CN102731505B - A kind of preparation method of S-4661 - Google Patents
A kind of preparation method of S-4661 Download PDFInfo
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Abstract
The present invention relates to the preparation method of the S-4661 shown in a kind of formula 1, described method comprises with Doripenem intermediate II for raw material, under alkali and catalyzer exist, with single solvent water for action solvent, carries out hydrogenation deprotection.The inventive method adopts single solvent water as action solvent, solves the series of problems with an organic solvent brought in action solvent, reduces product degraded, improves product purity, and economy, safety, environmental protection, be more suitable for industrial scale operation.
Description
Technical field
The invention belongs to carbapenem antibiotics synthesis field, be specifically related to a kind of preparation method of carbapenem compounds S-4661.
Background technology
S-4661, Doripenem, chemistry (4R by name, 5S, 6S)-3-[((3S, 5S)-5-[[(sulphonamide) amino] methyl]-3-pyrrolidyl) sulfydryl-6-[(1R)-1-hydroxyethyl] 4-methyl-7-Oxy-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxylic acid], structural formula as shown in Equation 1:
S-4661 is a kind of new carbapenem antibiotic, and 2 side chains are Pyrrolidine rings that SULFAMIDE replaces.Structure activity study shows; the acidylate of its side-chain amino group or sulfonylation are conducive to the increase of anti-microbial activity; its to the inhibit activities of gram-positive microorganism higher than meropenem; to the inhibit activities of Gram-negative bacteria higher than imipenum; also effective to imipenem-resistant bacterium, serine beta-lactamase and dehydropeptidase of kidney are stablized to the treatment of severe infections that can be used for brain, kidney and lung.
First US5317046 discloses S-4661 compound and preparation method thereof.The S-4661 preparation method of this patent report is for raw material obtains through deprotection reaction with the Doripenem intermediate shown in general formula I.
Wherein, X is worked as
1for H or SiMe
3, X
2for PMB, Y
2for Boc or Pmz,
for-NHSO
2nH
2,
or
time, what this patent adopted is that aluminum chloride remove-insurance is defended the doctrine, and the method needs the low temperature of-60 ~-30 DEG C, and post-reaction treatment process needs styrene-divinylbenzene copolymer resin column chromatography purifying.The method is raw materials used to be not easy to obtain, and refrigeration equipment, conversion unit and column chromatography equipment that reaction needed is special, higher to industrialization production requirements, cost is also high.
Work as X
1for H, X
2for PNB, Y
2for Pnz,
for-NHSO
2nH
2time (now; the compound of formula I representative is Doripenem intermediate 2, and as shown in Equation 2), what deprotection reaction adopted is hydrogenolysis method; with tetrahydrofuran solvent and MES damping fluid (pH7.0) for action solvent, 10% palladium carbon is adopted to be catalyzer.
Although the method no longer need be carried out under condition of ultralow temperature, but still there is following shortcoming: first employ MES damping fluid, and owing to reacting raw materials used Doripenem intermediate 2 and products therefrom S-4661 is all dissolved in reaction solution, speed of response is fast, degradation product is many, will remove buffer reagent and other impurity, so still need to carry out column chromatography purification after reaction terminates, complex operation, is unfavorable for scale operation.
Document Organic Process research & Development 2003,7, the S-4661 preparation method reported in 846-850 is also for raw material with compound 2, with 10% palladium carbon for catalyzer, carry out that hydrogenolysis deprotection reaction obtains, difference is: 1. in tetrahydrofuran (THF) and water reaction system, add magnesium chloride hexahydrate, and do not re-use MES damping fluid; 2. post-reaction treatment process no longer needs purification by column chromatography, but needs repeatedly to add magnesium chloride hexahydrate, repeatedly layering, complicated operation, and has magnesium ion to remain.CN1896057 and CN101935321 discloses the preparation method of similar S-4661, and difference is: 1. do not use magnesium chloride hexahydrate in two application method reaction systems; 2. CN1896057 have employed compound 3 for raw material; 3. employ organic bases-3,5-lutidine in CN101935321 reaction system, employing be solvent crystallization method but not freeze-drying obtains finished product.
Above-mentioned document and the hydrogenolysis deprotection method described in patent application; all adopt tetrahydrofuran (THF) and water as action solvent; owing to reacting raw materials used Doripenem intermediate and products therefrom S-4661 is all dissolved in reaction solution; speed of response is fast; degradation product is many; products therefrom yield is low, purity difference, aftertreatment difficulty.
CN1995040A discloses a kind of preparation method of carbapenem compounds of improvement, and wherein, the preparation method of described S-4661 is still with Doripenem intermediate 2 for raw material, carries out hydrogenolysis deprotection reaction and obtain S-4661 1 under palladium carbon makes catalyst action.With above-mentioned document unlike, it no longer adopts tetrahydrofuran (THF) and water as action solvent, but adopts the two-phase solvent that is made up of the organic solvent that Shui Heshui is immiscible as action solvent, does not also re-use MES or other damping fluid.The method simplifies processing step to a certain extent, improves product purity, but last handling process still needs a point equal step, complex operation, and needing in the industrial production increases relevant device.
In addition, in the S-4661 preparation method that prior art is recorded, all containing organic solvent in the action solvent that deprotection reaction adopts, there is following drawback: be 1. unfavorable for environmental protection; 2. because organic solvent mostly is inflammable and explosive reagent, and smell is not good, high to production plant design requirements, and adds the risk level of operating post, and it is healthy to be not easy to workman; 3. be dissolved with part palladium complex in solution, and not easily remove, cause heavy metals exceeding standard in product.
Therefore, need to provide a kind of simple to operate, be beneficial to environmental protection and workers ' health, be more suitable for the S-4661 preparation method of suitability for industrialized production.
Summary of the invention
For the problem existing for prior art, the invention provides a kind of S-4661 preparation method adopting new catalytic hydrogenation system.
Therefore, the invention provides a kind of preparation method of S-4661, described method Doripenem intermediate II is raw material, under alkali and catalyzer exist, with single solvent water for action solvent, carries out hydrogenation deprotection.Reaction scheme is as shown in flow process 1:
Wherein:
R
1represent H or hydroxyl protecting group, preferably, hydroxyl protecting group is benzyl or allyl group, and described benzyl or allyl group are optionally by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6alkyl or C
1-C
6alkoxyl group replaces.
R
2representation carboxy protecting group, preferably, R
2for benzyl or allyl group, described benzyl or allyl group are optionally by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6alkyl or C
1-C
6alkoxyl group replaces, more preferably, and R
2for to nitrobenzyl.
R
3represent amino protecting group, preferably, R
3for carbobenzoxy-(Cbz), described carbobenzoxy-(Cbz) is optionally by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6alkyl or C
1-C
6alkoxyl group replaces, more preferably, and R
3for to nitrobenzyloxycarbonyl.
R
4represent H or amino protecting group, preferably, amino protecting group is carbobenzoxy-(Cbz), and described carbobenzoxy-(Cbz) is optionally by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6alkyl or C
1-C
6alkoxyl group replaces, and more preferably, amino protecting group is to nitrobenzyloxycarbonyl.
Described alkali can be mineral alkali, organic bases, or its arbitrary combination, and they exist with any suitable concentration.Mineral alkali is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, Sodium phosphate dibasic, preferred sodium bicarbonate; Organic bases is selected from diethylamine, triethylamine, ammoniacal liquor, diisopropylethylamine, diisopropylamine, N-methylmorpholine, tetramethyl guanidine, aniline or substituted aniline, pyridine or substituted pyridines; The substituting group of described substituted aniline is selected from C
1~ C
4alkyl, C
1~ C
4alkoxyl group, halogen, described substituted aniline is preferably 2,6-xylidine, 3,5-xylidine; The substituting group of described substituted pyridines is selected from C
1~ C
4alkyl, C
1~ C
4alkoxyl group, halogen, described substituted pyridines is preferably 2,6-lutidine, 3,5-lutidine.The consumption of alkali is 0.5 ~ 5 molar equivalent of Doripenem intermediate II, is preferably 1 ~ 3 molar equivalent.
Described single solvent water is any water containing less impurity, and wherein foreign matter content is for being less than 10wt%, such as, be less than 5wt%, such as, be less than 1wt%, is preferably less than 0.1wt%, is more preferably less than 0.01wt%, is also more preferably less than 0.001wt%.Described impurity comprises suspended matter, soluble material, insoluble substance, such as metal-salt, organic solvent etc.When single solvent water comprises organic solvent, the content of organic solvent should be less than 1wt%, is preferably less than 0.1wt%, is more preferably less than 0.01wt%, be also more preferably less than 0.001wt%, most preferably, not containing organic solvent.Organic solvent described here is organic solvent well known to the skilled person, comprise alcohols, ethers, ester class, replace the materials such as hydro carbons, arene, ketone, amides and nitrile, such as, alcohols comprises methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, 2-butanols, Pentyl alcohol etc.; Ethers comprises tetrahydrofuran (THF), ether, diox, methyl-phenoxide etc.; Ester class comprises methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate, isobutyl acetate, tert.-butyl acetate etc.; Replace hydro carbons and comprise methylene dichloride, chloroform, tetracol phenixin, Nitromethane 99Min. etc.; Arene comprises toluene, ethylbenzene etc.; Ketone comprises acetone, 2-butanone, 3-methyl-2-butanone, 2 pentanone, 4-methyl-2 pentanone, methyl-n-butyl ketone; Amides comprises DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, N-ethyl pyrrolidone; Acetonitrile is comprised with nitrile.Water described herein comprises soft water and hard water, fresh water and salt water, surface water and groundwater, preferably, single solvent water is through the water of purifying, and described purifying comprises the methods well known to those skilled in the art such as throw out filtration, water softening, charcoal absorption, deionization, reverse osmosis, electrodialysis, ultra-filtration, distillation, disinfection by ultraviolet light, biochemistry treatment, forward osmosis.Such as, single solvent water can be tap water or as tap water, deionized water, reverse osmosis water, electrodialytic water, exceed the water of the purifying that this areas such as drainage, distilled water, sterilized water are commonly used.The weight ratio of described water and Doripenem intermediate II is 5 ~ 80: 1, is preferably 20 ~ 40: 1.
Catalyzer is selected from palladium carbon or platinum carbon, is preferably 5% ~ 10% palladium carbon (mass percent concentration); The weight ratio of catalyzer and Doripenem intermediate II is 0.05 ~ 0.8: 1, is preferably 0.1 ~ 0.5: 1.
Described hydrogen pressure is preferably 0.5 ~ 2.5Mpa, is more preferably 1.0 ~ 2.0Mpa.
Temperature of reaction is-10 ~ 40 DEG C, is preferably 10 ~ 30 DEG C.
Reaction times is 15min ~ 10h, is preferably 1 ~ 5h.
Described raw material Doripenem intermediate II can refer to CN1071428A, Organic Process research & Development 2003,7, the open method of the documents such as 846-850, CN1896057A prepares, and above-mentioned literature content is hereby incorporated by.
Hydrogenation is complete, the finished product can be obtained through well known to a person skilled in the art a series of last handling processes such as being suitable for filtration of the present invention, concentrated, crystallization, purifying or freeze-drying, be preferably hydrogenation complete, Filtration of catalyst, add recrystallisation solvent in filtrate, crystallization obtains S-4661.Wherein, recrystallisation solvent be selected from methyl alcohol, ethanol, Virahol, n-propyl alcohol one or more, be preferably Virahol.
The inventive method adopts single solvent water as action solvent; in dynamic buffering system, hydrogenation is carried out by Doripenem intermediate II; solve the problems of dissolution of action solvent to catalyzer; reduce product degraded; improve product purity; and economy, safety, environmental protection, be more suitable for industrial scale operation.
In the application, abbreviation used represents following implication:
PNB: p-nitrophenyl methyl;
PNZ (Pnz): to nitrobenzyloxycarbonyl,
Boc: tertbutyloxycarbonyl,
PMB: to methoxy-benzyl,
Pmz: to methbxybenzyl-oxycarbonyl,
Embodiment
Below in conjunction with embodiment, the present invention is further elaborated, but these embodiments do not form any restriction to the present invention.
Embodiment 1: the preparation of S-4661
Doripenem intermediate 2 1.0kg (1.36mol) is added successively in 50L hydriding reactor, 10%Pd/C0.5Kg, 2,6-lutidine 0.32L (2.75mol), deionized water 15L, for several times, hydrogen exchange is for several times for nitrogen replacement, hydrogenation is to still internal pressure 2.0Mpa, 3h is reacted at 25 DEG C, by reacting liquid filtering, the recycling of palladium carbon, 45L Virahol is added in filtrate, stirring and crystallizing 5h at 0 ~ 5 DEG C, suction filtration obtains S-4661 0.42Kg, molar yield 73.5%, HPLC purity 99.2%, heavy metal content < 10ppm.
Embodiment 2: the preparation of S-4661
Doripenem intermediate 2 1.0kg (1.36mol) is added successively in 50L hydriding reactor, 10%Pd/C0.5Kg, 2,6-lutidine 0.08L (0.68mol), deionized water 15L, for several times, hydrogen exchange is for several times for nitrogen replacement, hydrogenation is to still internal pressure 2.0Mpa, 4h is reacted at 40 DEG C, by reacting liquid filtering, the recycling of palladium carbon, 75L ethanol is added in filtrate, stirring and crystallizing 5h at 0 ~ 5 DEG C, suction filtration obtains S-4661 0.40Kg, molar yield 70.0%, HPLC purity 98.2%, heavy metal content < 10ppm.
Embodiment 3: the preparation of S-4661
Doripenem intermediate 3 1.0Kg (1.09mol) is added successively in 50L hydriding reactor, 10%Pd/C0.5Kg, 3,5-lutidine 0.32L (5.45mol), deionized water 15L, for several times, hydrogen exchange is for several times for nitrogen replacement, hydrogenation is to still internal pressure 1.5Mpa, 5h is reacted at-10 DEG C, by reacting liquid filtering, the recycling of palladium carbon, 45L ethanol is added in filtrate, stirring and crystallizing 5h at 0 ~ 5 DEG C, suction filtration obtains S-4661 0.31Kg, molar yield 67.7%, HPLC purity 98.5%, heavy metal content < 10ppm.
Embodiment 4: the preparation of S-4661
Doripenem intermediate 21.0Kg (1.36mol) is added successively in 50L hydriding reactor, 10%Pd/C0.5Kg, sodium carbonate 0.43g (4.08mol), deionized water 15L, nitrogen replacement for several times, for several times, hydrogenation, to still internal pressure 1.0Mpa, reacts 4.5h at 10 DEG C to hydrogen exchange, by reacting liquid filtering, the recycling of palladium carbon, adds 45L Virahol in filtrate, stirring and crystallizing 5h at 0 ~ 5 DEG C, suction filtration obtains S-4661 0.41Kg, molar yield 71.8%, HPLC purity 98.9%, heavy metal content < 10ppm.
Embodiment 5: the preparation of S-4661
Doripenem intermediate 21.0Kg (1.36mol) is added successively in 50L hydriding reactor, 10%Pd/C0.5Kg, 3,5-lutidine 0.11g (1.36mol), deionized water 15L, for several times, hydrogen exchange is for several times for nitrogen replacement, hydrogenation is to still internal pressure 2.0Mpa, 5h is reacted at 5 DEG C, by reacting liquid filtering, the recycling of palladium carbon, 45L Virahol is added in filtrate, stirring and crystallizing 5h at 0 ~ 5 DEG C, suction filtration obtains S-4661 0.37Kg, molar yield 64.7%, HPLC purity 98.7%, heavy metal content < 10ppm.
Embodiment 6: the preparation of S-4661
Doripenem intermediate 21.0Kg (1.36mol) is added successively in 50L hydriding reactor, 10%Pd/C0.5Kg, sodium bicarbonate 0.32L (2.72mol), deionized water 15L, nitrogen replacement for several times, for several times, hydrogenation, to still internal pressure 2.0Mpa, reacts 4h at 30 DEG C to hydrogen exchange, by reacting liquid filtering, the recycling of palladium carbon, adds 45L Virahol in filtrate, stirring and crystallizing 5h at 0 ~ 5 DEG C, suction filtration obtains S-4661 0.40Kg, molar yield 70.0%, HPLC purity 98.7%, heavy metal content < 10ppm.
Claims (28)
1. a preparation method for the S-4661 shown in formula 1,
Described method comprises with Doripenem intermediate II for raw material, under alkali and catalyzer exist, with single solvent water for action solvent, carries out hydrogenation deprotection,
Wherein:
R
1represent H or hydroxyl protecting group, described hydroxyl protecting group is benzyl or allyl group, and described benzyl or allyl group are optionally by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6alkyl or C
1-C
6alkoxyl group replaces;
R
2representation carboxy protecting group, described carboxyl-protecting group is benzyl or allyl group, and described benzyl or allyl group are optionally by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6alkyl or C
1-C
6alkoxyl group replaces;
R
3represent amino protecting group, described amino protecting group is carbobenzoxy-(Cbz), and described carbobenzoxy-(Cbz) is optionally by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6alkyl or C
1-C
6alkoxyl group replaces;
R
4represent H or amino protecting group, described amino protecting group is carbobenzoxy-(Cbz), and described carbobenzoxy-(Cbz) is optionally by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6alkyl or C
1-C
6alkoxyl group replaces;
Wherein said alkali is selected from mineral alkali, organic bases, or its arbitrary combination, and described mineral alkali is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, Sodium phosphate dibasic; Described organic bases is selected from diethylamine, triethylamine, ammoniacal liquor, diisopropylethylamine, diisopropylamine, N-methylmorpholine, tetramethyl guanidine, aniline or substituted aniline, pyridine or substituted pyridines, and the substituting group of described substituted aniline is selected from C
1~ C
4alkyl, C
1~ C
4alkoxyl group, halogen, the substituting group of described substituted pyridines is selected from C
1~ C
4alkyl, C
1~ C
4alkoxyl group, halogen;
Wherein said catalyzer is selected from palladium carbon or platinum carbon, and the weight ratio of described catalyzer and Doripenem intermediate II is 0.05 ~ 0.8 ︰ 1;
Wherein hydrogen pressure is 0.5 ~ 2.5Mpa;
Wherein temperature of reaction is-10 ~ 40 DEG C.
2. method as claimed in claim 1, is characterized in that: R
2for to nitrobenzyl.
3. method as claimed in claim 1, is characterized in that: R
3for to nitrobenzyloxycarbonyl.
4. method as claimed in claim 1, is characterized in that: R
4when representing amino protecting group, described amino protecting group is to nitrobenzyloxycarbonyl.
5. method as claimed in claim 1, is characterized in that: described single solvent water is the water that foreign matter content is less than 10wt%.
6. method as claimed in claim 1, is characterized in that: described single solvent water is the water that foreign matter content is less than 5wt%.
7. method as claimed in claim 1, is characterized in that: described single solvent water is the water that foreign matter content is less than 1wt%.
8. method as claimed in claim 1, is characterized in that: described single solvent water is the water that foreign matter content is less than 0.1wt%.
9. method as claimed in claim 1, is characterized in that: described single solvent water is the water that foreign matter content is less than 0.01wt%.
10. method as claimed in claim 1, is characterized in that: described single solvent water is the water that foreign matter content is less than 0.001wt%.
11. methods as claimed in claim 1, is characterized in that: described single solvent water is not containing organic solvent and foreign matter content is less than the water of 10wt%.
12. methods as claimed in claim 1, is characterized in that: described single solvent water is not containing organic solvent and foreign matter content is less than the water of 5wt%.
13. methods as claimed in claim 1, is characterized in that: described single solvent water is not containing organic solvent and foreign matter content is less than the water of 1wt%.
14. methods as claimed in claim 1, is characterized in that: described single solvent water is not containing organic solvent and foreign matter content is less than the water of 0.1wt%.
15. methods as claimed in claim 1, is characterized in that: described single solvent water is not containing organic solvent and foreign matter content is less than the water of 0.01wt%.
16. methods as claimed in claim 1, is characterized in that: described single solvent water is not containing organic solvent and foreign matter content is less than the water of 0.001wt%.
17. methods as claimed in claim 1, is characterized in that: described single solvent wet concentration from tap water, tap water, deionized water, reverse osmosis water, electrodialytic water, exceed drainage, distilled water, sterilized water or its combination.
18. methods as claimed in claim 1, is characterized in that: the weight ratio of described aqueous solvent and Doripenem intermediate II is 5 ~ 80 ︰ 1.
19. methods as claimed in claim 1, is characterized in that: the weight ratio of described aqueous solvent and Doripenem intermediate II is 20 ~ 40 ︰ 1.
20. methods as claimed in claim 1, is characterized in that: the consumption of described alkali is 0.5 ~ 5 molar equivalent of Doripenem intermediate II.
21. methods as claimed in claim 1, is characterized in that: the consumption of described alkali is 1 ~ 3 molar equivalent of Doripenem intermediate II.
22. methods as claimed in claim 1, is characterized in that: described catalyzer is 5 ~ 10% palladium carbon.
23. methods as claimed in claim 1, is characterized in that: the weight ratio of described catalyzer and Doripenem intermediate II is 0.1 ~ 0.5 ︰ 1.
24. methods as claimed in claim 1, is characterized in that: hydrogen pressure is 1.0 ~ 2.0Mpa.
25. methods as claimed in claim 1, is characterized in that: temperature of reaction is 10 ~ 30 DEG C.
26. methods as claimed in claim 1, is characterized in that: hydrogenation is complete, carry out aftertreatment to product.
27. methods as claimed in claim 26, is characterized in that: described aftertreatment is filtered by hydrogenation liquid, in filtrate, then adds organic solvent carry out crystallization.
28. methods as claimed in claim 27, is characterized in that: described organic solvent be selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol one or more.
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|---|---|---|---|---|
| CN1896057A (en) * | 2005-07-15 | 2007-01-17 | 成都地奥九泓制药厂 | Pentazane derivative intermediate, its preparation and use |
| CN1995040A (en) * | 2006-01-05 | 2007-07-11 | 上海医药工业研究院 | 4-methyl-7-oxy-1-azabicyclo [3.2.0] hepta-2-olefin-2-carboxylic acid derivative preparation method |
| CN101880282A (en) * | 2009-05-04 | 2010-11-10 | 江苏正大天晴药业股份有限公司 | Purification method of pyrrolidine carbapenem antibiotics |
| CN101935321A (en) * | 2010-07-20 | 2011-01-05 | 深圳市海滨制药有限公司 | Method for synthesizing 1 beta methyl carbapenem antibiotic |
-
2011
- 2011-04-13 CN CN201110092906.7A patent/CN102731505B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1896057A (en) * | 2005-07-15 | 2007-01-17 | 成都地奥九泓制药厂 | Pentazane derivative intermediate, its preparation and use |
| CN1995040A (en) * | 2006-01-05 | 2007-07-11 | 上海医药工业研究院 | 4-methyl-7-oxy-1-azabicyclo [3.2.0] hepta-2-olefin-2-carboxylic acid derivative preparation method |
| CN101880282A (en) * | 2009-05-04 | 2010-11-10 | 江苏正大天晴药业股份有限公司 | Purification method of pyrrolidine carbapenem antibiotics |
| CN101935321A (en) * | 2010-07-20 | 2011-01-05 | 深圳市海滨制药有限公司 | Method for synthesizing 1 beta methyl carbapenem antibiotic |
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| Title |
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| Yutaka Nishino et al.Practical Large-Scale Synthesis of Doripenem: A Novel 1-Methylcarbapenem Antibiotic.《Organic Process Research Development》.2003,第7卷(第6期),846-850. * |
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