CN102264744A - 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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- CN102264744A CN102264744A CN2009801525729A CN200980152572A CN102264744A CN 102264744 A CN102264744 A CN 102264744A CN 2009801525729 A CN2009801525729 A CN 2009801525729A CN 200980152572 A CN200980152572 A CN 200980152572A CN 102264744 A CN102264744 A CN 102264744A
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- 0 C[C@](*CCC[C@@]1[C@](C)[C@]2[C@]3C1CC[C@@]23)C1CC1 Chemical compound C[C@](*CCC[C@@]1[C@](C)[C@]2[C@]3C1CC[C@@]23)C1CC1 0.000 description 2
- NPSFOELXSLXZOG-UHFFFAOYSA-N CC(CCCC1)N1P Chemical compound CC(CCCC1)N1P NPSFOELXSLXZOG-UHFFFAOYSA-N 0.000 description 1
- YNTLOEJSAYVJSU-UHNVWZDZSA-N C[C@H](C[C@@H](C1)S)N1I Chemical compound C[C@H](C[C@@H](C1)S)N1I YNTLOEJSAYVJSU-UHNVWZDZSA-N 0.000 description 1
- MOJCDPXUTZRFCJ-CQMSUOBXSA-N C[C@H]1N(C)C(C2)[C@@H]2C1 Chemical compound C[C@H]1N(C)C(C2)[C@@H]2C1 MOJCDPXUTZRFCJ-CQMSUOBXSA-N 0.000 description 1
Classifications
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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
Abstract
Disclosed is a process for producing a pyrrolidine derivative usable as an intermediate for the production of a side chain of a carbapenem compound in a simple manner and in high yield, which utilizes a readily applicable and relatively inexpensive reagent and is not required to isolate a thiocarboxylic acid (an intermediate). Specifically, a reaction is carried out by adding an aqueous metal sulfide solution to a compound represented by formula (2) at an agitation power consumption per unit volume of 0.2 kW/m3 or more while adjusting the value calculated by dividing the amount of the aqueous metal sulfide solution added per second by the total amount of the aqueous metal sulfide solution added to 0.003 to 0.2.
Description
Technical field
The present invention relates to the manufacture method of carbapenem (carbapenem) side chain.Manufacture method in particular to the intermediate of the carbapenem side chain that contains pyrrolidyl.
Background technology
The compound (be referred to as " compound (1) " in this specification sheets sometimes, other compounds are also identical) of following formula (1) representative uses when constructing 2 pendant moieties of the carbapenem compounds with excellent anti-microbial activity,
[Chemical formula 1]
(in the following formula, P represents amino protecting group).
As the existing manufacture method of compound (1), for example, following method is known.
1) in methylene dichloride and under the condition of triethylamine existence, make the compound and the reaction of chlorine isobutyl carbonate propyl ester of following formula (4) representative, generate the compound of following formula (3a) representative,
[Chemical formula 2]
(in the following formula, P is same as described above),
[chemical formula 3]
(in the following formula, P is same as described above, and R represents sec.-propyl).Then, under the condition that triethylamine exists, make this compound (3a) and methylsulfonyl chloride reaction, thereby generate the compound of following formula (2a) representative,
[chemical formula 4]
(in the following formula, P and R are same as described above, and R ' represents methyl).Further, under the condition that triethylamine exists, make excessive hydrogen sulfide and compound (2a) reaction obtain thiocarboxylic acid (acid of チ オ カ Le ボ Application) compound, earlier with its separation, in methylene dichloride and under the condition of triethylamine existence, reflux then with synthetic compound (1) (patent documentation 1, non-patent literature 1).
2) in THF and under the condition of diisopropylethylamine existence, make compound (4) and diphenyl phosphinyl chloride (ジ Off エ ニ Le ホ ス Off イ ン Suan salt thing) reaction, generate the compound that is equivalent to above-claimed cpd (3a).Then, under the condition that pyridine exists,, generate the compound that is equivalent to above-claimed cpd (2a) with this compound and methylsulfonyl chloride reaction.Further, make the reaction of this compound and sodium sulfide solution, synthetic compound (1) (patent documentation 2, non-patent literature 2).
The prior art document
Patent documentation
Patent documentation 1: Japanese kokai publication hei 5-186476 communique
Patent documentation 2:WO97/06154
Non-patent literature
Non-patent literature 1:Heterocycles, pp147-159,1995
Non-patent literature 2:Tetrahedron Letters, Vol.37 (7), pp2919-2922,1996
Summary of the invention
The problem that invention will solve
In patent documentation 1 and non-patent literature 1 described method, used the anhydrous hydrogen sulfide of strong toxicity.In addition, need first separation of intermediates thiocarboxylic acid.Therefore, from the viewpoint of security and operability, existing problems when technical scale is made.
In addition, in patent documentation 2 and non-patent literature 2 described methods, use diisopropylethylamine and diphenyl phosphinyl chloride as the reagent of preparation corresponding to the compound of compound (3a).In addition, by using pyridine and methylsulfonyl chloride reagent, use sodium sulfide solution as source of sulphide, with good efficiency synthetic compound (1) as the methylsulfonylization of hydroxyl.In described method,, use special reagent diphenyl phosphinyl chloride in order to improve corresponding to the mixed acid anhydride of compound (2a) stability with respect to water.Yet diphenyl phosphinyl chloride is difficult for obtaining, and in addition, price is high.Further, be used as the THF of solvent and to be used as the diisopropylethylamine or the equal price of pyridine of alkali high.Therefore, from the stability of acquisition raw material and the viewpoint of economy, can not be satisfactory.
Further, in non-patent literature 2 described methods, proposition can also use chlorine isobutyl carbonate butyl ester to replace diphenyl phosphinyl chloride, yet, in the methylsulfonylization of hydroxyl, use relatively more expensive pyridine, from the viewpoint of economy, can not be satisfactory.
The method of dealing with problems
In view of the above problems, the inventor etc. are to easy operation, and use the raw material that obtains easily, the method for making compound (1) with high yield furthers investigate, thereby finished the present invention.
That is, the present invention relates to:
The manufacture method of the pyrrolidin derivatives of following formula (1) representative, it is characterized in that: Yi Bian control the required stirring power of per unit volume is 0.2kW/m
3More than and the value of following formula (I) be 0.003～0.2, on one side in the compound of following formula (2) representative, add the metallic sulfide aqueous solution,
(per 1 second the metallic sulfide aqueous solution addition) ÷ (total addition level of the metallic sulfide aqueous solution) ... (I)
[chemical formula 5]
(in the following formula, P represents amino protecting group.R
1The optional substituted carbonatoms of expression is that 1～7 alkyl, optional substituted carbonatoms are that 3～6 thiazolinyl or optional substituted carbonatoms are 6～12 aryl.R
2Optional substituted alkyl of expression or optional substituted aryl),
[chemical formula 6]
(in the following formula, P is same as described above).
In addition, the present invention relates to:
The manufacture method of the 4-mercaptopyrrolidine derivatives of following formula (7) representative, this method react the amine compound represented according to above-mentioned compound that obtains (1) and following formula (6) or their inorganic acid salt,
NHR
3R
4 (6)
(in the following formula, R
3And R
4Represent that independently of one another hydrogen atom, optional substituted carbonatoms are that 1～6 alkyl, optional substituted carbonatoms are that 2～6 thiazolinyl, optional substituted carbonatoms are that 6～12 aryl, optional substituted carbonatoms are any group in 4～12 the heteroaryl.Perhaps, optional R
3And R
4Form the optional substituted cyclic amine compound of 4～8 yuan of rings respectively with the nitrogen-atoms of bonding),
[chemical formula 7]
(in the following formula, P, R
3And R
4Same as described above).
Further, the present invention relates to:
The 4-mercaptopyrrolidine derivatives of following formula (8) representative or the manufacture method of their inorganic acid salt, this method makes the protecting group P deprotection of the above-mentioned compound that makes (7) by using deprotection agent,
[chemical formula 8]
(in the following formula, R
3, R
4Same as described above).
The effect of invention
According to the method for the invention, use to obtain easily and cheap reagent, in addition, do not need the intermediate thiocarboxylic acid is separated, by easy operation, can make compound (1) with high yield.
The embodiment of invention
Below will be elaborated to each operation of the present invention.
Operation (A)
In this operation, in the slightly water-soluble organic solvent and under the condition of trialkylamine existence, make the compound of following formula (4) representative and the chlorine carbonate reaction of following formula (5) representative, synthesize the compound of following formula (3) representative.
[chemical formula 9]
CICOOR
1 (5)
[Chemical formula 1 0]
P represents amino protecting group.Particularly, can use the 4th edition (JOHN WILEY﹠amp of PROTECTIVE GROUPS IN ORGANIC SYNTHESIS; SONS publishes (2006)) in the protecting group put down in writing.
As P, can be listed below, for example: optional substituted carbonatoms is that 1～6 alkoxy carbonyl, optional substituted carbonatoms are that 2～6 allyloxycarbonyl, optional substituted benzyloxycarbonyl, optional substituted benzyl, optional substituted carbonatoms are that 3～9 trialkylsilkl, optional substituted carbonatoms are that 8～12 di alkylaryl silyl, optional substituted carbonatoms are 13～16 alkyl diaryl silyl or diarye silyl etc.
Preferably: 4-nitro benzyloxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, allyloxy carbonyl, more preferably: 4-nitro benzyloxycarbonyl, tert-butoxycarbonyl, most preferably tert-butoxycarbonyl.
As the compound of compound (4) representative, can enumerate amino protected optically active trans-4-hydroxy-l-proline.
In the present invention, the compound (4) that is used as raw material can utilize known method synthetic.When P is 4-nitro benzyloxycarbonyl, for example, can under the condition that alkali exists, trans-4-hydroxy-l-proline and chlorine carbonic acid 4-nitrobenzyl ester be reacted prepare according to the method for putting down in writing in the Japanese kokai publication hei 4-217661 communique.
R
1For optional substituted carbonatoms is that 1～7 alkyl, optional substituted carbonatoms are that 3～6 thiazolinyl, optional substituted carbonatoms are 6～12 aryl.
It as optional substituted carbonatoms 1～7 alkyl, can be listed below, for example: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, isobutyl-, n-pentyl, 3-amyl group, neo-pentyl, cyclopentyl, n-hexyl, cyclohexyl, 2-chloroethyl, 2-cyano ethyl, 2-methoxy ethyl, 2-nitro-ethyl, benzyl, 4-nitrobenzyl, 4-methoxy-benzyl, 4-benzyl chloride base etc.
As optional substituted carbonatoms is 3～6 thiazolinyl, can be listed below: allyl group, crotyl etc.
As optional substituted carbonatoms is 6～12 aryl, can be listed below: phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-nitrophenyl, 4-chloro-phenyl-etc.
With respect to 1 mole compound (4), the consumption of chlorine carbonic ether (5) is generally more than 1.0 moles, and is preferred more than 1.05 moles.Its upper limit is not particularly limited, usually below 2.0 moles, preferably below 1.5 moles.
As trialkylamine, can be listed below, for example: triethylamine, Trimethylamine 99, Tributylamine, diisopropylethylamine etc.As trialkylamine, preferred triethylamine and/or Trimethylamine 99.
With respect to 1 mole compound (4), the consumption of trialkylamine is generally more than 1.0 moles, and is preferred more than 1.05 moles.Its upper limit is not particularly limited, usually below 2.5 moles, preferably below 2.0 moles.Yet from the viewpoint of economic aspect and the generation of inhibition impurity, preferably with respect to 1 mole of chlorine carbonic ether, its consumption is more than 1.0 moles and below 1.5 moles.
As reaction solvent, use the slightly water-soluble organic solvent.Said slightly water-soluble organic solvent is meant that under the normal temperature, water saturation solubleness is the following solvent of 1 weight % in the solvent.
As the slightly water-soluble organic solvent, can be listed below methylene dichloride, chloroform, 1, the halogenated hydrocarbon solvent that the 2-ethylene dichloride is such; Aromatic hydrocarbon solvents such as benzene,toluene,xylene, chlorobenzene, oil of mirbane; Varsol such as normal hexane, hexanaphthene depends on the needs, and also can select use more than 2 kinds wherein.Wherein, preferred halogenated hydrocarbon solvent and aromatic hydrocarbon solvent are from suppressing the viewpoint that yield reduces, preferred especially methylene dichloride, chloroform, 1,2-ethylene dichloride, toluene, chlorobenzene and oil of mirbane.
Come in the weight of solvent ratio with respect to compound (4), solvent load is generally 5～50, from suppressing the viewpoint that yield reduces, preferred 15～40 scope.
Temperature of reaction is generally-25～0 ℃, from suppressing the viewpoint that yield reduces, preferred-20～-5 ℃ scope.
Interpolation to reagent is not particularly limited in proper order, from suppressing the viewpoint that impurity generates, after preferably in solvent, compound (4) and chlorine carbonic ether being mixed, add trialkylamine again, perhaps in the solvent that has dissolved the chlorine carbonic ether, add the mixture (solution, salt etc.) of compound (4) and trialkylamine.
The compound that obtains as mentioned above (3) can be directly used in the following operation without separation.
Operation (B)
Then; operation to the compound that obtains following formula (2) representative describes, and under the condition that trialkylamine exists, makes the halide reaction of compound (3) and sulfonic acid; make hydroxyl by sulfonylation, thereby obtain compound as following formula (2) representative of mixed acid anhydride.
[Chemical formula 1 1]
In the general formula (2), P, R
1And R
2Same as described above.
As the halogenide of sulfonic acid, can be listed below, for example: methylsulfonyl chloride, benzene sulfonyl chloride, toluene sulfonyl chloride etc., wherein, from the viewpoint of economy, preferably use methylsulfonyl chloride and/or optional substituted benzene sulfonyl chloride.
With respect to 1 mole compound (3), the halid consumption of sulfonic acid is generally more than 1.0 moles, and is preferred more than 1.05 moles.Its upper limit is not particularly limited, usually below 3.0 moles,, preferred below 2.5 moles from the viewpoint of economic aspect and the generation of inhibition impurity.
As trialkylamine, can be listed below, for example: triethylamine, Trimethylamine 99, Tributylamine, diisopropylethylamine etc.As trialkylamine, preferred triethylamine and/or Trimethylamine 99.Need to prove, in this reaction, when using always as the pyridine of alkali etc., inventor's discovery of etc.ing:, can prepare target compound with high yield by using the trialkylamine of cheapness.
With respect to 1 mole compound (3), the consumption of trialkylamine is generally more than 1.0 moles, and is preferred more than 1.05 moles.Its upper limit is not particularly limited, usually below 3.5 moles,, preferred below 3.0 moles from the viewpoint of economic aspect and the generation of inhibition impurity.
Temperature of reaction is generally-25～0 ℃, from suppressing the viewpoint that yield reduces, preferred-20～-5 ℃ scope.
Interpolation to reagent is not particularly limited in proper order, after can in the solution that contains compound (3), mixing the halogenide of sulfonic acid, add trialkylamine again, after perhaps in the solution that contains compound (3), mixing trialkylamine, the halogenide that adds sulfonic acid again, perhaps in the solution that contains compound (3) simultaneously or alternately add the halogenide and the trialkylamine of sulfonic acid.
The compound that obtains as mentioned above (2) can be directly used in following operation without separation.
Need to prove, in this operation, can use the compound that makes by operation (A), also can use the compound that makes by additive method as compound (3).
Operation (C)
Then, the operation of the compound of acquisition formula (1) representative is described, make compound (2) and metallic sulfide reactant aqueous solution, thereby obtain the compound that following formula (1) is represented.
[Chemical formula 1 2]
In the general formula (1), P is same as described above.
As metallic sulfide, can be listed below, for example: sodium sulphite, lithium sulfide, potassium sulphide, sulfurated lime, sodium sulfhydrate etc.Wherein, from viewpoint acquired, economy, preferred sodium sulphite, sodium sulfhydrate.In addition, metallic sulfide can be an anhydride, also can be hydrate.
With respect to 1 mole compound (2), the consumption of metallic sulfide is generally more than 1.0 moles, and is preferred more than 1.05 moles.Its upper limit is not particularly limited, usually below 2.0 moles,, preferred below 1.5 moles from the viewpoint of economic aspect and the generation of inhibition impurity.
Metallic sulfide can the aqueous solution form use preferred 10～50 weight % of the concentration of metallic sulfide, more preferably 15～40 weight %.Compound (2) hydrolabil, if therefore the concentration of metallic sulfide is below 10 weight %, then not only yield descends, impurity increases, and needs to increase the size of employed reaction vessel, and is therefore from the productivity aspect, not preferred.In addition, from the viewpoint of the solubleness of metallic sulfide, if the concentration of metallic sulfide more than 50 weight %, then metallic sulfide is difficult to abundant dissolving in water, and is from the operability aspect, not preferred.Temperature to the metallic sulfide aqueous solution is not particularly limited, and is generally 0～50 ℃, from the viewpoint of operability, and preferred 10～30 ℃.
Need in the reaction soln that contains compound (2), add the described metallic sulfide aqueous solution rapidly.Discoveries such as the inventor: by controlling the interpolation speed of the described metallic sulfide aqueous solution, the value that makes following formula (I) is 0.003～0.2, can obtain target compound with high yield.
(per 1 second the metallic sulfide aqueous solution addition) ÷ (total addition level of the metallic sulfide aqueous solution) ... (I)
This value is lower than 0.003, and the time of promptly adding, then impurity level sharply increased more than 5 minutes, thereby causes the yield of compound (1) to reduce.Think that above-mentioned phenomenon is owing to compound (2) the chance water capacity causes easy the decomposition.On the other hand, the value of above-mentioned formula (I) is greater than 0.2, i.e. the interpolation time is less than 5 seconds, then needs special equipment in industrial production, and is from the viewpoint of industrial implementation, not preferred.
In addition, discoveries such as the inventor: when making the solution reaction that contains the metallic sulfide aqueous solution and compound (2),, can obtain target compound with high yield by under high current is moving, reacting.The flowability of reaction solution is poor, and then the yield of compound (1) significantly reduces, and impurity level increases, and is therefore not preferred.In order to keep good yield, the needed stirring power of per unit volume is 0.2kW/m
3More than, preferred 0.3kW/m
3More than.Its upper limit is not particularly limited, is generally 10kW/m
3Below.In addition, normally the revolution by stirring rake imposes above-mentioned flowing, as long as but can obtain above-mentioned flowing, must not use stirring rake, for example, can utilize the method for liquid circulation.
At the time point that begins to add the metallic sulfide aqueous solution, temperature of reaction is generally-25～0 ℃, from suppressing the viewpoint that yield reduces, preferred-20～-5 ℃ scope.After adding the metallic sulfide aqueous solution, the temperature of reaction that raises is rapidly proceeded reaction.
Reaction behind the interpolation metallic sulfide aqueous solution is carried out to the scope of solvent boiling point at 0 ℃ usually, and preferred 10～60 ℃, from suppressing the viewpoint that impurity generates, more preferably 20～50 ℃.The subsequent reactions time, can suitably judge by the process of tracking reactions such as HPLC.
Synthetic compound (1) as mentioned above also can be if necessary in implementing separatory, cleaning, drying, concentrate, after the column chromatography analysis etc., carry out crystallization to separate out, thereby obtain the crystal of compound (1).
Need to prove, in this operation, can use the compound that obtains by operation (B), also can use the compound that makes by additive method to be used as compound (2).
Operation (D)
In addition, can prepare the compound of following formula (7) representative by the amine compound reaction of the compound (1) that obtains as mentioned above with following formula (6) representative.
NHR
3R
4 (6)
[Chemical formula 1 3]
The R of above-mentioned formula (6), (7)
3And R
4Represent independently that respectively hydrogen atom, optional substituted carbonatoms are that 1～6 alkyl, optional substituted carbonatoms are that 2～6 thiazolinyl, optional substituted carbonatoms are that 6～12 aryl and optional substituted carbonatoms are any group in 4～12 the heteroaryl.In addition, R
3And R
4The optional optional substituted cyclic amine compound that forms 4～8 yuan of rings respectively with the nitrogen-atoms of bonding,
As optional substituted carbonatoms is 1～6 alkyl, can be listed below, as methyl, ethyl, sec.-propyl etc.As optional substituted carbonatoms is 2～6 thiazolinyl, can be listed below, as vinyl, allyl group, crotyl etc.As optional substituted carbonatoms is 6～12 aryl, can be listed below, as phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-nitrophenyl, 4-chloro-phenyl-, 3-carboxyl phenyl, 4-carboxyl phenyl etc.As optional substituted carbonatoms is 4～12 heteroaryl, can be listed below, as furyl, pyridyl, thienyl, 5-carboxy thiophene base etc.In addition, the optional substituted cyclic amine compound of 4～8 yuan of rings that form with the nitrogen-atoms of mutual bonding can be listed below, as azetidine, tetramethyleneimine, piperidines, 4-methyl piperidine, 4-propyl group piperidines etc.
Wherein, as R
3, R
4, preferred hydrogen atom, optional substituted carbonatoms are that 1～6 alkyl or optional substituted carbonatoms are 6～12 aryl.In addition, preferred R
3And R
4Be combined as: R
3And R
4Be methyl, perhaps R
3Be hydrogen atom, R
4Be the 3-carboxyl phenyl.
The amine compound of compound (6) can use their inorganic acid salt state or be used for reaction in the presence of alkali.Employed alkali during as enforcement reaction in the presence of alkali for example can be enumerated: alkalimetal hydrides such as sodium hydride, potassium hydride KH; Alkali metal hydroxide such as sodium hydroxide, potassium hydroxide; Alkaline carbonate such as yellow soda ash, salt of wormwood; Alkali metal hydrocarbonate such as sodium bicarbonate, saleratus; Trialkylamine such as triethylamine, diisopropylamine; Pyridine compounds such as pyridine, lutidine.
With respect to 1 mole compound (1), the consumption of amine compound is generally more than 1.0 moles, and is preferred more than 1.05 moles.Its upper limit is not particularly limited, and is generally below 2.0 moles, and is from the viewpoint of economic aspect and the generation of inhibition impurity, preferred below 1.5 moles.
As reaction solvent, for example can enumerate: carboxylic-acid solvents such as acetate, propionic acid; Methylene dichloride, 1, halogenated hydrocarbon solvents such as 2-ethylene dichloride; Nitrile solvents such as acetonitrile; Ether solvent such as THF or ether; Esters solvent such as ethyl acetate, butylacetate; Aromatic hydrocarbon solvent such as benzene, toluene; Water.In addition, can also optionally use in them more than 2 kinds.
Weight ratio in solvent comes, and with respect to compound (1), the consumption of solvent is generally 5～50, preferred 15～40 scope.
Temperature of reaction is generally-10～70 ℃, and impurity generates and the deliquescent viewpoint of amine compound from suppressing, preferred-5～50 ℃ scope.
In the reaction times, can suitably judge by the process of tracking reactions such as HPLC.
Synthetic compound (7) as mentioned above also can be if necessary in implementing separatory, cleaning, drying, concentrate, after the column chromatography analysis etc., carry out crystallization by ordinary method to separate out, thereby obtain the crystal of compound (7).
Operation (E)
By using deprotection agent, the protecting group P of the compound (7) that obtains is as mentioned above carried out deprotection, can prepare the 4-mercaptopyrrolidine derivatives of following formula (8) representative or their inorganic acid salt,
[Chemical formula 1 4]
In the above-mentioned formula (8), R
3, R
4Same as described above.
As deprotection agent, particularly, can use the deprotection method of being put down in writing among the above-mentioned PROTECTIVE GROUPS IN ORGANIC SYNTHESIS the 4th edition to carry out protecting group.
Particularly, be under the situation of tert-butoxycarbonyl when protecting group, can carry out deprotection by reacting with protonic acid.
As protonic acid, for example can enumerate: hydrochloric acid or Hydrogen bromide, hydroiodic acid HI, sulfuric acid, methylsulfonic acid, 4-toluenesulphonic acids, preferred hydrochloric acid.
With respect to 1 mole compound (1), the consumption of protonic acid is generally more than 1.0 moles.Its upper limit is not particularly limited, and is generally below 5.0 moles, and is from suppressing the viewpoint that impurity generates, preferred below 3.0 moles.
As reaction solvent, for example can enumerate: carboxylic-acid solvents such as acetate, propionic acid; Methylene dichloride, 1, halogenated hydrocarbon solvents such as 2-ethylene dichloride; Nitrile solvents such as acetonitrile; Ether solvent such as THF or ether; Esters solvent such as ethyl acetate, butylacetate; Aromatic hydrocarbon solvent such as benzene, toluene; Water.In addition, can also optionally use in them more than 2 kinds.
Weight ratio in solvent comes, and with respect to compound (1), the consumption of solvent is generally 5～50, preferred 5～30 scope.
Temperature of reaction is generally-10～50 ℃, from suppressing the viewpoint that impurity generates, preferred-5～30 ℃ scope.
In the reaction times, can suitably judge by the process of tracking reactions such as HPLC.
Synthetic compound (8) as mentioned above also can be if necessary in implementing separatory, cleaning, drying, concentrate, after the column chromatography analysis etc., carry out crystallization by ordinary method to separate out, thereby obtain the crystal of compound (8).
Embodiment
Below by describing embodiment and comparative example, next the present invention will be further described, and the present invention is not limited to following embodiment and comparative example.
Need to prove, in following embodiment and comparative example, use following HPLC analysis condition to analyze.
[HPLC analysis condition]
The instrument kind: (strain) Shimadzu Seisakusho Ltd. makes LC-10A Series
Post: Nacalai Tesque makes the ODS post
Cosmosil?5C18AR-II(4.6mm×250mm)
Elutriant: acetonitrile/phosphoric acid buffer (pH3.0)=40/60 (v/v)
Flow velocity: 1.0ml/min
Detect wavelength: 274nm (UV detector)
Temperature: 40 ℃
(embodiment 1)
Under-15 ℃ of conditions, to methylene dichloride 666mL, chlorine isobutyl carbonate propyl ester 16.4g (133.8mmol) and P is in the mixed solution of compound (4) 36.0g (116.0mmol) of 4-nitro benzyloxycarbonyl, add triethylamine 15.3g (0.151mol), synthermal down stir 1 hour after, add methylsulfonyl chloride 15.3g (133.6mmol) and triethylamine 14.1g (139.3mmol) successively, stirred 1 hour down synthermal.Then, will stir the needed power of per unit volume and be set at 1.4kW/m
3, add in advance sodium sulfide solution by 30 seconds (formula (I)=0.033) by sodium sulphite nonahydrate 33.4g (139.1mmol) and water 72g preparation after, refluxed 2 hours.Subsequently, reaction solution is cooled to 25 ℃, behind the separatory, uses dilute hydrochloric acid, sodium bicarbonate water and water to clean the organic layer that obtains successively.In the above-mentioned organic layer that obtains, the amount of compound (1) is 30.4g (98.6mmol, a yield 85%).After the cleaning, distillation removes and desolvates, and uses silica gel chromatography (ethyl acetate/hexane=1/1 volume ratio) purifying residue, obtains the solid of compound (1).
The gained solid
1H-NMR (CDCl
3) be:
1H-NMR (CDCl
3) δ 2.11-2.27 (2H, m), 3.67-3.72 (1H, m), 3.85-3.90 (1H, m), 4.15-4.19 (1H, m), 4.62-4.70 (1H, m), 5.21 (1H, d, J=13.7Hz), 5.31 (1H, d, J=13.7Hz), 7.54 (2H, d, J=8.6Hz), 8.23 (2H, d, J=8.6Hz), with heterocycle (Heterocycles), 147～159 pages, the data consistent of nineteen ninety-five record.
(embodiment 2)
Under-15 ℃ of conditions, to toluene 300mL, chlorine isobutyl carbonate propyl ester 4.5g (36.7mmol) and P is in the mixed solution of compound (4) 10.0g (32.2mmol) of 4-nitro benzyloxycarbonyl, add triethylamine 4.2g (41.5mmol), synthermal down stir 1 hour after, add methylsulfonyl chloride 4.9g (42.8mmol) and triethylamine 4.5g (44.5mmol) successively, stirred 1 hour down synthermal.Then, will stir the needed power of per unit volume and be set at 1.0kW/m
3, add in advance sodium sulfide solution by 30 seconds (formula (I)=0.033) by sodium sulphite nonahydrate 9.3g (38.7mmol) and water 20g preparation after, begin rapidly to reflux, and stirred 2 hours on backflow limit, limit.Subsequently, reaction solution is cooled to 25 ℃, behind the separatory, uses dilute hydrochloric acid, sodium bicarbonate water and water to clean the organic layer that obtains successively.Using HPLC quantitative, is 6.7g (21.7mmol, yield 67%) according to the amount of the compound (1) in the above-mentioned organic layer that obtains.
(comparative example 1)
Under-15 ℃ of conditions, to methylene dichloride 185mL, chlorine isobutyl carbonate propyl ester 4.5g (36.7mmol) and P is in the mixed solution of compound (4) 10.0g (32.2mmol) of 4-nitro benzyloxycarbonyl, add triethylamine 4.2g (41.5mmol), synthermal down stir 1 hour after, add methylsulfonyl chloride 4.9g (42.8mmol) and triethylamine 4.5g (44.5mmol) successively, stirred 1 hour down synthermal.Then, will stir the needed power of per unit volume and be set at 0.1kW/m
3, add in advance sodium sulfide solution by 10 seconds (formula (I)=0.1) by sodium sulphite nonahydrate 9.3g (38.7mmol) and water 20g preparation after, begin rapidly to reflux, stirred 2 hours on backflow limit, limit.Subsequently, reaction solution is cooled to 25 ℃, behind the separatory, uses dilute hydrochloric acid, sodium bicarbonate water and water to clean the organic layer that obtains successively.Using HPLC quantitative, is 4.2g (13.6mmol, yield 43%) according to the amount of the compound (1) in the above-mentioned organic layer that obtains.
(comparative example 2)
Under-15 ℃ of conditions, to methylene dichloride 185mL, chlorine isobutyl carbonate propyl ester 4.5g (36.7mmol) and P is in the mixed solution of compound (4) 10.0g (32.2mmol) of 4-nitro benzyloxycarbonyl, add triethylamine 4.2g (41.5mmol), synthermal down stir 1 hour after, add methylsulfonyl chloride 4.9g (42.8mmol) and triethylamine 4.5g (44.5mmol) successively, stirred 1 hour down synthermal.Then, will stir the needed power of per unit volume and be set at 0.01kW/m
3, add in advance sodium sulfide solution by 10 seconds (formula (I)=0.1) by sodium sulphite nonahydrate 9.3g (38.7mmol) and water 20g preparation after, begin rapidly to reflux, stirred 2 hours on backflow limit, limit.Subsequently, reaction solution is cooled to 25 ℃, behind the separatory, uses dilute hydrochloric acid, sodium bicarbonate water and water to clean the organic layer that obtains successively.Using HPLC quantitative, is 3.0g (9.7mmol, yield 30%) according to the amount of the compound (1) in the above-mentioned organic layer that obtains.
(embodiment 3)
Under-10 ℃ of conditions, to methylene dichloride 185mL, chlorine isobutyl carbonate propyl ester 4.5g (36.7mmol) and P is in the mixed solution of compound (4) 10.0g (32.2mmol) of 4-nitro benzyloxycarbonyl, add triethylamine 4.2g (41.5mmol), synthermal down stir 1 hour after, add methylsulfonyl chloride 4.9g (42.8mmol) and triethylamine 4.5g (44.5mmol) successively, stirred 1 hour down synthermal.Then, will stir the needed power of per unit volume and be set at 0.3kW/m
3, add in advance sodium sulfide solution by 10 seconds (formula (I)=0.1) by sodium sulphite nonahydrate 9.3g (38.7mmol) and water 20g preparation after, begin rapidly to reflux, stirred 2 hours on backflow limit, limit.Subsequently, reaction solution is cooled to 25 ℃, behind the separatory, uses dilute hydrochloric acid, sodium bicarbonate water and water to clean the organic layer that obtains successively.Using HPLC quantitative, is 8.0g (25.9mmol, yield 81%) according to the amount of the compound (1) in the above-mentioned organic layer that obtains.
(embodiment 4)
Under-10 ℃ of conditions, to methylene dichloride 2220mL, chlorine isobutyl carbonate propyl ester 54.4g (443.9mmol) and P is in the mixed solution of compound (4) 120g (386.8mmol) of 4-nitro benzyloxycarbonyl, add triethylamine 50.8g (502.0mmol), synthermal down stir 1 hour after, add methylsulfonyl chloride 70.8g (618.1mmol) and triethylamine 64.4g (636.4mmol) successively, stirred 1 hour down synthermal.Then, will stir the needed power of per unit volume and be set at 0.7kW/m
3, add in advance sodium sulfide solution by 30 seconds (formula (I)=0.033) by sodium sulphite nonahydrate 112g (466.3mmol) and water 240g preparation after, begin rapidly to reflux, stirred 2 hours on backflow limit, limit.Subsequently, reaction solution is cooled to 25 ℃, behind the separatory, uses dilute hydrochloric acid, sodium bicarbonate water and water to clean the organic layer that obtains successively.Using HPLC quantitative, is 100.1g (324.7mmol, yield 84%) according to the amount of the compound (1) in the above-mentioned organic layer that obtains.
(embodiment 5)
Under-10 ℃ of conditions, to methylene dichloride 555mL, chlorine isobutyl carbonate propyl ester 14.4g (117.5mmol) and P is in the mixed solution of compound (4) 30.0g (96.7mmol) of 4-nitro benzyloxycarbonyl, add triethylamine 12.8g (126.5mmol), synthermal down stir 1 hour after, add methylsulfonyl chloride 12.7g (110.9mmol) and triethylamine 11.9g (117.6mmol) successively, stirred 1 hour down synthermal.Then, will stir the needed power of per unit volume and be set at 1.0kW/m
3, add in advance sodium sulfide solution by 2 minutes (formula (I)=0.008) by sodium sulphite nonahydrate 28.4g (118.2mmol) and water 62g preparation after, begin rapidly to reflux, stirred 2 hours on backflow limit, limit.Subsequently, reaction solution is cooled to 25 ℃, behind the separatory, uses dilute hydrochloric acid, sodium bicarbonate water and water to clean the organic layer that obtains successively.Using HPLC quantitative, is 25.1g (81.4mmol, yield 84%) according to the amount of the compound (1) in the above-mentioned organic layer that obtains.
(comparative example 3)
Under-10 ℃ of conditions, to methylene dichloride 555mL, chlorine isobutyl carbonate propyl ester 14.4g (117.5mmol) and P is in the mixed solution of compound (4) 30.0g (96.7mmol) of 4-nitro benzyloxycarbonyl, add triethylamine 12.8g (126.5mmol), synthermal down stir 1 hour after, add methylsulfonyl chloride 12.7g (110.9mmol) and triethylamine 11.9g (117.6mmol) successively, stirred 1 hour down synthermal.Then, will stir the needed power of per unit volume and be set at 1.0kW/m
3, add in advance sodium sulfide solution by 15 minutes (formula (I)=0.001) by sodium sulphite nonahydrate 28.4g (118.2mmol) and water 62g preparation after, begin rapidly to reflux, stirred 2 hours on backflow limit, limit.Subsequently, reaction solution is cooled to 25 ℃, behind the separatory, uses dilute hydrochloric acid, sodium bicarbonate water and water to clean the organic layer that obtains successively.Using HPLC quantitative, is 15.5g (50.3mmol, yield 52%) according to the amount of the compound (1) in the above-mentioned organic layer that obtains.
(embodiment 6)
Under-20 ℃ of conditions, spending 1 hour to methylene dichloride 1200mL, chlorine isobutyl carbonate propyl ester 36.5g (297.8mmol) and P is in the mixed solution of compound (4) 60.0g (259.5mmol) of tert-butoxycarbonyl, add triethylamine 34.2g (338.0mmol), synthermal down stir 30 minutes after, add methylsulfonyl chloride 34.6g (302.1mmol) and triethylamine 31.6g (312.3mmol) successively, stirred 20 minutes down synthermal.Then, will stir the needed power of per unit volume and be set at 0.4kW/m
3, add sodium sulfide solution by 60 seconds (formula (I)=0.017) by sodium sulphite nonahydrate 68.7g (286.0mmol) and water 109.3g preparation after, be warming up to room temperature rapidly, stirred 4 hours.Subsequently, it is carried out separatory, and use dilute hydrochloric acid, sodium bicarbonate water and water to clean the organic layer that obtains successively.To carrying out quantitatively according to the amount of the compound (1) in the above-mentioned organic layer that obtains, the result is 49.2g (214.6mmol, a yield 83%).
(embodiment 7)
Under-15 ℃ of conditions, to methylene dichloride 37mL, chlorine isobutyl carbonate butyl ester 1.4g (11.4mmol) and P is in the mixed solution of compound (4) 2.0g (8.6mmol) of tert-butoxycarbonyl, add triethylamine 1.1g (10.9mmol), synthermal down stir 1 hour after, add methylsulfonyl chloride 1.1g (9.6mmol) and triethylamine 1.1g (10.9mmol) successively, stirred 1 hour down synthermal.After adding sodium sulfide solution by 5 seconds (formula (I)=0.2), be warming up to room temperature rapidly, stirred 4 hours by sodium sulphite nonahydrate 2.5g (10.4mmol) and water 4g preparation.Subsequently, it is carried out separatory, and use dilute hydrochloric acid, sodium bicarbonate water and water to clean the organic layer that obtains successively.To carrying out quantitatively according to the amount of the compound (1) in the above-mentioned organic layer that obtains, the result is 1.6g (7.0mmol, a yield 81%).
(comparative example 4)
Under-15 ℃ of conditions, to methylene dichloride 40mL, chlorine isobutyl carbonate propyl ester 1.1g (9.0mmol) and P is in the mixed solution of compound (4) 2.0g (8.6mmol) of tert-butoxycarbonyl, add triethylamine 1.88g (18.6mmol), synthermal down stir 1 hour after, add methylsulfonyl chloride 1.1g (9.6mmol) and pyridine 0.7g (8.8mmol), stirred 1 hour down synthermal.After adding sodium sulfide solution in 5 seconds by sodium sulphite nonahydrate 2.5g (10.4mmol) and water 15g preparation, be warming up to room temperature rapidly, stirred 4 hours.Subsequently, it is carried out separatory, use dilute hydrochloric acid, sodium bicarbonate water and water to clean the organic layer that obtains successively.Using HPLC quantitative, is 0.79g (3.4mmol, yield 40%) according to the amount of the compound (1) in the above-mentioned organic layer that obtains.
(embodiment 8)
Ice-cooled be in the THF202mL solution of compound (1) 30.0g (97.3mmol) of 4-nitro benzyloxycarbonyl down to P, add the dimethylamine agueous solution 10.5g (116.4mmol) of 50 weight %, stirs after 1 hour, use dilute hydrochloric acid cleans.Using HPLC quantitative, is 33.8g (95.6mmol, yield 98%) according to the amount of the compound (7) in the above-mentioned organic layer that obtains.Then, distillation removes and desolvates, and uses silica gel chromatography (ethyl acetate/hexane=1/1 volume ratio) that residue is carried out purifying, obtains the solid of compound (7).
The solid that obtains
1H-NMR (CDCl
3) be:
δ1.90(1H，d，J＝8.0Hz)，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＝9.0Hz)，8.15(2H，d，J＝9.0Hz)。
(embodiment 9)
Under-15 ℃ of conditions, to methylene dichloride 663mL, chlorine isobutyl carbonate propyl ester 16.3g (133mmol) and P is in the mixed solution of compound (4) 36g (116mmol) of 4-nitro benzyloxycarbonyl, add triethylamine 15.3g (151mmol), synthermal down stir 1 hour after, add methylsulfonyl chloride 15.3g (133mmol) and triethylamine 14.1g (140mmol) successively, stirred 1 hour down synthermal.Then, will stir the needed power of per unit volume and be set at 3.5kW/m
3, add in advance sodium hydrosulfide aqueous solution by 10 seconds (formula (I)=0.1) by sodium sulfhydrate n hydrate 10.9g (140mmol) and water 36.3g preparation after, begin rapidly to reflux, stirred 2 hours on backflow limit, limit.Subsequently, reaction solution is cooled to 25 ℃, behind the separatory, uses dilute hydrochloric acid, sodium bicarbonate water and water to clean the organic layer that obtains successively.Using HPLC quantitative, is 32.7g (106mmol, yield 91%) according to the amount of the compound (1) in the above-mentioned organic layer that obtains.
(embodiment 10)
Under 50 ℃ of conditions, in the acetic acid solution 188.1g that contains 3-benzaminic acid 9.43g, slowly adding P is the dichloromethane solution 80.1g (content 25 weight %, 64.2mmol) of the compound (1) of 4-nitro benzyloxycarbonyl, stirs 1 hour down synthermal then.The slurry reaction liquid cooling is but also filtered, obtain white crystal.Crystal cleaning, drying with obtaining obtain compound (7) 28.3g (63.5mmol, yield 99%).
The crystalline that obtains
1H-NMR (DMSO-d6) is:
δ1.85(1H，m)，2.70(1H，m)，3.27(2H，m)，3.97(1H，m)，4.35(1H，m)，5.13(2H，m)，7.82(8H，m)，10.28(1H，d，J＝9.0Hz)。
(embodiment 11)
Identical with method described in the public table of the Japanese Patent 2002-504157, in the acetic acid solution 104.4g that contains 3-benzaminic acid 9.68g, after interpolation P is the dichloromethane solution 178.4g (content 8.6 weight %, 67.1mmol) of the compound (1) of tert-butoxycarbonyl, stirred 18 hours.After using HPLC to confirm to generate compound (7) in the organic layer, add concentrated hydrochloric acid 25.1g, stirred 15 minutes.After using HPLC to confirm to generate compound (8) in the organic layer, the amount of the compound (8) that distillation obtains except that desolvating is 17.1g (56.5mmol, a yield 84%).
Claims (18)
1. the manufacture method of the pyrrolidin derivatives of following formula (1) representative is characterized in that:
Controlling the required stirring power of per unit volume on one side is 0.2kW/m
3More than and the value of following formula (I) be 0.003～0.2, on one side in the compound of following formula (2) representative, add the metallic sulfide aqueous solution,
In the formula (2), P represents amino protecting group, R
1The optional substituted carbonatoms of expression is that 1～7 alkyl, optional substituted carbonatoms are that 3～6 thiazolinyl or optional substituted carbonatoms are 6～12 aryl; R
2Optional substituted alkyl of expression or optional substituted aryl;
Formula (I):
(per 1 second the metallic sulfide aqueous solution addition) ÷ (total addition level of the metallic sulfide aqueous solution) ... (I)
In the formula (1), P is same as described above.
2. the described manufacture method of claim 1, wherein, the compound of above-mentioned formula (2) representative, be trialkylamine exist and the non-existent condition of pyridine under, the halogenide of the compound of following formula (3) representative and sulfonic acid is reacted makes,
In the formula (3), P and R
1Same as described above.
3. the described manufacture method of claim 2, wherein, the compound of above-mentioned formula (3) representative, be in the slightly water-soluble organic solvent, under the condition that trialkylamine exists, the compound of following formula (4) representative and the chlorine carbonate reaction of following formula (5) representative are made
In the formula (4), P is same as described above,
CICOOR
1 (5)
In the formula (5), R
1Same as described above.
4. claim 2 or 3 described manufacture method, wherein, trialkylamine is triethylamine and/or Trimethylamine 99.
5. each described manufacture method in the claim 2～4, wherein, the halogenide of sulfonic acid is methylsulfonyl chloride and/or optional substituted benzene sulfonyl chloride.
6. each described manufacture method in the claim 3～5, wherein, the compound of above-mentioned formula (4) representative is amino protected optically active trans-4-hydroxy-l-proline.
7. each described manufacture method in the claim 1～6, wherein, metallic sulfide is a sodium sulphite.
8. the described manufacture method of claim 7, wherein, the concentration of sodium sulfide solution is 10～50 weight %.
9. each described manufacture method in the claim 1～6, wherein, metallic sulfide is a sodium sulfhydrate.
10. the described manufacture method of claim 9, wherein, the concentration of sodium hydrosulfide aqueous solution is 10～50 weight %.
11. the manufacture method of the 4-mercaptopyrrolidine derivatives of following formula (7) representative is characterized in that:
Amine compound that the compound (1) made by each described method in the claim 1～10 and following formula (6) represent or their inorganic acid salt are reacted,
NHR
3R
4 (6)
In the formula (6), R
3And R
4Represent that independently of one another hydrogen atom, optional substituted carbonatoms are that 1～6 alkyl, optional substituted carbonatoms are that 2～6 thiazolinyl, optional substituted carbonatoms are that 6～12 aryl, optional substituted carbonatoms are any group in 4～12 the heteroaryl; Perhaps, R
3And R
4The optional optional substituted cyclic amine compound that forms 4～8 yuan of rings respectively with the nitrogen-atoms of bonding,
In the formula (7), P, R
3And R
4Same as described above.
12. the 4-mercaptopyrrolidine derivatives of following formula (8) representative or the manufacture method of its salt; it is characterized in that: the compound of being made by method described in the claim 11 (7) is reacted with deprotection agent; thereby the protecting group P of 4-mercaptopyrrolidine derivatives is carried out deprotection
In the formula (8), R
3, R
4Same as described above.
13. each described manufacture method in the claim 1～12, wherein, P is any one in 4-nitro benzyloxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl and the allyl group oxygen base carbonyl.
14. the described manufacture method of claim 13, wherein, P is a tert-butoxycarbonyl.
15. each described manufacture method in the claim 12～14, wherein, deprotection agent is a protonic acid.
16. the described manufacture method of claim 15, wherein, protonic acid is a hydrochloric acid.
17. each described manufacture method in the claim 11～16, wherein, R
3And R
4Represent that independently of one another hydrogen atom, optional substituted carbonatoms are that 1～6 alkyl or optional substituted carbonatoms are any group in 6～12 the aryl.
18. the described manufacture method of claim 17, wherein, R
3And R
4Be methyl, or R
3Be hydrogen atom, R
4Be the 3-carboxyl phenyl.
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| CN102976994A (en) * | 2012-12-27 | 2013-03-20 | 天津市敬业精细化工有限公司 | Crystal form meropenem side chain and preparation method thereof |
| CN106565579A (en) * | 2016-06-26 | 2017-04-19 | 宁夏海诚电化信息科技有限公司 | Ertapenem side chain production technology |
| CN107118222A (en) * | 2017-05-27 | 2017-09-01 | 合肥利夫生物科技有限公司 | A kind of preparation method of Meropenem side chain intermediate mercaptan lactone |
| CN115490625A (en) * | 2022-11-18 | 2022-12-20 | 山东鑫泉医药有限公司 | Synthesis and refining method of meropenem side chain |
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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 |
| 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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| US5322952A (en) * | 1992-01-10 | 1994-06-21 | Sumitomo Pharmaceuticals Company, Limited | Pyrrolidine derivatives and process for preparing the same |
| WO1997006154A1 (en) * | 1995-08-04 | 1997-02-20 | Merck & Co., Inc. | Process for synthesizing carbapenem side chain intermediates |
| WO1999002492A1 (en) * | 1997-07-10 | 1999-01-21 | Merck & Co., Inc. | Crystalline forms of antibiotic side chain intermediates |
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| EP1019411A4 (en) * | 1997-07-09 | 2003-08-13 | Merck & Co Inc | Process for synthesizing carbapenem side chain intermediates |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5322952A (en) * | 1992-01-10 | 1994-06-21 | Sumitomo Pharmaceuticals Company, Limited | Pyrrolidine derivatives and process for preparing the same |
| WO1997006154A1 (en) * | 1995-08-04 | 1997-02-20 | Merck & Co., Inc. | Process for synthesizing carbapenem side chain intermediates |
| WO1999002492A1 (en) * | 1997-07-10 | 1999-01-21 | Merck & Co., Inc. | Crystalline forms of antibiotic side chain intermediates |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102976994A (en) * | 2012-12-27 | 2013-03-20 | 天津市敬业精细化工有限公司 | Crystal form meropenem side chain and preparation method thereof |
| CN106565579A (en) * | 2016-06-26 | 2017-04-19 | 宁夏海诚电化信息科技有限公司 | Ertapenem side chain production technology |
| CN107118222A (en) * | 2017-05-27 | 2017-09-01 | 合肥利夫生物科技有限公司 | A kind of preparation method of Meropenem side chain intermediate mercaptan lactone |
| CN115490625A (en) * | 2022-11-18 | 2022-12-20 | 山东鑫泉医药有限公司 | Synthesis and refining method of meropenem side chain |
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