CN103254147B - A kind of preparation method of D-Su-Type-2--(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol - Google Patents
A kind of preparation method of D-Su-Type-2--(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol Download PDFInfo
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- CN103254147B CN103254147B CN201310137654.4A CN201310137654A CN103254147B CN 103254147 B CN103254147 B CN 103254147B CN 201310137654 A CN201310137654 A CN 201310137654A CN 103254147 B CN103254147 B CN 103254147B
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Abstract
The present invention relates to a kind of chemical preparation process, specifically, is the preparation method of a kind of florfenicol midbody D-Su-Type-2--(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol.The present invention with D-Su Shi-p-methylsulfonyl benzene serine ethyl ester for starting raw material, D-Su-Type-2--amino-1-[(p-methylsulfonyl) phenyl]-1 is become with potassium borohydride reduction, ammediol, adjust pH value to subacidity with short chain fatty acid, target compound D-Su-Type-2--(dichloromethyl)-4 is obtained by reacting under elevated pressure conditions again with two chloromethyl cyanides, 5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol, technical scheme of the present invention avoids D-Su-Type-2--(dichloromethyl)-4, glycerine is used in 5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol preparation process, shorten the reaction times, improve benefit, protect environment.
Description
Technical field
The present invention relates to a kind of chemical preparation process, specifically, is the preparation method of a kind of florfenicol midbody D-Su-Type-2--(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol.
Background technology
The structural formula of D-Su-Type-2--(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol is as follows:
It is the key intermediate of synthesis florfenicol.Florfenicol (Florfenicol) chemistry [R--(R* by name, S*)]-2, the chloro-N-{ methyl fluoride of 2-bis-)-2-hydroxyl-2-[4-(sulfonyloxy methyl) phenyl] ethyl } ethanamide, be a kind of broad spectrum antimicrobicide, can be used for the infection that treatment gram-positive microorganism, Gram-negative bacteria and rickettsia cause.
The synthesis of relevant D-Su-Type-2--(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol has had patent CN97198768 to report:
By D-Su-Type-2--amino-1-[(p-methylsulfonyl) phenyl]-1, ammediol prepares D-Su-Type-2--(dichloromethyl)-4, use glycerine as solvent in the process of 5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol, there is glycerine and not easily reclaim in this technique, large water gaging is needed to wash, blowdown flow rate is large, and cost is high, and the reaction times reaches the shortcoming of more than 20 hours.
Summary of the invention
The object of the invention is the use avoiding glycerine in the building-up process of D-Su-Type-2--(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol, provide a kind of environmental friendliness, the preparation method that cost is low.
For achieving the above object, the technical solution used in the present invention is:
The present invention is a kind of preparation method of florfenicol midbody, with D-Su Shi-p-methylsulfonyl benzene serine ethyl ester for starting raw material, D-Su-Type-2--amino-1-[(p-methylsulfonyl) phenyl]-1 is become with potassium borohydride reduction, ammediol, adjust pH value to subacidity with short chain fatty acid, target compound D-Su-Type-2--(dichloromethyl)-4 is obtained by reacting under elevated pressure conditions again with two chloromethyl cyanides, 5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol, chemical equation is as follows:
Concrete preparation process is as follows:
(1) ester is reduced into alcohol: D-Su Shi-p-methylsulfonyl benzene serine ethyl ester is with methanol as solvent, become containing D-Su-Type-2--amino-1-[(p-methylsulfonyl) phenyl]-1 with potassium borohydride reduction, the solution of ammediol, temperature of reaction is 35 DEG C to 60 DEG C, and the reaction times is 4 to 10 hours;
(2) annulation: reaction mixture short chain fatty acid step (1) obtained adjusts pH value to subacidity, react under elevated pressure conditions with two chloromethyl cyanides again, temperature of reaction is 60 DEG C ~ 120 DEG C, reaction times is 5 hours ~ 12 hours, rear normal pressure or the appropriate recycling design of underpressure distillation are reacted, residue adds water for cooling crystallization, filter, filter cake washes with water and obtains target compound D-Su-Type-2--(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol;
Described reactions steps (1) is identical with (2) solvent for use, and adopt one kettle way directly to prepare, described reactions steps (2) is carried out under reaction under high pressure condition.
After tune PH of the present invention, the pH value of reaction solution is between 6 to 7.
Short chain fatty acid of the present invention is acetic acid or propionic acid or oxalic acid or propanedioic acid.
The pressure of reaction under high pressure of the present invention is at 0.4MPa ~ 2.0MPa.
The pressure of reaction under high pressure of the present invention is at 0.6MPa ~ 1.2MPa.
The temperature of reaction under high pressure of the present invention is between 80 DEG C ~ 100 DEG C.
Reaction under high pressure soaking time of the present invention is 6 ~ 8 hours.
In synthetic method of the present invention, two-step reaction step adopts one kettle way technique, same reaction solvent is adopted in reactions steps (1) and (2), without the need to carrying out separation and purification treatment to intermediate product after reactions steps (1) completes, directly reaction soln is used for the reaction in reactions steps (2).In step (1) and step (2), same reaction solvent is methyl alcohol.
The advantage that the present invention has: avoid in D-Su-Type-2--(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol preparation process and use glycerine, shorten the reaction times, improve benefit, protect environment.
Embodiment
The present invention is described in further detail technical scheme of the present invention below in conjunction with embodiment, but scope of the present invention is not limited to embodiment.
Embodiment 1
Be that starting raw material and 30 grams of POTASSIUM BOROHYDRIDE join in 800mL methyl alcohol by 100 grams of D-Su Shi-p-methylsulfonyl benzene serine ethyl ester, 35 DEG C are reacted 10 hours, adding 30 grams of Glacial acetic acid adjusts PH to 6.5, add 50 gram of two chloromethyl cyanide again, being filled with nitrogen to pressure to autoclave is 0.4MPa, be warming up to 80 DEG C, pressure is react 8 hours under the condition of 0.6MPa, discharging, distill out 750mL solvent, be cooled to 25 DEG C, add 200mL water, continue to be cooled to 5 DEG C, filter, filter cake 100mL water washing, dry, obtain 101.8 grams of target compound D-Su-Type-2--s (dichloromethyl)-4, 5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol, yield 87%, measure fusing point 142 ~ 144 DEG C.
Embodiment 2
Be that starting raw material and 30 grams of POTASSIUM BOROHYDRIDE join in 800mL methyl alcohol by 100 grams of D-Su Shi-p-methylsulfonyl benzene serine ethyl ester, 40 DEG C are reacted 8 hours, adding 37 grams of propionic acid adjusts PH to 6.5, add 50 gram of two chloromethyl cyanide again, being filled with nitrogen to pressure to autoclave is 0.8MPa, be warming up to 100 DEG C, react 6 hours under the condition of pressure 1.2MPa, discharging, distill out 750mL solvent, be cooled to 25 DEG C, add 200mL water, continue to be cooled to 5 DEG C, filter, filter cake 100mL water washing, dry, obtain 101.2 grams of target compound D-Su-Type-2--s (dichloromethyl)-4, 5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol, yield 86%, measure fusing point 141 ~ 143 DEG C.
Embodiment 3
Be that starting raw material and 30 grams of POTASSIUM BOROHYDRIDE join in 800mL methyl alcohol by 100 grams of D-Su Shi-p-methylsulfonyl benzene serine ethyl ester, 60 DEG C are reacted 4 hours, adding 23 grams of oxalic acid adjusts PH to 6.5, add 50 gram of two chloromethyl cyanide again, being filled with nitrogen to pressure to autoclave is 1.2MPa, be warming up to 120 DEG C, react 5 hours under the condition of pressure 2.0MPa, discharging, distill out 750mL solvent, be cooled to 25 DEG C, add 200mL water, continue to be cooled to 5 DEG C, filter, filter cake 100mL water washing, dry, obtain 100.8 grams of target compound D-Su-Type-2--s (dichloromethyl)-4, 5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol, yield 85%, measure fusing point 141 ~ 143 DEG C.
Embodiment 4
Be that starting raw material and 30 grams of POTASSIUM BOROHYDRIDE join in 800mL methyl alcohol by 100 grams of D-Su Shi-p-methylsulfonyl benzene serine ethyl ester, 50 DEG C are reacted 5 hours, adding 26 grams of propanedioic acid adjusts PH to 6.5, add 50 gram of two chloromethyl cyanide again, being filled with nitrogen to pressure to autoclave is 0.3MPa, be warming up to 60 DEG C, pressure reacts 12 hours under the condition of 0.4MPa, discharging, distill out 750mL solvent, be cooled to 25 DEG C, add 200mL water, continue to be cooled to 5 DEG C, filter, filter cake 100mL water washing, dry, obtain 99.8 grams of target compound D-Su-Type-2--s (dichloromethyl)-4, 5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol, yield 85%, measure fusing point 141 ~ 143 DEG C.
What more than enumerate is only some embodiments of the present invention; obviously, the invention is not restricted to above embodiment, many distortion can also be had; all distortion that those of ordinary skill in the art can directly derive from content disclosed by the invention or associate, all should think protection scope of the present invention.
Claims (3)
1. the preparation method of a florfenicol midbody, it is characterized in that, with D-Su Shi-p-methylsulfonyl benzene serine ethyl ester for starting raw material, D-Su-Type-2--amino-1-[(p-methylsulfonyl) phenyl]-1 is become with potassium borohydride reduction, ammediol, with short chain fatty acid adjust pH to subacidity, target compound D-Su-Type-2--(dichloromethyl)-4 is obtained by reacting under elevated pressure conditions again with two chloromethyl cyanides, 5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol, chemical equation is as follows:
Concrete preparation process is as follows:
(1) ester is reduced into alcohol: D-Su Shi-p-methylsulfonyl benzene serine ethyl ester is with methanol as solvent, become containing D-Su-Type-2--amino-1-[(p-methylsulfonyl) phenyl]-1 with potassium borohydride reduction, the solution of ammediol, temperature of reaction is 35 DEG C to 60 DEG C, and the reaction times is 4 to 10 hours;
(2) annulation: reaction mixture short chain fatty acid adjust pH step (1) obtained is to subacidity, react under elevated pressure conditions with two chloromethyl cyanides again, temperature of reaction is 60 DEG C ~ 120 DEG C, reaction times is 5 hours ~ 12 hours, rear normal pressure or the appropriate recycling design of underpressure distillation are reacted, residue adds water for cooling crystallization, filter, filter cake washes with water and obtains target compound D-Su-Type-2--(dichloromethyl)-4,5-dihydro-5-[p-(methylsulfonyl) phenyl]-4-oxazole methyl alcohol;
Described reactions steps (1) is identical with (2) solvent for use, one kettle way is adopted directly to prepare, described reactions steps (2) is carried out under reaction under high pressure condition, after described tune pH, the pH value of reaction solution is between 6 to 7, the pressure of reaction under high pressure is at 0.4MPa ~ 2.0MPa, the temperature of reaction under high pressure is between 80 DEG C ~ 100 DEG C, and reaction under high pressure soaking time is 6 ~ 8 hours.
2. the preparation method of florfenicol midbody according to claim 1, is characterized in that: described short chain fatty acid is acetic acid or propionic acid or oxalic acid or propanedioic acid.
3. the preparation method of florfenicol midbody according to claim 1, is characterized in that: the pressure of described reaction under high pressure is at 0.6MPa ~ 1.2MPa.
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| CN103570638A (en) * | 2013-11-07 | 2014-02-12 | 湖北中牧安达药业有限公司 | Synthetic method of florfenicol intermediate cyclic product |
| CN106278964B (en) * | 2016-07-31 | 2018-01-16 | 浙江润康药业有限公司 | The preparation method of Florfenicol |
| CN108329240B (en) * | 2018-03-27 | 2020-06-26 | 深圳蓝新科技有限公司 | Preparation method of florfenicol intermediate |
| CN113402475A (en) * | 2021-06-07 | 2021-09-17 | 山东国邦药业有限公司 | Preparation method of florfenicol intermediate |
| CN116041271A (en) * | 2022-12-29 | 2023-05-02 | 山东微研生物科技有限公司 | Preparation method of florfenicol intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1233244A (en) * | 1996-08-19 | 1999-10-27 | 先灵公司 | Process for preparing intermediates to florfenicol |
| CN101812000A (en) * | 2009-11-10 | 2010-08-25 | 张家港市恒盛药用化学有限公司 | Preparation method of thiamphenicol |
| CN102131772A (en) * | 2008-07-30 | 2011-07-20 | 英特威国际有限公司 | Process for preparing oxazoline-protected aminodiol compounds useful as intermediates to florfenicol |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1233244A (en) * | 1996-08-19 | 1999-10-27 | 先灵公司 | Process for preparing intermediates to florfenicol |
| CN102131772A (en) * | 2008-07-30 | 2011-07-20 | 英特威国际有限公司 | Process for preparing oxazoline-protected aminodiol compounds useful as intermediates to florfenicol |
| CN101812000A (en) * | 2009-11-10 | 2010-08-25 | 张家港市恒盛药用化学有限公司 | Preparation method of thiamphenicol |
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Inventor after: Li Guoneng Inventor after: Zhang Zhiguo Inventor after: Zhang Weilue Inventor after: Chen Shuai Inventor after: Wang Jiuyan Inventor before: Zhang Zhiguo Inventor before: Zhang Weilue Inventor before: Chen Shuai Inventor before: Wang Jiuyan |
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Effective date of registration: 20180110 Address after: 431800 Jingshan Economic Development Zone, Hubei province people's road, Jingmen Patentee after: Jingshan Ruisheng Pharmaceutical Co., Ltd. Address before: 310023 Hangzhou Province, Zhejiang Province, and road, No. 318 Co-patentee before: Jingshan Ruisheng Pharmaceutical Co., Ltd. Patentee before: Zhejiang University of Science and Technology |