CN105439931A - Method for purifying doripenem side chain of doripenem drug intermediate - Google Patents
Method for purifying doripenem side chain of doripenem drug intermediate Download PDFInfo
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- CN105439931A CN105439931A CN201510807601.8A CN201510807601A CN105439931A CN 105439931 A CN105439931 A CN 105439931A CN 201510807601 A CN201510807601 A CN 201510807601A CN 105439931 A CN105439931 A CN 105439931A
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- side chain
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- pharmaceutical intermediate
- doripenem
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
Abstract
The invention discloses a method for purifying the doripenem side chain of a doripenem drug intermediate. The major impurity compound doripenem side chain disulfide in the doripenem side chain synthesis of a doripenem drug intermediate is removed in a recrystallization way; and the purity of the doripenem side chain is increased so as to provide reliable guarantee for improving the quality of doripenem drugs.
Description
Technical field
The present invention relates to a kind of purification process of S-4661 pharmaceutical intermediate S-4661 side chain, belong to medicinal chemistry arts.
Background technology
The new Broad spectrum antibiotics of carbapenems that S-4661 (Doripenem, S-4661) is developed for Japanese Yan Yeyi company, has has a broad antifungal spectrum, to the stable feature of most β-lactamase.Johson & Johnson obtains the exploitation listing power of this medicine from Japanese Yan Yeyi company.In September, 2005, S-4661 was first in Japan's listing, and commodity are called Finibax.In October, 2007, U.S. FDA ratified this medicine injection for infecting and complicacy urinary tract infection in clinical treatment complicacy abdomen.Its chemical name is: (1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-2-[(3S, 5S)-5-sulphonamide aminomethyl pyrrolidin-3-yl] sulfenyl-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxylic acid, monohydrate.Structural formula is as follows:
S-4661 synthetic route is: by (2S; 4S)-4-acetylthio-2-[[N-amino-sulfonyl-N-(tertbutyloxycarbonyl) is amino] methyl] tetramethyleneimine-1-formic acid carries out deprotection to p-Nitrobenzyl (S-4661 side chain); again with [4R-[4a; 5b; 6b (R*)]]-3-diphenylphosphine acyloxy-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene"-2-carboxy acid mutual-nitro carbobenzoxy (MAP) carries out condensation, and last shortening generates target product.S-4661 side chain is the important intermediate of S-4661.
Report S-4661 side chain synthetic route is a lot, and entirety can be summarized as four steps: (1), by (L)-4-oxyproline, esterification, protects hydroxyl, amino; (2) ester reduction is become alcohol; (3) SN2 reaction makes C4 positional configuration overturn, the hydroxyl having made sulfocompound replacement protected; (4) alcohol is transformed into sulphonamide product by Mitsunobu reaction, obtains complete side chain.Wherein alcohol is transformed into the key that this step of aminoderivative is the synthesis of whole side chain.
The synthetic route of the S-4661 side chain that existing document is reported has following 6; all with trans-(L)-4-oxyproline (1) for starting raw material, then through protection pyrrole ring on the series reaction such as nitrogen, esterification, Mesylation, sodium borohydride reduction, SN2 reaction, Mitsunobu reaction obtain S-4661 side chain.Wherein route A with to methbxybenzyl-oxycarbonyl (PMZ) for protecting group, carry out amido protecting after first esterification; Route B, C all with tertbutyloxycarbonyl (Boc) for amino protecting group, but esterification is different with the order of protection; Route D, E all with to nitrobenzyloxycarbonyl (PNZ) for protecting group, route D first protects amino, and route E carries out amido protecting again after esterification.
Route A: trans-(L)-4-oxyproline (1) first esterification obtains 2A, use S-p-methoxybenzyloxycarbonyl-4 again, 6-dimethyl-2-mercaptopyrimidine (MZ-SDP) protects the nitrogen on 2A, 2A reacts to obtain methanesulfonates 4A at the dichloromethane solution of triethylamine and methylsulfonyl chloride generation Mesylation, cis-N-(4-methoxybenzyloxycarbonyl)-4-(triphen first the sulfo-)-L-PROLINE methyl esters 5A of configuration reversal is obtained again with the process of trityl sodium sulphite, 5A is reduced into corresponding alcohol 6A in tetrahydrofuran solution with lithium borohydride again, 6A carries out Mesylation again and obtains 7A, 8A is obtained again with the condensation of phthalimide potassium, hydrazinolysis obtains (2S, 4S)-2-(aminomethyl)-1-(4-methoxybenzyloxycarbonyl)-4-(triphen first sulfo-) tetramethyleneimine 9A, 9A is at triethylamine, diethyl azodiformate (DEAD), 10A is obtained with N-(4-methoxybenzyloxycarbonyl) sulphonamide chlorine generation condensation reaction under the effect of triphenyl phosphorus, the trityl-protecting group sloughed above with Silver Nitrate and pyridine again obtains 11A, the i.e. side chain of synthetic route A.
Route B: trans-(L)-4-oxyproline Boc acid anhydrides protection obtains 2B; there is Mesylation after making mixed acid anhydride with methyl chloroacetate and obtain 4B; (2S is obtained again with sodium borohydride reduction; 4R)-1-(N-tertbutyloxycarbonyl)-2-methylol-4-methylsulfonyl tetramethyleneimine, that is: 5B.5B and thioacetic acid potassium are obtained by reacting the product 6B that C-4 positional configuration overturns; 6B carries out Mitsunobu with N-(tertbutyloxycarbonyl) SULFAMIDE and is obtained by reacting the tetramethyleneimine SULFAMIDE protected, i.e. the side-chain product of B route under the effect of triphenyl phosphorus, diethyl azodiformate (DEAD).
Route C: trans-(L)-4-oxyproline (1) under sulfur oxychloride or hydrochloric acid condition, esterification occurs in methanol solution obtains 3B; 3B obtains with Boc anhydride reaction the compound 4B that on pyrrole ring, nitrogen is protected by Boc at Methanesulfonyl chloride, triethylamine under existing; (2S is obtained again by POTASSIUM BOROHYDRIDE, Zinc Chloride Anhydrous reduction; 4R)-1-(N-tertbutyloxycarbonyl)-2-methylol-4-methylsulfonyl tetramethyleneimine, that is: 5B.5B passes through the process identical with route B again: be obtained by reacting the tetramethyleneimine SULFAMIDE protected, i.e. the side-chain product 7B of B, C route through SN2 reaction, Mitsunobu.
Route D: first obtain 2D with the amino protected nitrobenzyloxycarbonyl chlorine (PNZ-Cl) in trans-(L)-4-oxyproline; carry out esterification reaction of organic acid more in acid condition and obtain 3D; 3D is obtained by reacting 4D with Methanesulfonyl chloride generation Mesylation under triethylamine exists; being obtained by reacting 6D with there is SN2 with thioacetic acid potassium after sodium borohydride reduction, eventually passing the S-4661 side chain 7D of the obtained route D of Mitsunobu reaction.
Route E: route E and route D similar; difference first carries out carrying out PNZ protection after esterification obtains 3B again to obtain 3D; follow-up Mesylation reaction, sodium borohydride reduction, SN2, Mitsunobu are all basically identical with route D; final obtained S-4661 side chain 7D; or first three step carries out-and one kettle way ‖ reacts, and directly obtained 4D is also a kind of method that PNZ protects route; three kinds of mode bibliographical information yields are close, are all good selections.Relatively above several routes we learn: it is protecting group that route A adopts methbxybenzyl-oxycarbonyl (PMZ), the tediously long complexity of route.Adopt trityl sodium sulphite as configuration reversal reagent, not only price and remove complex steps.The introducing of the upper sulphonamide amido of tetramethyleneimine 2 also needs four-step reaction could realize in addition, and is all that employing Mitsunobu reaction optimization completes in four routes thereafter, and step is shortened.In addition the side chain that obtains of A route again with parent nucleus (1R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-2-benzene oxygen adjacent acyloxy-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxylic acid, also need during cyclization to use silicagel column separation and purification, be not suitable for industrial production, obvious route A inadequacy thus.Route B, C adopt tertbutyloxycarbonyl (Boc) to be protecting group, and difference is that protection is different from the order of esterification, and subsequent step is similar.Relative A route, B, C route seems and simplifies many, but its former step reaction requires harsh (-20 ~-30 DEG C) experimental temperature, industrially relatively not easily realizes, also bad to environmental influence.Particularly use poisonous reagent in route B: Vinyl chloroformate, the phase-transfer catalyst that adopts during reduction ester group: tetra-n-butyl ammonium bromide and sodium borohydride coupling, expensive, also also non-optimal.C is slightly more excellent than route B comparatively speaking.But in Deprotection process, aluminum chloride/methyl-phenoxide deprotection also needs to use resin column purifying after route B, C obtain side chain, be difficult to carry out industrial production.It is protecting group that route D, E all adopt nitrobenzyloxycarbonyl (PNZ).Two lines are similar, the order of difference also just esterification and PNZ protection, and follow-up Mesylation reaction, sodium borohydride reduction, SN2, Mitsunobu are basically identical, finally obtain S-4661 side chain 7D.Or first three step carries out-and pot method ‖ reacts, and directly obtained 4D, then whole side chain synthetic route 3 step can obtain.Three kinds of modes all do not use poisonous reagent, and experiment condition also easily reaches, and bibliographical information yield is ideal, and three route yields are close, are all good selections.
But in all these synthetic routes, generating two polymkeric substance during S-4661 side chain is exactly S-4661 side chain disulphide, for the major impurity of S-4661 side chain, find through multiple batches of inspection, this impurity being present in the finished product S-4661 more or less, be unfavorable for the purifying of S-4661.
Summary of the invention
The invention provides a kind of purification process of S-4661 pharmaceutical intermediate S-4661 side chain.
Wherein the structure of S-4661 side chain and major impurity S-4661 side chain disulphide thereof is as follows:
Object of the present invention can be achieved through the following technical solutions:
The invention provides a kind of purification process of S-4661 pharmaceutical intermediate S-4661 side chain, comprise the following steps:
1) the S-4661 side chain containing two sulphur things 0.5% ~ 1% is joined in ethanol;
2) by step 1) formation system is rapidly heated to 70 ~ 72 DEG C, reflux 30 ~ 35 minutes;
3) to step 2) add pure water in backflow system, stir;
4) by step 3) form system slow cooling to 5 ~ 10 DEG C, slowly stir, crystallization 4 ~ 6 hours;
5) by step 4) filtration of gained crystal, obtain filter cake; Filter cake ethanol water mixed solvent washing, drying, obtain the S-4661 side chain being less than 0.3% containing two sulphur things, purity is greater than 99.3%.
Preferably, described step 1) in S-4661 side chain the add-on of ethanol be 8 ~ 9 times of weight parts.
Preferably, described step 2) in, the time being warming up to reflux temperature is 5 ~ 10 minutes.
Preferably, described step 3) in, the add-on of pure water is 0.5 ~ 0.6 weight part, stirs 10 ~ 15 minutes.
Preferably, described step 4) in, slow cooling to 5 ~ 10 DEG C, slowly stir; 4 ~ 6 hours crystallization time.The time of being down to recrystallization temperature is 50 ~ 60 minutes, and slow mixing speed is 50 ~ 60 revs/min.
Preferably, described step 5) in filter, washing ethanol water mixed liquid be chilled to 0 ~ 5 DEG C in advance.
Preferably, described step 5) in the ratio of second alcohol and water be 80 ~ 81:10 ~ 11.
Preferably, described step 5) in, the condition of forced air drying is: 40 ~ 50 DEG C, 5 ~ 6 hours.
Experimental data shows, under condition of different temperatures, and S-4661 side chain and S-4661 side chain disulphide, the difference of the dissolving in methyl alcohol, ethanol and ethyl acetate, as shown in Table 1, preferably carry out recrystallization with ethanol, remove S-4661 side two sulphur thing in S-4661 side chain.Meanwhile, add a certain proportion of water in ethanol, can better improve the yield of recrystallization, from table (two): ethanol: when water weight ratio is 90:10, recrystallization weight yield is 90%, and yield is on the low side; Ethanol: during water weight ratio 80:20, recrystallization weight yield is 95.5%, but two sulphur things in the S-4661 side chain that obtains of recrystallization are greater than 3%, does not reach the object of two sulphur things in removing S-4661 side chain.Thus, in S-4661 side chain recrystallization process, ethanol: the preferred 80:10 of water weight ratio.
Table one: S-4661 side chain and S-4661 side chain disulphide, the contrast of the dissolving in methyl alcohol, ethanol and ethyl acetate
| Solubleness (temperature 70 C) | Methyl alcohol | Ethanol | Ethyl acetate |
| S-4661 side chain disulphide (10 grams) | 50 grams | 80 grams | 30 grams |
| S-4661 side chain (10 grams) | 10 grams | 10 grams | 80 grams |
| Solubleness (temperature 5 DEG C) | Methyl alcohol | Ethanol | Ethyl acetate |
| S-4661 side chain disulphide (10 grams) | 30 grams | 30 grams | 240 grams |
| S-4661 side chain (10 grams) | 500 grams | 1600 grams | 155 grams |
Table two: recrystallization Buddhist nun trains the ethanol of southern side chain and the ratio of water
Beneficial effect of the present invention is as follows:
Under obtaining differing temps by many experiments, in different solvents, molten S-4661 side chain and major impurity S-4661 side chain disulphide solution degree, determine the mode purifying S-4661 side chain compound with recrystallization, and give optimum solvent and the solvent ratios of recrystallization, improve the purity of S-4661 side chain, the raising for S-4661 drug quality provides good precursor conditions.
Embodiment
Below by embodiment, concrete elaboration is done to the present invention, those skilled in the art can be made to understand the present invention more comprehensively, but be not used for limiting the scope of the invention.
Embodiment 1
The invention provides a kind of purification process of S-4661 pharmaceutical intermediate S-4661 side chain, comprise the following steps:
1) the S-4661 side chain 20 grams containing two sulphur things 1% is joined in 160 grams of ethanol;
2) by step 1) gained system is warming up to 70 DEG C in 5 minutes, reflux 30 minutes;
3) to step 2) in add pure water 10 grams, stir 10 minutes;
4) by step 3) gained system is cooled to 5 DEG C, crystallization 4 hours for 50 minutes, 50 revs/min of stirrings;
5) by step 4) filtration of gained crystal, obtain filter cake; Ratio is that the ethanol water mixing of 80:10 is moltenly chilled to 5 DEG C in advance, washing leaching cake, 40 DEG C of dryings 5 hours S-4661 side chain 19 grams, purity 99.3%, S-4661 side chain disulphide 0.25%.
Embodiment 2
A purification process for S-4661 pharmaceutical intermediate S-4661 side chain, comprises the following steps:
1) the S-4661 side chain 20 grams containing two sulphur things 0.5% is joined in 165 grams of ethanol;
2) by step 1) gained system intensification in 10 minutes 72 DEG C, reflux 35 minutes;
3) to step 2) in add pure water 12 grams, stir 15 minutes;
4) by step 3) gained system is cooled to 10 DEG C, crystallization 6 hours for 60 minutes, 60 revs/min of stirrings;
5) by step 4) filtration of gained crystal, obtain filter cake; Ratio is that the ethanol water mixing of 81:10 is moltenly chilled to 0 DEG C in advance, washing leaching cake, 50 DEG C of dryings 6 hours S-4661 side chain 19.1 grams, purity 99.4%, S-4661 side chain disulphide 0.2%.
Embodiment 3
A purification process for S-4661 pharmaceutical intermediate S-4661 side chain, comprises the following steps:
1) the S-4661 side chain 20 grams containing two sulphur things 0.8% is joined in 162 grams of ethanol;
2) by step 1) gained system intensification in 8 minutes 71 DEG C, reflux 32 minutes;
3) to step 2) in add pure water 11 grams, stir 12 minutes;
4) by step 3) gained system slow 55 minutes temperature to 12 DEG C, crystallization 5 hours, 55 revs/min of stirrings;
5) by step 4) filtration of gained crystal, obtain filter cake; Ratio is that the ethanol water mixing of 80:11 is moltenly chilled to 3 DEG C in advance, washing leaching cake, 45 DEG C of dryings 5.5 hours S-4661 side chain 19.2 grams, purity 99.5%, S-4661 side chain disulphide 0.2%.
Embodiment 4
A purification process for S-4661 pharmaceutical intermediate S-4661 side chain, comprises the following steps:
1) the S-4661 side chain 20 grams containing two sulphur things 0.8% is joined in 160 grams of ethanol;
2) by step 1) gained system intensification in 7 minutes 72 DEG C, reflux 30 minutes;
3) to step 2) in add pure water 10 grams, stir 15 minutes;
4) by step 3) gained system is cooled to 10 DEG C, crystallization 4 hours for 58 minutes, 58 revs/min of stirrings;
5) by step 4) filtration of gained crystal, obtain filter cake; Ratio is that the ethanol water mixing of 80:10 is moltenly chilled to 0 DEG C in advance, washing leaching cake, 50 DEG C of dryings 6 hours S-4661 side chain 19.1 grams, purity 99.4%, S-4661 side chain disulphide 0.21%.
Claims (8)
1. a purification process for S-4661 pharmaceutical intermediate S-4661 side chain, is characterized in that, comprise the following steps:
1) the S-4661 side chain containing two sulphur things 0.5% ~ 1% is joined in ethanol;
2) by step 1) formation system is rapidly heated to 70 ~ 72 DEG C, reflux 30 ~ 35 minutes;
3) to step 2) add pure water in backflow system, stir;
4) by step 3) form system slow cooling to 5 ~ 10 DEG C, slowly stir, crystallization 4 ~ 6 hours;
5) by step 4) filtration of gained crystal, obtain filter cake; Filter cake ethanol water mixed solvent washing, drying, obtain the S-4661 side chain being less than 0.3% containing two sulphur things, purity is greater than 99.3%.
2. the purification process of a kind of S-4661 pharmaceutical intermediate S-4661 side chain as claimed in claim 1, is characterized in that, step 1) in S-4661 side chain the add-on of ethanol be 8 ~ 9 times of weight parts.
3. the purification process of a kind of S-4661 pharmaceutical intermediate S-4661 side chain as claimed in claim 1, is characterized in that, step 2) in, the time being warming up to reflux temperature is 5 ~ 10 minutes.
4. the purification process of a kind of S-4661 pharmaceutical intermediate S-4661 side chain as claimed in claim 1, is characterized in that, step 3) in, the add-on of pure water is 0.5 ~ 0.6 weight part, stirs 10 ~ 15 minutes.
5. the purification process of a kind of S-4661 pharmaceutical intermediate S-4661 side chain as claimed in claim 1, is characterized in that, step 4) in, the time of being down to recrystallization temperature is 50 ~ 60 minutes, and slow mixing speed is 50 ~ 60 revs/min.
6. the purification process of a kind of S-4661 pharmaceutical intermediate S-4661 side chain as claimed in claim 1, is characterized in that, step 5) in filter, washing ethanol water mixed liquid be chilled to 0 ~ 5 DEG C in advance.
7. the purification process of a kind of S-4661 pharmaceutical intermediate S-4661 side chain as claimed in claim 1, is characterized in that, step 5) in the ratio of second alcohol and water be 80 ~ 81:10 ~ 11.
8. the purification process of a kind of S-4661 pharmaceutical intermediate S-4661 side chain as claimed in claim 1, is characterized in that, step 5) in, the condition of forced air drying is: 40 ~ 50 DEG C, 5 ~ 6 hours.
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| CN201510807601.8A CN105439931B (en) | 2015-11-21 | 2015-11-21 | A kind of purification process of donipenem pharmaceutical intermediate donipenem side chain |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010097686A1 (en) * | 2009-02-26 | 2010-09-02 | Orchid Chemicals & Pharmaceuticals Ltd | An improved process for the preparation of carbapenem antibiotic |
| CN102093278A (en) * | 2011-03-09 | 2011-06-15 | 北京莱瑞森医药科技有限公司 | Preparation process for intermediate of doripenem |
| CN102249970A (en) * | 2011-05-09 | 2011-11-23 | 黄山市歙县宏辉化工有限公司 | Process for synthesizing doripenem lateral chain |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010097686A1 (en) * | 2009-02-26 | 2010-09-02 | Orchid Chemicals & Pharmaceuticals Ltd | An improved process for the preparation of carbapenem antibiotic |
| CN102093278A (en) * | 2011-03-09 | 2011-06-15 | 北京莱瑞森医药科技有限公司 | Preparation process for intermediate of doripenem |
| CN102249970A (en) * | 2011-05-09 | 2011-11-23 | 黄山市歙县宏辉化工有限公司 | Process for synthesizing doripenem lateral chain |
Non-Patent Citations (2)
| Title |
|---|
| 姜玉钦，等: "多尼培南的新合成路线", 《中国新药杂志》 * |
| 陈鸿平主编: "《理化基本技能训练》", 31 August 2014 * |
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