CN105218474B - The synthetic method of (4R, 5R) 2 dichloromethyl 4,5 dihydro 5 (4 methylsulfonyl phenyl) 4 oxazole methanol - Google Patents
The synthetic method of (4R, 5R) 2 dichloromethyl 4,5 dihydro 5 (4 methylsulfonyl phenyl) 4 oxazole methanol Download PDFInfo
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- 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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Abstract
The invention belongs to the synthesis technical field of florfenicol midbody, more particularly to the synthetic method of (4R, 5R) 2 dichloromethyl 4,5 dihydro 5 (4 methylsulfonyl phenyl) 4 oxazole methanol, comprise the following steps：Sodium hydrate aqueous solution is added dropwise in 2 nitroethyl alcohols, then adds bromine, reaction obtains the nitroethyl alcohol of 2 bromine 2；The nitroethyl alcohol of 2 bromine 2 and ethanol are taken, hydrogenation catalyst and hydrogen reaction is added, adds alcohols solvent, be then added dropwise to dichloro acetonitrile reaction；Magnesium, tetrahydrofuran and 4 MSM benzaldehydes are added, obtain cyclocomplex II；Cyclocomplex II is subjected to isomerization reaction in alcohols solvent, produced.The present invention uses brand-new synthetic route, avoids the generation of a large amount of reluctant copper-containing wastewaters；Avoided with hydrogen reducing and produce a large amount of three wastes, reduce cost, total recovery is high, and its yield improves benefit, protect environment up to more than 98%.
Description
Technical field
The invention belongs to the synthesis technical field of florfenicol midbody, more particularly to (4R, 5R) -2- dichloromethyl -4,
The synthetic method of 5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole methanol.
Background technology
Florfenicol midbody (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole methanol
Structural formula be：
Florfenicol is a kind of currently used veterinary antibiotic, and has a broad antifungal spectrum, bacteriostasis is strong, have it is safe,
The features such as nontoxic, noresidue, the hidden danger without potential induced aplastic anemia, it is adapted to scale large-scale plant that raises to use, mainly
For treating cattle respiratory disease caused by pasteurella and haemophilus.There is preferable treatment to cattle footrot caused by Fusobacterium
Effect.Also the bacteriosis for the pig caused by sensitive bacteria, chicken infectious disease and fish.
Florfenicol is not likely to produce drug resistance, because instead of the hydroxyl in Thiamphenicol molecular structure with fluorine atom, has
Solve to effect and drug resistance problems are produced to chloramphenicol, Thiamphenicol.Serious cause aplastic because chloramphenicol has
The adverse reaction such as anaemia and immunosupress, prohibitted the use of in food animal production.And Florfenicol is then with CH3SO4It instead of
NO2Group, changed chemical constitution, therefore for not producing the adverse reaction of alpastic anemia in animal body, because
This has broad application prospects.
At present be industrially using to MSM benzaldehyde as initiation material, with glycine, copper sulphate reaction generation mantoquita, then
Split to obtain D- D-4-methylsulfonylphserine serine ethyl esters (being commonly called as D- ethyl esters) through over-churning, tartaric acid, then by potassium borohydride also
Former and dichloro acetonitrile reaction cyclization obtains florfenicol midbody (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- MSMs
Base phenyl) -4- oxazole methanol.Its technological process is as follows：
The synthetic method is disadvantageous in that：It is difficult to handle first, producing a large amount of copper-containing wastewaters when preparing mantoquita；Second,
The synthetic route is a kind of " linear pattern " synthetic route, and total recovery is low；Third, the reduction reaction potassium borohydride that is related to or
Sodium borohydride, its cost is higher and is also easy to produce a large amount of three wastes.
The content of the invention
The technical problems to be solved by the invention are：In view of the deficienciess of the prior art, it is relatively low to provide a kind of cost, receive
Rate is higher, and the conjunction of free of contamination (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole methanol
Into method.
In order to solve the above technical problems, the technical scheme is that：
The synthetic method of (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole methanol, institute
Synthetic method is stated to comprise the following steps：
(1) sodium hydrate aqueous solution is added dropwise in 2- nitroethyl alcohols, it is -20~10 DEG C to control temperature, and reaction obtains 2-
Nitroethyl alcohol sodium salt, then adds bromine, and it is -20~10 DEG C to continue to control temperature, and reaction obtains the bromo- 2- nitroethyl alcohols of 2-；
(2) the bromo- 2- nitroethyl alcohols of the 2- and ethanol are taken, adds hydrogenation catalyst, then is passed through hydrogen, it is 0 to keep pressure
~0.5MPa, it is 0~60 DEG C to control temperature, and reaction obtains the bromo- 2- ethylaminoethanols of 2-；
(3) the bromo- 2- ethylaminoethanols of 2- are taken, alcohols solvent is added, is then added dropwise to two chloroacetonitriles, it is 0~80 to control temperature
DEG C, reaction obtains the bromo- 5- hydrogen oxazoles of 2- dichloromethyls -4-；
(4) magnesium metal is taken, tetrahydrofuran is added, stirring, is slowly added dropwise into the bromo- 5- hydrogen oxazoles of 2- dichloromethyls -4-, control
RMgBr is made in 30~100 DEG C of temperature, reaction, then adds 4- MSM benzaldehydes, stirring reaction, is acidified, filtering, obtains
(4R, 5R) -2- dichloromethyl -4,5- dihydros-α-(4- methylsulfonyls phenyl) -4- oxazoles methanol (hereinafter referred to as cyclocomplex II)；
(5) it is (4R, 5R) -2- dichloromethyl -4,5- dihydros-α-(4- methylsulfonyls phenyl) -4- oxazole methanol is molten in alcohols
Isomerization reaction is carried out in agent, produces (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole first
Alcohol (hereinafter referred to as cyclocomplex).
As an improvement in step (1), the mol ratio of the sodium hydroxide and 2- nitroethyl alcohols is 0.9~1.2, excellent
Elect 1.0~1.1 as, the mol ratio of the bromine and 2- nitroethyl alcohols is 0.9~1.2, preferably 1.0~1.1.
As an improvement in step (1), the mass concentration of the sodium hydrate aqueous solution is 25%.
As an improvement in step (1), the temperature is preferably -10~0 DEG C,
As an improvement in step (1), reaction dissolvent is preferably water.
As an improvement in step (2), the hydrogenation catalyst is palladium carbon or Raney's nickel.
As an improvement in step (2), the temperature is preferably 20~40 DEG C, the pressure is preferably 0.1~
0.3MPa。
As an improvement in step (3), the mol ratio of two chloroacetonitrile and the bromo- 2- ethylaminoethanols of 2- for 0.9~
1.2, preferably 1.0~1.1.
As an improvement in step (3), the temperature is preferably 30~50 DEG C.
As an improvement in step (4), the mol ratio of the magnesium metal and the bromo- 5- hydrogen oxazoles of 2- dichloromethyls -4- is
0.9~1.2, preferably 1.0~1.1, the mol ratio of the 4- MSMs benzaldehyde and the bromo- 5- hydrogen oxazoles of 2- dichloromethyls -4-
For 0.9~1.2, preferably 0.95~1.05.
As an improvement in step (4), the temperature is preferably 50~80 DEG C.
As an improvement in step (5), the process of the isomerization reaction is：80 DEG C are incubated 2 hours, then cool
To 60~65 DEG C, 18 hours are incubated, 5~10 DEG C is then cooled to, filtering, produces.
As an improvement in step (3) neutralization procedure (5), the alcohols solvent is preferably methanol, ethanol or isopropyl
Alcohol.
The course of reaction of synthetic method provided by the invention is as follows：
The present invention prepares florfenicol midbody (4R, 5R) -2- dichloromethyls -4,5- two using brand-new synthetic route
Hydrogen -5- (4- methylsulfonyls phenyl) -4- oxazole methanol, avoid the generation of a large amount of reluctant copper-containing wastewaters in industrialization at present；
Reduction, which is carried out, with hydrogen avoids a large amount of three wastes of reduction reaction generation, and significantly reduce cost in the prior art；First structure is disliked
Oxazoline ring, then docked with to MSM benzaldehyde, total recovery is high, and its yield improves benefit, protect ring up to more than 98%
Border, there is good industrial prospect.
Embodiment
In order to make the purpose , technical scheme and advantage of the present invention be clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
Embodiment one
(1) 2- nitroethyl alcohols 91.1g is taken to add into churned mechanically four-hole boiling flask, cooling control temperature -10~0
DEG C, it is slowly added dropwise under stirring into the sodium hydrate aqueous solution 192.0g that mass concentration is 25%, continues reaction 20 after being added dropwise
Minute, 191.8g bromines are then added dropwise to, continue reaction after being added dropwise completely, is evaporated under reduced pressure and the isolated 2- of rectifying is bromo-
2- nitroethyl alcohol 156.4g, yield 92.0%, content 99.2%；
(2) the bromo- 2- nitroethyl alcohols 85.0g of 2- are taken in autoclave, add 250.0g ethanol, put into palladium carbon 5.0g,
Hydrogen is passed through to 0~0.1MPa and it is kept the pressure in course of reaction hydrogen make-up, is reacted at 20~30 DEG C to pressure
Constant, reacting liquid filtering recovery catalyst, filtrate rectifying obtains the bromo- 2- ethylaminoethanols 66.6g of 2-, yield 95.1%, content
99.2%；
(3) the bromo- 2- ethylaminoethanols 70.0g of 2- are taken in four-hole boiling flask, add 250.0g ethanol, are warming up to 30 DEG C, are added dropwise
Enter the chloroacetonitriles of 65.9g bis-, be incubated 4 hours at 30~50 DEG C, solvent is evaporated off, obtain the viscous liquid i.e. bromo- 5- of 2- dichloromethyls -4-
Hydrogen oxazole 116.3g, yield 99.8%, content 97.7%；
(4) 5.8g magnesium chips is taken in four-hole boiling flask, adds 250.0g tetrahydrofurans, and stirring is warming up to 50 DEG C, is slowly added dropwise
Enter the bromo- 5- hydrogen oxazole 46.6g of 2- dichloromethyls -4-, exothermic heat of reaction, control rate of addition is added dropwise with 50~60 DEG C of keeping temperature
Bi Jixu back flow reactions 30 minutes, 4- MSM benzaldehyde 36.9g are added, stir lower temperature reaction, keep 70~80 DEG C of reactions 4
Hour, 10 DEG C are cooled to, about 15ml watery hydrochloric acid is added dropwise to, is filtered after acidifying, filter cake is washed with water, dry 64.1g cyclocomplex
II, yield 94.8%, content 98.3%；
(5) 67.6g cyclocomplex II is taken in four-hole boiling flask, adds 250.0g ethanol, and it is small that 80 DEG C of reactions 2 are warming up under stirring
When, then it is cooled to 60~65 DEG C and is incubated 18 hours, is then cooled to 5~10 DEG C of filterings, filtration cakes torrefaction obtains cyclocomplex 66.5g,
Yield 98.1%, content 99.3%.
Embodiment two
(1) 2- nitroethyl alcohols 91.1g is taken to add into churned mechanically four-hole boiling flask, cooling control temperature -10~0
DEG C, it is slowly added dropwise under stirring into the sodium hydrate aqueous solution 168.0g that mass concentration is 25%, continues reaction 20 after being added dropwise
Minute, 167.8g bromines are then added dropwise to, continue reaction after being added dropwise completely, is evaporated under reduced pressure and the isolated 2- of rectifying is bromo-
2- nitroethyl alcohol 168.3g, yield 99.0%, content 99.5%；
(2) the bromo- 2- nitroethyl alcohols 85.0g of 2- are taken in autoclave, add 250.0g ethanol, put into palladium carbon 5.0g,
Hydrogen is passed through to 0.1~0.2MPa and it is kept the pressure in course of reaction hydrogen make-up, the reaction extremely pressure at 20~30 DEG C
Power is constant, and reacting liquid filtering recovery catalyst, filtrate rectifying obtains the bromo- 2- ethylaminoethanols 69.5g of 2-, yield 99.3%, content
99.4%；
(3) the bromo- 2- ethylaminoethanols 70.0g of 2- are taken in four-hole boiling flask, add 250.0g ethanol, are warming up to 30 DEG C, are added dropwise
Enter the chloroacetonitriles of 55.5g bis-, be incubated 4 hours at 30~50 DEG C, solvent is evaporated off, obtain the viscous liquid i.e. bromo- 5- of 2- dichloromethyls -4-
Hydrogen oxazole 115.9g, yield 99.5%, content 99.2%；
(4) 5.1g magnesium chips is taken in four-hole boiling flask, adds 250.0g tetrahydrofurans, and stirring is warming up to 50 DEG C, is slowly added dropwise
Enter the bromo- 5- hydrogen oxazole 46.6g of 2- dichloromethyls -4-, exothermic heat of reaction, control rate of addition is added dropwise with 50~60 DEG C of keeping temperature
Bi Jixu back flow reactions 30 minutes, 4- MSM benzaldehyde 36.9g are added, stir lower temperature reaction, keep 70~80 DEG C of reactions 4
Hour, 10 DEG C are cooled to, about 15ml watery hydrochloric acid is added dropwise to, is filtered after acidifying, filter cake is washed with water, dry 64.5g cyclocomplex
II, yield 95.4%, content 99.2%；
(5) 67.6g cyclocomplex II is taken in four-hole boiling flask, adds 250.0g methanol, and it is small that 80 DEG C of reactions 2 are warming up under stirring
When, then it is cooled to 60~65 DEG C and is incubated 18 hours, is then cooled to 5~10 DEG C of filterings, filtration cakes torrefaction obtains cyclocomplex 66.5g,
Yield 98.4%, content 99.1%.
Embodiment three
(1) 2- nitroethyl alcohols 91.1g is taken to add into churned mechanically four-hole boiling flask, cooling control temperature -10~0
DEG C, it is slowly added dropwise under stirring into the sodium hydrate aqueous solution 144.0g that mass concentration is 25%, continues reaction 20 after being added dropwise
Minute, 143.8g bromines are then added dropwise to, continue reaction after being added dropwise completely, is evaporated under reduced pressure and the isolated 2- of rectifying is bromo-
2- nitroethyl alcohol 152.1g, yield 89.5%, content 99.4%；
(2) the bromo- 2- nitroethyl alcohols 85.0g of 2- are taken in autoclave, add 250.0g ethanol, put into palladium carbon 5.0g,
Hydrogen is passed through to 0.1~0.2MPa and it is kept the pressure in course of reaction hydrogen make-up, is reacted at 0~10 DEG C to pressure
Constant, reacting liquid filtering recovery catalyst, filtrate rectifying obtains the bromo- 2- ethylaminoethanols 65.7g of 2-, yield 93.8%, content
99.5%；
(3) the bromo- 2- ethylaminoethanols 70.0g of 2- are taken in four-hole boiling flask, add 250.0g ethanol, are warming up to 30 DEG C, are added dropwise
Enter the chloroacetonitriles of 49.5g bis-, be incubated 4 hours at 30~50 DEG C, solvent is evaporated off, obtain the viscous liquid i.e. bromo- 5- of 2- dichloromethyls -4-
Hydrogen oxazole 102.5g, yield 88.0%, content 98.5%；
(4) 4.4g magnesium chips is taken in four-hole boiling flask, adds 250.0g tetrahydrofurans, and stirring is warming up to 50 DEG C, is slowly added dropwise
Enter the bromo- 5- hydrogen oxazole 46.6g of 2- dichloromethyls -4-, exothermic heat of reaction, control rate of addition is added dropwise with 50~60 DEG C of keeping temperature
Bi Jixu back flow reactions 30 minutes, 4- MSM benzaldehyde 36.9g are added, stir lower temperature reaction, keep 70~80 DEG C of reactions 4
Hour, 10 DEG C are cooled to, about 15ml watery hydrochloric acid is added dropwise to, is filtered after acidifying, filter cake is washed with water, dry 57.8g cyclocomplex
II, yield 85.5%, content 97.6%；
(5) 67.6g cyclocomplex II is taken in four-hole boiling flask, adds 250.0g isopropanols, and 80 DEG C of reactions 2 are warming up under stirring
Hour, then it is cooled to 60~65 DEG C and is incubated 18 hours, is then cooled to 5~10 DEG C of filterings, filtration cakes torrefaction obtains cyclocomplex
66.5g, yield 98.4%, content 99.1%.
Example IV
(1) 2- nitroethyl alcohols 91.1g is taken to add into churned mechanically four-hole boiling flask, cooling 0~10 DEG C of temperature of control,
It is slowly added dropwise under stirring into the sodium hydrate aqueous solution 168.0g that mass concentration is 25%, continues 20 points of reaction after being added dropwise
Clock, 167.8g bromines are then added dropwise to, continue reaction after being added dropwise completely, be evaporated under reduced pressure the simultaneously bromo- 2- of the isolated 2- of rectifying
Nitroethyl alcohol 150.1g, yield 88.3%, content 98.9%；
(2) the bromo- 2- nitroethyl alcohols 85.0g of 2- are taken in autoclave, add 250.0g ethanol, put into Raney's nickel
5.0g, hydrogen is passed through to 0.2~0.3MPa and it is kept the pressure in course of reaction hydrogen make-up, is reacted at 30~40 DEG C
Constant to pressure, reacting liquid filtering recovery catalyst, filtrate rectifying obtains the bromo- 2- ethylaminoethanols 69.6g of 2-, yield 99.4%,
Content 99.3%；
(3) the bromo- 2- ethylaminoethanols 70.0g of 2- are taken in four-hole boiling flask, add 250.0g ethanol, are warming up to 60 DEG C, are added dropwise
Enter the chloroacetonitriles of 55.5g bis-, be incubated 4 hours at 60~80 DEG C, solvent is evaporated off, obtain the viscous liquid i.e. bromo- 5- of 2- dichloromethyls -4-
Hydrogen oxazole 115.0g, yield 98.7%, content 97.2%；
(4) 5.1g magnesium chips is taken in four-hole boiling flask, adds 250.0g tetrahydrofurans, and stirring is warming up to 30 DEG C, is slowly added dropwise
Enter the bromo- 5- hydrogen oxazole 46.6g of 2- dichloromethyls -4-, exothermic heat of reaction, control rate of addition is added dropwise with 30~50 DEG C of keeping temperature
Bi Jixu back flow reactions 30 minutes, 4- MSM benzaldehyde 36.9g are added, stir lower temperature reaction, keep 30~50 DEG C of reactions 4
Hour, 10 DEG C are cooled to, about 15ml watery hydrochloric acid is added dropwise to, is filtered after acidifying, filter cake is washed with water, dry 63.1g cyclocomplex
II, yield 93.3%, content 99.5%；
(5) 67.6g cyclocomplex II is taken in four-hole boiling flask, adds 250.0g methanol, and it is small that 80 DEG C of reactions 2 are warming up under stirring
When, then it is cooled to 60~65 DEG C and is incubated 18 hours, is then cooled to 5~10 DEG C of filterings, filtration cakes torrefaction obtains cyclocomplex 66.5g,
Yield 98.4%, content 99.1%.
Embodiment five
(1) 2- nitroethyl alcohols 91.1g is taken to add into churned mechanically four-hole boiling flask, cooling control temperature -20~-10
DEG C, it is slowly added dropwise under stirring into the sodium hydrate aqueous solution 168.0g that mass concentration is 25%, continues reaction 20 after being added dropwise
Minute, 167.8g bromines are then added dropwise to, continue reaction after being added dropwise completely, is evaporated under reduced pressure and the isolated 2- of rectifying is bromo-
2- nitroethyl alcohol 160.5g, yield 94.4%, content 99.5%；
(2) the bromo- 2- nitroethyl alcohols 85.0g of 2- are taken in autoclave, add 250.0g ethanol, put into Raney's nickel
5.0g, hydrogen is passed through to 0.4~0.5MPa and it is kept the pressure in course of reaction hydrogen make-up, is reacted at 50~60 DEG C
Constant to pressure, reacting liquid filtering recovery catalyst, filtrate rectifying obtains the bromo- 2- ethylaminoethanols 69.2g of 2-, yield 98.9%,
Content 99.0%；
(3) the bromo- 2- ethylaminoethanols 70.0g of 2- are taken in four-hole boiling flask, 250.0g ethanol is added, is cooled to 0 DEG C, is added dropwise to
The chloroacetonitriles of 55.5g bis-, 4 hours are incubated at 0~20 DEG C, solvent is evaporated off, obtains the bromo- 5- hydrogen of viscous liquid i.e. 2- dichloromethyls -4-
Oxazole 107.5g, yield 92.3%, content 98.2%；
(4) 5.1g magnesium chips is taken in four-hole boiling flask, adds 250.0g tetrahydrofurans, and stirring is warming up to 60 DEG C, is slowly added dropwise
Enter the bromo- 5- hydrogen oxazole 46.6g of 2- dichloromethyls -4-, exothermic heat of reaction, control rate of addition is added dropwise with 60~80 DEG C of keeping temperature
Bi Jixu back flow reactions 30 minutes, 4- MSM benzaldehyde 36.9g are added, stir lower temperature reaction, keep 90~100 DEG C of reactions
4 hours, 10 DEG C are cooled to, about 15ml watery hydrochloric acid is added dropwise to, is filtered after acidifying, filter cake is washed with water, dry 61.1g cyclocomplex
II, yield 90.4%, content 98.2%；
(5) 67.6g cyclocomplex II is taken in four-hole boiling flask, adds 250.0g ethanol, and it is small that 80 DEG C of reactions 2 are warming up under stirring
When, then it is cooled to 60~65 DEG C and is incubated 18 hours, is then cooled to 5~10 DEG C of filterings, filtration cakes torrefaction obtains cyclocomplex 66.5g,
Yield 98.4%, content 99.1%.
Embodiment six
(1) 2- nitroethyl alcohols 91.1g is taken to add into churned mechanically four-hole boiling flask, cooling control temperature -20~-10
DEG C, it is slowly added dropwise under stirring into the sodium hydrate aqueous solution 168.0g that mass concentration is 25%, continues reaction 20 after being added dropwise
Minute, 167.8g bromines are then added dropwise to, continue reaction after being added dropwise completely, is evaporated under reduced pressure and the isolated 2- of rectifying is bromo-
2- nitroethyl alcohol 160.5g, yield 94.4%, content 99.5%；
(2) the bromo- 2- nitroethyl alcohols 85.0g of 2- are taken in autoclave, add 250.0g ethanol, put into Raney's nickel
5.0g, hydrogen is passed through to 0.3~0.4MPa and it is kept the pressure in course of reaction hydrogen make-up, is reacted at 10~20 DEG C
Constant to pressure, reacting liquid filtering recovery catalyst, filtrate rectifying obtains the bromo- 2- ethylaminoethanols 69.5g of 2-, yield 99.3%,
Content 98.3%；
(3) the bromo- 2- ethylaminoethanols 70.0g of 2- are taken in four-hole boiling flask, add 250.0g methanol, are warming up to 20 DEG C, are added dropwise
Enter the chloroacetonitriles of 55.5g bis-, be incubated 4 hours at 30~50 DEG C, solvent is evaporated off, obtain the viscous liquid i.e. bromo- 5- of 2- dichloromethyls -4-
Hydrogen oxazole 115.2g, yield 99.1%, content 99.4%；
(4) 5.1g magnesium chips is taken in four-hole boiling flask, adds 250.0g tetrahydrofurans, and stirring is warming up to 60 DEG C, is slowly added dropwise
Enter the bromo- 5- hydrogen oxazole 46.6g of 2- dichloromethyls -4-, exothermic heat of reaction, control rate of addition is added dropwise with 80~90 DEG C of keeping temperature
Bi Jixu back flow reactions 30 minutes, 4- MSM benzaldehyde 36.9g are added, stir lower temperature reaction, keep 90~100 DEG C of reactions
4 hours, 10 DEG C are cooled to, about 15ml watery hydrochloric acid is added dropwise to, is filtered after acidifying, filter cake is washed with water, dry 61.1g cyclocomplex
II, yield 90.4%, content 98.2%；
(5) 67.6g cyclocomplex II is taken in four-hole boiling flask, adds 250.0g isopropanols, and 80 DEG C of reactions 2 are warming up under stirring
Hour, then it is cooled to 60~65 DEG C and is incubated 18 hours, is then cooled to 5~10 DEG C of filterings, filtration cakes torrefaction obtains cyclocomplex
66.5g, yield 98.4%, content 99.1%.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
All any modification, equivalent and improvement made within refreshing and principle etc., should be included in the scope of the protection.
Claims (10)
- The synthetic method of (1. 4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole methanol, it is special Sign is that the synthetic method comprises the following steps：(1) sodium hydrate aqueous solution is added dropwise in 2- nitroethyl alcohols, it is -20 DEG C~10 DEG C to control temperature, and reaction obtains 2- nitre Base ethanol sodium salt, then adds bromine, and it is -20 DEG C~10 DEG C to continue to control temperature, and reaction obtains the bromo- 2- nitroethyl alcohols of 2-；(2) take the bromo- 2- nitroethyl alcohols of the 2- and ethanol, add hydrogenation catalyst, then be passed through hydrogen, keep pressure be 0~ 0.5MPa, it is 0~60 DEG C to control temperature, and reaction obtains the bromo- 2- ethylaminoethanols of 2-；(3) the bromo- 2- ethylaminoethanols of 2- are taken, alcohols solvent is added, is then added dropwise to two chloroacetonitriles, it is 0~80 DEG C to control temperature, instead The bromo- 5- hydrogen oxazoles of 2- dichloromethyls -4- should be obtained；(4) magnesium metal is taken, tetrahydrofuran is added, stirring, is slowly added dropwise into the bromo- 5- hydrogen oxazoles of 2- dichloromethyls -4-, controls temperature 30~100 DEG C, RMgBr is made in reaction, then adds 4- MSM benzaldehydes, stirring reaction, is acidified, filtering, obtain (4R, 5R) -2- dichloromethyls -4,5- dihydros-α-(4- methylsulfonyls phenyl) -4- oxazole methanol；(5) by (4R, 5R) -2- dichloromethyl -4,5- dihydros-α-(4- methylsulfonyls phenyl) -4- oxazole methanol in alcohols solvent Isomerization reaction is carried out, produces (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole methanol.
- 2. (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole first as claimed in claim 1 The synthetic method of alcohol, it is characterised in that in step (1), the mol ratio of the sodium hydroxide and 2- nitroethyl alcohols is 0.9~1.2, The mol ratio of the bromine and 2- nitroethyl alcohols is 0.9~1.2.
- 3. (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole first as claimed in claim 1 The synthetic method of alcohol, it is characterised in that in step (1), the mass concentration of the sodium hydrate aqueous solution is 25%.
- 4. (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole first as claimed in claim 1 The synthetic method of alcohol, it is characterised in that in step (2), the hydrogenation catalyst is palladium carbon or Raney's nickel.
- 5. (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole first as claimed in claim 1 The synthetic method of alcohol, it is characterised in that in step (2), the temperature is preferably 20 DEG C~40 DEG C, and the pressure is preferably 0.1 ~0.3MPa.
- 6. (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole first as claimed in claim 1 The synthetic method of alcohol, it is characterised in that in step (3), the mol ratio of two chloroacetonitrile and the bromo- 2- ethylaminoethanols of 2- is 0.9 ~1.2.
- 7. (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole first as claimed in claim 1 The synthetic method of alcohol, it is characterised in that in step (3), the temperature is preferably 30 DEG C~50 DEG C.
- 8. (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole first as claimed in claim 1 The synthetic method of alcohol, it is characterised in that in step (4), mole of the magnesium metal and the bromo- 5- hydrogen oxazoles of 2- dichloromethyls -4- Than for 0.9~1.2, the mol ratio of the 4- MSMs benzaldehyde and the bromo- 5- hydrogen oxazoles of 2- dichloromethyls -4- is 0.9~1.2.
- 9. (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole first as claimed in claim 1 The synthetic method of alcohol, it is characterised in that in step (4), the temperature is preferably 50 DEG C~80 DEG C.
- 10. (4R, 5R) -2- dichloromethyl -4,5- dihydros -5- (4- methylsulfonyls phenyl) -4- oxazole first as claimed in claim 1 The synthetic method of alcohol, it is characterised in that in step (5), the process of the isomerization reaction is：80 DEG C are incubated 2 hours, then drop Temperature is incubated 18 hours to 60 DEG C~65 DEG C, is then cooled to 5 DEG C~10 DEG C, filtering, produces.
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