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WO2010073706A1 - Procédé de production amélioré d'un intermédiaire pour chaîne latérale de carbapénème - Google Patents

Procédé de production amélioré d'un intermédiaire pour chaîne latérale de carbapénème Download PDF

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Publication number
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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group
optionally substituted
compound
mmol
carbon atoms
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Japanese (ja)
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揚野貴文
岡島基範
古賀照義
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Kaneka Corp
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Kaneka Corp
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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
    • 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

Le procédé ci-décrit permet de produire, de manière simple et à un rendement élevé, un dérivé de pyrrolidine pouvant être utilisé comme intermédiaire pour la production d'une chaîne latérale de composé de carbapénème. Ledit procédé utilise un réactif facile à appliquer et relativement bon marché et ne nécessite pas l'isolement d'un acide thiocarboxylique (intermédiaire). Plus spécifiquement, une réaction est mise en oeuvre par ajout d'une solution aqueuse de sulfure métallique à un composé représenté par la formule (2) à une consommation d'énergie d'agitation par volume unitaire de 0,2 kW/m3 ou plus, avec ajustement simultané de la valeur calculée en divisant la quantité de la solution aqueuse de sulfure métallique ajoutée par seconde par la quantité totale de la solution aqueuse de sulfure métallique ajoutée à 0,003-0,2.
PCT/JP2009/007261 2008-12-25 2009-12-25 Procédé de production amélioré d'un intermédiaire pour chaîne latérale de carbapénème Ceased WO2010073706A1 (fr)

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CN102351861A (zh) * 2011-08-16 2012-02-15 湖南欧亚生物有限公司 一种厄他培南的工业化制备方法

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CN106565579A (zh) * 2016-06-26 2017-04-19 宁夏海诚电化信息科技有限公司 一种尔它培南侧链生产工艺
CN107118222A (zh) * 2017-05-27 2017-09-01 合肥利夫生物科技有限公司 一种美罗培南侧链中间体硫醇内酯的制备方法
CN115490625A (zh) * 2022-11-18 2022-12-20 山东鑫泉医药有限公司 美罗培南侧链的合成及精制方法
CN116874499A (zh) * 2023-07-14 2023-10-13 北京金城泰尔制药有限公司沧州分公司 美罗培南侧链的合成方法

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