WO2010073706A1 - Improved process for producing intermediate for side chain of carbapenem - Google Patents
Improved process for producing intermediate for side chain of carbapenem Download PDFInfo
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- WO2010073706A1 WO2010073706A1 PCT/JP2009/007261 JP2009007261W WO2010073706A1 WO 2010073706 A1 WO2010073706 A1 WO 2010073706A1 JP 2009007261 W JP2009007261 W JP 2009007261W WO 2010073706 A1 WO2010073706 A1 WO 2010073706A1
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- 0 *OC(OC([C@](C[C@@](C1)OS(*)(=O)=O)N1P)=O)=O Chemical compound *OC(OC([C@](C[C@@](C1)OS(*)(=O)=O)N1P)=O)=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/08—Bridged systems
Definitions
- 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.
- 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.
- diisopropylethylamine and diphenylphosphine acid chloride are used as reagents for preparing a compound corresponding to compound (3a).
- 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.
- a special reagent diphenylphosphinic acid chloride is used in order to improve the stability of the mixed acid anhydride corresponding to the compound (2a) to water.
- diphenylphosphine acid chloride is not readily available and expensive.
- 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.
- 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.
- 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.
- 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):
- 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): ):
- 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:
- 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.
- Step (A) In this step, the following formula (4):
- 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.
- Examples thereof include 13 to 16 alkyldiarylsilyl groups or triarylsilyl groups.
- Preferred examples of the compound represented by compound (4) include optically active trans-4-hydroxy-L-proline in which an amino group is protected.
- the compound (4) used as a raw material can be synthesized by a known method.
- P is a 4-nitrobenzyloxycarbonyl group
- 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.
- trialkylamine examples 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.
- the reaction solvent a poorly water-soluble organic solvent is used.
- 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.
- the poorly water-soluble organic solvent examples 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.
- 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.
- 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.
- trialkylamine examples include triethylamine, trimethylamine, tributylamine, diisopropylethylamine and the like.
- the trialkylamine is preferably triethylamine and / or trimethylamine.
- 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 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, 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.
- the compound (3) may be the one obtained by the step (A) or the one obtained by other methods.
- metal sulfide examples 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.
- 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.
- step (B) one obtained by the step (B) may be used, or one obtained by other methods may be used.
- 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.
- 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.
- a base used in the reaction in the presence of a base
- 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.
- reaction solvent examples 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.
- solvent examples include ester solvents such as ethyl acetate and butyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, and water.
- 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.
- the 4-mercaptopyrrolidine derivative represented by the formula (1) or a mineral acid salt thereof can be produced.
- R ⁇ 3 >, R ⁇ 4 > is the same as the above.
- the deprotecting agent can be deprotected by the deprotecting method described in the above-mentioned Protective Groups in Organic Synthesis 4th edition.
- 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.
- reaction solvent examples 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.
- solvent examples include ester solvents such as ethyl acetate and butyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, and water.
- 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 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.
- the reaction time can be appropriately determined by tracking the progress of the reaction with HPLC or the like.
- 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.
- 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.
- 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%).
- 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.
- 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.
- 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.
- 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%).
- 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.
- 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.
- 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%).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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. .
- 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.
- 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.
- 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.
- the reflux was immediately started and stirred for 2 hours while refluxing.
- 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%).
- 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.
- 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%).
- 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 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.
- 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).
- 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%).
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Abstract
Description
(一秒当たりの金属硫化物水溶液の添加量)÷(金属硫化物水溶液の全添加量)・・・(I)
の値が0.003~0.2になるように制御しながら金属硫化物水溶液を添加することを特徴とする下記式(1): (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):
NHR3R4 (6)
(式中、R3及びR4はそれぞれ独立しており、水素原子、置換されていてもよい炭素数1~6のアルキル基、置換されていてもよい炭素数2~6のアルケニル基、置換されていてもよい炭素数6~12のアリール基、および置換されていてもよい炭素数4~12のヘテロアリール基のいずれかを表す。また、R3及びR4は、それぞれが結合している窒素原子と共に、4~8員環の置換されていてもよい環状アミン化合物を形成していてもよい。)で表されるアミン化合物またはそれらの鉱酸塩とを反応させる、下記式(7): 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): ):
本工程においては、下記式(4): Step (A)
In this step, the following formula (4):
ClCOOR1 (5)
で表されるクロロ炭酸エステルを、水難溶性有機溶媒中、トリアルキルアミン存在下に反応させることにより、下記式(3): 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):
次に、化合物(3)をトリアルキルアミンの存在下にスルホン酸のハロゲン化物と反応させて、水酸基がスルホニル化された、混合酸無水物である下記式(2): 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):
次に、化合物(2)と金属硫化物水溶液と反応させて、下記式(1): Process (C)
Next, the compound (2) is reacted with a metal sulfide aqueous solution to form the following formula (1):
(一秒当たりの金属硫化物水溶液の添加量)÷(金属硫化物水溶液の全添加量)・・・(I)
の値が0.003~0.2となるようにすることにより、目的化合物が収率よく得られることを見出した。この値が0.003未満、すなわち添加時間が5分以上になると不純物量が劇的に増加し、化合物(1)の収率低下を招く。これは、化合物(2)が水によって分解されやすくなるためであると考えられる。一方、上記式(I)の値が0.2より大きくなるようにする、すなわち添加時間を5秒より小さくするには、工業生産において特殊な設備が必要になり、工業的実施の点から好ましくない。 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.
また、上記のようにして取得した化合物(1)を下記式(6):
NHR3R4 (6)
で表されるアミン化合物と反応させることにより下記式(7): 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):
上記のようにして取得した化合物(7)は、保護基Pを脱保護剤で脱保護することにより、下記式(8): Process (E)
The compound (7) obtained as described above has the following formula (8) by deprotecting the protecting group P with a deprotecting agent:
機種 :(株)島津製作所製 LC-10Aシリーズ
カラム:ナカライテスク製ODSカラム
Cosmosil 5C18 AR-II(4.6mm×250mm)
溶離液:アセトニトリル/燐酸緩衝液(pH3.0)=40/60(v/v)
流速 :1.0ml/min
検出 :274nm(UV検出器)
温度 :40℃ [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
塩化メチレン666mL、クロロ炭酸イソプロピル16.4g(133.8mmol)、Pが4-ニトロベンジルオキシカルボニル基である化合物(4)36.0g(116.0mmol)の混合液に、-15℃でトリエチルアミン15.3g(0.151mol)を添加し、同温度で1時間撹拌後、塩化メタンスルホニル15.3g(133.6mmol)とトリエチルアミン14.1g(139.3mmol)を順次添加し、同温度で1時間撹拌した。その後、単位体積当たりの撹拌所要動力を1.4kW/m3に設定し、硫化ナトリウム九水和物33.4g(139.1mmol)と水72gで予め調製しておいた硫化ナトリウム水溶液を30秒(式(I)=0.033)で添加後、2時間還流した。その後、反応液を25℃に冷却し、分液した後、取得した有機層を希塩酸、重曹水、水にて順次洗浄した。このようにして取得した有機層中の化合物(1)の量は30.4g(98.6mmol、収率85%)であった。洗浄後、溶媒を留去し、残渣をシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン=1/1容量比)にて精製して化合物(1)を固体として得た。 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.
トルエン300mL、クロロ炭酸イソプロピル4.5g(36.7mmol)、Pが4-ニトロベンジルオキシカルボニル基である化合物(4)10.0g(32.2mmol)の混合液に、-15℃でトリエチルアミン4.2g(41.5mmol)を添加し、同温度で1時間撹拌後、塩化メタンスルホニル4.9g(42.8mmol)とトリエチルアミン4.5g(44.5mmol)を順次添加し、同温度で1時間撹拌した。その後、単位体積当たりの撹拌所要動力を1.0kW/m3に設定し、硫化ナトリウム九水和物9.3g(38.7mmol)と水20gで予め調製しておいた硫化ナトリウム水溶液を30秒(式(I)=0.033)で添加後、速やかに還流を開始し、還流しながら2時間撹拌を行った。その後、反応液を25℃に冷却し、分液した後、取得した有機層を希塩酸、重曹水、水にて順次洗浄した。このようにして取得した有機層中の化合物(1)の量をHPLCで定量したところ6.7g(21.7mmol、収率67%)であった。 (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%).
塩化メチレン185mL、クロロ炭酸イソプロピル4.5g(36.7mmol)、Pが4-ニトロベンジルオキシカルボニル基である化合物(4)10.0g(32.2mmol)の混合液に、-15℃でトリエチルアミン4.2g(41.5mmol)を添加し、同温度で1時間撹拌後、塩化メタンスルホニル4.9g(42.8mmol)とトリエチルアミン4.5g(44.5mmol)を順次添加し、同温度で1時間撹拌した。その後、単位体積当たりの撹拌所要動力を0.1kW/m3に設定し、硫化ナトリウム九水和物9.3g(38.7mmol)と水20gで予め調製しておいた硫化ナトリウム水溶液を10秒(式(I)=0.1)で添加後、速やかに還流を開始し、還流しながら2時間撹拌を行った。その後、反応液を25℃に冷却し、分液した後、取得した有機層を希塩酸、重曹水、水にて順次洗浄した。このようにして取得した有機層中の化合物(1)の量をHPLCで定量したところ4.2g(13.6mmol、収率43%)であった。 (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%).
塩化メチレン185mL、クロロ炭酸イソプロピル4.5g(36.7mmol)、Pが4-ニトロベンジルオキシカルボニル基である化合物(4)10.0g(32.2mmol)の混合液に、-15℃でトリエチルアミン4.2g(41.5mmol)を添加し、同温度で1時間撹拌後、塩化メタンスルホニル4.9g(42.8mmol)とトリエチルアミン4.5g(44.5mmol)を順次添加し、同温度で1時間撹拌した。その後、単位体積当たりの撹拌所要動力を0.01kW/m3に設定し、硫化ナトリウム九水和物9.3g(38.7mmol)と水20gで予め調製しておいた硫化ナトリウム水溶液を10秒(式(I)=0.1)で添加後、速やかに還流を開始し、還流しながら2時間撹拌を行った。その後、反応液を25℃に冷却し、分液した後、取得した有機層を希塩酸、重曹水、水にて順次洗浄した。このようにして取得した有機層中の化合物(1)の量をHPLCで定量したところ3.0g(9.7mmol、収率30%)であった。 (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%).
塩化メチレン185mL、クロロ炭酸イソプロピル4.5g(36.7mmol)、Pが4-ニトロベンジルオキシカルボニル基である化合物(4)10.0g(32.2mmol)の混合液に、-10℃でトリエチルアミン4.2g(41.5mmol)を添加し、同温度で1時間撹拌後、塩化メタンスルホニル4.9g(42.8mmol)とトリエチルアミン4.5g(44.5mmol)を順次添加し、同温度で1時間撹拌した。その後、単位体積当たりの撹拌所要動力を0.3kW/m3に設定し、硫化ナトリウム九水和物9.3g(38.7mmol)と水20gで予め調製しておいた硫化ナトリウム水溶液を10秒(式(I)=0.1)で添加後、速やかに還流を開始し、還流しながら2時間撹拌を行った。その後、反応液を25℃に冷却し、分液した後、取得した有機層を希塩酸、重曹水、水にて順次洗浄した。このようにして取得した有機層中の化合物(1)の量をHPLCで定量したところ、8.0g(25.9mmol、収率81%)であった。 (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%).
塩化メチレン2220mL、クロロ炭酸イソプロピル54.4g(443.9mmol)、Pが4-ニトロベンジルオキシカルボニル基である化合物(4)120g(386.8mmol)の混合液に、-10℃でトリエチルアミン50.8g(502.0mmol)を添加し、同温度で1時間撹拌後、塩化メタンスルホニル70.8g(618.1mmol)とトリエチルアミン64.4g(636.4mmol)を順次添加し、同温度で1時間撹拌した。その後、単位体積当たりの撹拌所要動力を0.7kW/m3に設定し、硫化ナトリウム九水和物112g(466.3mmol)と水240gで予め調製しておいた硫化ナトリウム水溶液を30秒(式(I)=0.033)で添加後、速やかに還流を開始し、還流しながら2時間撹拌を行った。その後、反応液を25℃に冷却し、分液した後、取得した有機層を希塩酸、重曹水、水にて順次洗浄した。このようにして取得した有機層中の化合物(1)の量をHPLCで定量したところ、100.1g(324.7mmol、収率84%)であった。 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%).
塩化メチレン555mL、クロロ炭酸イソプロピル14.4g(117.5mmol)、Pが4-ニトロベンジルオキシカルボニル基である化合物(4)30.0g(96.7mmol)の混合液に、-10℃でトリエチルアミン12.8g(126.5mmol)を添加し、同温度で1時間撹拌後、塩化メタンスルホニル12.7g(110.9mmol)とトリエチルアミン11.9g(117.6mmol)を順次添加し、同温度で1時間撹拌した。その後、単位体積当たりの撹拌所要動力を1.0kW/m3に設定し、硫化ナトリウム九水和物28.4g(118.2mmol)と水62gで予め調製しておいた硫化ナトリウム水溶液を2分(式(I)=0.008)で添加後、速やかに還流を開始し、還流しながら2時間撹拌を行った。その後、反応液を25℃に冷却し、分液した後、取得した有機層を希塩酸、重曹水、水にて順次洗浄した。このようにして取得した有機層中の化合物(1)の量をHPLCで定量したところ、25.1g(81.4mmol、収率84%)であった。 (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%).
塩化メチレン555mL、クロロ炭酸イソプロピル14.4g(117.5mmol)、Pが4-ニトロベンジルオキシカルボニル基である化合物(4)30.0g(96.7mmol)の混合液に、-10℃でトリエチルアミン12.8g(126.5mmol)を添加し、同温度で1時間撹拌後、塩化メタンスルホニル12.7g(110.9mmol)とトリエチルアミン11.9g(117.6mmol)を順次添加し、同温度で1時間撹拌した。その後、単位体積当たりの撹拌所要動力を1.0kW/m3に設定し、硫化ナトリウム九水和物28.4g(118.2mmol)と水62gで予め調製しておいた硫化ナトリウム水溶液を15分(式(I)=0.001)で添加後、速やかに還流を開始し、還流しながら2時間撹拌を行った。その後、反応液を25℃に冷却し、分液した後、取得した有機層を希塩酸、重曹水、水にて順次洗浄した。このようにして取得した有機層中の化合物(1)の量をHPLCで定量したところ、15.5g(50.3mmol、収率52%)であった。 (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%).
塩化メチレン1200mL、クロロ炭酸イソプロピル36.5g(297.8mmol)、Pがt-ブチルオキシカルボニル基である化合物(4)60.0g(259.5mmol)の混合液に、-20℃でトリエチルアミン34.2g(338.0mmol)を1時間かけて添加し、同温度で30分撹拌後、塩化メタンスルホニル34.6g(302.1mmol)とトリエチルアミン31.6g(312.3mmol)を順次添加し、同温度で20分撹拌した。その後、単位体積当たりの撹拌所要動力を0.4kW/m3に設定し、硫化ナトリウム九水和物68.7g(286.0mmol)と水109.3gで調製した硫化ナトリウム水溶液を60秒(式(I)=0.017)で添加後、速やかに室温まで昇温し、4時間撹拌した。その後、分液して、取得した有機層を希塩酸、重曹水、水にて順次洗浄した。このようにして取得した有機層中の化合物(1)の量を定量したところ、49.2g(214.6mmol、収率83%)であった。 (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%).
塩化メチレン37mL、クロロ炭酸イソブチル1.4g(11.4mmol)、Pがt-ブチルオキシカルボニル基である化合物(4)2.0g(8.6mmol)の混合液に、-15℃でトリエチルアミン1.1g(10.9mmol)を添加し、同温度で1時間撹拌後、塩化メタンスルホニル1.1g(9.6mmol)とトリエチルアミン1.1g(10.9mmol)を順次添加し、同温度で1時間撹拌した。硫化ナトリウム九水和物2.5g(10.4mmol)と水4gで調製した硫化ナトリウム水溶液を5秒(式(I)=0.2)で添加後、速やかに室温まで昇温し、4時間撹拌した。その後、分液して、取得した有機層を希塩酸、重曹水、水にて順次洗浄した。このようにして取得した有機層中の化合物(1)の量を定量したところ、1.6g(7.0mmol、収率81%)であった。 (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%).
塩化メチレン40mL、クロロ炭酸イソプロピル1.1g(9.0mmol)、Pがt-ブチルオキシカルボニル基である化合物(4)2.0g(8.6mmol)の混合液に、-15℃でトリエチルアミン1.88g(18.6mmol)を添加し、同温度で1時間撹拌後、塩化メタンスルホニル1.1g(9.6mmol)とピリジン0.7g(8.8mmol)を添加し、同温度で1時間撹拌した。硫化ナトリウム九水和物2.5g(10.4mmol)と水15gで調製した硫化ナトリウム水溶液を5秒で添加後、速やかに室温まで昇温し、4時間撹拌した。その後、分液して、取得した有機層を希塩酸、重曹水、水にて順次洗浄した。このようにして取得した有機層中の化合物(1)の量をHPLCで定量したところ、0.79g(3.4mmol、収率40%)であった。 (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%).
Pが4-ニトロベンジルオキシカルボニル基である化合物(1)30.0g(97.3mmol)のTHF202mL溶液に、氷冷下、50wt%ジメチルアミン水溶液10.5g(116.4mmol)を加え、1時間撹拌後、希塩酸で洗浄した。このようにして取得した有機層中の化合物(7)の量をHPLCで定量したところ、33.8g(95.6mmol、収率98%)であった。その後、溶媒を留去し、残渣をシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン=1/1容量比)にて精製して化合物(7)を固体として得た。 (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.
(実施例9)
塩化メチレン663mL、クロロ炭酸イソプロピル16.3g(133mmol)、Pが4-ニトロベンジルオキシカルボニル基である化合物(4)36g(116mmol)の混合液に、-15℃でトリエチルアミン15.3g(151mmol)を添加し、同温度で1時間撹拌後、塩化メタンスルホニル15.3g(133mmol)とトリエチルアミン14.1g(140mmol)を順次添加し、同温度で1時間撹拌した。その後、単位体積当たりの撹拌所要動力を3.5kW/m3に設定し、水硫化ナトリウムn水和物10.9g(140mmol)と水36.3gで予め調製しておいた水硫化ナトリウム水溶液を10秒(式(I)=0.1)で添加後、速やかに還流を開始し、還流しながら2時間撹拌を行った。その後、反応液を25℃に冷却し、分液した後、取得した有機層を希塩酸、重曹水、水にて順次洗浄した。このようにして取得した有機層中の化合物(1)の量をHPLCで定量したところ、32.7g(106mmol、収率91%)であった。 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%).
3-アミノ安息香酸9.43gを含む酢酸溶液188.1g中に50℃でPが4-ニトロベンジルオキシカルボニル基である化合物(1)の塩化メチレン溶液80.1g(含量25wt%、64.2mmol)をゆっくり添加後、同温度で1時間撹拌した。スラリーの反応液を冷却・濾過し、白色結晶を取得した。得られた結晶を洗浄、乾燥し化合物(7)を28.3g(63.5mmol、収率99%)得た。 (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).
特許公表2002-504157に記載の方法と同様に、3-アミノ安息香酸9.68gを含む酢酸溶液104.4g中にPがt-ブチルオキシカルボニル基である化合物(1)の塩化メチレン溶液178.4g(含量8.6wt%、67.1mmol)を添加後、18時間撹拌した。HPLCにて有機層中の化合物(7)の生成を確認後、濃塩酸を25.1g添加し、15分撹拌した。HPLCにて有機層中の化合物(8)の生成を確認後、溶媒留去して得られた化合物(8)の量は、17.1g(56.5mmol、収率84%)であった。 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 (18)
- 下記式(2):
(一秒当たりの金属硫化物水溶液の添加量)÷(金属硫化物水溶液の全添加量)・・・(I)
の値が0.003~0.2になるように制御しながら金属硫化物水溶液を添加することを特徴とする下記式(1):
(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):
- 前記式(2)で表される化合物が、下記式(3):
- 前記式(3)で表される化合物が、下記式(4):
ClCOOR1 (5)
(式中、R1は前記に同じ)で表されるクロロ炭酸エステルを、水難溶性有機溶媒中、トリアルキルアミン存在下に反応させて得られたものである請求項2に記載の製造方法。 The compound represented by the formula (3) is represented by the following formula (4):
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. - トリアルキルアミンが、トリエチルアミンおよび/またはトリメチルアミンである請求項2または3に記載の製造方法。 The production method according to claim 2 or 3, wherein the trialkylamine is triethylamine and / or trimethylamine.
- スルホン酸のハロゲン化物が、塩化メタンスルホニルおよび/または置換されていてもよい塩化ベンゼンスルホニルである請求項2~4のいずれかに記載の製造方法。 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.
- 前記式(4)で表される化合物が、アミノ基を保護された光学活性なトランス-4-ヒドロキシ-L-プロリンである請求項3~5のいずれかに記載の製造方法。 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.
- 金属硫化物が硫化ナトリウムである請求項1~6のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 6, wherein the metal sulfide is sodium sulfide.
- 硫化ナトリウム水溶液の濃度が10~50wt%である請求項7に記載の製造方法。 The production method according to claim 7, wherein the concentration of the sodium sulfide aqueous solution is 10 to 50 wt%.
- 金属硫化物が水硫化ナトリウムである請求項1~6のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 6, wherein the metal sulfide is sodium hydrosulfide.
- 水硫化ナトリウム水溶液の濃度が10~50wt%である請求項9に記載の製造方法。 The method according to claim 9, wherein the concentration of the aqueous sodium hydrosulfide solution is 10 to 50 wt%.
- 請求項1~10のいずれかに記載の方法で製造した化合物(1)と、下記式(6):
NHR3R4 (6)
(式中、R3及びR4はそれぞれ独立しており、水素原子、置換されていてもよい炭素数1~6のアルキル基、置換されていてもよい炭素数2~6のアルケニル基、および置換されていてもよい炭素数6~12のアリール基、置換されていてもよい炭素数4~12のヘテロアリール基のいずれかを表す。また、R3及びR4は、それぞれが結合している窒素原子と共に、4~8員環の置換されていてもよい環状アミン化合物を形成していてもよい。)で表されるアミン化合物またはそれらの鉱酸塩とを反応させることを特徴とする、下記式(7):
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):
- 請求項11に記載の方法で製造した化合物(7)を脱保護剤と反応させ、4-メルカプトピロリジン誘導体の保護基Pを脱保護することを特徴とする、下記式(8):
- Pが、4-ニトロベンジルオキシカルボニル基、t-ブチルオキシカルボニル基、ベンジルオキシカルボニル基、4-メトキシベンジルオキシカルボニル基、およびアリルオキシカルボニル基のいずれか1種である請求項1~12のいずれかに記載の製造方法。 P is any one of 4-nitrobenzyloxycarbonyl group, t-butyloxycarbonyl group, benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, and allyloxycarbonyl group. The manufacturing method of crab.
- Pが、t-ブチルオキシカルボニル基である請求項13に記載の製造方法。 The production method according to claim 13, wherein P is a t-butyloxycarbonyl group.
- 脱保護剤がプロトン酸である請求項12~14のいずれかに記載の製造方法。 15. The production method according to claim 12, wherein the deprotecting agent is a protonic acid.
- プロトン酸が塩酸である請求項15に記載の製造方法。 The production method according to claim 15, wherein the protonic acid is hydrochloric acid.
- R3及びR4がそれぞれ独立しており、水素原子、置換されていてもよい炭素数1~6のアルキル基、または置換されていてもよい6~12のアリール基のいずれかである請求項11~16のいずれかに記載の製造方法。 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.
- R3及びR4がメチル基、またはR3が水素原子でありR4が3-カルボキシフェニル基である請求項17に記載の製造方法。 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.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102002069A (en) * | 2010-11-12 | 2011-04-06 | 上海巴迪生物医药科技有限公司 | Preparation method of dicyclic intermediate for synthesizing carbapenem side chains and application thereof |
WO2012062036A1 (en) * | 2010-11-12 | 2012-05-18 | 上海巴迪生物医药科技有限公司 | Preparation method and applications of a two-ring intermediate including a penem-type side chain |
CN102351861A (en) * | 2011-08-16 | 2012-02-15 | 湖南欧亚生物有限公司 | Industrial preparation method of ertapenem |
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