CN105566257B - A kind of industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran - Google Patents
A kind of industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran Download PDFInfo
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- CN105566257B CN105566257B CN201610000556.XA CN201610000556A CN105566257B CN 105566257 B CN105566257 B CN 105566257B CN 201610000556 A CN201610000556 A CN 201610000556A CN 105566257 B CN105566257 B CN 105566257B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/12—Radicals substituted by oxygen atoms
Abstract
The invention discloses a kind of industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran; belong to the field of chemical synthesis, using tetrahydrofuran formic acid as raw material, tetrahydrofuran formyl chloride is obtained through chlorination; it is condensed again with Maxwell acid, target compound acetyl group tetrahydrofuran is obtained through hydrolysis；The preparation method of the present invention, cost of material is low, it is not necessary to use RMgBr, and product characteristics are stable, and purity is up to more than 98%, and optical purity is up to more than 99%, and yield is up to more than 70%；This method have passed through the production checking of actual industrial metaplasia, and steady quality, reaction condition is gentle; safe operation is reliable, and dichloromethane is recyclable to be applied mechanically, technique favorable reproducibility; prepare cost low, be a kind of industrialized process for preparing of reliable high-optical-purity acetyl group tetrahydrofuran.
Description
Technical field
The present invention relates to technical field of medicine synthesis, more particularly to a kind of industry of high-optical-purity acetyl group tetrahydrofuran
Change preparation method.
Background technology
Acetyl group tetrahydrofuran（Chemical name：1- [(2S)-tetrahydrochysene -2- furyls] ethyl ketone, CAS #: 131328-27-3）
It is synthetic antibacterial drug cephalo dimension star（Cefovecin）And the key intermediate of new carbapenem, structure such as formula compound（Ia）.
That reports both at home and abroad at present mainly has following two conventional preparation methods.
Method one：United States Patent (USP) US2003-114693A, using S-2- tetrahydrofurans formonitrile HCN as initiation material, through with methyl chloride
Change reactive magnesium and prepare S- acetyl group tetrahydrofurans, yield 60%.
This method step is simple, but reagent S-2- tetrahydrofuran formonitrile HCNs used are expensive, and source is limited, is not suitable for big
Technical scale, and this method needs absolute, and completely cut off air, it is unfavorable for realizing industrialization.
Method two：Such as document：（S）-1-（Tetrahydrofuran -2- bases）Ethyl ketone improvement in synthesis is studied（Chai Hongwei）, with S-
Tetrahydrofuran formic acid is raw material, and ester is reacted into thionyl chloride and methanol, then reacts into acid amides with ammonia methanol, dehydration of amide into
Nitrile, then synthesizes S- acetyl group tetrahydrofuran crude products, crude product is with sodium hydrogensulfite into salt, and hydrolyzing to close with methyl chloride reactive magnesium
Lattice product.
This method complex steps, equally use grignard reagent, and condition is harsh, it is difficult to realize production amplification, and product quality
It is unqualified, need to be refined with sodium hydrogensulfite.
Therefore, in the case where ensureing product purity and yield, existing preparation method is all hardly formed reliable and stable
Big production technology.
The content of the invention
The goal of the invention of the present invention is：A kind of preparation of industrialization side of high-optical-purity acetyl group tetrahydrofuran is provided
Method, so that the complex operation, the cost that solve existing process be higher, product is difficult to purify, the problems such as yield is relatively low.
The technical solution adopted by the present invention is such：With tetrahydrofuran formic acid（Ⅳ）（Compounds Ⅳ can be S- tetrahydrochysenes
The tetrahydrofuran formic acid of furancarboxylic acid, R- tetrahydrofuran formic acids or racemization）For raw material, tetrahydrofuran formyl chloride is obtained through chlorination
（Ⅲ）, then it is sour with Maxwell（Chemical name：Malonic acid ring (Asia) isopropyl ester）Condensation, target compound acetyl group tetrahydrochysene is obtained through hydrolysis
Furans（I）, specifically include following steps：
(1) with tetrahydrofuran formic acid（Ⅳ）For raw material, under catalyst action, under organic solvent environment, acyl is added dropwise to
Chlorination reagent, carries out substitution reaction and obtains tetrahydrofuran formyl chloride（Ⅲ）；
(2) step（1）The tetrahydrofuran formyl chloride of gained, in the presence of a base, in organic solvent with the sub- isopropyl of malonic acid
Ester condensation, obtains condensation product（Ⅱ）；
（3）Step（2）The condensation product of gained（Ⅱ）In presence of an acid, it is hydrolyzed, then by extraction, concentration, distillation
Obtain product acetyl group tetrahydrofuran（Ⅰ）.
Its course of reaction is as follows：
It is used as preferred technical scheme, step（1）In, the catalyst is selected from DMF, pyridine, triethylamine, piperidines, aniline
In one kind, preferably DMF；The yield of reaction can be made higher from DMF.
It is used as preferred technical scheme, step（1）In, the chloride reagent is selected from thionyl chloride, oxalyl chloride, trichlorine oxygen
One kind in phosphorus, preferably thionyl chloride, it is less expensive from thionyl chloride, and the yield of reaction can be made higher.
It is used as preferred technical scheme, step（1）In, the tetrahydrofuran formic acid（Ⅳ）With the mol ratio of chloride reagent
For 1：1~1：20.
It is used as preferred technical scheme, step（1）In, the organic solvent is selected from dichloromethane, 1,2- dichloroethanes, four
At least one of hydrogen furans, toluene, methyl tertiary butyl ether(MTBE), preferably dichloromethane, can make reaction from dichloromethane
Yield is higher.
It is used as preferred technical scheme, step（2）In, the one kind of the alkali in pyridine, triethylamine, piperidines, aniline,
Preferably pyridine, less expensive from pyridine, and the yield of reaction can be made higher.
It is used as preferred technical scheme, step（2）In, the organic solvent is selected from dichloromethane, 1,2- dichloroethanes, four
At least one of hydrogen furans, toluene, methyl tertiary butyl ether(MTBE), preferably dichloromethane, can make reaction from dichloromethane
Yield is higher.
It is used as preferred technical scheme, step（3）In, used during hydrolysis acid in hydrochloric acid, acetic acid, sulfuric acid one
Kind.
It is used as preferred technical scheme, step（3）In, condensation product during hydrolysis（Ⅱ）Mol ratio with acid is 1：0.1~1：
10, preferably 1:0.3-1:0.5, the preferably proportional cost is lower, and yield is higher.
It is used as preferred technical scheme, step（3）In, it is 6-10 that pH value is adjusted during extraction.
" purity " involved in the present invention, unless stated otherwise, each means the purity that HPLC is determined（Normalization method）.
" optical purity " involved in the present invention, each means enantiomeric excess, i.e. ee, Enantiomeric excess, i.e.,
（R-S）/(R+S)×100%.
Proved by lot of experiments, acetyl group tetrahydrofuran has strong volatility, during vacuum distillation, pass through the cold of reduction
Condenser temperature can significantly reduce the loss of product, improve yield.
In summary, by adopting the above-described technical solution, the beneficial effects of the invention are as follows：The preparation method of the present invention,
Cost of material is low, it is not necessary to use RMgBr, and product characteristics are stable, purity up to more than 98%, optical purity up to 99% with
On, yield is up to more than 70%；This method have passed through the production checking of actual industrial metaplasia, and steady quality, reaction condition is gentle, operation
Safe and reliable, dichloromethane is recyclable to be applied mechanically, technique favorable reproducibility, and preparation cost is low, is a kind of reliable high-optical-purity second
The industrialized process for preparing of acyl group tetrahydrofuran.
Embodiment
The present invention is described in detail below.
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 1
A kind of industrialized process for preparing of high-optical-purity S- acetyl group tetrahydrofurans, comprises the following steps：
（1）S- tetrahydrofuran formyl chlorides（Ⅲ）Preparation
The Kg of S- tetrahydrofuran formic acids 100,5 Kg of Kg, DMF of dichloromethane 100 are added into dry reaction kettle, is slowly taken out
Enter thionyl chloride 160 Kg, the 20-30 DEG C of h of insulated and stirred 3, tail gas liquid caustic soda（That is the sodium hydroxide of liquid state）Absorb, Ran Housheng
Temperature is concentrated under reduced pressure to 50 DEG C, when vacuum no longer increases, and 50 Kg dichloromethane are pumped into respectively, continues to concentrate three times；Concentration
It is complete, 270 Kg dichloromethane are added, is down in room temperature, barrelling and is ready for use on the next step, optical purity：99.3%；
（2）Condensation product（Ⅱ）Preparation
The Kg of dichloromethane 270, the Kg of isopropylidene malonate 132 are added into reactor, stirring is cooled to 5~10 DEG C,
The Kg of pyridine 265 is added, is added, control temperature is added dropwise to the S- tetrahydrofuran formyl chlorides prepared at -5~0 DEG C（Ⅲ）Dichloro
Dichloromethane（Step（1）Obtained material）, add, the h of stirring reaction 5 continued at -5~0 DEG C, be then 10% with mass fraction
Hydrochloric acid adjust pH=3~4, stratification, aqueous phase is extracted 2 times with 200 Kg dichloromethane again, merging organic phase, and 45 DEG C of decompressions are dense
It is reduced to solid, chemical purity 96.2%, optical purity 99.5%（HPLC）；
（3）S- acetyl group tetrahydrofurans（Ⅰ）Preparation
To step（2）The condensation product of gained（Ⅱ）The Kg of water 155, the Kg of acetic acid 15 are added in material, stirring is warming up to 65-70
DEG C, insulation reaction 1.5-2 h are cooled to -5~0 DEG C and are added dropwise to liquid caustic soda, adjust pH=7-9, extracted respectively with 250 Kg dichloromethane
Take three times, organic phase merges, with 10 Kg anhydrous sodium sulfate dryings, filtering, 45 DEG C of filtrate is concentrated under reduced pressure into aneroid and gone out, is warming up to
60-90 DEG C is distilled in vacuum to give colourless liquid：76 Kg, yield 77.6%, chemical purity 99.1%, optical purity 99.6%.
Embodiment 2
A kind of industrialized process for preparing of high-optical-purity S- acetyl group tetrahydrofurans, comprises the following steps：
（1）S- tetrahydrofuran formyl chlorides（Ⅲ）Preparation
The Kg of S- tetrahydrofuran formic acids 100, the Kg of toluene 120, the Kg of pyridine 4 are added into dry reaction kettle, it is slow to be pumped into
POCl3 200 Kg, the 20-40 DEG C of h of insulated and stirred 4, tail gas liquid caustic soda（That is the sodium hydroxide of liquid state）Absorb, then
50 DEG C are warming up to, is concentrated under reduced pressure, when vacuum no longer increases, 50 Kg toluene are pumped into respectively, continues to concentrate three times；It has been concentrated that,
270 Kg toluene are added, is down in room temperature, barrelling and is ready for use on the next step, optical purity：99.3%；
（2）Condensation product（Ⅱ）Preparation
The Kg of toluene 270, the Kg of isopropylidene malonate 132 are added into reactor, stirring is cooled to 5~10 DEG C, addition
The Kg of triethylamine 255, is added, and control temperature is added dropwise to the S- tetrahydrofuran formyl chlorides prepared at -5~0 DEG C（Ⅲ）Toluene it is molten
Liquid（Step（1）Obtained material）, add, the h of stirring reaction 5 continued at -5~0 DEG C, then adjust pH=3~4 with 10% hydrochloric acid,
Stratification, aqueous phase is extracted 2 times with 200 Kg toluene again, merges organic phase, 45 DEG C are concentrated under reduced pressure into solid, chemical purity
96.1%, optical purity 99.4%（HPLC）；
（3）S- acetyl group tetrahydrofurans（Ⅰ）Preparation
To step（2）The condensation product of gained（Ⅱ）Material in add water 165 Kg, the Kg of hydrochloric acid 14, stirring is warming up to 65-
70 DEG C, insulation reaction 1.5-2 h are cooled to -5~0 DEG C and are added dropwise to liquid caustic soda, pH=8-9 adjusted, respectively with 250 Kg ethyl acetate
Extraction three times, organic phase merges, with 10 Kg anhydrous sodium sulfate dryings, filtering, and 45 DEG C of filtrate is concentrated under reduced pressure into aneroid and gone out, and heats up
Colourless liquid is distilled in vacuum to give to 60-90 DEG C：70 Kg, yield 71.4%, chemical purity 99.2%, optical purity 99.5%.
Embodiment 3
A kind of industrialized process for preparing of high-optical-purity R- acetyl group tetrahydrofurans, comprises the following steps：
（1）R- tetrahydrofuran formyl chlorides（Ⅲ）Preparation
The Kg of R- tetrahydrofuran formic acids 100,5 Kg of Kg, DMF of tetrahydrofuran 100 are added into dry reaction kettle, is slowly taken out
Enter thionyl chloride 160 Kg, the 20-30 DEG C of h of insulated and stirred 3, tail gas liquid caustic soda（That is the sodium hydroxide of liquid state）Absorb, Ran Housheng
Temperature is concentrated under reduced pressure to 50 DEG C, when vacuum no longer increases, and 50 Kg dichloromethane are pumped into respectively, continues to concentrate three times.Concentration
It is complete, 270 Kg tetrahydrofurans are added, is down in room temperature, barrelling and is ready for use on the next step, optical purity：99.4%；
（2）Condensation product（Ⅱ）Preparation
The Kg of tetrahydrofuran 270, the Kg of isopropylidene malonate 132 are added into reactor, stirring is cooled to 5~10 DEG C,
The Kg of piperidines 273 is added, is added, control temperature is added dropwise to the R- tetrahydrofuran formyl chlorides prepared at -5~0 DEG C（Ⅲ）Tetrahydrochysene
Tetrahydrofuran solution（Step（1）Obtained material）, add, the h of stirring reaction 5 continued at -5~0 DEG C, then adjust pH with 10% hydrochloric acid
=3~4, stratification, aqueous phase is extracted 2 times with 200 Kg toluene again, merges organic phase, 45 DEG C are concentrated under reduced pressure into solid, chemistry
Purity 97.2%, optical purity 99.5%（HPLC）；
（3）R- acetyl group tetrahydrofurans（Ⅰ）Preparation
To step（2）The condensation product of gained（Ⅱ）Material in add water 155 Kg, the Kg of acetic acid 15, stirring is warming up to 65-
70 DEG C, insulation reaction 1.5-2 h are cooled to -5~0 DEG C and are added dropwise to liquid caustic soda, adjust pH=7-9, extracted respectively with 250 Kg toluene
Three times, organic phase merges, with 10 Kg anhydrous sodium sulfate dryings, filtering, and 45 DEG C of filtrate is concentrated under reduced pressure into aneroid and gone out, and is warming up to 60-
90 DEG C are distilled in vacuum to give colourless liquid：75 Kg, yield 76.5%, chemical purity 99.1%, optical purity 99.5%.
Embodiment 4
A kind of industrialized process for preparing of high-optical-purity DL- acetyl group tetrahydrofurans, comprises the following steps：
（1）DL- tetrahydrofuran formyl chlorides（Ⅲ）Preparation
The Kg of DL- tetrahydrofuran formic acids 100,5 Kg of Kg, DMF of dichloromethane 100 are added into dry reaction kettle, slowly
It is pumped into thionyl chloride 160 Kg, the 20-30 DEG C of h of insulated and stirred 3, tail gas liquid caustic soda（That is the sodium hydroxide of liquid state）Absorb, then
50 DEG C are warming up to, is concentrated under reduced pressure, when vacuum no longer increases, 50 Kg dichloromethane are pumped into respectively, continues to concentrate three times.Concentration
It is complete, 270 Kg dichloromethane are added, is down in room temperature, barrelling and is ready for use on the next step.
（2）Condensation product（Ⅱ）Preparation
The Kg of dichloromethane 270, the Kg of isopropylidene malonate 132 are added into reactor, stirring is cooled to 5~10 DEG C,
The Kg of aniline 287 is added, is added, control temperature is added dropwise to the DL- tetrahydrofuran formyl chlorides prepared at -5~0 DEG C（Ⅲ）First
Base tertbutyl ether solution（Step（1）Obtained material）, add, -5~0 DEG C continue the h of stirring reaction 5, then with 10% salt
Acid adjusts pH=3~4, and stratification, aqueous phase is extracted 2 times with 200 Kg dichloromethane again, merges organic phase, 45 DEG C are concentrated under reduced pressure into
Solid, chemical purity >=95.0%.
（3）DL- acetyl group tetrahydrofurans（Ⅰ）Preparation
To step（2）Gained condensation product（Ⅱ）Material in add water 155 Kg, the Kg of acetic acid 15, stirring is warming up to 65-70
DEG C, insulation reaction 1.5-2 h are cooled to -5~0 DEG C and are added dropwise to 30%NaOH solution, pH=7-9 adjusted, respectively with 250 Kg dichloros
Methane is extracted three times, and organic phase merges, with 10 Kg anhydrous sodium sulfate dryings, filtering, and 45 DEG C of filtrate is concentrated under reduced pressure into aneroid and gone out,
It is warming up to 60-90 DEG C and is distilled in vacuum to give colourless liquid：74 Kg, yield 75.5%, chemical purity 99.2%.
Claims (16)
1. a kind of industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran, it is characterised in that comprise the following steps：
(1) with tetrahydrofuran formic acid（Ⅳ）For raw material, under catalyst action, under organic solvent environment, chloride is added dropwise to
Reagent, carries out substitution reaction and obtains tetrahydrofuran formyl chloride（Ⅲ）；
(2) step（1）The tetrahydrofuran formyl chloride of gained, in the presence of a base, contracts with isopropylidene malonate in organic solvent
Close, obtain condensation product（Ⅱ）；
（3）Step（2）The condensation product of gained（Ⅱ）In presence of an acid, it is hydrolyzed, then by extracting, concentrating, distilling and must produce
Thing acetyl group tetrahydrofuran（Ⅰ）；
Wherein, tetrahydrofuran formic acid（Ⅳ）Tetrahydrofuran first selected from S- tetrahydrofuran formic acids, R- tetrahydrofuran formic acids or racemization
Acid.
2. the industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran according to claim 1, it is characterised in that
Step（1）In, the one kind of the catalyst in DMF, pyridine, triethylamine, piperidines, aniline.
3. the industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran according to claim 2, it is characterised in that
Step（1）In, the catalyst is DMF.
4. the industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran according to claim 1, it is characterised in that
Step（1）In, the chloride reagent is selected from one kind in thionyl chloride, oxalyl chloride, POCl3.
5. the industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran according to claim 4, it is characterised in that
Step（1）In, the chloride reagent is thionyl chloride.
6. the industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran according to claim 1, it is characterised in that
Step（1）In, the tetrahydrofuran formic acid（Ⅳ）Mol ratio with chloride reagent is 1：1~1：20.
7. the industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran according to claim 1, it is characterised in that
Step（1）In, the organic solvent is selected from dichloromethane, 1,2- dichloroethanes, tetrahydrofuran, toluene, methyl tertiary butyl ether(MTBE)
At least one.
8. the industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran according to claim 7, it is characterised in that
Step（1）In, the organic solvent is dichloromethane.
9. the industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran according to claim 1, it is characterised in that
Step（2）In, the one kind of the alkali in pyridine, triethylamine, piperidines, aniline.
10. the industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran according to claim 9, its feature exists
In step（2）In, the alkali is pyridine.
11. the industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran according to claim 1, its feature exists
In step（2）In, the organic solvent is selected from dichloromethane, 1,2- dichloroethanes, tetrahydrofuran, toluene, methyl tertiary butyl ether(MTBE)
At least one of.
12. the industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran according to claim 11, its feature exists
In step（2）In, the organic solvent is dichloromethane.
13. the industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran according to claim 1, its feature exists
In step（3）In, the one kind of the acid used during hydrolysis in hydrochloric acid, acetic acid, sulfuric acid.
14. the industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran according to claim 1, its feature exists
In step（3）In, condensation product during hydrolysis（Ⅱ）Mol ratio with acid is 1：0.1~1：10.
15. the industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran according to claim 14, its feature exists
In step（3）In, condensation product during hydrolysis（Ⅱ）Mol ratio with acid is 1:0.3-1:0.5.
16. the industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran according to claim 1, its feature exists
In step（3）In, it is 6-10 that pH value is adjusted during extraction.
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