CN102911133B - Purification method of (4R,5R)-2- dichloromethyl-4,5- dihydro-5-(4-methylsulfonyl-phenyl)-4-oxazol methanol - Google Patents
Purification method of (4R,5R)-2- dichloromethyl-4,5- dihydro-5-(4-methylsulfonyl-phenyl)-4-oxazol methanol Download PDFInfo
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Abstract
The invention relates to a purification method of (4R,5R)-2- dichloromethyl-4,5- dihydro-5-(4-methylsulfonyl-phenyl)-4-oxazol methanol. The purification method includes steps of firstly, adding a certain quantity of alkyl alcohol and organic amine into wet crude product of the (4R,5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl-phenyl)-4-oxazol methanol, heating to dissolve, stirring at the temperature of 45-75 DEG C, adding water slowly to precipitate crystals, cooling to be 0-20 DEG C, stirring for 1-3 hours, filtering and drying to obtain the purified product. The weight ratio of the wet crude product, the alkyl alcohol, the organic amine and water is equal to 1:(0.6-3):(0.002-0.02):(1.5-10), the wet crude product is metered by gram, and the alkyl alcohol, the organic amine and water are metered by milliliter. The purification method has good purification effect, products are high in quality, production in scale is facilitated, cost for raw materials is reduced, production cycle is shortened and energy consumption is reduced.
Description
Technical field
The present invention relates to a kind of purification process of florfenicol midbody, especially relate to (4R, 5R)-2-dichloromethyl-4, the purification process of 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
Background technology
Florfenicol has broad spectrum antibiotic activity, can be used for treating the infection that gram-positive microorganism, Gram-negative bacteria and the rickettsia etc. of animal cause, and the drug tolerant bacteria of thiamphenicol, paraxin is had to stronger restraining effect, residual lower in vivo, be now widely used.Its main production flow process is as follows:
In the production process of florfenicol, in ring-closure reaction process can because two chloromethyl cyanides and D-Su Shi-1-to methylsulfonyl phenyl-2-amino-1, condensation position difference when ammediol (ADS) becomes ring, except generating target intermediate (4R, 5R)-2-dichloromethyl-4, outside 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole oxazole methyl alcohol (cyclocomplex), also can generate (α R, 4R)-2-dichloromethyl 4, 5-dihydro-α-(4-methylsulfonyl phenyl)-impurity such as 4-oxazole methyl alcohol, these impurity can directly affect the impurity situation of the finished product florfenicol, impurity in cyclocomplex is by further fluoridizing, hydrolysis, some derivative impurity is difficult to by effectively removing from florfenicol as process for refining such as recrystallizations thus, make quality product be difficult to reach the requirement of the states such as America and Europe.
In existing cyclocomplex Industrial processes, the following step of the general employing of its purge process: by cyclocomplex crude product heating for dissolving, filter through activated carbon decolorizing after heat with the methyl alcohol of large doubly amount, again that filtrate is concentrated, by feed liquid barrelling, be placed in freezer and leave standstill, freezing and crystallizing afterwards.Its shortcoming is: after (1) excessive methyl alcohol adds, steam again, not only increased raw materials cost, and increased energy consumption; (2) because the amount of liquid in system after concentrated is relatively little, after material crystallization, system is tending towards curing, and discharging is difficulty particularly; (3) for being unlikely to solidify in reactor, material adopt barrelling to leave standstill freezing and crystallizing, complicated operation, and the production cycle is long.
Summary of the invention
Technical problem to be solved by this invention is to provide one to be suitable for suitability for industrialized production, easy and simple to handle and can effectively reduce florfenicol midbody (4R, 5R)-2-dichloromethyl-4, the purification process of foreign matter content in 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
A kind of (4R, 5R)-2-dichloromethyl-4, the purification process of 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol, the step that described purge process comprises is: first, to (4R, 5R)-2-dichloromethyl-4, in 5-dihydro-5-(4-methylsulfonyl phenyl)-thick wet product of 4-oxazole methyl alcohol, add a certain amount of alkyl alcohol and organic amine, after heating for dissolving, under 45～75 DEG C of temperature stir, the crystallization that slowly adds water, is then cooled to 0～20 DEG C and stirs 1～3 hour, filter product after dry purifying;
Wherein, the weightmeasurement ratio of described thick wet product and alkyl alcohol, organic amine, water is: thick wet product: alkyl alcohol: organic amine: water=1:0.6～3:0.002～0.02:1.5～10, the measure unit gram meter by weight of thick wet product, the measure unit of alkyl alcohol, organic amine and water is milliliter meter by volume;
Described alkyl alcohol is one or two or more kinds the arbitrary combination in methyl alcohol, ethanol, n-propyl alcohol, propyl carbinol and isomer thereof;
The structural formula of described organic amine is as shown in formula I:
In formula I, R
1for H or C
1～C
4alkyl; R
2for H or C
1～C
4alkyl; R
3for H or C
1～C
4alkyl.
Preferably, the weightmeasurement ratio of described thick wet product and alkyl alcohol, organic amine, water is: thick wet product: alkyl alcohol: organic amine: water=1:0.65～1:0.004～0.01:3～6.
Preferably, the weightmeasurement ratio of described thick wet product and alkyl alcohol, organic amine, water is: thick wet product: alkyl alcohol: organic amine: water=1:0.8:0.006:5.
Preferably, the temperature while adding water described in is 55～65 DEG C.
Preferably, described organic amine is any in methylamine, ethamine, propylamine, butylamine and isomer thereof.
Preferably, described alkyl alcohol is ethanol, and described organic amine is isobutylamine, and the weightmeasurement ratio of described thick wet product and ethanol, isobutylamine, water is: 1:0.65～1:0.004～0.01:3～6.
Preferably, described alkyl alcohol is the combination of methyl alcohol and the trimethyl carbinol, and described organic amine is diethylamine, and the weightmeasurement ratio of described thick wet product and alkyl alcohol, diethylamine, water is: 1:0.65～1:0.004～0.01:3～6.
Preferably, described alkyl alcohol is the combination of ethanol and Virahol, and described organic amine is triethylamine, and the weightmeasurement ratio of described thick wet product and alkyl alcohol, triethylamine, water is: 1:0.65～1:0.004～0.01:3～6.
Preferably, the concrete steps of described purge process are: in 1000ml four-hole boiling flask, drop into (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl the phenyl)-thick wet product 100g of 4-oxazole methyl alcohol, triethylamine 0.6ml and Virahol 80ml, be heated to reflux and insulated and stirred, to be dissolved to clarification, at 55～65 DEG C, be slowly added dropwise to 500ml water, be after water injection cooled to afterwards 15 DEG C, stirred crystallization 2 hours, filter, wet product in 85 DEG C dry, (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
Preferably, the concrete steps of described purge process are: in 20L reactor, drop into (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl the phenyl)-thick wet product 2000g of 4-oxazole methyl alcohol, diethylamine 12ml and methyl alcohol 1600ml, be heated to reflux and insulated and stirred, to be dissolved to clarification, at 55～65 DEG C, be slowly added dropwise to 10L water, be after water injection cooled to afterwards 15 DEG C, stirred crystallization 3 hours, centrifugal, wet product in 85 DEG C dry, (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
Compared with prior art, the beneficial effect having is in the present invention:
1. use the inventive method to carry out after purifying, product purity high (HPLC), can reach more than 99.3%, and impurity is less than 0.3% arbitrarily;
2. the mixture of selecting four small molecules alkyl alcohol, organic amine and water below carbon is that solvent carries out purifying to the thick wet product obtaining in production process, can effectively avoid system to solidify phenomenon, more easily realizes amplifying and produces;
3. in system, add a certain amount of organic amine can effectively contain (4R, 5R)-2-dichloromethyl-4 when purifying, the decomposition of 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol, improves the quality of product;
4. the present invention has avoided the use of doubly measuring alkyl alcohol greatly, just utilizes the alkyl alcohol of little times of amount to dissolve the thick wet product of cyclocomplex, thereby effectively reduces raw materials cost;
5. the present invention has avoided concentrated steaming to desolventize and has left standstill for a long time the process of freezing and crystallizing, has significantly shortened the production cycle, has reduced energy consumption.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described, but protection scope of the present invention is not limited to this.
Embodiment 1
In 2000ml four-hole boiling flask, drop into (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol (cyclocomplex) thick wet product 150g, diethylamine 0.9ml and methyl alcohol 120ml, be heated to reflux and insulated and stirred, system molten clear after, in system, slowly drip 750ml water in 55 ~ 65 DEG C, after water injection be cooled to afterwards 14 DEG C, stirred crystallization 3 hours, filter, wet product in 85 DEG C dry, (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
Embodiment 2
In 1000ml four-hole boiling flask, drop into (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol (cyclocomplex) thick wet product 100g, triethylamine 0.6ml and Virahol 80ml, be heated to reflux and insulated and stirred, system molten clear after, in system, slowly drip 500ml water in 55 ~ 65 DEG C, after water injection be cooled to afterwards 15 DEG C, stirred crystallization 2 hours, filter, wet product in 85 DEG C dry, (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
Embodiment 3
In 1000ml four-hole boiling flask, drop into (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol (cyclocomplex) thick wet product 100g, Isopropylamine 0.4ml and ethanol 65ml, be heated to reflux and insulated and stirred, system molten clear after, in system, slowly drip 300ml water in 45 ~ 55 DEG C, after water injection be cooled to afterwards 0 DEG C, stirred crystallization 1 hour, filter, wet product in 85 DEG C dry, (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
Embodiment 4
In 1000ml four-hole boiling flask, drop into (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol (cyclocomplex) thick wet product 100g, triethylamine 1ml and methyl alcohol 100ml, be heated to reflux and insulated and stirred, system molten clear after, in system, slowly drip 600ml water in 65 ~ 75 DEG C, after water injection be cooled to afterwards 20 DEG C, stirred crystallization 3 hours, filter, wet product in 85 DEG C dry, (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
Embodiment 5
In 2000ml four-hole boiling flask, drop into (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol (cyclocomplex) thick wet product 150g, isobutylamine 0.9ml and ethanol 120ml, be heated to reflux and insulated and stirred, system molten clear after, in system, slowly drip 750ml water in 55 ~ 65 DEG C, after water injection be cooled to afterwards 14 DEG C, stirred crystallization 3 hours, filter, wet product in 85 DEG C dry, (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
Embodiment 6
In 1000ml four-hole boiling flask, drop into (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol (cyclocomplex) thick wet product 100g, diethylamine 0.6ml, methyl alcohol 48ml and trimethyl carbinol 32ml, be heated to reflux and insulated and stirred, system molten clear after, in system, slowly drip 500ml water in 55 ~ 65 DEG C, after water injection be cooled to afterwards 15 DEG C, stirred crystallization 3 hours, filter, wet product in 85 DEG C dry, (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
Embodiment 7
In 2000ml four-hole boiling flask, drop into (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol (cyclocomplex) thick wet product 150g, triethylamine 0.9ml, ethanol 60 ml and Virahol 60ml, be heated to reflux and insulated and stirred, system molten clear after, in system, slowly drip 750ml water in 55 ~ 65 DEG C, after water injection be cooled to afterwards 14 DEG C, stirred crystallization 3 hours, filter, wet product in 85 DEG C dry, (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
Embodiment 8
In 20L reactor, drop into (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol (cyclocomplex) thick wet product 2000g, diethylamine 12ml and methyl alcohol 1600ml, be heated to reflux and insulated and stirred, system molten clear after, in system, slowly drip 10L water in 55 ~ 65 DEG C, after water injection be cooled to afterwards 15 DEG C, stirred crystallization 3 hours, centrifugal, wet product in 85 DEG C dry, (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
Embodiment 9
In 20L reactor, drop into (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol (cyclocomplex) thick wet product 2000g, triethylamine 12ml and Virahol 1600ml, be heated to reflux and insulated and stirred, system molten clear after, in system, slowly drip 10L water in 55 ~ 65 DEG C, after water injection be cooled to afterwards 15 DEG C, stirred crystallization 3 hours, centrifugal, wet product in 85 DEG C dry, (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
Embodiment 10
In 20L reactor, drop into (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol (cyclocomplex) thick wet product 2000g, diethylamine 12ml, ethanol 800ml and Virahol 800ml, be heated to reflux and insulated and stirred, system molten clear after, in system, slowly drip 10L water in 55 ~ 65 DEG C, after water injection be cooled to afterwards 14 DEG C, stirred crystallization 3 hours, centrifugal, wet product in 85 DEG C dry, (4R, 5R)-2-dichloromethyl-4,5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
(4R, 5R)-2-dichloromethyl-4 that embodiment 1～10 obtains, 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol detects through HPLC, and its result is as shown in table 1.
Presentation of results, no matter little or measure large in the situation that and utilize the inventive method to carry out purifying in amount, its purification effect is good, and the purity (HPLC) of product can reach more than 99.3%, and impurity is less than 0.3% arbitrarily.
Table 1
Claims (10)
1. (a 4R, 5R)-2-dichloromethyl-4, the purification process of 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol, it is characterized in that: the step that described purge process comprises is: first, to (4R, 5R)-2-dichloromethyl-4, in 5-dihydro-5-(4-methylsulfonyl phenyl)-thick wet product of 4-oxazole methyl alcohol, add a certain amount of alkyl alcohol and organic amine, after heating for dissolving, under 45～75 DEG C of temperature stir, the crystallization that slowly adds water, is then cooled to 0～20 DEG C and stirs 1～3 hour, filter product after dry purifying;
Wherein, the weightmeasurement ratio of described thick wet product and alkyl alcohol, organic amine, water is: thick wet product: alkyl alcohol: organic amine: water=1:0.6～3:0.002～0.02:1.5～10, the measure unit gram meter by weight of thick wet product, the measure unit of alkyl alcohol, organic amine and water is milliliter meter by volume;
Described alkyl alcohol is one or two or more kinds the arbitrary combination in methyl alcohol, ethanol, n-propyl alcohol, propyl carbinol and isomer thereof;
The structural formula of described organic amine is as shown in formula I:
In formula I, R
1for C
1～C
4alkyl; R
2for H or C
1～C
4alkyl; R
3for H or C
1～C
4alkyl.
2. (4R according to claim 1,5R)-2-dichloromethyl-4, the purification process of 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol, is characterized in that: the weightmeasurement ratio of described thick wet product and alkyl alcohol, organic amine, water is: thick wet product: alkyl alcohol: organic amine: water=1:0.65～1:0.004～0.01:3～6.
3. (4R according to claim 2,5R)-2-dichloromethyl-4, the purification process of 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol, is characterized in that: the weightmeasurement ratio of described thick wet product and alkyl alcohol, organic amine, water is: thick wet product: alkyl alcohol: organic amine: water=1:0.8:0.006:5.
4. (4R, 5R) according to claim 1-2-dichloromethyl-4, the purification process of 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol, is characterized in that: described in temperature while adding water be 55～65 DEG C.
5. (4R according to claim 1,5R)-2-dichloromethyl-4, the purification process of 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol, is characterized in that: described organic amine is any in methylamine, ethamine, propylamine, butylamine and isomer thereof.
6. (4R according to claim 1,5R)-2-dichloromethyl-4, the purification process of 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol, it is characterized in that: described alkyl alcohol is ethanol, described organic amine is isobutylamine, and the weightmeasurement ratio of described thick wet product and ethanol, isobutylamine, water is: 1:0.65～1:0.004～0.01:3～6.
7. (4R according to claim 1,5R)-2-dichloromethyl-4, the purification process of 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol, it is characterized in that: described alkyl alcohol is the combination of methyl alcohol and the trimethyl carbinol, described organic amine is diethylamine, and the weightmeasurement ratio of described thick wet product and alkyl alcohol, diethylamine, water is: 1:0.65～1:0.004～0.01:3～6.
8. (4R according to claim 1,5R)-2-dichloromethyl-4, the purification process of 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol, it is characterized in that: described alkyl alcohol is the combination of ethanol and Virahol, described organic amine is triethylamine, and the weightmeasurement ratio of described thick wet product and alkyl alcohol, triethylamine, water is: 1:0.65～1:0.004～0.01:3～6.
9. (4R according to claim 1, 5R)-2-dichloromethyl-4, the purification process of 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol, it is characterized in that: the concrete steps of described purge process are: in 1000ml four-hole boiling flask, drop into (4R, 5R)-2-dichloromethyl-4, 5-dihydro-5-(4-methylsulfonyl phenyl)-thick wet product 100g of 4-oxazole methyl alcohol, triethylamine 0.6ml and Virahol 80ml, be heated to reflux and insulated and stirred, to be dissolved to clarification, at 55～65 DEG C, slowly be added dropwise to 500ml water, after water injection be cooled to afterwards 15 DEG C, stirred crystallization 2 hours, filter, wet product is dry in 85 DEG C, obtain (4R, 5R)-2-dichloromethyl-4, 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
10. (4R according to claim 1, 5R)-2-dichloromethyl-4, the purification process of 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol, it is characterized in that: the concrete steps of described purge process are: in 20L reactor, drop into (4R, 5R)-2-dichloromethyl-4, 5-dihydro-5-(4-methylsulfonyl phenyl)-thick wet product 2000g of 4-oxazole methyl alcohol, diethylamine 12ml and methyl alcohol 1600ml, be heated to reflux and insulated and stirred, to be dissolved to clarification, at 55～65 DEG C, slowly be added dropwise to 10L water, after water injection be cooled to afterwards 15 DEG C, stirred crystallization 3 hours, centrifugal, wet product is dry in 85 DEG C, obtain (4R, 5R)-2-dichloromethyl-4, 5-dihydro-5-(4-methylsulfonyl phenyl)-4-oxazole methyl alcohol.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5352832A (en) * | 1992-12-18 | 1994-10-04 | Schering Corporation | Asymmetric process for preparing florfenicol, thiamphenicol chloramphenicol and oxazoline intermediates |
| US5382673A (en) * | 1990-10-25 | 1995-01-17 | Schering Corporation | Process for preparing florfenicol, its analogs and oxazoline intermediates thereto |
| CN1233244A (en) * | 1996-08-19 | 1999-10-27 | 先灵公司 | Process for preparing intermediates to florfenicol |
| CN101550110B (en) * | 2009-06-12 | 2010-12-29 | 张家港市恒盛药用化学有限公司 | Preparation method of D-threo-2-(dichloromethyl)-4, 5-dihydro-5-(p-(methylsulfonyl) phenyl)-4-oxazole methanol |
| CN101020666B (en) * | 2006-12-12 | 2011-09-28 | 柯保桂 | Preparation of florfenicol intermediate |
-
2012
- 2012-10-31 CN CN201210424505.1A patent/CN102911133B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5382673A (en) * | 1990-10-25 | 1995-01-17 | Schering Corporation | Process for preparing florfenicol, its analogs and oxazoline intermediates thereto |
| US5352832A (en) * | 1992-12-18 | 1994-10-04 | Schering Corporation | Asymmetric process for preparing florfenicol, thiamphenicol chloramphenicol and oxazoline intermediates |
| CN1233244A (en) * | 1996-08-19 | 1999-10-27 | 先灵公司 | Process for preparing intermediates to florfenicol |
| CN101020666B (en) * | 2006-12-12 | 2011-09-28 | 柯保桂 | Preparation of florfenicol intermediate |
| CN101550110B (en) * | 2009-06-12 | 2010-12-29 | 张家港市恒盛药用化学有限公司 | Preparation method of D-threo-2-(dichloromethyl)-4, 5-dihydro-5-(p-(methylsulfonyl) phenyl)-4-oxazole methanol |
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