CN102617433B - Method for preparing (2S, 4R)-1-paranitro carbobenzoxy-4-methylsulfonyl pyrrolidine-2-methanol - Google Patents
Method for preparing (2S, 4R)-1-paranitro carbobenzoxy-4-methylsulfonyl pyrrolidine-2-methanol Download PDFInfo
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Abstract
The invention provides a method for preparing (2S, 4R)-1-paranitro carbobenzoxy-4-methylsulfonyl pyrrolidine-2-methanol by four steps. The technological operation steps are simplified, technological continuity is higher, an intermediate does not need to be refined, industrial production is easily realized, production cost is reduced, types and consumption of organic solvents are greatly decreased, the single solvent is conveniently recycled and reused, and the novel technology is more environment-friendly. By the aid of the method, higher yield can be achieved, compound I hydroxyproline serves as a standard, total molar yield is higher than or equal to 75%, and final product purity is higher than or equal to 98.0%.
Description
Technical field
The present invention relates to prepare the preparation method of the intermediate of 1 beta-methylcarbapenem antibiotics-S-4661, the preparation method of relate in particular to (2S, 4R)-1-to nitro carbobenzoxy-(Cbz)-4-methylsulfonyl tetramethyleneimine-2-methyl alcohol.
Background technology
Carbapenem antibiotic has the feature of very strong anti-microbial activity and has a broad antifungal spectrum, stable to β-lactamase, has clinically very high using value.This similar drug having gone on the market has imipenum, biapenem, meropenem etc.S-4661 (formula VI) is a kind of novel beta-methylcarbapenem antibiotics of Japanese Shionogi limited-liability company research and development.
S-4661 is to anaerobism or aerobic Gram-positive and gram negative bacterium and the resistant organism of cynnematin and penicillins is had to powerful anti-microbial activity.It has high avidity to streptococcus aureus, Pseudomonas aeruginosa, intestinal bacteria PBP2 and other sensitive organism PBP.S-4661 is also stable to dehydropeptidase of kidney (DHP-1), and it can be hydrolyzed by DHP-1 in human body, can use separately.
(2S, 4R) at present-1-has developed several different methods to the preparation of nitro carbobenzoxy-(Cbz)-4-methylsulfonyl tetramethyleneimine-2-methyl alcohol, and wherein, representative synthetic route mainly contains following two:
The first is disclosed in Organic Process Research & Development 2003,7 (5): 649-654:
Article one, the shortcoming of route is that low-temp reaction is many, and long reaction time increases industrial cost; Dichloromethane solvent used, relative toxicity is large, is difficult to reclaim completely.
The shortcoming of second route is respectively to walk all purified crystals of intermediate, and it is not very high causing yield, and has increased the storage problem of each intermediate, has brought unnecessary trouble.
Summary of the invention
Technical problem to be solved by this invention is: the preparation method of a kind of (2S, 4R)-1-to nitro carbobenzoxy-(Cbz)-4-methylsulfonyl tetramethyleneimine-2-methyl alcohol is provided, simplified processing step, technique continuity is stronger, and intermediate does not need to refine, and yield is high.
For this reason, the present invention is by the following technical solutions: it makes (2S, 4R)-1-to nitro carbobenzoxy-(Cbz)-4-methylsulfonyl tetramethyleneimine-2-methyl alcohol by following four-step reaction:
The prepared final product of preparation method of the present invention (2S, 4R)-1-has the structure of formula (V) to nitro carbobenzoxy-(Cbz)-4-methylsulfonyl tetramethyleneimine-2-methyl alcohol:
Wherein, PNZ is to nitro carbobenzoxy-(Cbz), and Ms is methyl sulphonyl (CH
3sO
2-);
The temperature of reaction of described the first step reaction is-20～50 ℃, and preferred temperature is-10～10 ℃, and optimum temps is 20～50 ℃, and the reaction times is 5～10 hours, and the preferred reaction time is 7～9 hours.Compound oxyproline (I): mol ratio=1 of the vitriol oil: 1～1: 2.5, preferred molar ratio is 1: 1.5～1: 2.5, reaction solvent is methyl alcohol (MeOH), compound oxyproline (I): mol ratio=1 of methyl alcohol: 1～1: 20, preferred molar ratio is 1: 3～1: 15, reacts complete, system is cooled to-20 ℃, add water, then with salt of wormwood, regulate PH to 7～12, preferably pH value is adjusted to 7～9.
Described second step reaction directly adds nitroxyl chloride benzyl formate in the reacted system of the first step, compound oxyproline (I): mol ratio=1 to nitroxyl chloride benzyl formate: 0.8～1: 2.0, preferred molar ratio is 1: 1～1: 1.5, and more excellent mol ratio is 1: 1.2～1: 1.4.Temperature of reaction is-10～20 ℃, and preferred temperature is-10～10 ℃, and better temperature is-5～0 ℃.Reaction times is 1～8 hour, and the preferred reaction time is 2～7 hours, and the more excellent reaction times is 3～6 hours.React complete, use methyl tertiary butyl ether extraction product, after dried over sodium sulfate, filter out sodium sulfate, obtain the methyl tertbutyl ethereal solution of intermediate (III);
The methyl tertbutyl ethereal solution that described three-step reaction directly reacts second step gained intermediate (III) is cooled to-20～15 ℃, and more excellent temperature is-15～10 ℃, and more excellent temperature is 10～0 ℃.Add triethylamine, then drip Methanesulfonyl chloride, compound oxyproline (I): triethylamine: mol ratio=1 of Methanesulfonyl chloride: 0.8: 0.8～1: 2.0: 1.5, preferred molar ratio is 1: 0.9: 0.8～1: 1.8: 1.4, and more excellent mol ratio is 1: 1.0: 1.0～1: 1.5: 1.3.Temperature of reaction is-10～15 ℃, preferably-8～12 ℃ of temperature of reaction, and more excellent temperature of reaction is-5～5 ℃.Reaction times is 5～15 hours, and in preferably 7～12 hours reaction times, the more excellent reaction times is 10～11 hours.React complete, first use dilute hydrochloric acid washing reaction system once, then use purified water washing reaction system once, then with saturated sodium-chloride washing reaction system twice, obtain the methyl tertbutyl ethereal solution of intermediate (IV).
Described four-step reaction is directly cooled to-20～15 ℃ by the solution of the methyl tertiary butyl ether of three-step reaction gained intermediate (IV), and preferably temperature is-15～15 ℃, and more excellent temperature is-10～5 ℃.Add sodium borohydride, drip methyl alcohol, temperature of reaction is-10～15 ℃, compound oxyproline (I): mol ratio=1 of sodium borohydride: 1～1: 5, and mol ratio preferably 1: 1.5～1: 5, more excellent mol ratio is 1: 3～1: 5.Reaction times is 5～15 hours, and the preferred reaction time is 6～13 hours, and the more excellent reaction times is 8～11 hours.React complete, first use dilute hydrochloric acid washing reaction system once, then saturated nacl aqueous solution washing reaction system twice, obtain the methyl tertbutyl ethereal solution of the finished product (V).
After having reflected, four steps carry out the purifying of the finished product; the solution of the methyl tertiary butyl ether of the finished product that four-step reaction is obtained (V) is concentrated into supersaturation; slow crystallization under room temperature; be cooled to again-10～5 ℃; so that crystallization is relatively complete; then filter; methyl tertiary butyl ether washing with ice; at 40～60 ℃, vacuum-drying obtains white or off-white color solid chemical compound; be final product (2S, 4R)-1-after purifying to nitro carbobenzoxy-(Cbz)-4-methylsulfonyl tetramethyleneimine-2-methyl alcohol.
Owing to adopting technical scheme of the present invention, the present invention has simplified technological operation step, and technique continuity is stronger, intermediate does not need to refine, be easy to suitability for industrialized production, reduce production costs, greatly reduced organic solvent kind and consumption, be convenient to the recovery of single solvent, make this novel process environment more friendly, the present invention simultaneously can obtain higher yield, take Compound I oxyproline as standard, mole total recovery >=75%, the finished product purity >=98.0%.
Embodiment
Below in conjunction with embodiment, further illustrate processing method of the present invention.
Embodiment 1.
In 3kg oxyproline (I), add 3.8kg methyl alcohol, add the 2.3kg vitriol oil, temperature of reaction is 45 ℃, and keeping this thermotonus is 6 hours, reacts complete, system is cooled to-20 ℃, adds water, with salt of wormwood, adjusts pH to 8.At-5 ℃, add 4.9kg to nitroxyl chloride benzyl formate, keep this thermotonus 4～5 hours, reaction finishes, and directly uses methyl tertiary butyl ether extraction product, after anhydrous sodium sulfate drying, filters out sodium sulfate, obtains the methyl tertbutyl ethereal solution of intermediate III.Be cooled to 0 ℃, add 2.3kg triethylamine, then drip 2.6kg methylsulfonyl chloride, react reaction in 6～8 hours complete, first use 5% dilute hydrochloric acid washing reaction system once, then use purified water washing reaction system once, then with saturated sodium-chloride washing reaction system twice, obtain the solution of the methyl tertiary butyl ether of intermediate compound IV.The solution of the methyl tertiary butyl ether of intermediate compound IV is cooled to-5 ℃, add 11kg sodium borohydride, drip 1.3kg methyl alcohol, temperature of reaction is-5 ℃, reacting reaction in 6～8 hours finishes, first use 5% dilute hydrochloric acid washing reaction system once, then use saturated sodium-chloride washing reaction system twice, obtain the methyl tertbutyl ethereal solution of the finished product V.The solution of the methyl tertiary butyl ether of the finished product V is concentrated into supersaturation, slow crystallization under room temperature, then be cooled to-10～5 ℃, and then filter, with the methyl tertiary butyl ether washing of ice, vacuum-drying 5h at 40～60 ℃, obtains 6.5kg white solid compound.Take Compound I oxyproline as standard, total molar yield 75.4%, product purity 98.3%.
Embodiment 2.
In 30kg oxyproline (I), add 38kg methyl alcohol, add the 50kg vitriol oil, temperature of reaction is 50 ℃, and keeping this thermotonus is 8 hours, reacts complete, system is cooled to-20 ℃, adds water, with salt of wormwood, adjusts pH to 8.At-2 ℃, add 55kg to nitroxyl chloride benzyl formate, keep this thermotonus 4～5 hours, reaction finishes, and directly uses methyl tertiary butyl ether extraction product, after anhydrous sodium sulfate drying, filters out sodium sulfate, obtains the methyl tertbutyl ethereal solution of intermediate III.Be cooled to 0 ℃, add 25kg triethylamine, then drip 30kg methylsulfonyl chloride, react reaction in 7 hours complete, by dilute hydrochloric acid washing reaction system once, purified water washing reaction system once, saturated sodium-chloride washing reaction system twice, obtains the solution of the methyl tertiary butyl ether of intermediate compound IV.The solution of the methyl tertiary butyl ether of intermediate compound IV is cooled to-5 ℃, add 12kg sodium borohydride, drip 20kg methyl alcohol, temperature of reaction is 0 ℃, reacting reaction in 8 hours finishes, by 5% dilute hydrochloric acid washing reaction system once, saturated sodium-chloride washing reaction system twice, obtains the solution of the methyl tertiary butyl ether of the finished product V.The solution of the methyl tertiary butyl ether of the finished product V is concentrated into supersaturation, slow crystallization under room temperature, then be cooled to-10～5 ℃, and then filter, with the methyl tertiary butyl ether washing of ice, vacuum-drying 5h at 40～60 ℃, obtains 64.9kg white solid compound.Take Compound I oxyproline as standard, total molar yield 76.4%, product purity 98.2%.
Embodiment 3.
In 30kg oxyproline (I), add 38kg methyl alcohol, add the 56kg vitriol oil, temperature of reaction is 50 ℃, and keeping this thermotonus is 9 hours, reacts complete, system is cooled to-20 ℃, adds water, with salt of wormwood, adjusts pH to 7.At 0 ℃, add 69kg to nitroxyl chloride benzyl formate, keep this thermotonus 6 hours, reaction finishes, and directly uses methyl tertiary butyl ether extraction product, after dried over sodium sulfate, filters out sodium sulfate, obtains the solution of the methyl tertiary butyl ether of intermediate III.Be cooled to-5 ℃, add 32.4kg triethylamine, then drip 40kg methylsulfonyl chloride, react reaction in 9 hours complete, by dilute hydrochloric acid washing reaction system once, purified water washing reaction system once, saturated sodium-chloride washing reaction system twice, obtains the solution of the methyl tertiary butyl ether of intermediate compound IV.The solution of the methyl tertiary butyl ether of intermediate compound IV is cooled to 3 ℃, add 13kg sodium borohydride, drip 25kg methyl alcohol, temperature of reaction is 5 ℃, reacting reaction in 8～9 hours finishes, by 5% dilute hydrochloric acid washing reaction system once, saturated sodium-chloride washing reaction system twice, obtains the solution of the methyl tertiary butyl ether of the finished product V.The solution of the methyl tertiary butyl ether of the finished product V is concentrated into supersaturation, slow crystallization under room temperature, then be cooled to-10～5 ℃, and then filter, with the methyl tertiary butyl ether washing of ice, vacuum-drying 5h at 40～60 ℃, obtains 65.6kg white solid compound.Take Compound I oxyproline as standard, total molar yield 77.1%, product purity 98.4%.
Above the disclosed embodiments only for making those skilled in the art can realize or use illustrating that the present invention makes, be not limitation of the present invention.Do not depart from modifications or improvements on basis of the present invention, all belonging to the scope of protection.
Claims (10)
1. the preparation method of (2S, 4R)-1-to nitro carbobenzoxy-(Cbz)-4-mesyloxy tetramethyleneimine-2-methyl alcohol, is characterized in that, it makes (2S, 4R)-1-to nitro carbobenzoxy-(Cbz)-4-mesyloxy tetramethyleneimine-2-methyl alcohol by following four-step reaction:
The temperature of reaction of described the first step reaction is-20～50 ℃, reaction times is 5～10 hours, compound oxyproline I: mol ratio=1 of 98% the vitriol oil: 1～1: 2.5, reaction solvent is methyl alcohol, react complete, compound ii (2S, 4R)-4-hydroxyl-2-methoxycarbonyl tetramethyleneimine system is cooled to-20 ℃, add water, with salt of wormwood, regulate pH to 7～12;
Described second step reaction adds nitroxyl chloride benzyl formate in above-mentioned reaction system, compound oxyproline I: mol ratio=1 to nitroxyl chloride benzyl formate: 0.8～1: 2.0, temperature of reaction is-10～20 ℃, reaction times is 1～8 hour, reacts complete, uses methyl tertiary butyl ether extraction product, after dried over sodium sulfate, filter out sodium sulfate, obtain the methyl tertbutyl ethereal solution of intermediate III (2S, 4R)-1-to nitro carbobenzoxy-(Cbz)-4-hydroxyl-2-methoxycarbonyl-tetramethyleneimine;
The methyl tertbutyl ethereal solution that described three-step reaction directly reacts second step gained intermediate III is cooled to-20～15 ℃, add triethylamine, then drip Methanesulfonyl chloride, compound oxyproline I: triethylamine: mol ratio=1 of Methanesulfonyl chloride: 0.8: 0.8～1: 2.0: 1.5, temperature of reaction is-10～15 ℃, reaction times is 5～15 hours, react complete, first use 5% dilute hydrochloric acid washing reaction system once, then use purified water washing reaction system once, again with twice of saturated sodium-chloride washing reaction system, obtain the methyl tertbutyl ethereal solution of intermediate IV,
Described four-step reaction is directly by three-step reaction gained intermediate IV (2S, 4R)-1-is cooled to-20～15 ℃ to the methyl tertbutyl ethereal solution of nitro carbobenzoxy-(Cbz)-4-mesyloxy-2-methoxycarbonyl tetramethyleneimine, add sodium borohydride, drip methyl alcohol, temperature of reaction is-10～15 ℃, compound oxyproline I: mol ratio=1 of sodium borohydride: 1～1: 5, reaction times is 5～15 hours, react complete, first use 5% dilute hydrochloric acid washing reaction system once, again with twice of saturated nacl aqueous solution washing reaction system, obtain the methyl tertbutyl ethereal solution of the finished product V.
2. a kind of (2S as claimed in claim 1, the preparation method of 4R)-1-to nitro carbobenzoxy-(Cbz)-4-mesyloxy tetramethyleneimine-2-methyl alcohol, it is characterized in that, after four-step reaction, carry out the purifying of the finished product, the solution of the methyl tertiary butyl ether of the finished product V that four-step reaction is obtained is concentrated into supersaturation, crystallization under room temperature, be cooled to again-10～5 ℃, then filter, with methyl tertiary butyl ether washing, at 40～60 ℃, vacuum-drying obtains white or off-white color solid chemical compound.
3. a kind of (2S as claimed in claim 1, the preparation method of 4R)-1-to nitro carbobenzoxy-(Cbz)-4-mesyloxy tetramethyleneimine-2-methyl alcohol, it is characterized in that, in described the first step reaction, compound oxyproline I: the mol ratio of 98% the vitriol oil preferably 1: 1～1: 2.5, compound oxyproline I: mol ratio=1 of methyl alcohol: 1～1: 20; Preferably-10～10 ℃ of the temperature of reaction of described the first step reaction, preferably 7～9 hours reaction times of described the first step reaction; After completion of the reaction, with salt of wormwood, regulate pH preferably to 7～9.
4. a kind of (2S as claimed in claim 1, the preparation method of 4R)-1-to nitro carbobenzoxy-(Cbz)-4-mesyloxy tetramethyleneimine-2-methyl alcohol, it is characterized in that, in described the first step reaction, compound oxyproline I: the mol ratio of 98% the vitriol oil preferably 1: 1.5～1: 2.5, compound oxyproline I: the mol ratio of methyl alcohol preferably 1: 3～1: 15, preferably 20～50 ℃ of the temperature of reaction of described the first step reaction.
5. a kind of (2S as claimed in claim 1, the preparation method of 4R)-1-to nitro carbobenzoxy-(Cbz)-4-mesyloxy tetramethyleneimine-2-methyl alcohol, it is characterized in that, in described second step reaction, compound oxyproline I: to the mol ratio of nitroxyl chloride benzyl formate preferably 1: 1～1: 1.5, preferably-10～10 ℃ of the temperature of reaction of described second step reaction, preferably 2～7 hours reaction times of described second step reaction.
6. a kind of (2S as claimed in claim 5, the preparation method of 4R)-1-to nitro carbobenzoxy-(Cbz)-4-mesyloxy tetramethyleneimine-2-methyl alcohol, it is characterized in that, compound oxyproline I: to the mol ratio of nitroxyl chloride benzyl formate preferably 1: 1.2～1: 1.4, preferably-5～0 ℃ of the temperature of reaction of described second step reaction, preferably 3～6 hours reaction times of described second step reaction.
7. a kind of (2S as claimed in claim 1, the preparation method of 4R)-1-to nitro carbobenzoxy-(Cbz)-4-mesyloxy tetramethyleneimine-2-methyl alcohol, it is characterized in that, in described three-step reaction, the solution of the methyl tertiary butyl ether of intermediate III is cooled to preferably-15～10 ℃, compound oxyproline I: triethylamine: the mol ratio of Methanesulfonyl chloride preferably 1: 0.9: 0.8～1: 1.8: 1.4, preferably-8～12 ℃ of the temperature of reaction of described three-step reaction, preferably 7～12 hours reaction times of described three-step reaction.
8. a kind of (2S as claimed in claim 7, the preparation method of 4R)-1-to nitro carbobenzoxy-(Cbz)-4-mesyloxy tetramethyleneimine-2-methyl alcohol, it is characterized in that, in described three-step reaction, the solution of the methyl tertiary butyl ether of intermediate III is cooled to preferably-10～0 ℃, compound oxyproline I: triethylamine: the mol ratio of Methanesulfonyl chloride preferably 1: 1.0: 1.0～1: 1.5: 1.3, preferably-5～5 ℃ of the temperature of reaction of described three-step reaction, preferably 10～11 hours reaction times of described three-step reaction.
9. a kind of (2S as claimed in claim 1, the preparation method of 4R)-1-to nitro carbobenzoxy-(Cbz)-4-mesyloxy tetramethyleneimine-2-methyl alcohol, it is characterized in that, in described four-step reaction, the solution of the methyl tertiary butyl ether of intermediate IV is cooled to preferably-15～15 ℃, compound oxyproline I: the mol ratio of sodium borohydride preferably 1: 1.5～1: 5, preferably-8～12 ℃ of the temperature of reaction of described four-step reaction, preferably 6～13 hours reaction times of described four-step reaction.
10. a kind of (2S as claimed in claim 9, the preparation method of 4R)-1-to nitro carbobenzoxy-(Cbz)-4-mesyloxy tetramethyleneimine-2-methyl alcohol, it is characterized in that, in described four-step reaction, the solution of the methyl tertiary butyl ether of intermediate IV is cooled to preferably-10～5 ℃, compound oxyproline I: the mol ratio of sodium borohydride preferably 1: 3～1: 5, preferably-5～5 ℃ of the temperature of reaction of described four-step reaction, preferably 8～11 hours reaction times of described four-step reaction.
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| 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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| 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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| Title |
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| Development》.2003,第7卷(第5期),649-654. * |
| JP特开2003-26680A 2003.01.29 |
| Yutaka Nishino et al.Practical Large-Scale Synthesis of the 2-Aminomethylpyrrolidin-4-ylthio-Containing Side Chain of the Novel Carbapenem Antibiotic Doripenem.《Organic Process Research & Development》.2003,第7卷(第5期),649-654. |
| Yutaka Nishino et al.Practical Large-Scale Synthesis of the 2-Aminomethylpyrrolidin-4-ylthio-Containing Side Chain of the Novel Carbapenem Antibiotic Doripenem.《Organic Process Research & * |
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