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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- CN102911133B CN102911133B CN201210424505.1A CN201210424505A CN102911133B CN 102911133 B CN102911133 B CN 102911133B CN 201210424505 A CN201210424505 A CN 201210424505A CN 102911133 B CN102911133 B CN 102911133B
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 title claims abstract description 189
- 238000000746 purification Methods 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 56
- 125000005233 alkylalcohol group Chemical group 0.000 claims abstract description 33
- 150000001412 amines Chemical class 0.000 claims abstract description 31
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 238000002425 crystallisation Methods 0.000 claims description 17
- 230000008025 crystallization Effects 0.000 claims description 17
- 238000002347 injection Methods 0.000 claims description 14
- 239000007924 injection Substances 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 14
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical group CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 claims description 10
- 238000009835 boiling Methods 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 8
- 238000010926 purge Methods 0.000 claims description 7
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 4
- 238000005352 clarification Methods 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- UEKQGZQLUMSLNW-UHFFFAOYSA-N Propyl isome Chemical compound C1=C2C(C(=O)OCCC)C(C(=O)OCCC)C(C)CC2=CC2=C1OCO2 UEKQGZQLUMSLNW-UHFFFAOYSA-N 0.000 claims description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 44
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 239000012043 crude product Substances 0.000 abstract description 4
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 238000001816 cooling Methods 0.000 abstract 1
- 239000013078 crystal Substances 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- 239000012264 purified product Substances 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 7
- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 description 6
- 229960003760 florfenicol Drugs 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical class ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 241000606701 Rickettsia Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229940049547 paraxin Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- OTVAEFIXJLOWRX-NXEZZACHSA-N thiamphenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CO)NC(=O)C(Cl)Cl)C=C1 OTVAEFIXJLOWRX-NXEZZACHSA-N 0.000 description 1
- 229960003053 thiamphenicol Drugs 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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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US5352832A (en) * | 1992-12-18 | 1994-10-04 | Schering Corporation | Asymmetric process for preparing florfenicol, thiamphenicol chloramphenicol and oxazoline intermediates |
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CN1233244A (en) * | 1996-08-19 | 1999-10-27 | 先灵公司 | Process for preparing intermediates to florfenicol |
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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 |
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