CN101747334A - Method for preparing double protection imipenem - Google Patents
Method for preparing double protection imipenem Download PDFInfo
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- CN101747334A CN101747334A CN200810204646A CN200810204646A CN101747334A CN 101747334 A CN101747334 A CN 101747334A CN 200810204646 A CN200810204646 A CN 200810204646A CN 200810204646 A CN200810204646 A CN 200810204646A CN 101747334 A CN101747334 A CN 101747334A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention discloses a method for preparing double protection imipenem as shown in a formula IX, comprising the following steps: under the action of the organic base, a compound IV and a compound VI react; wherein R1 is a carboxyl protecting group; R2 is an imidogen protection group; and R4 is C1-C6 alkyl or C7-C12 aralkyl. The method solves the problem of decomposition and isomerization of a raw material compound VII in the existing method for preparing imipenem. The method can realize the 'in one pot' process and has the advantages of low cost, simple operation and post treatment and high purity and yield.
Description
Technical field
The present invention relates to a kind of method for preparing double protection imipenem.
Background technology
Imipenum is a kind of microbiotic that Merck ﹠ Co., Inc. produces, and is the member of first clinical application in the carbapenem antibiotic family.Imipenum has the resisting gram-positive of unusual wide spectrum and Gram-negative is aerobic and the activity of anerobe.The patent US4292436 of Merck ﹠ Co., Inc.'s application has reported a kind of synthetic method of imipenum: compound 6 makes compound 7, makes compound 2 through reaction more afterwards; The compound 1 activated compound 1a that makes, again with compound 2 react imipenem 1 compound VI of two protections, hydrogenation afterwards obtains imipenum 3.
Wherein, R
4Be C
1-C
6Alkyl or C
7-C
12Aralkyl; R
1Be carboxyl-protecting group; R
2Be the imido grpup protecting group; R
3Be C
1-C
6Alkyl, C
7-C
12The benzene alkyl or phenyl; X is a leavings group.
But there are some defectives in aforesaid method:
(1) compound 2 is very unstable, under the situation of air, water and acid or alkali, very easily decomposes, and structural changes as follows perhaps takes place.And in this method, need compound is carried out conventional purification process, in treating processes, compound 2 will go bad, and makes overall yield reduce.
(2) compound 1a and compound 2 equimolar amounts reaction because compound 2 is very unstable, causes a large amount of 1a reactions not exclusively, and yield is low, is less than 50%, needs column chromatography purification, has increased operation easier, is unfavorable for suitability for industrialized production.
(3) in the process of compound 6 preparation compounds 7, document reported method adopts 0 ℃ temperature of reaction, and under this temperature condition, compound 6 instabilities, yield is on the low side.
Summary of the invention
Technical problem to be solved by this invention is in the method that overcomes the existing preparation double protection imipenem; raw material thing instability makes reaction yield lower; and the defective that aftertreatment is loaded down with trivial details; and provide a kind of this problem of avoiding; and can realize the flow process of " one kettle way ", cost is low, operation and aftertreatment simple, purity and the higher novel method of yield.
Method of the present invention comprises the steps: under the anhydrous condition, in the organic solvent, under the effect of organic bases, compound IV and compound VI is reacted, and can make double protection imipenem IX.
Wherein, R
1Be carboxyl-protecting group, preferable is benzyl, to nitrobenzyl (PNB) or methoxymethyl, and better is to nitrobenzyl (PNB); R
2Be the imino-protecting group, preferable is to nitro benzyloxycarbonyl (PNZ), phenylacetyl or TMS, and better is to nitro benzyloxycarbonyl (PNZ); Best, R
1For to nitrobenzyl (PNB), R
2For to nitro benzyloxycarbonyl (PNZ), when protecting group makes up for this reason, operate simplyr, have best yield and purity; R
4Be C
1-C
6Alkyl or C
7-C
12Aralkyl.
Wherein, the consumption of compound VI is preferable is 1～5 times of compound IV molar weight, and better is 1～1.3 times.Described organic bases is an organic bases commonly used in the nucleophilic substitution reaction of organic synthesis field, preferable is aminated compounds, as in tertiary amine, secondary amine and the heterocyclic amine one or more, and preferred triethylamine, diisopropylethylamine, Tributylamine, dicyclohexyl amine, Diisopropylamine, 2,2,6,6-tetramethyl piperidine, 1,1,3,3-tetramethyl guanidine, imidazoles, pyrimidine, 2, one or more in 6-lutidine and the 4-Dimethylamino pyridine.The consumption of described organic bases is preferable is 1～2 times of molar weight of compound IV.Described organic solvent is a water-miscible organic solvent, preferred dioxane, tetrahydrofuran (THF), acetonitrile, N, dinethylformamide, N, in N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, N-ethyl pyrrolidone and the N-methylpiperidone one or more, the mixed solvent of preferred acetonitrile and N,N-dimethylacetamide, the mixed solvent of acetonitrile and N-Methyl pyrrolidone, N-Methyl pyrrolidone, perhaps N,N-dimethylacetamide.The consumption of described organic solvent is generally 10～50ml/g compound IV.What the temperature of described reaction was preferable is-70～50 ℃, and better is-50～-10 ℃.The reaction time preferable run out of with detecting reactant till, be generally 1～3h.Reaction can be carried out aftertreatment by this area ordinary method after finishing.Preferable, can add entry, stirring can be separated out product, filter afterwards, washing, recrystallization, get final product solid double protection imipenem IX.
Among the present invention, described compound IV can make as follows: under the protection of inert gas, in the organic solvent, under the effect of organic bases, compound III and Mercaptamine through condensation reaction, are got final product.
Wherein, R
1Be carboxyl-protecting group, preferable is benzyl, to nitrobenzyl (PNB), methoxymethyl or diphenyl methyl, and better is to nitrobenzyl (PNB); X is a leavings group, and preferable is tolysulfonyl oxygen base, trifluoromethyl sulfonyloxy, sulfonyloxy methyl oxygen base, two (4-chloro-phenyl-) phosphorus acyloxy, two (three chloroethyls) phosphorus acyloxy or diphenylphosphine acyloxy.
Wherein, the consumption of described Mercaptamine is preferable is 1～5 times of molar weight of compound III, and better is 1～1.3 times.Preferable, Mercaptamine adds reaction system in the mode that drips.The selection of the kind of described organic bases is with the condition among the preparation method of aforementioned double protection imipenem IX.The consumption of described organic bases is preferable is 1～1.2 times of molar weight of compound III.The selection of described organic solvent is with the condition among the preparation method of aforementioned double protection imipenem IX.What the temperature of described condensation reaction was preferable is-70～30 ℃, and better is-20～0 ℃.The time of described condensation reaction is preferable run out of with detecting reactant till, be generally 0.5～3h.
Among the present invention, described compound III can make with reference to the method in the existing document (patent US4292436), and concrete steps are: under the anhydrous condition, in organic solvent, under the effect of organic bases, Compound I I and activating reagent are reacted, get final product.
Wherein, R
1Be carboxyl-protecting group, preferable is benzyl, to nitrobenzyl (PNB), methoxymethyl or diphenyl methyl, and better is to nitrobenzyl (PNB); X is a leavings group, and preferable is tolysulfonyl oxygen base, trifluoromethyl sulfonyloxy, sulfonyloxy methyl oxygen base, two (4-chloro-phenyl-) phosphorus acyloxy, two (three chloroethyls) phosphorus acyloxy or diphenylphosphine acyloxy.
Wherein, described activating reagent can be selected with reference to existing document (as patent US4292436), and that preferable is sulphonic acid anhydride or organophosphate X
1OP (OR)
2, wherein, X
1Be halogen, R is C
1～C
6Haloalkyl, perhaps replace or unsubstituted phenyl, that the group of described replacement is preferable is halogen, C
1～C
3Alkyl or C
1～C
3Alkoxyl group, preferred reagent is diphenyl phosphate chloride, chlorine di(2-ethylhexyl)phosphate (4-chloro-phenyl-) ester, chlorine di(2-ethylhexyl)phosphate (three chloroethyls) ester, tosic acid acid anhydride, methanesulfonic acid anhydride or Trifluoromethanesulfonic anhydride.In the above-mentioned preferred activating reagent, the preferred R of uniqueness of the present invention is C
1～C
6The organophosphate XOP (OR) of haloalkyl
2, it is for being used for above-mentioned reaction first, and it can shorten the reaction times, improves yield.The consumption of described activating reagent is preferable is 1～1.2 times of Compound I I molar weight.Preferable, activating reagent adds reaction system in the mode that drips.The selection of the kind of described organic bases is with the condition among the preparation method of aforementioned double protection imipenem IX.The consumption of described organic bases is preferable is 1～1.5 times of Compound I I molar weight.The selection of described organic solvent is with the condition among the preparation method of aforementioned double protection imipenem IX.What the temperature of described reaction was preferable is-70～30 ℃, and better is-60～0 ℃.The reaction time preferable run out of with detecting reactant till, be generally 20 minutes～2 hours.
Among the present invention, described compound VI can be made by following method: under the anhydrous condition, in the organic solvent, under the effect of organic bases, with compound V and R
2Cl reacts, and gets final product.
Wherein, R
2Be the imino-protecting group, preferable is to nitro benzyloxycarbonyl (PNZ), phenylacetyl or TMS, and better is to nitro benzyloxycarbonyl (PNZ); R
4Be C
1-C
6Alkyl or C
7-C
12Aralkyl.
Wherein, described R
2The consumption of Cl is preferable is 1～5 times of compound V molar weight, and better is 1～1.3 times.Preferable, R
2Cl adds reaction system in the mode that drips.The selection of the kind of described organic bases is with the condition among the preparation method of aforementioned double protection imipenem IX.The consumption of described organic bases is preferable is 1～2 times of compound V molar weight.The selection of described organic solvent is with the condition among the preparation method of aforementioned double protection imipenem IX.What the temperature of described reaction was preferable is-70～50 ℃, and better is-50～-40 ℃.The present invention preferred especially-50～-40 ℃ as temperature of reaction, (US4292436) compares with existing method, can improve yield.The reaction time preferable run out of with detecting reactant till, be generally 1～3h.
In the aforesaid method of the present invention, after each reaction finishes, can not separate being purified into each intermediate product, thereby realize the flow process of " one kettle way ".The best of the present invention " one kettle way " example comprises the steps:
(1) under the anhydrous condition, in the organic solvent, under the effect of organic bases, Compound I I and activating reagent are carried out priming reaction, make the solution that contains compound III, in solution, add Mercaptamine, carry out condensation reaction, make the solution A that contains imipenum midbody compound IV;
Under the anhydrous condition, in the organic solvent, under the effect of organic bases, with compound V and R
2Cl reacts, and makes the solution B that contains compound VI;
(2) under the anhydrous condition, solution B and solution A mixing are reacted, can make double protection imipenem IX;
Wherein, R
1Be carboxyl-protecting group, preferable is benzyl, to nitrobenzyl (PNB) or, methoxymethyl or diphenyl methyl, better is to nitrobenzyl (PNB); R
2Be the imino-protecting group, preferable is to nitro benzyloxycarbonyl (PNZ), phenylacetyl or TMS, and better is to nitro benzyloxycarbonyl (PNZ); Best, R
1For to nitrobenzyl (PNB), R
2For to nitro benzyloxycarbonyl (PNZ); R
4Be C
1-C
6Alkyl or C
7-C
12Aralkyl; X is a leavings group, and preferable is tolysulfonyl oxygen base, trifluoromethyl sulfonyloxy, sulfonyloxy methyl oxygen base, two (4-chloro-phenyl-) phosphorus acyloxy, two (three chloroethyls) phosphorus acyloxy or diphenylphosphine acyloxy.
Wherein, the selection of described organic solvent, organic bases and activating reagent kind is with aforementioned.The amount ratio of described Compound I I and activating reagent, and compound V and R
2The amount ratio of Cl is with aforementioned.The consumption of described cysteine hydrochloride is preferable is 1～5 times of molar weight of Compound I I, and better is 1～1.3 times.The consumption of described compound V is preferable is with Compound I I molar weight 1～5 times, and better is 1～1.3 times.In above-mentioned " one kettle way " flow process, the reaction of five steps all needs to carry out under the effect of organic bases.Can select to add in the reactions steps in front into, the reactions steps of back then can not added, and can add in the desired amount in the reaction of per step yet.The consumption of organic bases is selected by the required amount of aforementioned each step reaction.Preferable, in the step (1), when Compound I I and activating reagent react, adding the organic bases of 2.2～2.4 times of Compound I I molar weights, condensation reaction afterwards needn't add organic bases again; Compound V and R
2When Cl reacts, add the organic bases of 1～2 times of compound V molar weight; In the step (2), add the organic bases of 1.1～2 times of Compound I I molar weights.Preferable, Mercaptamine, activating reagent and R
2Cl adds reaction system in the mode that drips.Preferable, the solution compound VI adds solution A in the mode that drips and reacts.In above-mentioned " one kettle way " flow process, in the step (1), make in the step of compound IV by activated reaction of Compound I I and condensation reaction, when organic bases the first step reaction all disposable add fashionable, what the temperature of priming reaction was preferable is-60～-40 ℃, what the temperature of condensation reaction was preferable is-70～0 ℃, and better is-50～-40 ℃; Add 1/2 organic bases when at priming reaction, when adding 1/2 organic bases afterwards when condensation reaction, what the temperature of priming reaction was preferable is-20～0 ℃, and what the temperature of condensation reaction was preferable is-30～30 ℃, and better is-20～0 ℃.The selection of the time of the temperature of reaction of other steps and the reaction in each step is with the introduction in aforementioned each step reaction.
Reaction can be carried out aftertreatment by this area ordinary method after finishing.Preferable, can add entry, stirring can be separated out product, filter afterwards, washing, recrystallization, get final product solid double protection imipenem IX.
Among the present invention, described anhydrous condition can be by the control of organic synthesis field routine operation, as protection of inert gas.
Agents useful for same of the present invention and raw material are all commercially available to be got.
Positive progressive effect of the present invention is: method of the present invention has been avoided the method kind of existing preparation imipenum, the decomposition of starting compound VII and isomerized problem, and method of the present invention can realize the flow process of " one kettle way ", and cost is low, operation and aftertreatment simple, purity and yield are higher.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Embodiment 1
Under the nitrogen protection, Compound I I (R
1For to nitrobenzyl) (2.7g, 7.8mmol) be dissolved in the acetonitrile (30ml), be cooled to-10 ℃, drip diisopropylethylamine (2.45g, 3.32ml, 19.0mmol), diphenyl phosphate chloride (2.15g, 1.654ml, 8.0mmol), reaction 120min (detecting reactant runs out of), this solution is cooled to-40 ℃～-50 ℃, drips Mercaptamine (1.07g, N,N-DIMETHYLACETAMIDE 9.36mmol) (10ml) solution, slowly be warming up to-10 ℃ of reaction 1h (detecting reactant runs out of), obtain containing the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.72g, 10mmol) be dissolved in the acetonitrile (20ml), be cooled to-40 ℃～-50 ℃, the adding diisopropylethylamine (2.71g, 3.7ml, 21mmol), dropping is to nitroxyl chloride benzyl formate (2.0g, 9.2mmol) acetonitrile (10ml) solution, uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is cooled to-40 ℃～-50 ℃, adds diisopropylethylamine (2.0ml), drip solution B then; dropwise; reaction 20min is warming up to-15 ℃ of reaction 1h gradually, obtains suspended matter and adds entry (120ml); stir; filter washing, Virahol (50ml*2) washing; the ethyl acetate crystallization obtains two imipenum IX (R that protect
1For to nitrobenzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 85% (calculating) with Compound I I.(purity: 96%).
Embodiment 2
Under the nitrogen protection, Compound I I (R
1For to nitrobenzyl) (2.7g, 7.8mmol) be dissolved in the acetonitrile (30ml), be cooled to-10 ℃, drip diisopropylethylamine (1.15g, 9.0mmol), diphenyl phosphate chloride (2.15g, 1.654ml, 8.0mmol), reaction 120min (detecting reactant runs out of), this solution is cooled to-10 ℃, drips Mercaptamine (1.07g, N,N-DIMETHYLACETAMIDE 9.36mmol) (10ml) solution, drip diisopropylethylamine (1.15g, 9.0mmol), slowly be warming up to-10 ℃ of reaction 1h (detecting reactant runs out of), obtain containing the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.72g, 10mmol) be dissolved in the acetonitrile (20ml), be cooled to-40 ℃～-50 ℃, the adding diisopropylethylamine (2.71g, 3.7ml, 21mmol), dropping is to nitroxyl chloride benzyl formate (2.0g, 9.2mmol) acetonitrile (10ml) solution, uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is cooled to-40 ℃～-50 ℃, adds diisopropylethylamine (2.0ml), drip solution B then; dropwise; reaction 20min is warming up to-15 ℃ of reaction 1h gradually, obtains suspended matter and adds entry (120ml); stir; filter washing, Virahol (50ml*2) washing; the ethyl acetate crystallization obtains two imipenum IX (R that protect
1For to nitrobenzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 87%.(purity: 95%).
Embodiment 3
Under the nitrogen protection, Compound I I (R
1For to nitrobenzyl) (2.7g, 7.8mmol) be dissolved in the acetonitrile (30ml), be cooled to-10 ℃, drip diisopropylethylamine (1.15g, 9.0mmol), Trifluoromethanesulfonic anhydride (2.26g, 8.0mmol), reaction 120min (detecting reactant runs out of) is cooled to-10 ℃ with this solution, drip Mercaptamine (1.07g, 9.36mmol) N-Methyl pyrrolidone (10ml) solution, drip diisopropylethylamine (1.15g, 9.0mmol), slowly be warming up to-10 ℃ of reaction 1h (detecting reactant runs out of), obtain containing the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.4g, 8mmol) be dissolved in the acetonitrile (20ml), be cooled to-40 ℃～-50 ℃, the adding diisopropylethylamine (2.71g, 3.7ml, 21mmol), dropping is to nitroxyl chloride benzyl formate (2.0g, 9.2mmol) acetonitrile (10ml) solution, uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is cooled to-40 ℃～-50 ℃, adds diisopropylethylamine (2.0ml), drip solution B then; dropwise; reaction 20min is warming up to-15 ℃ of reaction 1h gradually, obtains suspended matter and adds entry (120ml); stir; filter washing, Virahol (50ml*2) washing; the ethyl acetate crystallization obtains two imipenum IX (R that protect
1For to nitrobenzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 81%.(purity: 98%).
Embodiment 4
Under the nitrogen protection, Compound I I (R
1For to nitrobenzyl) (2.7g, 7.8mmol) be dissolved in N, in the dinethylformamide (15ml), be cooled to-10 ℃, drip diisopropylethylamine (2.45g, 3.32ml, 19.0mmol), chlorine di(2-ethylhexyl)phosphate (4-chlorobenzene) ester (2.7g, 8.0mmol), reaction 120min (detecting reactant runs out of) is cooled to-40 ℃～-50 ℃ with this solution, drips Mercaptamine (1.07g, 9.36mmol) N, dinethylformamide (10ml) solution slowly is warming up to-10 ℃ of reaction 1h (detecting reactant runs out of), obtains containing the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.72g, 10mmol) be dissolved in N, in the dinethylformamide (20ml), be cooled to-40 ℃～-50 ℃, add diisopropylethylamine (2.71g, 3.7ml, 21mmol), drip nitroxyl chloride benzyl formate (2.0g, acetonitrile 9.2mmol) (10ml) solution, uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is cooled to-40 ℃～-50 ℃, adds diisopropylethylamine (2.0ml), drip solution B then; dropwise; reaction 20min is warming up to-15 ℃ of reaction 1h gradually, obtains suspended matter and adds entry (120ml); stir; filter washing, Virahol (50ml*2) washing; the ethyl acetate crystallization obtains two imipenum IX (R that protect
1For to nitrobenzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 79%.(purity: 97%).
Embodiment 5
Under the nitrogen protection; Compound I I (R1 is a benzyl) (2.44g; 7.8mmol) be dissolved in the N-Methyl pyrrolidone (15ml); be cooled to-10 ℃; the dropping diisopropylethylamine (1.15g, 9.0mmol), diphenyl phosphate chloride (2.15g; 1.654ml; 8.0mmol), reaction 80min (detecting reactant runs out of) is cooled to-10 ℃ with this solution; drip Mercaptamine (1.07g; 9.36mmol) N-Methyl pyrrolidone (10ml) solution, drip diisopropylethylamine (1.15g, 9.0mmol); slowly be warming up to-10 ℃ of reaction 1h (detecting reactant runs out of), obtain containing the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.72g, 10mmol) be dissolved in the N-Methyl pyrrolidone (20ml), be cooled to-40 ℃～-50 ℃, the adding diisopropylethylamine (2.71g, 3.7ml, 21mmol), dropping is to nitroxyl chloride benzyl formate (2.0g, 9.2mmol) acetonitrile (10ml) solution, uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is cooled to-40 ℃～-50 ℃, adds diisopropylethylamine (2.0ml), drip solution B then; dropwise, reaction 20min is warming up to-15 ℃ of reaction 1h gradually; obtain suspended matter and add entry (120ml); stir ethyl acetate extraction, washing; the salt water washing; concentrating under reduced pressure, column chromatography purification obtains two imipenum IX (R that protect
1Be benzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 84%.(purity: 98.5%).
Embodiment 6
Under the nitrogen protection, Compound I I (R
1Be diphenyl-methyl) (3.65g, 7.8mmol) be dissolved in the N-Methyl pyrrolidone (15ml), be cooled to-10 ℃, drip triethylamine (0.91g, 9.0mmol), diphenyl phosphate chloride (2.15g, 1.654ml, 8.0mmol), reaction 100min (detecting reactant runs out of), this solution is cooled to-10 ℃, drips Mercaptamine (1.07g, N-Methyl pyrrolidone 9.36mmol) (10ml) solution, drip triethylamine (0.91g, 9.0mmol), slowly be warming up to-10 ℃ of reaction 1h (detecting reactant runs out of), obtain containing the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.72g, 10mmol) be dissolved in the N-Methyl pyrrolidone (20ml), be cooled to-40 ℃～-50 ℃, add triethylamine (2.11g, 21mmol), drip nitroxyl chloride benzyl formate (2.0g, acetonitrile 9.2mmol) (10ml) solution, uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is cooled to-40 ℃～-50 ℃, adds triethylamine (2.0ml), drip solution B then; dropwise, reaction 20min is warming up to-15 ℃ of reaction 1h gradually; obtain suspended matter and add entry (120ml); stir ethyl acetate extraction, washing; the salt water washing; concentrating under reduced pressure, column chromatography purification obtains two imipenum IX (R that protect
1Be diphenyl-methyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 81%.(purity: 97.5%).
Embodiment 7
Under the nitrogen protection, Compound I I (R
1For to nitrobenzyl) (2.7g, 7.8mmol) be dissolved in N, in the dinethylformamide (15ml), be cooled to-10 ℃, drip triethylamine (3.36g, 33.2mmol), diphenyl phosphate chloride (2.15g, 1.654ml, 8.0mmol), reaction 100min (detecting reactant runs out of) is cooled to-40 ℃～-50 ℃ with this solution, drips Mercaptamine (1.07g, 9.36mmol) N, dinethylformamide (10ml) solution slowly is warming up to-10 ℃ of reaction 1h (detecting reactant runs out of), obtains containing the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.72g, 10mmol) be dissolved in N, in the dinethylformamide (20ml), be cooled to-40 ℃～-50 ℃, and the adding triethylamine (2.11g, 21mmol), dropping is to nitroxyl chloride benzyl formate (2.0g, 9.2mmol) acetonitrile (10ml) solution, uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is cooled to-40 ℃～-50 ℃, drips solution B then, dropwise, reaction 20min; be warming up to-15 ℃ of reaction 1h gradually, obtain suspended matter and add entry (120ml), stir, filter; washing, Virahol (50ml*2) washing, the ethyl acetate crystallization obtains two imipenum IX (R that protect
1For to nitrobenzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 82%.(purity: 96%).
Embodiment 8
Under the nitrogen protection, Compound I I (R
1For to nitrobenzyl) (2.7g, 7.8mmol) be dissolved in the acetonitrile (30ml), be cooled to-10 ℃, drip Diisopropylamine (1.92g, 19.0mmol), diphenyl phosphate chloride (2.15g, 1.654ml, 8.0mmol), reaction 120min (detecting reactant runs out of) is cooled to-40 ℃～-50 ℃ with this solution, drip Mercaptamine (1.07g, 9.36mmol) N,N-DIMETHYLACETAMIDE (10ml) solution, slowly be warming up to-10 ℃ of reaction 1h (detecting reactant runs out of), obtain containing the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.72g, 10mmol) be dissolved in the acetonitrile (20ml), be cooled to-40 ℃～-50 ℃, add triethylamine (2.11g, 21mmol), drip nitroxyl chloride benzyl formate (2.0g, acetonitrile 9.2mmol) (10ml) solution, uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is cooled to-40 ℃～-50 ℃, adds Diisopropylamine (2.0ml), drip solution B then; dropwise; reaction 20min is warming up to-15 ℃ of reaction 1h gradually, obtains suspended matter and adds entry (120ml); stir; filter washing, Virahol (50ml*2) washing; the ethyl acetate crystallization obtains two imipenum IX (R that protect
1For to nitrobenzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 85%.(purity: 95%).
Embodiment 9
Under the nitrogen protection, Compound I I (R
1For to nitrobenzyl) (2.7g, 7.8mmol) be dissolved in the acetonitrile (30ml), be cooled to-10 ℃, drip diisopropylethylamine (2.45g, 3.3ml, 19mmol), chlorine di(2-ethylhexyl)phosphate (three chloroethyls) ester (2.8g, 8.0mmol), reaction 20min (detecting reactant runs out of) is cooled to-40 ℃～-50 ℃ with this solution, drip Mercaptamine (1.07g, 9.36mmol) N,N-DIMETHYLACETAMIDE (10ml) solution, slowly be warming up to-10 ℃ of reaction 1h (detecting reactant runs out of), obtain containing the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.72g, 10mmol) be dissolved in the acetonitrile (20ml), be cooled to-40 ℃～-50 ℃, the adding diisopropylethylamine (2.71g, 3.7ml, 21mmol), dropping is to nitroxyl chloride benzyl formate (2.0g, 9.2mmol) acetonitrile (10ml) solution, uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is cooled to-40 ℃～-50 ℃, adds diisopropylethylamine (2.0ml), drip solution B then; dropwise; reaction 20min is warming up to-15 ℃ of reaction 1h gradually, obtains suspended matter and adds entry (120ml); stir; filter washing, Virahol (50ml*2) washing; the ethyl acetate crystallization obtains two imipenum IX (R that protect
1For to nitrobenzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 89% (purity: 95%).
1HNMR(DMSO-d6)：1.10(s，3H)，3.06(s，2H)，3.14(s，1H)，3.54(s，2H)，3.94(s，2H)，4.16(s，2H)，5.18-5.40(m，4H)，7.60，7.69，8.21，8.32(m，8H)，8.41(d，2H)，C27H27N5O10S，m/z：613.15，mp：117-120℃
Embodiment 10
Under the nitrogen protection, Compound I I (R
1For to nitrobenzyl) (10mmol) be dissolved in acetonitrile (20ml) and N, in the N-N,N-DIMETHYLACETAMIDE (15ml), be cooled to-40 ℃, drip 2,2,6,6-tetramethyl piperidine (24mmol), tosic acid acid anhydride (10mmol), reaction 120min (detecting reactant runs out of), drip N,N-DIMETHYLACETAMIDE (10ml) solution of Mercaptamine (10mmol), slowly be warming up to 0 ℃ of reaction 1h (detecting reactant runs out of), obtain containing the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.72g, 10mmol) be dissolved in the N,N-dimethylacetamide (20ml), be cooled to-65 ℃～-70 ℃, add 2,2,6,6-tetramethyl piperidine (20mmol), dropping is to the N of nitroxyl chloride benzyl formate (15mmol), N-N,N-DIMETHYLACETAMIDE (10ml) solution, uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is cooled to-40 ℃～-50 ℃, adds diisopropylethylamine (10.45mmol), drip solution B then; dropwise; reaction 20min is warming up to-15 ℃ of reaction 1h gradually, obtains suspended matter and adds entry (120ml); stir; filter washing, Virahol (50ml*2) washing; the ethyl acetate crystallization obtains two imipenum IX (R that protect
1For to nitrobenzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 84% (purity: 95%).
Embodiment 11
Under the nitrogen protection, Compound I I (R
1For to nitrobenzyl) (9.5mmol) be dissolved in acetonitrile (15ml) and the N-Methyl pyrrolidone (15ml), be cooled to-60 ℃, drip 1,1,3,3-tetramethyl guanidine (20.9mmol), methanesulfonic acid anhydride (11.4mmol), reaction 90min (detecting reactant runs out of), N,N-DIMETHYLACETAMIDE (10ml) solution of dropping Mercaptamine (19mmol),-70 ℃ are reacted 1h (detecting reactant runs out of), obtain containing the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.72g, 10mmol) be dissolved in the acetonitrile (20ml), add 1,1,3,3-tetramethyl guanidine (15mmol) drips N-Methyl pyrrolidone (10ml) solution to nitroxyl chloride benzyl formate (40mmol), 50 ℃ are reacted 1h (detecting reactant runs out of) down, obtain containing the solution B of compound VI.
Solution A is added diisopropylethylamine (19mmol); drip solution B then, dropwise, reaction 20min; be warming up to-10 ℃ of reaction 1h gradually; obtain suspended matter and add entry (120ml), stir, filter; washing; Virahol (50ml*2) washing, the ethyl acetate crystallization obtains two imipenum IX (R that protect
1For to nitrobenzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 75% (purity: 95%).
Embodiment 12
Under the nitrogen protection, Compound I I (R
1For to nitrobenzyl) (8.3mmol) be dissolved in N, in the N-N,N-DIMETHYLACETAMIDE (30ml), be cooled to 0 ℃, drip imidazoles (16.6mmol), chlorine di(2-ethylhexyl)phosphate (three chloroethyls) ester (9.13mmol), reaction 20min (detecting reactant runs out of), drip imidazoles (16.6mmol), N,N-DIMETHYLACETAMIDE (20ml) solution that contains Mercaptamine (41.5mmol) slowly is warming up to 30 ℃ of reaction 1h (detecting reactant runs out of), obtains containing the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.72g, 10mmol) be dissolved in the acetonitrile (20ml), be cooled to-40 ℃～-50 ℃, add imidazoles (20mmol), dropping is to the N of nitroxyl chloride benzyl formate (30mmol), N-N,N-DIMETHYLACETAMIDE (10ml) solution, uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is cooled to-40 ℃～-50 ℃, adds diisopropylethylamine (16mmol), drip solution B then; dropwise; reaction 20min ,-70 ℃ of reaction 1h obtain suspended matter and add entry (120ml); stir; filter washing, Virahol (50ml*2) washing; the ethyl acetate crystallization obtains two imipenum IX (R that protect
1For to nitrobenzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 88% (purity: 95%).
Embodiment 13
Under the nitrogen protection, Compound I I (R
1For to nitrobenzyl) (7.7mmol) be dissolved in the tetrahydrofuran (THF) (30ml), be cooled to-20 ℃, drip pyrimidine (8.5mmol), chlorine di(2-ethylhexyl)phosphate (three chloroethyls) ester (2.8g, 8.0mmol), reaction 20min (detecting reactant runs out of), drip pyrimidine (8.5mmol), N,N-DIMETHYLACETAMIDE (10ml) solution of Mercaptamine (10mmol) ,-30 ℃ are reacted 1h (detecting reactant runs out of), obtain containing the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.72g, 10mmol) be dissolved in the tetrahydrofuran (THF) (20ml), be cooled to-40 ℃～-50 ℃, add pyrimidine (20mmol), dropping is to tetrahydrofuran (THF) (10ml) solution of nitroxyl chloride benzyl formate (20mmol), uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is cooled to-40 ℃～-50 ℃, adds diisopropylethylamine (15mmol), drip solution B then; dropwise; reaction 20min is warming up to 50 ℃ of reaction 1h gradually, obtains suspended matter and adds entry (120ml); stir; filter washing, Virahol (50ml*2) washing; the ethyl acetate crystallization obtains two imipenum IX (R that protect
1For to nitrobenzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 85% (purity: 95%).
Embodiment 14
Under the nitrogen protection, Compound I I (R
1For to nitrobenzyl) (8.5mmol) be dissolved in the dioxane (30ml), be cooled to-40 ℃, drip 4-Dimethylamino pyridine (20.4mmol), chlorine di(2-ethylhexyl)phosphate (three chloroethyls) ester (2.8g, 8.0mmol), reaction 20min (detecting reactant runs out of), N,N-DIMETHYLACETAMIDE (10ml) solution of dropping Mercaptamine (10.2mmol),-40 ℃ are reacted 1h (detecting reactant runs out of), contain the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.72g, 10mmol) be dissolved in the dioxane (20ml), be cooled to-40 ℃～-50 ℃, add 4-Dimethylamino pyridine (18mmol), dropping is to N,N-DIMETHYLACETAMIDE (10ml) solution of nitroxyl chloride benzyl formate (12mmol), uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is added two different interior basic ethamine (16mmol); drip solution B then, dropwise, reaction 20min; be warming up to-30 ℃ of reaction 1h gradually; obtain suspended matter and add entry (120ml), stir, filter; washing; Virahol (50ml*2) washing, the ethyl acetate crystallization obtains two imipenum IX (R that protect
1For to nitrobenzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 86% (purity: 95%).
Embodiment 15
Under the nitrogen protection, Compound I I (R
1For to nitrobenzyl) (8.5mmol) be dissolved in the acetonitrile (30ml), be cooled to-60 ℃, drip 4-Dimethylamino pyridine (20.4mmol), chlorine di(2-ethylhexyl)phosphate (three chloroethyls) ester (2.8g, 8.0mmol), reaction 20min (detecting reactant runs out of), N,N-DIMETHYLACETAMIDE (10ml) solution of dropping Mercaptamine (10.2mmol),-50 ℃ are reacted 1h (detecting reactant runs out of), contain the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.72g, 10mmol) be dissolved in the acetonitrile (20ml), be cooled to-40 ℃～-50 ℃, add 4-Dimethylamino pyridine (19mmol), dropping is to N,N-DIMETHYLACETAMIDE (10ml) solution of nitroxyl chloride benzyl formate (13mmol), uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is added diisopropylethylamine (2.0ml); drip solution B then, dropwise, reaction 20min; be warming up to-20 ℃ of reaction 1h gradually; obtain suspended matter and add entry (120ml), stir, filter; washing; Virahol (50ml*2) washing, the ethyl acetate crystallization obtains two imipenum IX (R that protect
1For to nitrobenzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 85% (purity: 95%).
Embodiment 16
Under the nitrogen protection, Compound I I (R
1For to nitrobenzyl) (8.5mmol) be dissolved in the acetonitrile (30ml), be cooled to-20 ℃, drip 4-Dimethylamino pyridine (9.35mmol), chlorine di(2-ethylhexyl)phosphate (three chloroethyls) ester (2.8g, 8.0mmol), reaction 20min (detecting reactant runs out of), drip 4-Dimethylamino pyridine (9.35mmol), N,N-DIMETHYLACETAMIDE (10ml) solution of Mercaptamine (10.2mmol) ,-70 ℃ are reacted 1h (detecting reactant runs out of), contain the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (1.72g, 10mmol) be dissolved in the acetonitrile (20ml), be cooled to-40 ℃～-50 ℃, add 4-Dimethylamino pyridine (15mmol), dropping is to N,N-DIMETHYLACETAMIDE (10ml) solution of nitroxyl chloride benzyl formate (50mmol), uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is cooled to-40 ℃～-50 ℃, adds diisopropylethylamine (16mmol), drip solution B then; dropwise; reaction 20min is warming up to-15 ℃ of reaction 1h gradually, obtains suspended matter and adds entry (120ml); stir; filter washing, Virahol (50ml*2) washing; the ethyl acetate crystallization obtains two imipenum IX (R that protect
1For to nitrobenzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 86% (purity: 95%).
Embodiment 17
Under the nitrogen protection, Compound I I (R
1For to nitrobenzyl) (8.5mmol) be dissolved in the acetonitrile (30ml), be cooled to 0 ℃, drip 4-Dimethylamino pyridine (10.2mmol), chlorine di(2-ethylhexyl)phosphate (three chloroethyls) ester (2.8g, 8.0mmol), 30 ℃ of reaction 20min (detecting reactant runs out of), drip 4-Dimethylamino pyridine (10.2mmol), N,N-DIMETHYLACETAMIDE (10ml) solution of Mercaptamine (10.2mmol), 0 ℃ is reacted 1h (detecting reactant runs out of), contains the solution A of compound IV.
Benzyl oxide inferior amine salt hydrochlorate (42.5mmol) is dissolved in the acetonitrile (30ml), be cooled to-40 ℃～-50 ℃, add 4-Dimethylamino pyridine (17mmol), dropping is to N,N-DIMETHYLACETAMIDE (20ml) solution of nitroxyl chloride benzyl formate (42.5mmol), uniform temp is reaction 1h (detecting reactant runs out of) down, obtains containing the solution B of compound VI.
Solution A is cooled to-40 ℃～-50 ℃, adds diisopropylethylamine (16mmol), drip solution B then; dropwise; reaction 20min is warming up to-50 ℃ of reaction 1h gradually, obtains suspended matter and adds entry (120ml); stir; filter washing, Virahol (50ml*2) washing; the ethyl acetate crystallization obtains two imipenum IX (R that protect
1For to nitrobenzyl, R
2For to the nitro carbobenzoxy-(Cbz)), yield: 87% (purity: 95%).
Claims (20)
1. a method for preparing suc as formula the double protection imipenem shown in the IX is characterized in that it comprises the steps: under the anhydrous condition, in the organic solvent, under the effect of organic bases, compound IV and compound VI is reacted, and gets final product;
Wherein, R
1Be carboxyl-protecting group; R
2Be the imino-protecting group; R
4Be C
1-C
6Alkyl or C
7-C
12Aralkyl.
2. the method for claim 1, it is characterized in that: the consumption of described compound VI is 1～5 times of compound IV molar weight; Described organic bases is an aminated compounds; The consumption of described organic bases is 1～2 times of molar weight of compound IV; Described organic solvent is dioxane, tetrahydrofuran (THF), acetonitrile, N, one or more in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, N-ethyl pyrrolidone and the N-methylpiperidone; The temperature of described reaction is-70～50 ℃; Till the time of reaction runs out of with detecting reactant.
3. method as claimed in claim 2 is characterized in that: the consumption of described compound VI is 1～1.3 times of compound IV molar weight; Described organic bases is triethylamine, diisopropylethylamine, Tributylamine, dicyclohexyl amine, Diisopropylamine, 2,2,6,6-tetramethyl piperidine, 1,1,3,3-tetramethyl guanidine, imidazoles, pyrimidine, 2, one or more in 6-lutidine and the 4-Dimethylamino pyridine; Described organic solvent is the mixed solvent of acetonitrile and N,N-dimethylacetamide, the mixed solvent of acetonitrile and N-Methyl pyrrolidone, N-Methyl pyrrolidone, perhaps N,N-dimethylacetamide; The temperature of described reaction is-50～-10 ℃.
4. the method for claim 1, it is characterized in that: described compound IV is made by following method: under the anhydrous condition, in the organic solvent, under the effect of organic bases, compound III and Mercaptamine through condensation reaction, are got final product;
Wherein, R
1Be carboxyl-protecting group; X is a leavings group.
5. the method for claim 1 is characterized in that: the consumption of described Mercaptamine is 1～5 times of molar weight of compound III; Described organic bases is an aminated compounds; The consumption of described organic bases is 1～1.2 times of molar weight of compound III; Described organic solvent is dioxane, tetrahydrofuran (THF), acetonitrile, N, one or more in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, N-ethyl pyrrolidone and the N-methylpiperidone; The temperature of described condensation reaction is-70～30 ℃; Till the time of described condensation reaction runs out of with detecting reactant.
6. method as claimed in claim 5 is characterized in that: the consumption of described Mercaptamine is 1～1.3 times of molar weight of compound III; Described organic bases is triethylamine, diisopropylethylamine, Tributylamine, dicyclohexyl amine, Diisopropylamine, 2,2,6,6-tetramethyl piperidine, 1,1,3,3-tetramethyl guanidine, imidazoles, pyrimidine, 2, one or more in 6-lutidine and the 4-Dimethylamino pyridine; Described organic solvent is the mixed solvent of acetonitrile and N,N-dimethylacetamide, the mixed solvent of acetonitrile and N-Methyl pyrrolidone, N-Methyl pyrrolidone, perhaps N,N-dimethylacetamide; The temperature of described condensation reaction is-20～0 ℃.
7. method as claimed in claim 4 is characterized in that: described compound III is made by following method: under the anhydrous condition, in organic solvent, under the effect of organic bases, Compound I I and activating reagent are reacted, get final product;
Wherein, R
1Be carboxyl-protecting group; X is a leavings group.
8. method as claimed in claim 7 is characterized in that: described activating reagent is sulphonic acid anhydride or organophosphate X
1OP (OR)
2, wherein, X
1Be halogen, R is C
1～C
6Haloalkyl, perhaps replace or unsubstituted phenyl, the group of described replacement is halogen, C
1～C
3Alkyl or C
1～C
3Alkoxyl group; The consumption of described activating reagent is 1～1.2 times of Compound I I molar weight; Described organic bases is an aminated compounds; The consumption of described organic bases is 1～1.5 times of Compound I I molar weight; Described organic solvent is dioxane, tetrahydrofuran (THF), acetonitrile, N, one or more in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, N-ethyl pyrrolidone and the N-methylpiperidone; The temperature of described reaction is-70～30 ℃; Till the time of described reaction runs out of with detecting reactant.
9. method as claimed in claim 8 is characterized in that: described activating reagent is diphenyl phosphate chloride, chlorine di(2-ethylhexyl)phosphate (4-chloro-phenyl-) ester, chlorine di(2-ethylhexyl)phosphate (three chloroethyls) ester, tosic acid acid anhydride, methanesulfonic acid anhydride or Trifluoromethanesulfonic anhydride; Described organic bases is triethylamine, diisopropylethylamine, Tributylamine, dicyclohexyl amine, Diisopropylamine, 2,2,6,6-tetramethyl piperidine, 1,1,3,3-tetramethyl guanidine, imidazoles, pyrimidine, 2, one or more in 6-lutidine and the 4-Dimethylamino pyridine; Described organic solvent is the mixed solvent of acetonitrile and N,N-dimethylacetamide, the mixed solvent of acetonitrile and N-Methyl pyrrolidone, N-Methyl pyrrolidone, perhaps N,N-dimethylacetamide; The temperature of described reaction is-60～0 ℃.
10. the method for claim 1, it is characterized in that: described compound VI is made by following method: under the anhydrous condition, in the organic solvent, under the effect of organic bases, with compound V and R
2Cl reacts, and gets final product;
Wherein, R
2Be the imino-protecting group; R
4Be C
1-C
6Alkyl or C
7-C
12Aralkyl.
11. method as claimed in claim 10 is characterized in that: described R
2The consumption of Cl is 1～5 times of compound V molar weight; Described organic bases is an aminated compounds; The consumption of described organic bases is 1～2 times of compound V molar weight; Described organic solvent is dioxane, tetrahydrofuran (THF), acetonitrile, N, one or more in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, N-ethyl pyrrolidone and the N-methylpiperidone; The temperature of described reaction is-70～50 ℃; Till the time of reaction runs out of with detecting reactant.
12. method as claimed in claim 11 is characterized in that: described R
2The consumption of Cl is 1～1.3 times of compound V molar weight; Described organic bases is triethylamine, diisopropylethylamine, Tributylamine, dicyclohexyl amine, Diisopropylamine, 2,2,6,6-tetramethyl piperidine, 1,1,3,3-tetramethyl guanidine, imidazoles, pyrimidine, 2, one or more in 6-lutidine and the 4-Dimethylamino pyridine; Described organic solvent is the mixed solvent of acetonitrile and N,N-dimethylacetamide, the mixed solvent of acetonitrile and N-Methyl pyrrolidone, N-Methyl pyrrolidone, perhaps N,N-dimethylacetamide; The temperature of described reaction is-50～-40 ℃.
13. the method for claim 1 is characterized in that: it is " one kettle way " flow process, comprises the steps:
(1) under the anhydrous condition, in the organic solvent, under the effect of organic bases, Compound I I and activating reagent are carried out priming reaction, make the solution that contains compound III, in solution, add Mercaptamine, carry out condensation reaction, make the solution A that contains imipenum midbody compound IV;
Under the anhydrous condition, in the organic solvent, under the effect of organic bases, with compound V and R
2Cl reacts, and makes the solution B that contains compound VI;
(2) under the anhydrous condition, solution B and solution A mixing are reacted, can make double protection imipenem IX;
Wherein, R
1Be carboxyl-protecting group; R
2Be the imino-protecting group; R
4Be C
1-C
6Alkyl or C
7-C
12Aralkyl; X is a leavings group.
14. the method for claim 1 is characterized in that:
The consumption of described compound V is 1～5 times of Compound I I molar weight; Described organic bases is an aminated compounds; Described organic solvent is dioxane, tetrahydrofuran (THF), acetonitrile, N, one or more in dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, N-ethyl pyrrolidone and the N-methylpiperidone;
In the step (1), during the preparation solution A, the consumption of described organic bases is 2.2～2.4 times of Compound I I molar weight; When organic bases adds fashionablely in that the first step reaction is all disposable, the temperature of priming reaction is-60～-40 ℃, and the temperature of condensation reaction is-70～0 ℃; Add 1/2 organic bases when at priming reaction, when adding 1/2 organic bases afterwards when condensation reaction, the temperature of priming reaction is-20～0 ℃, and the temperature of condensation reaction is-30～30 ℃; Described activating reagent is sulphonic acid anhydride or organophosphate X
1OP (OR)
2, wherein, X
1Be halogen, R is C
1～C
6Haloalkyl, perhaps replace or unsubstituted phenyl, the group of described replacement is halogen, C
1～C
3Alkyl or C
1～C
3Alkoxyl group; The consumption of described activating reagent is 1～1.2 times of Compound I I molar weight; The consumption of described cysteine hydrochloride is 1～5 times of molar weight of Compound I I;
During the preparation solution B, the consumption of described organic bases is 1～2 times of compound V molar weight; Described R
2The consumption of Cl is 1～5 times of compound V molar weight; The temperature of described reaction is-70～50 ℃;
In the step (2), add the organic bases of 1.1～2 times of Compound I I molar weights; The temperature of described reaction is-70～50 ℃;
Till the time of described each step reaction runs out of with detecting reactant.
15. method as claimed in claim 14 is characterized in that:
The consumption of described compound V is 1～1.3 times of Compound I I molar weight; Described organic bases is triethylamine, diisopropylethylamine, Tributylamine, dicyclohexyl amine, Diisopropylamine, 2,2,6,6-tetramethyl piperidine, 1,1,3,3-tetramethyl guanidine, imidazoles, pyrimidine, 2, one or more in 6-lutidine and the 4-Dimethylamino pyridine; Described organic solvent is the mixed solvent of acetonitrile and N,N-dimethylacetamide, the mixed solvent of acetonitrile and N-Methyl pyrrolidone, N-Methyl pyrrolidone, perhaps N,N-dimethylacetamide;
In the step (1), preparation is during solution A, and when organic bases adds fashionablely in that the first step reaction is all disposable, the temperature of priming reaction is-60～-40 ℃, and the temperature of condensation reaction is-50～-40 ℃; Add 1/2 organic bases when at priming reaction, when adding 1/2 organic bases afterwards when condensation reaction, the temperature of priming reaction is-20～0 ℃, and the temperature of condensation reaction is-20～0 ℃; Described activating reagent is diphenyl phosphate chloride, chlorine di(2-ethylhexyl)phosphate (4-chloro-phenyl-) ester, chlorine di(2-ethylhexyl)phosphate (three chloroethyls) ester, tosic acid acid anhydride, methanesulfonic acid anhydride or Trifluoromethanesulfonic anhydride; The consumption of described cysteine hydrochloride is 1～1.3 times of molar weight of Compound I I;
During the preparation solution B, described R
2The consumption of Cl is 1～1.3 times of compound V molar weight; The temperature of described reaction is-50～-40 ℃.
In the step (2), the temperature of described reaction is-50～-10 ℃.
16. as claim 1 or 13 described methods, it is characterized in that: after reaction finishes, add entry, stirring can be separated out product, filter afterwards, washing, recrystallization, get final product solid double protection imipenem IX.
17., it is characterized in that: described R as claim 1,4,7 or 13 described methods
1For benzyl, to nitrobenzyl, methoxymethyl or diphenyl methyl.
18., it is characterized in that: described R as claim 1,10 or 13 described methods
2For to nitro benzyloxycarbonyl, phenylacetyl or TMS.
19., it is characterized in that: described R as claim 1 or 13 described methods
1For to nitrobenzyl, R
2For to the nitro benzyloxycarbonyl.
20. as claim 4 or 7 described methods, it is characterized in that: described X is tolysulfonyl oxygen base, trifluoromethyl sulfonyloxy, sulfonyloxy methyl oxygen base, two (4-chloro-phenyl-) phosphorus acyloxy, two (three chloroethyls) phosphorus acyloxy or diphenylphosphine acyloxy.
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