CN102731505A - Preparation method of doripenem - Google Patents
Preparation method of doripenem Download PDFInfo
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- CN102731505A CN102731505A CN2011100929067A CN201110092906A CN102731505A CN 102731505 A CN102731505 A CN 102731505A CN 2011100929067 A CN2011100929067 A CN 2011100929067A CN 201110092906 A CN201110092906 A CN 201110092906A CN 102731505 A CN102731505 A CN 102731505A
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- 0 CC*(C)C(N([C@@]([C@@]1[C@@](C)O)[C@]2C)C1=O)=C2SC1C[C@@](C*C)*C1 Chemical compound CC*(C)C(N([C@@]([C@@]1[C@@](C)O)[C@]2C)C1=O)=C2SC1C[C@@](C*C)*C1 0.000 description 2
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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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to a preparation method of doripenem as shown in the formula 1. The method comprises the following steps of: using a doripenem intermediate II as a raw material, using a single solvent--water as a reaction solvent and conducting a hydrogenated deprotection reaction in the presence of alkali and a catalyst. The single solvent water is used as a reaction solvent, thus solving a series of problems caused by the use of an organic solvent in the reaction solvent, reducing product degradation and raising product purity. In addition, the preparation method is economical, safe and environmentally friendly, and is more suitable for industrial operation at large scale.
Description
Technical field
The invention belongs to the synthetic field of carbapenem antibiotics, 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)-and the 1-hydroxyethyl] 4-methyl-7-Oxy-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxylic acid], structural formula is suc as formula shown in 1:
S-4661 is a kind of new carbapenem antibiotic, and 2 side chains are the substituted Pyrrolidine rings of SULFAMIDE.Structure activity study shows; The increase that acidylate that its side chain is amino or sulfonylation help anti-microbial activity; Its inhibition activity to gram-positive microorganism is higher than meropenem; Inhibition activity to Gram-negative bacteria is higher than imipenum, and is also effective to the imipenum resistant organism, to Serine β-Nei Xiananmei and the stable treatment that can be used for the severe infections of brain, kidney and lung of dehydropeptidase of kidney.
US5317046 at first discloses S-4661 compound and preparation method thereof.The S-4661 preparation method of this patent report is, and to be raw material with the S-4661 midbody shown in the general formula I obtain through deprotection reaction.
Wherein, work as X
1Be H or SiMe
3, X
2Be PMB, Y
2Be Boc or Pmz,
For-NHSO
2NH
2,
Or
The time, what this patent adopted is that the aluminum chloride remove-insurance is defended the doctrine, and this method needs-60～-30 ℃ low temperature, and the post-reaction treatment process needs styrene-divinylbenzene copolymer resin column chromatography purifying.This method is raw materials used to be not easy to obtain, and special refrigeration equipment, conversion unit and the column chromatography equipment of reaction needed, and suitability for industrialized production is had relatively high expectations, and cost is also high.
Work as X
1Be H, X
2Be PNB, Y
2Be Pnz,
For-NHSO
2NH
2The time (at this moment, the compound of formula I representative is a S-4661 midbody 2, shown in 2), what deprotection reaction adopted is the hydrogenolysis method, is action solvent with tetrahydrofuran solvent and MES damping fluid (pH7.0), adopting 10% palladium carbon is catalyzer.
Though this method no longer needs under condition of ultralow temperature, to carry out, but still has following shortcoming: at first used the MES damping fluid, and because raw materials used S-4661 midbody 2 of reaction and products therefrom S-4661 all are dissolved in the reaction solution; Speed of response is fast; Degradation product is many, will remove buffer reagent and other impurity after reaction finishes, so still need carry out column chromatography purification; Complex operation is unfavorable for scale operation.
Document Organic Process research&Development 2003; 7; The S-4661 preparation method who reports among the 846-850 is also to be to be raw material with compound 2, is catalyzer with 10% palladium carbon, carries out that the hydrogenolysis deprotection reaction obtains; Different is: 1. in THF and water reaction system, add magnesium chloride hexahydrate, and do not re-use the MES damping fluid; 2. the post-reaction treatment process no longer needs purified, but need repeatedly add magnesium chloride hexahydrate, repeatedly layering, and complicated operation, and have mg ion residual.CN1896057 and CN101935321 disclose the preparation method of similar S-4661, and different is: 1. do not use magnesium chloride hexahydrate in the two application method reaction systems; 2. CN1896057 has adopted compound 3 to be raw material; 3. used organic bases-3 in the CN101935321 reaction system, the 5-lutidine, employing be solvent crystallization method but not freeze-drying obtains finished product.
The hydrogenolysis deprotection method that above-mentioned document and patented claim are put down in writing; All adopt THF and water as action solvent, because raw materials used S-4661 midbody of reaction and products therefrom S-4661 all are dissolved in the reaction solution, speed of response is fast; Degradation product is many; The products therefrom yield is low, purity difference, aftertreatment difficulty.
CN1995040A discloses a kind of preparation method of improved carbapenem compounds, and wherein, it is raw material that the preparation method of said S-4661 is still with S-4661 midbody 2, makes to carry out under the catalyst action hydrogenolysis deprotection reaction at palladium carbon and obtains S-4661 1.Different with above-mentioned document is that it no longer adopts THF and water as action solvent, but adopts the two-phase solvent of being made up of the immiscible organic solvent of Shui Heshui as action solvent, does not also re-use MES or other damping fluid.This method has been simplified process step to a certain extent, has improved product purity, but last handling process still need divide equal step, and complex operation needs to increase relevant device in industrial production.
In addition, among the S-4661 preparation method of prior art record, all contain organic solvent in the action solvent that deprotection reaction adopts, have following drawback: 1. be unfavorable for environmental protection; 2. because mostly organic solvent is inflammable and explosive reagent, and smell is not good, high to the production plant design requirements, and increased the risk level of operating post, it is healthy to be not easy to the workman; 3. be dissolved with the part palladium complex in the solution, and be difficult for removing, cause heavy metals exceeding standard in the product.
Therefore, need provide a kind of simple to operate, be beneficial to environmental protection and workers ' health, be more suitable for S-4661 preparation method in suitability for industrialized production.
Summary of the invention
To the existing in prior technology problem, the invention provides a kind of S-4661 preparation method who adopts new catalytic hydrogenation system.
Therefore, the invention provides a kind of preparation method of S-4661, said method S-4661 midbody II is a raw material, in the presence of alkali and catalyzer, is action solvent with single solvent water, carries out hydrogenation deprotection.Reaction scheme is shown in flow process 1:
Wherein:
R
1Represent H or hydroxyl protecting group, preferably, hydroxyl protecting group is benzyl or allyl group, and said benzyl or allyl group are randomly by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6Alkyl or C
1-C
6Alkoxyl group replaces.
R
2Representation carboxy protection base, preferably, R
2Be benzyl or allyl group, said benzyl or allyl group are randomly 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
3Be carbobenzoxy-(Cbz), said carbobenzoxy-(Cbz) is randomly by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6Alkyl or C
1-C
6Alkoxyl group replaces, more preferably, and R
3For to the nitro carbobenzoxy-(Cbz).
R
4Represent H or amino protecting group, preferably, amino protecting group is a carbobenzoxy-(Cbz), and said carbobenzoxy-(Cbz) is randomly 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 the nitro carbobenzoxy-(Cbz).
Said 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, yellow soda ash, sodium hydrogencarbonate, Sodium phosphate, dibasic, preferred sodium hydrogencarbonate; 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 said substituted aniline is selected from C
1～C
4Alkyl, C
1～C
4Alkoxyl group, halogen, said substituted aniline is preferably 2,6-xylidine, 3,5-xylidine; The substituting group of said substituted pyridines is selected from C
1～C
4Alkyl, C
1～C
4Alkoxyl group, halogen, said substituted pyridines is preferably 2,6-lutidine, 3,5-lutidine.The consumption of alkali is 0.5～5 molar equivalent of S-4661 midbody II, is preferably 1～3 molar equivalent.
Said single solvent water is any water that contains less impurity, and wherein foreign matter content is less than 10wt%, for example less than 5wt%, for example less than 1wt%, preferably less than 0.1wt%, more preferably less than 0.01wt%, also more preferably less than 0.001wt%.Said impurity comprises suspended matter, soluble material, insoluble substance, metal-salt for example, organic solvent etc.When single solvent water comprised organic solvent, the content of organic solvent should preferably less than 0.1wt%, more preferably less than 0.01wt%, also more preferably less than 0.001wt%, most preferably, not contain organic solvent less than 1wt%.Organic solvent described here is the well-known organic solvents of those skilled in the art; Comprise alcohols, ethers, ester class, replace materials such as hydro carbons, arene, ketone, amides and nitrile; For example, alcohols comprises methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, 2-butanols, Pentyl alcohol etc.; Ethers comprises THF, ether 、 diox, methyl-phenoxide etc.; The ester class comprises methyl acetate, ETHYLE 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 N, dinethylformamide, DMAC N,N, N-Methyl pyrrolidone, N-ethyl pyrrolidone; Comprise acetonitrile with nitrile.Water described in this paper comprises soft water and hard water; Fresh water and salt water; Surface water and underground water; Preferably, single solvent water is purified water, and said purifying comprises methods well known to those skilled in the art such as throw out filtration, water softening, charcoal absorption, de-ionized, r-o-, electrodialysis, ultra-filtration, distillation, disinfection by ultraviolet light, biological chemistry processing, forward osmosis.For example, single solvent water can be tap water or like tap water, deionized water, reverse osmosis water, electrodialytic water, surpass the water of this areas such as drainage, zero(ppm) water, sterilized water purifying commonly used.The weight ratio of said water and S-4661 midbody 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 S-4661 midbody II is 0.05～0.8: 1, is preferably 0.1～0.5: 1.
Said hydrogen pressure is preferably 0.5～2.5Mpa, more preferably 1.0～2.0Mpa.
Temperature of reaction is-10～40 ℃, is preferably 10～30 ℃.
Reaction times is 15min～10h, is preferably 1～5h.
Said raw material S-4661 midbody II can be with reference to CN1071428A, Organic Process research & Development 2003; 7; The open method of document such as 846-850, CN1896057A prepares, and above-mentioned literature content is hereby incorporated by.
Hydrogenation finishes; Can be suitable for filtration of the present invention through well known to a person skilled in the art, concentrate, a series of last handling processes such as crystallization, purifying or freeze-drying obtain the finished product; Being preferably hydrogenation finishes; Remove by filter catalyzer, add recrystallisation solvent in the filtrating, crystallization obtains S-4661.Wherein, recrystallisation solvent is selected from one or more in methyl alcohol, ethanol, Virahol, the n-propyl alcohol, is preferably Virahol.
The inventive method adopts single solvent water as action solvent; In the dynamic buffering system, carry out hydrogenation through S-4661 midbody II; Solved the problems of dissolution of action solvent, reduced the product degraded, improved product purity catalyzer; And economy, safety, environmental protection are more suitable for operating in industrial scale.
Among the application, following implication is represented in used abbreviation:
PNB: p-nitrophenyl methyl;
PNZ (Pnz): to the nitro carbobenzoxy-(Cbz),
Boc: tertbutyloxycarbonyl,
PMB: to methoxy-benzyl,
Pmz: to methoxyl group benzyloxy carbonyl,
Embodiment
Below in conjunction with embodiment the present invention is done further elaboration, but these embodiment do not constitute any restriction to the present invention.
Embodiment 1: the preparation of S-4661
In 50L hydrogenation still, add S-4661 midbody 2 1.0kg (1.36mol) successively, 10%Pd/C0.5Kg, 2,6-lutidine 0.32L (2.75mol); Deionized water 15L, the nitrogen replacement several, hydrogen exchange adds hydrogen to still internal pressure 2.0Mpa for several times; 25 ℃ are reacted 3h down, with reacting liquid filtering, and the recycling of palladium carbon; Add the 45L Virahol in the filtrating, 0～5 ℃ of following stirring and crystallizing 5h, suction filtration gets S-4661 0.42Kg; Molar yield 73.5%, HPLC purity 99.2%, heavy metal content＜10ppm.
Embodiment 2: the preparation of S-4661
In 50L hydrogenation still, add S-4661 midbody 2 1.0kg (1.36mol) successively, 10%Pd/C0.5Kg, 2,6-lutidine 0.08L (0.68mol); Deionized water 15L, the nitrogen replacement several, hydrogen exchange adds hydrogen to still internal pressure 2.0Mpa for several times; 40 ℃ are reacted 4h down, with reacting liquid filtering, and the recycling of palladium carbon; Add 75L ethanol in the filtrating, 0～5 ℃ of following stirring and crystallizing 5h, suction filtration gets S-4661 0.40Kg; Molar yield 70.0%, HPLC purity 98.2%, heavy metal content＜10ppm.
Embodiment 3: the preparation of S-4661
In 50L hydrogenation still, add S-4661 midbody 3 1.0Kg (1.09mol) successively, 10%Pd/C0.5Kg, 3,5-lutidine 0.32L (5.45mol); Deionized water 15L, the nitrogen replacement several, hydrogen exchange adds hydrogen to still internal pressure 1.5Mpa for several times;-10 ℃ are reacted 5h down, with reacting liquid filtering, and the recycling of palladium carbon; Add 45L ethanol in the filtrating, 0～5 ℃ of following stirring and crystallizing 5h, suction filtration gets S-4661 0.31Kg; Molar yield 67.7%, HPLC purity 98.5%, heavy metal content＜10ppm.
Embodiment 4: the preparation of S-4661
In 50L hydrogenation still, add S-4661 midbody 21.0Kg (1.36mol) successively, 10%Pd/C0.5Kg, yellow soda ash 0.43g (4.08mol), deionized water 15L; The nitrogen replacement several, hydrogen exchange adds hydrogen to still internal pressure 1.0Mpa for several times, and 10 ℃ are reacted 4.5h down; With reacting liquid filtering, the recycling of palladium carbon adds 45L Virahol, 0～5 ℃ of following stirring and crystallizing 5h in the filtrating; Suction filtration gets S-4661 0.41Kg, molar yield 71.8%, HPLC purity 98.9%, heavy metal content＜10ppm.
Embodiment 5: the preparation of S-4661
In 50L hydrogenation still, add S-4661 midbody 21.0Kg (1.36mol) successively, 10%Pd/C0.5Kg, 3,5-lutidine 0.11g (1.36mol); Deionized water 15L, the nitrogen replacement several, hydrogen exchange adds hydrogen to still internal pressure 2.0Mpa for several times; 5 ℃ are reacted 5h down, with reacting liquid filtering, and the recycling of palladium carbon; Add the 45L Virahol in the filtrating, 0～5 ℃ of following stirring and crystallizing 5h, suction filtration gets S-4661 0.37Kg; Molar yield 64.7%, HPLC purity 98.7%, heavy metal content＜10ppm.
Embodiment 6: the preparation of S-4661
In 50L hydrogenation still, add S-4661 midbody 21.0Kg (1.36mol) successively, 10%Pd/C0.5Kg, sodium hydrogencarbonate 0.32L (2.72mol), deionized water 15L; The nitrogen replacement several, hydrogen exchange adds hydrogen to still internal pressure 2.0Mpa for several times, and 30 ℃ are reacted 4h down; With reacting liquid filtering, the recycling of palladium carbon adds 45L Virahol, 0～5 ℃ of following stirring and crystallizing 5h in the filtrating; Suction filtration gets S-4661 0.40Kg, molar yield 70.0%, HPLC purity 98.7%, heavy metal content＜10ppm.
Claims (10)
1. the preparation method of the S-4661 shown in the formula 1,
Said method comprises that with S-4661 midbody II be raw material, in the presence of alkali and catalyzer, is action solvent with single solvent water, carries out hydrogenation deprotection,
Wherein:
R
1Represent H or hydroxyl protecting group, preferably, said hydroxyl protecting group is benzyl or allyl group, and said benzyl or allyl group are randomly by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6Alkyl or C
1-C
6Alkoxyl group replaces;
R
2Representation carboxy protection base, preferably, R
2Be benzyl or allyl group, said benzyl or allyl group are randomly 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
3Be carbobenzoxy-(Cbz), said carbobenzoxy-(Cbz) is randomly by nitro, fluorine, chlorine, bromine, iodine, C
1-C
6Alkyl or C
1-C
6Alkoxyl group replaces, more preferably, and R
3For to the nitro carbobenzoxy-(Cbz);
R
4Represent H or amino protecting group, preferably, amino protecting group is a carbobenzoxy-(Cbz), and said carbobenzoxy-(Cbz) is randomly 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 the nitro carbobenzoxy-(Cbz).
2. method according to claim 1, it is characterized in that: said single solvent water is any water that contains less impurity, for example, tap water, tap water, deionized water, reverse osmosis water, electrodialytic water, surpasses drainage, zero(ppm) water, sterilized water or its combination.
3. method according to claim 1, it is characterized in that: the weight ratio of said aqueous solvent and S-4661 midbody II is 5～80: 1, is preferably 20～40: 1.
4. method according to claim 1, it is characterized in that: said alkali is selected from mineral alkali, organic bases, or its arbitrary combination; They exist with any suitable concentration; Preferably, the consumption of said alkali is 0.5～5 molar equivalent of S-4661 midbody II, is preferably 1～3 molar equivalent.
5. like the said method of claim 4, it is characterized in that: said mineral alkali is selected from sodium hydroxide, yellow soda ash, sodium hydrogencarbonate, Sodium phosphate, dibasic; Said 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 said substituted aniline is selected from C
1～C
4Alkyl, C
1～C
4Alkoxyl group, halogen, the substituting group of said substituted pyridines is selected from C
1～C
4Alkyl, C
1～C
4Alkoxyl group, halogen.
6. method according to claim 1, it is characterized in that: said catalyzer is selected from palladium carbon or platinum carbon, is preferably 5～10% palladium carbon.
7. method according to claim 1, it is characterized in that: the weight ratio of said catalyzer and S-4661 midbody II is 0.05～0.8: 1, is preferably 0.1～0.5: 1.
8. method according to claim 1, it is characterized in that: hydrogen pressure is 0.5～2.5Mpa, is preferably 1.0～2.0Mpa.
9. method according to claim 1, it is characterized in that: temperature of reaction is-10～40 ℃, is preferably 10～30 ℃.
10. method according to claim 1; It is characterized in that: hydrogenation finishes; Product is carried out aftertreatment, preferably hydrogenation liquid is filtered, in filtrating, add organic solvent then and carry out crystallization; More preferably, said organic solvent is selected from one or more in methyl alcohol, ethanol, n-propyl alcohol, the Virahol.
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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 |
-
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 |
Non-Patent Citations (1)
| Title |
|---|
| YUTAKA NISHINO ET AL: "Practical Large-Scale Synthesis of Doripenem: A Novel 1â-Methylcarbapenem Antibiotic", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》, vol. 7, no. 6, 24 September 2003 (2003-09-24), pages 846 - 850 * |
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