CN101921240A - Synthesis method of 2- substituted (4S, 5R)-4-methyl fluoride-5-(4-sulfonylphenyl)-4,5-dihydrooxazoline - Google Patents
Synthesis method of 2- substituted (4S, 5R)-4-methyl fluoride-5-(4-sulfonylphenyl)-4,5-dihydrooxazoline Download PDFInfo
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- CN101921240A CN101921240A CN2010102820632A CN201010282063A CN101921240A CN 101921240 A CN101921240 A CN 101921240A CN 2010102820632 A CN2010102820632 A CN 2010102820632A CN 201010282063 A CN201010282063 A CN 201010282063A CN 101921240 A CN101921240 A CN 101921240A
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- fluoro
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- oxazole
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention belongs to the technical field of medicinal chemistry, in particular relating to a synthesis method of 2- substituted (4S, 5R)-4-methyl fluoride-5-(4-sulfonylphenyl)-4,5-dihydrooxazoline. In the method, fluoro reaction is carried out on 2-locus substituted (4R, 5R)-5-(4-sulfonylphenyl)-4,5-dihydrooxazoline-4-methanol by using 1-fluoroenamine as a fluoro reagent to obtain a 2- substituted (4S, 5R)-4-methyl fluoride-5-(4-sulfonylphenyl)-4,5-dihydrooxazoline product. The method has mild reaction condition, high yield, low cost and excellent industrial application prospect.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, be specifically related to (4 of 2 replacements
S,5
R)-4-methyl fluoride-5-(4-methylsulfonyl phenyl)-4, the synthetic method of 5-dihydro-oxazole quinoline.
Background technology
(4 of 2 replacements
S,5
R)-4-methyl fluoride-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole quinoline is the important intermediate of synthetic antibiotic Florfenicol (Florfenicol).Its structural formula is:
(
Ⅰ)
R is fatty alkyl or aromatic alkyl in the formula, and described fatty alkyl is selected from dichloromethyl, C
1~ C
6Alkyl, described aromatic alkyl is selected from phenyl, C
1~ C
3Alkyl-substituted phenyl, C
1~ C
3Alkoxy substituted phenyl, halogenophenyl;
European patent 14437 reported from the thiamphenicol intermediate by hydrolysis, amido protecting after, with the diethylin sulfonium triflate 3 hydroxyls are carried out fluoridation, make Florfenicol by two chlorine acetylations then.But this method fluoridation yield is lower, and has three kinds of fluorination byproducts, also exists fluoro reagent diethylin sulfonium triflate hazardness big, and problem such as cost an arm and a leg.United States Patent (USP) 4311857 has also been described behind paraxin intermediate process amido protecting, carries out fluoridation with the diethylin sulfonium triflate, makes Florfenicol by series reaction then.It is big that this method exists diethylin sulfonium triflate hazardness equally, expensive problem.
Jommi etc. (
Gazz. Chim. Ital.,
1985,
115, 653) to have narrated from the thiamphenicol intermediate after protection, the first sulfonation of 3 hydroxyl elder generations replaces with fluorion under phase-transfer catalysis again.But this method step is long, and it is low to fluoridize yield.
United States Patent (USP) 4876352 has been reported and has been made by chlorotrifluoroethylene and diethylamine
N-(2-chloro-1,1,2-trifluoroethyl) diethylamine is to (4 of 2 replacements
R,5
R)-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole-4-methyl alcohol (
II) carry out fluoridation, the making of high yield (
I)But this method produces the small amounts of chlorine by product in generation, must by separate just can obtain pure (
I), limited the application in suitability for industrialized production.
Schumacher etc. (
J. Org. Chem.,
1990,
55, 5291) described and made by R 1216 and diethylamine
N-(1,1,2,3,3,3-hexafluoro propyl group) diethylamine is to (4 of 2 replacements
R,5
R)-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole-4-methyl alcohol (
II) in enclosed system, be heated to 100 ℃ and carry out fluoridation, the making of high yield (
I)Wu etc. (
J. Org. Chem.,
1997,
62, 2996) also reported same method.But this method needs pyroreaction in enclosed system, and reaction vessel is had relatively high expectations, and fluoro reagent can not be recycled after having reacted.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, and (4 of a kind of 2 replacements of preparation of being convenient to suitability for industrialized production are provided
S,5
R)-4-methyl fluoride-5-(4-methylsulfonyl phenyl)-4, the novel method of 5-dihydro-oxazole quinoline.
Synthetic route of the present invention is as follows:
The present invention be 1-fluoro enamine (
III) be under the effect of fluoro reagent, (4 of 2 replacements
R,5
R)-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole-4-methyl alcohol (
II) in organic solvent, carry out fluoro-reaction and make (4 of 2 replacements
S,5
R)-4-methyl fluoride-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole quinoline (
I).
(4 of 2 replacements
R,5
R)-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole-4-methyl alcohol (
II) structural formula be:
（
Ⅱ）
R is fatty alkyl or aromatic alkyl in the formula, fatty alkyl such as dichloromethyl, C
1~ C
6Alkyl, aromatic alkyl such as phenyl, C
1~ C
3Alkyl-substituted phenyl, C
1~ C
3Alkoxy substituted phenyl, halogenophenyl.
The present invention is by (4 of 2 replacements
R,5
R)-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole-4-methyl alcohol (
II) preparation 2 replacements (4
S,5
R)-4-methyl fluoride-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole quinoline (
I), react used fluoro reagent 1-fluoro enamine (
III) have a following structural formula:
（
Ⅲ）
R ' is C in the formula
1~ C
6Alkyl.
(4 of 2 replacements
R,5
R)-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole-4-methyl alcohol (
II) and fluoro reagent 1-fluoro enamine (
III) mol ratio be 1:1 ~ 6.
Further, the used fluoro reagent 1-fluoro enamine of the present invention (
III) have a following structural formula:
（
Ⅲ）
R ' is methyl and sec.-propyl in the formula.
(4 of 2 replacements
R,5
R)-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole-4-methyl alcohol (
II) and fluoro reagent 1-fluoro enamine
IIIMol ratio be 1:1.05 ~ 3.
The present invention is by (4 of 2 replacements
R,5
R)-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole-4-methyl alcohol (
II) preparation 2 replacements (4
S,5
R)-4-methyl fluoride-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole quinoline (
I), the organic solvent that reacts used is halohydrocarbon such as methylene dichloride, chloroform or 1, the 2-ethylene dichloride.Be preferably methylene dichloride.
The present invention is by (4 of 2 replacements
R,5
R)-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole-4-methyl alcohol (
II) preparation 2 replacements (4
S,5
R)-4-methyl fluoride-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole quinoline (
I), the temperature of reaction is-5 ℃ ~ 50 ℃.Preferable reaction temperature is 0 ℃ ~ 30 ℃.
The present invention is by (4 of 2 replacements
R,5
R)-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole-4-methyl alcohol (
II) preparation 2 replacements (4
S,5
R)-4-methyl fluoride-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole quinoline (
I), the time of reaction is 0.5 ~ 10 hour.The preferred reaction time is 1 ~ 5 hour.
The present invention has overcome many deficiencies of prior art, the reaction conditions gentleness, and the yield height, cost is low, has excellent industrial application foreground.
Embodiment
Following embodiment illustrates content of the present invention better.But the invention is not restricted to following embodiment.
Embodiment 1 is with (4
R,5
R)-2-phenyl-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole-4-methyl alcohol
II(2.32 g, 7 mmol), methylene dichloride (10 mL) place the dry reaction bottle, are cooled to 0 ℃, slowly drip N, N-di-isopropyl-1-fluoro-2-methyl isophthalic acid-allylamine
III(1.21 g, 7 mmol) drip and finish, and rise to stirring at room reaction 3 hours.Reaction is finished, and adds entry (20 mL), and dichloromethane extraction is washed to neutrality, drying, and decompression and solvent recovery is cooled to room temperature and separates out solid, gets white powder
I(2.15 g, 93%), 118 ~ 119 ℃ of mp.
1H?NMR?（DMSO-
d 6）:δ＝3.22（s，3H，CH
3），4.30-4.50（m，1H，C
4-H），4.70-4.90（m，2H，CH
2F），5.80（d，1H，
J=6.0，C
2-H），7.40-7.70（m，5H，
J=8，PhH），8.01（d，4H，
J=9.0，ArH）ppm.
Embodiment 2 is with (4
R,5
R)-2-dichloromethyl-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole-4-methyl alcohol
II(2.34 g, 7 mmol), methylene dichloride (10 mL) place the dry reaction bottle, are cooled to 0 ℃, slowly drip N, N-di-isopropyl-1-fluoro-2-methyl isophthalic acid-allylamine
III(1.21 g, 7 mmol) drip and finish, and rise to stirring at room reaction 3 hours.Reaction is finished, and adds entry (20 mL), and dichloromethane extraction is washed to neutrality, drying, and decompression and solvent recovery is cooled to room temperature and separates out solid, gets white powder
I(2.12 g, 92%).
1H?NMR?（DMSO-
d 6）:δ＝3.04（s，3H，CH
3），4.29-4.61（m，2H，CH
2F），4.64-4.69（m，1H，C
4-H），5.72（d，1H，
?J=8.2，C
2-H），6.36（s，1H，CHCl
2），7.54（d，2H，
J=8.2，ArH），7.99（d，2H，
J=8.2，ArH）ppm.
Embodiment 3 is with (4
R,5
R)-2-phenyl-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole-4-methyl alcohol II (2.32 g, 7 mmol), methylene dichloride (10 mL) places the dry reaction bottle, be cooled to 0 ℃, slowly drip 1-fluoro-N, N, 2-trimethylammonium-1-allylamine III (0.82 g, 7 mmol), drip and finish, rise to stirring at room reaction 3 hours.Reaction is finished, and adds entry (20 mL), and dichloromethane extraction is washed to neutrality, drying, and decompression and solvent recovery is cooled to room temperature and separates out solid, gets white powder I (1.6 g, 70%), 117 ~ 118 ℃ of mp.
1H NMR is consistent with embodiment 1.
Claims (7)
1. (4 of 2 replacements
S,5
R)-4-methyl fluoride-5-(4-methylsulfonyl phenyl)-4, the 5-dihydro-oxazole
The synthetic method of quinoline is characterized in that concrete steps are: in the presence of fluoro reagent 1-fluoro enamine, and (4 of 2 replacements
R,5
R)-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole-4-methyl alcohol carries out fluoro-reaction and makes (4 of 2 replacements in organic solvent
S,5
R)-4-methyl fluoride-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole quinoline;
Wherein, (4 of 2 replacements
R,5
R)-5-(4-methylsulfonyl phenyl)-4,5-dihydro-oxazole-4-methyl alcohol has following structural formula:
R is fatty alkyl or aromatic alkyl in the formula, and described fatty alkyl is selected from dichloromethyl, C
1~ C
6Alkyl, described aromatic alkyl is selected from phenyl, C
1~ C
3Alkyl-substituted phenyl, C
1~ C
3Alkoxy substituted phenyl, halogenophenyl;
Fluoro reagent 1-fluoro enamine has following structural formula:
R ' is C in the formula
1~ C
6Alkyl;
(4 of 2 replacements
R,5
R)-5-(4-methylsulfonyl phenyl)-4, the mol ratio of 5-dihydro-oxazole-4-methyl alcohol and fluoro reagent 1-fluoro enamine is 1:1 ~ 6.
2. synthetic method as claimed in claim 1, in the structural formula of the fluoro reagent 1-fluoro enamine that it is characterized in that reacting used, R ' is methyl and sec.-propyl; (4 of 2 replacements
R,5
R)-5-(4-methylsulfonyl phenyl)-4, the mol ratio of 5-dihydro-oxazole-4-methyl alcohol and fluoro reagent 1-fluoro enamine is 1:1.05 ~ 3.
3. synthetic method as claimed in claim 1, it is characterized in that reacting used organic solvent is methylene dichloride, chloroform or 1, the 2-ethylene dichloride.
4. synthetic method as claimed in claim 1 is characterized in that temperature of reaction is-5 ℃ ~ 50 ℃.
5. as claim 1 or 4 described synthetic methods, it is characterized in that the reaction times is 0.5 ~ 10 hour.
6. synthetic method as claimed in claim 1 is characterized in that temperature of reaction is 0 ℃ ~ 30 ℃.
7. as claim 1 or 6 described synthetic methods, it is characterized in that the reaction times is 1 ~ 5 hour.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102820632A CN101921240A (en) | 2010-09-15 | 2010-09-15 | Synthesis method of 2- substituted (4S, 5R)-4-methyl fluoride-5-(4-sulfonylphenyl)-4,5-dihydrooxazoline |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102820632A CN101921240A (en) | 2010-09-15 | 2010-09-15 | Synthesis method of 2- substituted (4S, 5R)-4-methyl fluoride-5-(4-sulfonylphenyl)-4,5-dihydrooxazoline |
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|---|---|
| CN101921240A true CN101921240A (en) | 2010-12-22 |
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|---|---|---|---|
| CN2010102820632A Pending CN101921240A (en) | 2010-09-15 | 2010-09-15 | Synthesis method of 2- substituted (4S, 5R)-4-methyl fluoride-5-(4-sulfonylphenyl)-4,5-dihydrooxazoline |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103965085A (en) * | 2014-04-17 | 2014-08-06 | 上海恒晟药业有限公司 | Preparation method of substituted 1, 2-alkamine medicine |
| CN110330463A (en) * | 2019-08-02 | 2019-10-15 | 山东国邦药业股份有限公司 | A kind of preparation method of florfenicol midbody |
| CN113185473A (en) * | 2021-06-30 | 2021-07-30 | 山东国邦药业有限公司 | Preparation method of florfenicol intermediate fluoromethylsulfone oxazole |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010014566A2 (en) * | 2008-07-30 | 2010-02-04 | Intervet International B.V. | Process for preparing oxazoline-protected aminodiol compounds useful as intermediates to florfenicol |
-
2010
- 2010-09-15 CN CN2010102820632A patent/CN101921240A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010014566A2 (en) * | 2008-07-30 | 2010-02-04 | Intervet International B.V. | Process for preparing oxazoline-protected aminodiol compounds useful as intermediates to florfenicol |
Non-Patent Citations (1)
| Title |
|---|
| 《Tetrahedron Letters》 19891231 Francois Munyemana, et al. Synthesis of Alkyl Halides under neutral conditions 第3077-3080页，第3078页表2，第3079页Scheme 2 1-7 第30卷, 第23期 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103965085A (en) * | 2014-04-17 | 2014-08-06 | 上海恒晟药业有限公司 | Preparation method of substituted 1, 2-alkamine medicine |
| CN103965085B (en) * | 2014-04-17 | 2016-02-24 | 上海恒晟药业有限公司 | A kind of preparation method replacing 1,2-amino alcohol medicine |
| CN110330463A (en) * | 2019-08-02 | 2019-10-15 | 山东国邦药业股份有限公司 | A kind of preparation method of florfenicol midbody |
| CN110330463B (en) * | 2019-08-02 | 2021-05-14 | 山东国邦药业有限公司 | Preparation method of florfenicol intermediate |
| CN113185473A (en) * | 2021-06-30 | 2021-07-30 | 山东国邦药业有限公司 | Preparation method of florfenicol intermediate fluoromethylsulfone oxazole |
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Application publication date: 20101222 |