CN103694188A - Preparation method of florfenicol oxazoline intermediate - Google Patents
Preparation method of florfenicol oxazoline intermediate Download PDFInfo
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- CN103694188A CN103694188A CN201310728842.4A CN201310728842A CN103694188A CN 103694188 A CN103694188 A CN 103694188A CN 201310728842 A CN201310728842 A CN 201310728842A CN 103694188 A CN103694188 A CN 103694188A
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- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 229960003760 florfenicol Drugs 0.000 title claims abstract description 8
- 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 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 78
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 49
- 235000011187 glycerol Nutrition 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 6
- 125000003158 alcohol group Chemical group 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 66
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 24
- 230000002829 reductive effect Effects 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical class ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 claims description 13
- 125000004494 ethyl ester group Chemical group 0.000 claims description 13
- 238000010792 warming Methods 0.000 claims description 11
- 229960000583 acetic acid Drugs 0.000 claims description 10
- 239000012362 glacial acetic acid Substances 0.000 claims description 10
- 150000007530 organic bases Chemical class 0.000 claims description 10
- 238000006722 reduction reaction Methods 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- PZUUTJLAUKMLTH-UHFFFAOYSA-N [F].C1=CC=CC=C1 Chemical compound [F].C1=CC=CC=C1 PZUUTJLAUKMLTH-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000010719 annulation reaction Methods 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 11
- 238000005406 washing Methods 0.000 abstract description 11
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 5
- 239000001257 hydrogen Substances 0.000 abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000003638 chemical reducing agent Substances 0.000 abstract 3
- 238000007363 ring formation reaction Methods 0.000 abstract 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 abstract 1
- STZZWJCGRKXEFF-UHFFFAOYSA-N Dichloroacetonitrile Chemical compound ClC(Cl)C#N STZZWJCGRKXEFF-UHFFFAOYSA-N 0.000 abstract 1
- 239000003513 alkali Substances 0.000 abstract 1
- -1 amino diol sulfone Chemical class 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 abstract 1
- CEEHCOWSYFANRT-MNOVXSKESA-N ethyl (2r,3s)-2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propanoate Chemical compound CCOC(=O)[C@H](N)[C@@H](O)C1=CC=C(S(C)(=O)=O)C=C1 CEEHCOWSYFANRT-MNOVXSKESA-N 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 16
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
- 238000013019 agitation Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 238000004880 explosion Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000004080 punching Methods 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention relates to a preparation method of a florfenicol oxazoline intermediate, and belongs to the technical field of drug preparations. The preparation method of the florfenicol oxazoline intermediate as shown in a formula (I) comprises the following steps: using D-p-methyl sulfone phenyl ethyl serinate as a raw material, adding a reducing agent into an alcohol proton solution of organic alkali in one time, performing a reducing reaction to generate ADS (amino diol sulfone), and controlling a reaction endpoint by HPLC (high performance liquid chromatography); after the reducing reaction, concentrating a solvent; adding glycerin for destroying the excess reducing agent, adjusting the pH value to be 6-7 by acid, dropwise adding dichloroacetonitrile, heating to 50 DEG C, performing a cyclization reaction, and controlling a reaction endpoint by the HPLC; after the cyclization reaction, dropwise adding an ethanol water solution, conducting a centrifugal process, washing, and drying to obtain the florfenicol hydroxyl oxazoline intermediate as shown in the formula (I). According to the method, the reducing agent can be added in one time; meanwhile, the hydrogen release speed in the preparation process is very slow, so that the safety is greatly improved.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to the preparation method of Fu benzene Ni Kao oxazoline intermediate.
Background technology
Florfenicol is a kind of Broad spectrum antibiotics for animals, general in preparing the preparation process of florfenicol in order to protect one of them hydroxyl, first make Fu benzene Ni Kao oxazoline intermediate.The patent CN1233244A of Schering Corp provides the preparation method of preparation Fu benzene Ni Kao oxazoline intermediate: the D-pmethylsulfonyl phenyleneserine ethyl ester of take is raw material, alcohol protonic solvent as methyl alcohol, ethanol, ethylene glycol, glycerol and composition thereof in, slowly add reductive agent as NaBH
4, Ca (BH
4)
2, KBH
4, LiBH
4deng reduction, generate ADS (aminodiol sulfone), HPLC controls reaction end, adds glycerine to destroy excessive reductive agent after reduction reaction finishes, concentrated alcoholic solvent, to 6-7, drips two chloromethyl cyanides with acid for adjusting pH, be warming up to 50 ℃, insulation reaction, HPLC controls reaction end.Reaction finishes rear dropping aqueous ethanolic solution, centrifugal, and washing is dry, obtains Fu benzene Ni Kao oxazole woods intermediate.The method produces in reduction reaction process that the speed of hydrogen is very fast, and reductive agent cannot disposablely drop into, and not only loses time, and is absolutely unsafe in process of production, and punching material and explosion hazard easily occur.Therefore, how overcoming the deficiencies in the prior art is problems that current technical field of medicine is needed solution badly.
Summary of the invention
The object of the invention is in order to solve the deficiencies in the prior art, a kind of preparation method of Fu benzene Ni Kao oxazoline intermediate is provided, the method can add reductive agent is disposable, and meanwhile, the speed that hydrogen discharges in preparation process is extremely slow, and security strengthens greatly.
The technical solution used in the present invention is as follows:
The preparation method that fluorine benzene Buddhist nun as shown in formula I examines oxazoline intermediate is characterized in that first organic bases being dissolved in the alcohol proton solution that obtains organic bases in alcohol protonic solvent, then the D-pmethylsulfonyl phenyleneserine ethyl ester of take is raw material, in the alcohol proton solution of organic bases, the disposable reductive agent that adds carries out reduction reaction, generate ADS, reduction reaction temperature is 45 ~ 50 ℃, reduction reaction finishes rear concentrated solvent, add glycerine to destroy excessive reductive agent, acid for adjusting pH is to 6-7, drip two chloromethyl cyanides, be warming up to 45 ~ 55 ℃ and carry out annulation, HPLC controls reaction end, reaction finishes rear dropping aqueous ethanolic solution, centrifugal, washing, dry, obtain the florfenicol hydroxyl base oxazole woods intermediate as shown in formula I,
, formula I;
Wherein, each component, according to parts by weight meter, is respectively:
D-pmethylsulfonyl phenyleneserine ethyl ester 90-110 part
Organic bases 0.5-2.5 part
Alcohol protonic solvent 500-600 part
Reductive agent 15-20 part
Glycerine 150-200 part
Two chloromethyl cyanide 35-45 parts
Aqueous ethanolic solution 200-300 part.
Preparation method's the synthetic route that fluorine benzene Buddhist nun as shown in formula I examines oxazoline intermediate is as follows:
Further preferably described organic bases is sodium methylate, sodium ethylate or potassium tert.-butoxide.
Further preferably described alcohol protonic solvent is one or more mixture in methyl alcohol, ethanol, ethylene glycol and glycerol.
Further preferably described reductive agent is sodium borohydride.
Further preferably described acid is Glacial acetic acid
compared with prior art, its beneficial effect is in the present invention:the invention provides a kind of improvement preparation method of Fu benzene Ni Kao oxazole woods intermediate, it is very fast that former patent technique produces the speed of hydrogen in reduction reaction process, reductive agent cannot disposablely drop into, and in large-scale production process, is absolutely unsafe, and punching material and explosion hazard easily occur.Technique after improving, reductive agent can disposablely add, and in addition, the speed that hydrogen discharges is extremely slow, and easily operation in large-scale production process, is not easy to occur punching material and explosion hazard.
Accompanying drawing explanation
Fig. 1 is the color atlas that Fu benzene Ni Kao oxazole woods intermediate HPLC detects;
Fig. 2 is Fu benzene Ni Kao oxazole woods intermediate
1h-NMR figure;
Fig. 3 is Fu benzene Ni Kao oxazole woods intermediate
13c-NMR figure.
Specific embodiment
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1
In weight part, take 550 parts of methyl alcohol, be added in reaction flask, take 0.5 part of sodium methylate, be added to stirring and dissolving in methyl alcohol.Take 95 parts of D-pmethylsulfonyl phenyleneserine ethyl esters, under room temperature, stir and be added in reaction flask.Take 20 parts of sodium borohydrides, room temperature is disposable to be added in reaction flask, then under the condition of temperature 50 C, reacts 6h.After reaction finishes, concentrating under reduced pressure methyl alcohol, then add 150 parts of glycerine, with Glacial acetic acid, regulate pH to 6-7; Take 42 part of two chloromethyl cyanide and drop in reaction solution, be warming up to 50 ℃ of reaction 18h.Reaction finishes 250 parts of the aqueous ethanolic solutions of agitation and dropping 25% in backward reaction solution, is down to suction filtration after room temperature, and washing is dry, obtains 103 parts, white powder Fu benzene Ni Kao oxazoline intermediate, molar yield 87.5%, purity 99.1%, fusing point: 141.0-142.0 ℃.Embodiment 2
In weight part, take 600 parts of ethanol, be added in reaction flask, take 0.7 part of sodium ethylate, be added to stirring and dissolving in ethanol.Take 100 parts of D-pmethylsulfonyl phenyleneserine ethyl esters, under room temperature, stir and be added in reaction flask.Take 18 parts of sodium borohydrides, room temperature is disposable to be added in reaction flask, then under the condition of temperature 50 C, reacts 6h.After reaction finishes, concentrating under reduced pressure ethanol, then add 170 parts of glycerine, with Glacial acetic acid, regulate pH to 6-7.Take 45 part of two chloromethyl cyanide and drop in reaction solution, be warming up to 50 ℃ of reaction 18h., reaction finishes 250 parts of the aqueous ethanolic solutions of agitation and dropping 25% in backward reaction solution, is down to suction filtration after room temperature, and washing is dry, obtains 102 parts, white powder Fu benzene Ni Kao oxazoline intermediate, molar yield 86.7%, purity 99.5%, fusing point: 142.0-143.0 ℃.
Embodiment 3
In weight part, take 600 parts of methyl alcohol, be added in reaction flask, take 0.7 part of potassium tert.-butoxide, be added to stirring and dissolving in methyl alcohol.Take 100 parts of D-pmethylsulfonyl phenyleneserine ethyl esters, under room temperature, stir and be added in reaction flask.Take 18 parts of sodium borohydrides, room temperature is disposable to be added in reaction flask, then under the condition of 48 ℃ of temperature, reacts 6h.After reaction finishes, concentrating under reduced pressure methyl alcohol, then add 180 parts of glycerine, Glacial acetic acid regulates pH to 6-7.Take 40 part of two chloromethyl cyanide and drop in reaction solution, be warming up to 50 ℃ of reaction 18h.Reaction finishes 250 parts of the aqueous ethanolic solutions of agitation and dropping 25% in backward reaction solution, is down to suction filtration after room temperature, and washing is dry, obtains 102 parts, white powder Fu benzene Ni Kao oxazoline intermediate, molar yield 86.7%, purity 99.3%, fusing point: 142.5-143.0 ℃.
Embodiment 4
In weight part, take 550 parts of ethylene glycol, be added in reaction flask, take 0.7 part of potassium tert.-butoxide, be added to stirring and dissolving in ethylene glycol.Take 100 parts of D-pmethylsulfonyl phenyleneserine ethyl esters, under room temperature, stir and be added in reaction flask.Take 17 parts of sodium borohydrides, room temperature is disposable to be added in reaction flask, then under the condition of 47 ℃ of temperature, reacts 6h.After reaction finishes, concentrating under reduced pressure ethylene glycol, then add 150 parts of glycerine, Glacial acetic acid regulates pH to 6-7.Take 40 part of two chloromethyl cyanide and drop in reaction solution, be warming up to 48 ℃ of reaction 18h.Reaction finishes 250 parts of the aqueous ethanolic solutions of agitation and dropping 25% in backward reaction solution, is down to suction filtration after room temperature, and washing is dry, obtains 105 parts, white powder Fu benzene Ni Kao oxazoline intermediate, molar yield 89.2%, purity 99.5%, fusing point: 142.5-143.0 ℃.
Embodiment 5
In weight part, take 600 parts of glycerol, be added in reaction flask, take 0.7 part of potassium tert.-butoxide, be added to stirring and dissolving in glycerol.Take 105 parts of D-pmethylsulfonyl phenyleneserine ethyl esters, under room temperature, stir and be added in reaction flask.Take 20 parts of sodium borohydrides, room temperature is disposable to be added in reaction flask, then under the condition of temperature 50 C, reacts 6h.After reaction finishes, concentrating under reduced pressure ethanol, then add 180 parts of glycerine, Glacial acetic acid regulates pH to 6-7.Take 45 part of two chloromethyl cyanide and drop in reaction solution, be warming up to 47 ℃ of reaction 18h.Reaction finishes 250 parts of the aqueous ethanolic solutions of agitation and dropping 25% in backward reaction solution, is down to suction filtration after room temperature, and washing is dry, obtains 108 parts, white powder Fu benzene Ni Kao oxazoline intermediate, molar yield 91.8%, purity 99.3%, fusing point: 142.0-143.0 ℃.
In weight part, take 300 parts of methyl alcohol and 300 parts of ethanol, be added in reaction flask, take 0.7 part of sodium methylate, be added to stirring and dissolving in reaction flask.Take 95 parts of D-pmethylsulfonyl phenyleneserine ethyl esters, under room temperature, stir and be added in reaction flask.Take 15 parts of sodium borohydrides, room temperature is disposable to be added in reaction flask, then under the condition of 49 ℃ of temperature, reacts 6h.After reaction finishes, concentrating under reduced pressure solvent, then add 160 parts of glycerine, Glacial acetic acid regulates pH to 6-7.Take 42 part of two chloromethyl cyanide and drop in reaction solution, be warming up to 47 ℃ of reaction 17h.Reaction finishes 280 parts of the aqueous ethanolic solutions of agitation and dropping 25% in backward reaction solution, is down to suction filtration after room temperature, and washing is dry, obtains 107 parts, white powder Fu benzene Ni Kao oxazoline intermediate, molar yield 90.9%, purity 99.2%, fusing point: 142.5-143.5 ℃.
Embodiment 7
In weight part, take 200 parts of ethanol, 100 parts of ethylene glycol and 300 parts of glycerol, be added in reaction flask, take 0.7 part of potassium tert.-butoxide, be added to stirring and dissolving in reaction flask.Take 100 parts of D-pmethylsulfonyl phenyleneserine ethyl esters, under room temperature, stir and be added in reaction flask.Take 18 parts of sodium borohydrides, room temperature is disposable to be added in reaction flask, then under the condition of temperature 45 C, reacts 6h.After reaction finishes, concentrating under reduced pressure solvent, then add 190 parts of glycerine, Glacial acetic acid regulates pH to 6-7.Take 45 part of two chloromethyl cyanide and drop in reaction solution, be warming up to 45 ℃ of reaction 18h.Reaction finishes 300 parts of the aqueous ethanolic solutions of agitation and dropping 25% in backward reaction solution, is down to suction filtration after room temperature, and washing is dry, obtains 106 parts, white powder Fu benzene Ni Kao oxazoline intermediate, molar yield 90.1%, purity 99.5%, fusing point: 142.5-143.0 ℃.
Embodiment 8
In weight part, take 200 parts of ethanol, 100 parts of ethylene glycol and 300 parts of glycerol, be added in reaction flask, take 2.5 parts of potassium tert.-butoxides, be added to stirring and dissolving in reaction flask.Take 110 parts of D-pmethylsulfonyl phenyleneserine ethyl esters, under room temperature, stir and be added in reaction flask.Take 18 parts of sodium borohydrides, room temperature is disposable to be added in reaction flask, then under the condition of temperature 45 C, reacts 6h.After reaction finishes, concentrating under reduced pressure solvent, then add 200 parts of glycerine, Glacial acetic acid regulates pH to 6-7.Take 35 part of two chloromethyl cyanide and drop in reaction solution, be warming up to 55 ℃ of reaction 18h.Reaction finishes 200 parts of the aqueous ethanolic solutions of agitation and dropping 25% in backward reaction solution, is down to suction filtration after room temperature, and washing is dry, obtains 107 parts, white powder Fu benzene Ni Kao oxazoline intermediate, molar yield 90.9%, purity 99.3%, fusing point: 143.0-144.0 ℃.
Claims (5)
1. the preparation method that the fluorine benzene Buddhist nun as shown in formula I examines oxazoline intermediate is characterized in that first organic bases being dissolved in the alcohol proton solution that obtains organic bases in alcohol protonic solvent, then the D-pmethylsulfonyl phenyleneserine ethyl ester of take is raw material, in the alcohol proton solution of organic bases, the disposable reductive agent that adds, carry out reduction reaction, generate ADS, reduction reaction temperature is 45 ~ 50 ℃, reduction reaction finishes rear concentrated solvent, add glycerine to destroy excessive reductive agent, acid for adjusting pH is to 6-7, drip two chloromethyl cyanides, be warming up to 45 ~ 55 ℃ and carry out annulation, reaction finishes to obtain the florfenicol hydroxyl base oxazole woods intermediate as shown in formula I through aftertreatment,
Wherein, each component, according to parts by weight meter, is respectively:
D-pmethylsulfonyl phenyleneserine ethyl ester 90-110 part
Organic bases 0.5-2.5 part
Alcohol protonic solvent 500-600 part
Reductive agent 15-20 part
Glycerine 150-200 part
Two chloromethyl cyanide 35-45 parts.
2. the preparation method of Fu benzene Ni Kao oxazoline intermediate according to claim 1, is characterized in that described organic bases is sodium methylate, sodium ethylate or potassium tert.-butoxide.
3. the preparation method of Fu benzene Ni Kao oxazoline intermediate according to claim 1, is characterized in that described alcohol protonic solvent is one or more mixture in methyl alcohol, ethanol, ethylene glycol and glycerol.
4. the preparation method of Fu benzene Ni Kao oxazoline intermediate according to claim 1, is characterized in that described reductive agent is sodium borohydride.
5. the preparation method of Fu benzene Ni Kao oxazoline intermediate according to claim 1, is characterized in that described acid is Glacial acetic acid.
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Cited By (6)
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| CN106278964A (en) * | 2016-07-31 | 2017-01-04 | 浙江润康药业有限公司 | The preparation method of florfenicol |
| CN108329240A (en) * | 2018-03-27 | 2018-07-27 | 深圳蓝新科技有限公司 | The preparation method of florfenicol midbody |
| CN110229087A (en) * | 2019-07-02 | 2019-09-13 | 绍兴民生医药股份有限公司 | The purification process of (1R, 2R) -1- [(4- mesyl) phenyl] -2- amino -1,3- propylene glycol |
| CN113264892A (en) * | 2021-04-05 | 2021-08-17 | 复旦大学 | Method for continuously preparing florfenicol key intermediate by using micro-reaction system |
| CN114634459A (en) * | 2022-05-19 | 2022-06-17 | 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 |
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