichloroethane, toluene, chlorobenzene, and nitrobenzene are particularly preferable from the viewpoint of suppressing yield reduction.

The amount of the solvent used is usually 5 to 50 as the weight ratio of the solvent to the compound (4), and preferably 15 to 40 from the viewpoint of suppressing the yield reduction.

The reaction temperature is usually −25 to 0 ° C., preferably in the range of −20 to −5 ° C. from the viewpoint of suppressing the yield reduction.

The order of addition of the reagents is not particularly limited, but from the viewpoint of suppressing the formation of impurities, after mixing compound (4) and chlorocarbonate in a solvent, trialkylamine is added, or chlorocarbonate is dissolved in the solvent. It is preferable to add a mixture (solution, salt, etc.) of compound (4) and trialkylamine.

The compound (3) obtained as described above can be used as it is in the next step without isolation.

Process (B)
Next, the compound (3) is reacted with a sulfonic acid halide in the presence of a trialkylamine to give a sulfonylated hydroxyl group, which is a mixed acid anhydride represented by the following formula (2):

The process of obtaining the compound represented by this is demonstrated.

In general formula (2), P, R ¹ and R ² are the same as described above.

Examples of the sulfonic acid halide include methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride and the like. Among them, use of methanesulfonyl chloride and / or optionally substituted benzenesulfonyl chloride is preferable from the viewpoint of economy. .

The amount of the sulfonic acid halide used is usually 1.0 mol or more, preferably 1.05 mol or more, relative to 1 mol of the compound (3). Although an upper limit is not specifically limited, Usually, it is 3.0 mol or less, Preferably it is 2.5 mol or less from a viewpoint of economical aspect and impurity production suppression.

Examples of the trialkylamine include triethylamine, trimethylamine, tributylamine, diisopropylethylamine and the like. The trialkylamine is preferably triethylamine and / or trimethylamine. In this reaction, pyridine or the like has been conventionally used as a base, and the present inventors have found that the target compound can be obtained in a high yield by using an inexpensive trialkylamine.

The amount of the trialkylamine used is usually 1.0 mol or more, preferably 1.05 mol or more, relative to 1 mol of the compound (3). Although an upper limit is not specifically limited, Usually, it is 3.5 mol or less, Preferably it is 3.0 mol or less from an economical viewpoint and a viewpoint of impurity production suppression.

The order of addition of the reagents is not particularly limited, and the trialkylamine may be added to the solution containing the compound (3) after mixing the sulfonic acid halide with the solution containing the compound (3). After mixing, the sulfonic acid halide may be added, or the sulfonic acid halide and the trialkylamine may be added simultaneously or alternately to the solution containing the compound (3).

The compound (2) obtained as described above can be used as it is in the next step without isolation.

In this step, the compound (3) may be the one obtained by the step (A) or the one obtained by other methods.

Process (C)
Next, the compound (2) is reacted with a metal sulfide aqueous solution to form the following formula (1):

The process of obtaining the compound represented by this is demonstrated.

In general formula (1), P is the same as described above.

Examples of the metal sulfide include sodium sulfide, lithium sulfide, potassium sulfide, calcium sulfide, and sodium hydrosulfide. Of these, sodium sulfide and sodium hydrosulfide are preferable from the viewpoints of availability and economy. The metal sulfide may be an anhydride or a hydrate.

The amount of metal sulfide used is usually 1.0 mol or more, preferably 1.05 mol or more, relative to 1 mol of compound (2). Although an upper limit is not specifically limited, Usually, it is 2.0 mol or less, Preferably it is 1.5 mol or less from a viewpoint of economical aspect and impurity production suppression.

The metal sulfide is used as an aqueous solution, and the concentration of the metal sulfide is preferably 10 to 50 wt%, more preferably 15 to 40 wt%. Since the compound (2) is unstable with respect to water, if the concentration of the metal sulfide is 10 wt% or less, the yield decreases, impurities increase, and the size of the reaction vessel used increases. Therefore, it is not preferable from the viewpoint of productivity. Further, if the concentration of the metal sulfide is 50 wt% or more from the viewpoint of the solubility of the metal sulfide, the metal sulfide is not easily dissolved in water, which is not preferable from the viewpoint of operability. The temperature of the aqueous metal sulfide solution is not particularly limited, but is usually 0 to 50 ° C., and preferably 10 to 30 ° C. from the viewpoint of operability.

This metal sulfide aqueous solution needs to be quickly added to the reaction solution containing the compound (2). The inventors have determined the addition rate of this aqueous metal sulfide solution by the following formula (I):
(Amount of metal sulfide aqueous solution added per second) / (total amount of metal sulfide aqueous solution added) (I)
It was found that the target compound can be obtained in good yield by adjusting the value of to 0.003 to 0.2. When this value is less than 0.003, that is, when the addition time is 5 minutes or more, the amount of impurities increases dramatically, resulting in a decrease in the yield of compound (1). This is considered to be because the compound (2) is easily decomposed by water. On the other hand, in order to make the value of the above formula (I) larger than 0.2, that is, to make the addition time shorter than 5 seconds, special equipment is required in industrial production, which is preferable from the viewpoint of industrial implementation. Absent.

In addition, the present inventors have found that when the metal sulfide aqueous solution and the solution containing the compound (2) are reacted, the target compound can be obtained in a high yield by performing the reaction under strong flow. If the flow of the reaction solution is poor, the yield of the compound (1) is remarkably lowered and the amount of impurities increases, which is not preferable. The stirring power per unit volume for maintaining a good yield is 0.2 kW / m ³ or more, preferably 0.3 kW / m ³ or more. The upper limit is not particularly limited, but is usually 10 kW / m ³ or less. The flow is usually given by the rotation of a stirring blade, but it is not always necessary to use the stirring blade as long as the flow is obtained. For example, a method by circulating liquid may be used.

The reaction temperature is usually in the range of −25 to 0 ° C. and preferably in the range of −20 to −5 ° C. from the viewpoint of suppressing the yield reduction when the addition of the metal sulfide aqueous solution is started. After adding the metal sulfide aqueous solution, the reaction temperature is quickly raised and the reaction is continued.

The reaction after adding the metal sulfide aqueous solution is usually carried out in the range from 0 ° C. to the boiling point of the solvent, preferably 10 to 60 ° C., and more preferably 20 to 50 ° C. from the viewpoint of suppressing impurity formation. It is. The post-reaction time can be appropriately determined by tracking the progress of the reaction with HPLC or the like.

The compound (1) synthesized as described above is subjected to liquid separation, washing, drying, concentration, column chromatography, etc., if necessary, followed by crystallization to obtain crystals of the compound (1). You can also.

In this step, as the compound (2), one obtained by the step (B) may be used, or one obtained by other methods may be used.

Process (D)
Further, the compound (1) obtained as described above is represented by the following formula (6):
NHR ³ R ⁴ (6)
By reacting with an amine compound represented by the following formula (7):

The compound represented by these can be manufactured.

R ³ and R ^{4 in the} above formulas (6) and (7) are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted carbon number 2 to Or an optionally substituted aryl group having 6 to 12 carbon atoms and an optionally substituted heteroaryl group having 4 to 12 carbon atoms. R ³ and R ⁴ may form a 4- to 8-membered optionally substituted cyclic amine compound together with the nitrogen atom to which each is bonded.

Examples of the optionally substituted alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, and an isopropyl group. Examples of the optionally substituted alkenyl group having 2 to 6 carbon atoms include vinyl group, allyl group and 2-butenyl group. Examples of the optionally substituted aryl group having 6 to 12 carbon atoms include phenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 4-nitrophenyl group, 4-chlorophenyl group, 3-carboxyphenyl group, 4 -A carboxyphenyl group etc. can be illustrated. Examples of the optionally substituted heteroaryl group having 4 to 12 carbon atoms include a furyl group, a pyridyl group, a thienyl group, and a 5-carboxythienyl group. Examples of the optionally substituted cyclic amine compound that forms a 4- to 8-membered ring with the nitrogen atoms bonded to each other include azetidine, pyrrolidine, piperidine, 4-methylpiperidine, 4-propylpiperidine and the like.

Among these, R ³ and R ⁴ are preferably a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted aryl group having 6 to 12 carbon atoms. Further, preferably as a combination of ^{R 3} and ^{R 4,} ^{R 3} and ^{R 4} are methyl, or, ^{R 3} is a hydrogen atom ^{R 4} is 3-carboxyphenyl group.

The amine compound of compound (6) may be used in the reaction in the form of a mineral salt thereof or in the presence of a base. Examples of the base used in the reaction in the presence of a base include alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium carbonate, Examples thereof include alkali metal carbonates such as potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, trialkylamines such as triethylamine and diisopropylamine, and pyridine compounds such as pyridine and lutidine.

The amount of the amine compound used is usually 1.0 mol or more, preferably 1.05 mol or more, relative to 1 mol of the compound (1). Although an upper limit is not specifically limited, Usually, it is 2.0 mol or less, Preferably it is 1.5 mol or less from a viewpoint of economical aspect and impurity production suppression.

Examples of the reaction solvent include carboxylic acid solvents such as acetic acid and propionic acid, halogenated hydrocarbon solvents such as methylene chloride and 1,2-dichloroethane, nitrile solvents such as acetonitrile, and ether solvents such as THF and diethyl ether. Examples of the solvent include ester solvents such as ethyl acetate and butyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, and water. Moreover, those 2 or more types can also be used as needed.

The amount of the solvent used is usually in the range of 5 to 50, preferably 15 to 40, as the weight ratio of the solvent to the compound (1).

The reaction temperature is usually −10 to 70 ° C., preferably in the range of −5 to 50 ° C. from the viewpoint of suppressing impurity formation and solubility of the amine compound.

The reaction time can be appropriately determined by tracking the progress of the reaction with HPLC or the like.

Compound (7) synthesized as described above is subjected to liquid separation, washing, drying, concentration, column chromatography, and the like as necessary, followed by crystallization by a general method to obtain compound (7). Crystals can also be obtained.

Process (E)
The compound (7) obtained as described above has the following formula (8) by deprotecting the protecting group P with a deprotecting agent:

The 4-mercaptopyrrolidine derivative represented by the formula (1) or a mineral acid salt thereof can be produced.

In said formula (8), R < ³ >, R < ⁴ > is the same as the above.

Specifically, the deprotecting agent can be deprotected by the deprotecting method described in the above-mentioned Protective Groups in Organic Synthesis 4th edition.

In particular, when the protecting group is a t-butyloxycarbonyl group, it can be deprotected by reacting with a protonic acid.

Examples of the protonic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, methanesulfonic acid, and 4-toluenesulfonic acid, with hydrochloric acid being preferred.

The amount of protonic acid used is usually 1.0 mol or more per 1 mol of compound (1). Although an upper limit is not specifically limited, Usually, it is 5.0 mol or less, Preferably it is 3.0 mol or less from a viewpoint of impurity production suppression.

The amount of the solvent used is usually in the range of 5 to 50, preferably 5 to 30, as the weight ratio of the solvent to the compound (1).

The reaction temperature is usually −10 to 50 ° C., preferably from −5 to 30 ° C. from the viewpoint of suppressing impurity formation.

Compound (8) synthesized as described above is subjected to liquid separation, washing, drying, concentration, column chromatography, and the like as necessary, followed by crystallization by a general method to obtain compound (8). Crystals can also be obtained.

Hereinafter, the present invention will be further clarified by describing examples and comparative examples, but the present invention is not limited thereto.

In the following Examples and Comparative Examples, analysis was performed using the following HPLC analysis conditions.

[HPLC analysis conditions]
Model: LC-10A series manufactured by Shimadzu Corporation Column: ODS column manufactured by Nacalai Tesque Cosmosil 5C18 AR-II (4.6 mm × 250 mm)
Eluent: acetonitrile / phosphate buffer (pH 3.0) = 40/60 (v / v)
Flow rate: 1.0 ml / min
Detection: 274 nm (UV detector)
Temperature: 40 ° C

Example 1
A mixture of 666 mL of methylene chloride, 16.4 g (133.8 mmol) of isopropyl chlorocarbonate and 36.0 g (116.0 mmol) of the compound (4) in which P is a 4-nitrobenzyloxycarbonyl group was mixed with triethylamine 15 at −15 ° C. .3 g (0.151 mol) was added, and the mixture was stirred at the same temperature for 1 hour. Then, 15.3 g (133.6 mmol) of methanesulfonyl chloride and 14.1 g (139.3 mmol) of triethylamine were sequentially added, and the mixture was stirred at the same temperature for 1 hour. Stir. Thereafter, the power required for stirring per unit volume was set to 1.4 kW / m ³ , and a sodium sulfide aqueous solution prepared in advance using sodium sulfide nonahydrate 33.4 g (139.1 mmol) and water 72 g was added for 30 seconds. After addition in (formula (I) = 0.033), the mixture was refluxed for 2 hours. Thereafter, the reaction solution was cooled to 25 ° C. and separated, and the obtained organic layer was washed successively with dilute hydrochloric acid, sodium bicarbonate water, and water. The amount of the compound (1) in the organic layer thus obtained was 30.4 g (98.6 mmol, yield 85%). After washing, the solvent was distilled off, and the residue was purified by silica gel chromatography (ethyl acetate / hexane = 1/1 volume ratio) to obtain compound (1) as a solid.

¹ H-NMR (CDCl ₃ ) of the obtained solid was ¹ H-NMR (CDCl ₃ ) δ2.11-2.27 (2H, m), 3.67-3.72 (1H, m), 3. 85-3.90 (1H, m), 4.15-4.19 (1H, m), 4.62-4.70 (1H, m), 5.21 (1H, d, J = 13.7 Hz) ), 5.31 (1H, d, J = 13.7 Hz), 7.54 (2H, d, J = 8.6 Hz), 8.23 (2H, d, J = 8.6 Hz), and the heterocycle In line with Heterocycles, pages 147-159, 1995.

(Example 2)
To a mixed solution of 300 mL of toluene, 4.5 g (36.7 mmol) of isopropyl chlorocarbonate and 10.0 g (32.2 mmol) of the compound (4) in which P is a 4-nitrobenzyloxycarbonyl group, triethylamine 4. After adding 2 g (41.5 mmol) and stirring at the same temperature for 1 hour, 4.9 g (42.8 mmol) of methanesulfonyl chloride and 4.5 g (44.5 mmol) of triethylamine were sequentially added and stirred at the same temperature for 1 hour. did. Thereafter, the power required for stirring per unit volume was set to 1.0 kW / m ³ , and a sodium sulfide aqueous solution prepared in advance with 9.3 g (38.7 mmol) of sodium sulfide nonahydrate and 20 g of water was added for 30 seconds. After the addition in (Formula (I) = 0.033), the reflux was started immediately, and the mixture was stirred for 2 hours while refluxing. Thereafter, the reaction solution was cooled to 25 ° C. and separated, and the obtained organic layer was washed successively with dilute hydrochloric acid, sodium bicarbonate water, and water. The amount of the compound (1) in the organic layer thus obtained was quantified by HPLC and found to be 6.7 g (21.7 mmol, yield 67%).

(Comparative Example 1)
A mixture of 185 mL of methylene chloride, 4.5 g (36.7 mmol) of isopropyl chlorocarbonate and 10.0 g (32.2 mmol) of the compound (4) in which P is a 4-nitrobenzyloxycarbonyl group was mixed with triethylamine 4 at −15 ° C. 0.2 g (41.5 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. Then, 4.9 g (42.8 mmol) of methanesulfonyl chloride and 4.5 g (44.5 mmol) of triethylamine were sequentially added, and the mixture was stirred at the same temperature for 1 hour. Stir. Thereafter, the power required for stirring per unit volume was set to 0.1 kW / m ³ , and a sodium sulfide aqueous solution prepared in advance with 9.3 g (38.7 mmol) of sodium sulfide nonahydrate and 20 g of water was added for 10 seconds. After the addition according to (Formula (I) = 0.1), the reflux was immediately started, and the mixture was stirred for 2 hours while refluxing. Thereafter, the reaction solution was cooled to 25 ° C. and separated, and the obtained organic layer was washed successively with dilute hydrochloric acid, sodium bicarbonate water, and water. The amount of compound (1) in the organic layer thus obtained was determined by HPLC and found to be 4.2 g (13.6 mmol, yield 43%).

(Comparative Example 2)
A mixture of 185 mL of methylene chloride, 4.5 g (36.7 mmol) of isopropyl chlorocarbonate and 10.0 g (32.2 mmol) of the compound (4) in which P is a 4-nitrobenzyloxycarbonyl group was mixed with triethylamine 4 at −15 ° C. 0.2 g (41.5 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. Then, 4.9 g (42.8 mmol) of methanesulfonyl chloride and 4.5 g (44.5 mmol) of triethylamine were sequentially added, and the mixture was stirred at the same temperature for 1 hour. Stir. Thereafter, the power required for stirring per unit volume was set to 0.01 kW / m ³ , and a sodium sulfide aqueous solution prepared in advance with 9.3 g (38.7 mmol) of sodium sulfide nonahydrate and 20 g of water was added for 10 seconds. After the addition according to (Formula (I) = 0.1), the reflux was immediately started, and the mixture was stirred for 2 hours while refluxing. Thereafter, the reaction solution was cooled to 25 ° C. and separated, and the obtained organic layer was washed successively with dilute hydrochloric acid, sodium bicarbonate water, and water. The amount of the compound (1) in the organic layer thus obtained was quantified by HPLC and found to be 3.0 g (9.7 mmol, yield 30%).

(Example 3)
A mixture of 185 mL of methylene chloride, 4.5 g (36.7 mmol) of isopropyl chlorocarbonate and 10.0 g (32.2 mmol) of the compound (4) in which P is a 4-nitrobenzyloxycarbonyl group was mixed with triethylamine 4 at −10 ° C. 0.2 g (41.5 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. Then, 4.9 g (42.8 mmol) of methanesulfonyl chloride and 4.5 g (44.5 mmol) of triethylamine were sequentially added, and the mixture was stirred at the same temperature for 1 hour. Stir. Thereafter, the power required for stirring per unit volume was set to 0.3 kW / m ³ , and a sodium sulfide aqueous solution prepared in advance with 9.3 g (38.7 mmol) of sodium sulfide nonahydrate and 20 g of water was added for 10 seconds. After the addition according to (Formula (I) = 0.1), the reflux was immediately started, and the mixture was stirred for 2 hours while refluxing. Thereafter, the reaction solution was cooled to 25 ° C. and separated, and the obtained organic layer was washed successively with dilute hydrochloric acid, sodium bicarbonate water, and water. The amount of the compound (1) in the organic layer thus obtained was quantified by HPLC, and it was 8.0 g (25.9 mmol, yield 81%).

Example 4
To a mixed solution of 2220 mL of methylene chloride, 54.4 g (443.9 mmol) of isopropyl chlorocarbonate and 120 g (386.8 mmol) of the compound (4) in which P is a 4-nitrobenzyloxycarbonyl group, 50.8 g of triethylamine at −10 ° C. (502.0 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. Then, 70.8 g (618.1 mmol) of methanesulfonyl chloride and 64.4 g (636.4 mmol) of triethylamine were sequentially added, and the mixture was stirred at the same temperature for 1 hour. . Thereafter, the power required for stirring per unit volume was set to 0.7 kW / m ³ , and an aqueous sodium sulfide solution prepared in advance with 112 g (466.3 mmol) of sodium sulfide nonahydrate and 240 g of water was added for 30 seconds (formula After the addition at (I) = 0.033), the reflux was immediately started and stirred for 2 hours while refluxing. Thereafter, the reaction solution was cooled to 25 ° C. and separated, and the obtained organic layer was washed successively with dilute hydrochloric acid, sodium bicarbonate water, and water. The amount of the compound (1) in the organic layer thus obtained was quantified by HPLC, and it was 100.1 g (324.7 mmol, yield 84%).

(Example 5)
To a mixture of 555 mL of methylene chloride, 14.4 g (117.5 mmol) of isopropyl chlorocarbonate and 30.0 g (96.7 mmol) of the compound (4) in which P is a 4-nitrobenzyloxycarbonyl group, triethylamine 12 was added at −10 ° C. 0.8 g (126.5 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. Then, 12.7 g (110.9 mmol) of methanesulfonyl chloride and 11.9 g (117.6 mmol) of triethylamine were sequentially added, and the mixture was stirred at the same temperature for 1 hour. Stir. Thereafter, the power required for stirring per unit volume was set to 1.0 kW / m ³ , and a sodium sulfide aqueous solution prepared beforehand with 28.4 g (118.2 mmol) of sodium sulfide nonahydrate and 62 g of water was added for 2 minutes. After the addition according to (Formula (I) = 0.008), the reflux was immediately started and stirred for 2 hours while refluxing. Thereafter, the reaction solution was cooled to 25 ° C. and separated, and the obtained organic layer was washed successively with dilute hydrochloric acid, sodium bicarbonate water, and water. The amount of the compound (1) in the organic layer thus obtained was quantified by HPLC. As a result, it was 25.1 g (81.4 mmol, yield 84%).

(Comparative Example 3)
To a mixture of 555 mL of methylene chloride, 14.4 g (117.5 mmol) of isopropyl chlorocarbonate and 30.0 g (96.7 mmol) of compound (4) in which P is a 4-nitrobenzyloxycarbonyl group, triethylamine 12 was added at −10 ° C. 0.8 g (126.5 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. Then, 12.7 g (110.9 mmol) of methanesulfonyl chloride and 11.9 g (117.6 mmol) of triethylamine were sequentially added, and the mixture was stirred at the same temperature for 1 hour. Stir. Thereafter, the power required for stirring per unit volume was set to 1.0 kW / m ³ , and a sodium sulfide aqueous solution prepared in advance with sodium sulfide nonahydrate 28.4 g (118.2 mmol) and water 62 g was added for 15 minutes. After the addition according to (Formula (I) = 0.001), the reflux was immediately started, followed by stirring for 2 hours while refluxing. Thereafter, the reaction solution was cooled to 25 ° C. and separated, and the obtained organic layer was washed successively with dilute hydrochloric acid, sodium bicarbonate water, and water. The amount of compound (1) in the organic layer thus obtained was quantified by HPLC, and it was 15.5 g (50.3 mmol, yield 52%).

(Example 6)
To a mixed solution of 1200 mL of methylene chloride, 36.5 g (297.8 mmol) of isopropyl chlorocarbonate and 60.0 g (259.5 mmol) of the compound (4) in which P is a t-butyloxycarbonyl group, triethylamine 34. 2 g (338.0 mmol) was added over 1 hour, and after stirring at the same temperature for 30 minutes, 34.6 g (302.1 mmol) of methanesulfonyl chloride and 31.6 g (312.3 mmol) of triethylamine were sequentially added at the same temperature. For 20 minutes. Thereafter, the power required for stirring per unit volume was set to 0.4 kW / m ³ , and a sodium sulfide aqueous solution prepared with 68.7 g (286.0 mmol) of sodium sulfide nonahydrate and 109.3 g of water was added for 60 seconds (formula After the addition at (I) = 0.017), the mixture was quickly warmed to room temperature and stirred for 4 hours. Thereafter, liquid separation was performed, and the obtained organic layer was washed successively with dilute hydrochloric acid, sodium bicarbonate water, and water. When the amount of the compound (1) in the organic layer thus obtained was quantified, it was 49.2 g (214.6 mmol, yield 83%).

(Example 7)
To a mixed solution of 37 mL of methylene chloride, 1.4 g (11.4 mmol) of isobutyl chlorocarbonate, and 2.0 g (8.6 mmol) of compound (4) in which P is a t-butyloxycarbonyl group, triethylamine 1. 1 g (10.9 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. Then, 1.1 g (9.6 mmol) of methanesulfonyl chloride and 1.1 g (10.9 mmol) of triethylamine were sequentially added, and the mixture was stirred at the same temperature for 1 hour. did. A sodium sulfide aqueous solution prepared with 2.5 g (10.4 mmol) of sodium sulfide nonahydrate and 4 g of water was added in 5 seconds (formula (I) = 0.2), and then the temperature was quickly raised to room temperature and 4 hours. Stir. Thereafter, liquid separation was performed, and the obtained organic layer was washed successively with dilute hydrochloric acid, sodium bicarbonate water, and water. When the amount of the compound (1) in the organic layer thus obtained was quantified, it was 1.6 g (7.0 mmol, yield 81%).

(Comparative Example 4)
A mixture of 40 mL of methylene chloride, 1.1 g (9.0 mmol) of isopropyl chlorocarbonate and 2.0 g (8.6 mmol) of the compound (4) in which P is a t-butyloxycarbonyl group was mixed with triethylamine 1. After adding 88 g (18.6 mmol) and stirring at the same temperature for 1 hour, 1.1 g (9.6 mmol) of methanesulfonyl chloride and 0.7 g (8.8 mmol) of pyridine were added and stirred at the same temperature for 1 hour. . A sodium sulfide aqueous solution prepared with 2.5 g (10.4 mmol) of sodium sulfide nonahydrate and 15 g of water was added in 5 seconds, and then the temperature was quickly raised to room temperature and stirred for 4 hours. Thereafter, liquid separation was performed, and the obtained organic layer was washed successively with dilute hydrochloric acid, sodium bicarbonate water, and water. The amount of the compound (1) in the organic layer thus obtained was quantified by HPLC and found to be 0.79 g (3.4 mmol, yield 40%).

(Example 8)
To a 202 mL THF solution of 30.0 g (97.3 mmol) of the compound (1) in which P is a 4-nitrobenzyloxycarbonyl group, 10.5 g (116.4 mmol) of a 50 wt% dimethylamine aqueous solution was added under ice cooling for 1 hour. After stirring, it was washed with dilute hydrochloric acid. When the amount of the compound (7) in the organic layer thus obtained was quantified by HPLC, it was 33.8 g (95.6 mmol, yield 98%). Thereafter, the solvent was distilled off, and the residue was purified by silica gel chromatography (ethyl acetate / hexane = 1/1 volume ratio) to obtain compound (7) as a solid.

¹ H-NMR (CDCl ₃ ) of the obtained solid was δ1.90 (1H, d, J = 8.0 Hz), 2.77 (1H, m), 2.97 (3H, s), 3.08. (3H, s), 3.27 (1H, m), 3.46 (1H, m), 4.10 (1H, m), 4.69 (1H, m), 5.19 (2H, s) 7.48 (2H, d, J = 9.0 Hz), 8.15 (2H, d, J = 9.0 Hz).
Example 9
To a mixed solution of 663 mL of methylene chloride, 16.3 g (133 mmol) of isopropyl chlorocarbonate, and 36 g (116 mmol) of the compound (4) in which P is a 4-nitrobenzyloxycarbonyl group, 15.3 g (151 mmol) of triethylamine at −15 ° C. After the addition and stirring at the same temperature for 1 hour, 15.3 g (133 mmol) of methanesulfonyl chloride and 14.1 g (140 mmol) of triethylamine were sequentially added, followed by stirring at the same temperature for 1 hour. Thereafter, the power required for stirring per unit volume was set to 3.5 kW / m ³ , and an aqueous sodium hydrosulfide solution prepared in advance with 10.9 g (140 mmol) of sodium hydrosulfide n hydrate and 36.3 g of water was used. After addition in 10 seconds (formula (I) = 0.1), refluxing was started immediately, and stirring was performed for 2 hours while refluxing. Thereafter, the reaction solution was cooled to 25 ° C. and separated, and the obtained organic layer was washed successively with dilute hydrochloric acid, sodium bicarbonate water, and water. When the amount of the compound (1) in the organic layer thus obtained was quantified by HPLC, it was 32.7 g (106 mmol, yield 91%).

(Example 10)
80.1 g of methylene chloride solution of compound (1) in which P is 4-nitrobenzyloxycarbonyl group at 50 ° C. in 188.1 g of acetic acid solution containing 9.43 g of 3-aminobenzoic acid (content 25 wt%, 64.2 mmol) ) Was added slowly, followed by stirring at the same temperature for 1 hour. The reaction solution in the slurry was cooled and filtered to obtain white crystals. The obtained crystals were washed and dried to obtain 28.3 g (63.5 mmol, yield 99%) of compound (7).

¹ H-NMR (DMSO-d6) of the obtained crystals is δ1.85 (1H, m), 2.70 (1H, m), 3.27 (2H, m), 3.97 (1H, m). 4.35 (1H, m), 5.13 (2H, m), 7.82 (8H, m), 10.28 (1H, d, J = 9.0 Hz).

Example 11
Similarly to the method described in Patent Publication 2002-504157, a methylene chloride solution of compound (1) in which P is a t-butyloxycarbonyl group in 104.4 g of an acetic acid solution containing 9.68 g of 3-aminobenzoic acid. After adding 4 g (content 8.6 wt%, 67.1 mmol), the mixture was stirred for 18 hours. After confirming the formation of the compound (7) in the organic layer by HPLC, 25.1 g of concentrated hydrochloric acid was added and stirred for 15 minutes. After confirming the formation of the compound (8) in the organic layer by HPLC, the amount of the compound (8) obtained by distilling off the solvent was 17.1 g (56.5 mmol, yield 84%).

Claims

Following formula (2):

(In the formula, P represents an amino-protecting group. R 1 is an optionally substituted alkyl group having 1 to 7 carbon atoms, an optionally substituted alkenyl group having 3 to 6 carbon atoms, or a substituted group.) Represents an optionally substituted aryl group having 6 to 12 carbon atoms, and R 2 represents an optionally substituted alkyl group or an optionally substituted aryl group. The required stirring power per hit is 0.2 kW / m 3 or more, and the following formula (I):
(Amount of metal sulfide aqueous solution added per second) / (total amount of metal sulfide aqueous solution added) (I)
The metal sulfide aqueous solution is added while controlling so that the value of is 0.003 to 0.2, the following formula (1):

(Wherein P is the same as defined above).
The compound represented by the formula (2) is represented by the following formula (3):

(Wherein P and R 1 are as defined above) and a sulfonic acid halide in the absence of pyridine and in the presence of a trialkylamine. 2. The production method according to 1.
The compound represented by the formula (3) is represented by the following formula (4):

(Wherein P is the same as above) and the following formula (5):
ClCOOR 1 (5)
The production method according to claim 2, wherein the chlorocarbonate represented by the formula (wherein R 1 is the same as above) is obtained by reacting in a water-insoluble organic solvent in the presence of a trialkylamine.
The production method according to claim 2 or 3, wherein the trialkylamine is triethylamine and / or trimethylamine.
The process according to any one of claims 2 to 4, wherein the sulfonic acid halide is methanesulfonyl chloride and / or optionally substituted benzenesulfonyl chloride.
6. The production method according to claim 3, wherein the compound represented by the formula (4) is an optically active trans-4-hydroxy-L-proline in which an amino group is protected.
The production method according to any one of claims 1 to 6, wherein the metal sulfide is sodium sulfide.
The production method according to claim 7, wherein the concentration of the sodium sulfide aqueous solution is 10 to 50 wt%.
The production method according to any one of claims 1 to 6, wherein the metal sulfide is sodium hydrosulfide.
The method according to claim 9, wherein the concentration of the aqueous sodium hydrosulfide solution is 10 to 50 wt%.
A compound (1) produced by the method according to any one of claims 1 to 10 and the following formula (6):
NHR 3 R 4 (6)
(Wherein R 3 and R 4 are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted alkenyl group having 2 to 6 carbon atoms, and It represents either an optionally substituted aryl group having 6 to 12 carbon atoms or an optionally substituted heteroaryl group having 4 to 12 carbon atoms, and R 3 and R 4 are bonded to each other. A 4- to 8-membered optionally substituted cyclic amine compound may be formed together with the nitrogen atom, and the amine compound represented by the above or a mineral acid salt thereof. The following formula (7):

(Wherein P, R 3 and R 4 are the same as above), a method for producing a 4-mercaptopyrrolidine derivative.
The compound (7) produced by the method according to claim 11 is reacted with a deprotecting agent to deprotect the protecting group P of the 4-mercaptopyrrolidine derivative, which is represented by the following formula (8):

(Wherein R 3 and R 4 are the same as defined above), and a method for producing a 4-mercaptopyrrolidine derivative represented by the formula or a salt thereof.
P is any one of 4-nitrobenzyloxycarbonyl group, t-butyloxycarbonyl group, benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, and allyloxycarbonyl group. The manufacturing method of crab.
The production method according to claim 13, wherein P is a t-butyloxycarbonyl group.
15. The production method according to claim 12, wherein the deprotecting agent is a protonic acid.
The production method according to claim 15, wherein the protonic acid is hydrochloric acid.
R 3 and R 4 are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted aryl group having 6 to 12 carbon atoms. The production method according to any one of 11 to 16.
The production method according to claim 17, wherein R 3 and R 4 are methyl groups, or R 3 is a hydrogen atom and R 4 is a 3-carboxyphenyl group.