CN109761829A - A kind of preparation method of high chiral purity efavirenz intermediate - Google Patents
A kind of preparation method of high chiral purity efavirenz intermediate Download PDFInfo
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Abstract
The invention discloses a kind of preparation methods of high chiral purity efavirenz intermediate, specifically includes the following steps: step (1): efavirenz intermediate crude product is mixed with benign organic solvent, heating is kept the temperature after efavirenz intermediate crude product all dissolution；Step (2): certain temperature is kept, bad organic solvent is slowly dropped in the dissolution system of step (1)；Step (3): after being added dropwise, certain temperature is kept, a certain amount of mixing organic solvent is concentrated under reduced pressure；Step (4): cooling crystallization is filtered, is washed, and drying obtains the efavirenz intermediate of high chiral purity；The present invention preparation method is easy to operate, high income, the method being convenient for industrialized production, and efavirenz intermediate chiral purity >=99.90% obtained, and even as high as 100%.
Description
Technical field
The present invention relates to a kind of preparation methods of high chiral purity efavirenz intermediate, belong to pharmaceutical synthesis field.
Background technique
Efavirenz, also known as efavirenz are pure optical isomer, and medicinal is its S- isomers, and R- isomers is almost
There is no bioactivity, obtains within 1998 U.S. FDA approval and infected for anti human immune deficiency virus, controlled for existing international AIDS
Treat the non-core former times class reverse transcriptase inhibitor class choice drug that guilding principle is recommended.Efavirenz combines 2 core former times class reverse transcriptions
Enzyme inhibitor class drug can be used as the first-line treatment scheme of anti AIDS virus infection.
Efavirenz intermediate, chemical name (S) -1- (2- amino -5- chlorphenyl) -1- trifluoromethyl -3- cyclopropyl -2- third
Alkynes -1- alcohol is S- isomers, is the key intermediate for synthesizing efavirenz, and the chiral purity of the intermediate is directly affected according to non-
The chiral purity of Wei Lun.
There are many document report in relation to efavirenz intermediate study on the synthesis, are broadly divided into two classes: one kind is closed to be asymmetric
Cheng Fa；One kind is chemical resolution method.Wherein the atom utilization of chemical resolution method is low, is gradually eliminated；Dissymmetric synthesis mesh
Before can not only realize that chiral catalysis synthesizes, and chiral catalyst also can be recycled effectively, but its chiral catalysis closes
Inevitably generate R- isomers at process, how by post-processing removal R- isomers, be prepared high chiral purity according to
Fei Weilun intermediate becomes key factor.
A kind of synthetic method of efavirenz intermediate is disclosed in patent WO9851676Al, with 1- (2- amino -5- chlorine
Phenyl) -2,2,2- trifluoroethanones are raw material, through asymmetric catalysis synthesis, lemon acid elution, after organic layer is concentrated to dryness, directly
The efavirenz intermediate of chiral purity is prepared with toluene-normal heptane recrystallization；It obtains in the embodiment of the patent according to non-
The chiral purity of Wei Lun intermediate minimum 95.0%, highest >=99.0%, chiral purity is unstable, is not suitable for industry metaplasia
It produces.
A kind of synthetic method of efavirenz intermediate is disclosed in patent CN101786959A, with 1- (2- amino -5- chlorine
Phenyl) -2,2,2- trifluoroethanones are raw material, and through asymmetric catalysis synthesis, lemon acid elution after organic layer is concentrated to dryness, uses pole
Property solvent dissolution, by be added dropwise nonpolar solvent crystallization or concentration polar solvent crystallization, be prepared chiral purity >=
99.0% efavirenz intermediate；The efavirenz intermediate of chiral purity >=99.0% can be prepared in this method, but
It is that purification yield is low, is not suitable for large-scale production.
A kind of synthetic method of efavirenz intermediate is disclosed in patent WO2012048887A1, with 1- (2- amino -5-
Chlorphenyl) -2,2,2- trifluoroethanones are raw material, and through asymmetric catalysis synthesis, lemon acid elution after organic layer is concentrated to dryness, adds
Enter toluene and isopropanol, Loprazolam is then added, so that the methane sulfonates of efavirenz intermediate, chiral purity be prepared
Degree >=99%；The efavirenz intermediate of chiral purity >=99% can be prepared in this method, but increased newly methanesulfonic acid at
Salt technique, it is subsequent need with alkali carry out it is free efavirenz intermediate is prepared, while methanesulfonic acid can make in efavirenz
Mesosome decomposes, and generates acid degradation impurity, reduces the purity and yield of final efavirenz product.
A kind of synthetic method of efavirenz intermediate is disclosed in patent US20120264933, with 1- (2- amino -5-
Chlorphenyl) -2,2,2- trifluoroethanones are raw material, and through asymmetric catalysis synthesis, lemon acid elution after organic layer is concentrated to dryness, adds
Entering methanol dissolution, elutriation crystalline substance is added dropwise and obtains crude product, again with toluene is refining to obtain efavirenz intermediate, chiral purity >=
99.7%；This method first arrives crude product with what methanol-water refined, and again with toluene purification, purification causes yield to reduce twice, is not suitable for
Industrialized production.
In conclusion the chiral purity for the efavirenz intermediate being prepared in existing literature is substantially >=99.0%, most
A height of 99.8%, the pertinent literature for finding no the efavirenz intermediate that chiral purity >=99.90% is prepared is registered, and is
This, my company develops a kind of easy to operate, high income, the method that is convenient for industrialized production be prepared chiral purity according to non-
Wei Lun intermediate, chiral purity >=99.90%, even as high as 100%.
Summary of the invention
The technical problem to be solved by the present invention is to propose a kind of high chiral for the above disadvantage of the existing technology
The preparation method of purity efavirenz intermediate, the preparation method is easy to operate, high income, the method being convenient for industrialized production,
And efavirenz intermediate chiral purity obtained is high.
The technical solution that the present invention solves the above technical problem is:
A kind of preparation method of high chiral purity efavirenz intermediate, specifically includes the following steps:
Step (1): efavirenz intermediate crude product is mixed with benign organic solvent, heating, in efavirenz
Mesosome crude product all after dissolution, is kept the temperature；
Step (2): certain temperature is kept, bad organic solvent is slowly dropped in the dissolution system of step (1)；
Step (3): after being added dropwise, certain temperature is kept, a certain amount of mixing organic solvent is concentrated under reduced pressure；
Step (4): cooling crystallization is filtered, is washed, and drying obtains the efavirenz intermediate of high chiral purity.
The technical solution that the present invention further limits are as follows:
In the preparation method of aforementioned high chiral purity efavirenz intermediate, efavirenz intermediate crude product is 1- (2- ammonia
Base -5- chlorphenyl) -2,2,2- trifluoroethanones and cyclopropyl chlorination of acetylene magnesium grignard reagent are quenched through asymmetric syntheses, and washing has
Machine layer is directly concentrated under reduced pressure obtained to dry.
In the preparation method of aforementioned high chiral purity efavirenz intermediate, the chiral purity of efavirenz intermediate crude product
For 95.0%-99.0%.
In the preparation method of aforementioned high chiral purity efavirenz intermediate,
Benign organic solvent is selected from one of methyl tertiary butyl ether(MTBE), tetrahydrofuran, acetone, preferably methyl in step (1)
Tertbutyl ether；
Bad organic solvent is selected from one of normal heptane, n-hexane, petroleum ether, preferably normal heptane in step (2).
In the preparation method of aforementioned high chiral purity efavirenz intermediate,
The weight ratio of efavirenz intermediate crude product and benign organic solvent is 1:(0.5-5)；
The weight ratio of efavirenz intermediate crude product and bad organic solvent is 1:(5-100).
In the preparation method of aforementioned high chiral purity efavirenz intermediate, the dropping temperature range of step (2) is 25-80
℃。
In the preparation method of aforementioned high chiral purity efavirenz intermediate, the negative pressure of step (3) concentration vacuum degree is-
0.01~-0.09Mpa, thickening temperature are 25~80 DEG C.
In the preparation method of aforementioned high chiral purity efavirenz intermediate, efavirenz intermediate crude product and step (3)
The weight ratio of a certain amount of mixing organic solvent of the reduced pressure is 1:(1-100).
In the preparation method of aforementioned high chiral purity efavirenz intermediate, the cooling crystallization temperature of step (4) is 10-25
℃。
In the preparation method of aforementioned high chiral purity efavirenz intermediate, high chiral purity that step (4) obtains according to
Chiral purity degree >=99.90% of Fei Weilun intermediate.
The beneficial effects of the present invention are:
The present invention is had found by a large number of experiments, in the subtractive process of efavirenz intermediate crude product, bad organic solvent
Dropping temperature and speed, the temperature of reduced pressure, the concentration amount for mixing organic solvent and crystallization temperature influence among efavirenz
The crystallization effect of body, dropping temperature is too low, and rate of addition is too fast, and the temperature of reduced pressure is too low, and organic solvent is concentrated under reduced pressure
Measure that excessive and crystallization temperature is too low all to cause efavirenz intermediate isomers to be precipitated, it is final to influence efavirenz intermediate hand
Property purity, therefore, the present invention is not under the premise of influencing product quality and not reducing optical purity of products, so that the yield of product
It is greatly improved.
Compared with prior art, the present invention has the advantage that
The method of the present invention is easy to operate, and high income, cost is relatively low, is suitble to industrialized production.
Efavirenz intermediate chiral purity >=99.90% that the present invention is prepared, even as high as 100%.
Specific embodiment
The following example illustrates that these embodiments of an are used to illustrate the present invention for of the invention, but must not be recognized as
Limitation of the scope of the invention.
Embodiment 1
A kind of preparation method of high chiral purity efavirenz intermediate provided in this embodiment, specifically includes following step
It is rapid:
Step (1): by 15.71g efavirenz intermediate crude product (chiral purity 97.6%) and 9.9g methyl tertiary butyl ether(MTBE)
It is added in reaction flask, is warming up to 55 DEG C, stirring and dissolving keeps the temperature 30min after Fei Weilun crude intermediate whole dissolved clarification；
Step (2): it is kept for 50~55 DEG C, 105.26g normal heptane is slowly dropped in the dissolution system of step (1), body
Tying up to dropwise addition process just has a large amount of solids to be precipitated；
Step (3): being added dropwise, and slow cooling keeps the temperature crystallization 1h, filtering to 15 DEG C, and normal heptane washing is dried, obtained
Efavirenz intermediate 11.32g, chiral purity 100%, yield 72.06%.
Embodiment 2
A kind of preparation method of high chiral purity efavirenz intermediate provided in this embodiment, specifically includes following step
It is rapid:
Step (1): by 15.6g efavirenz intermediate crude product (chiral purity 97.6%) and 9.83g methyl tertiary butyl ether(MTBE)
It is added in reaction flask, is warming up to 55 DEG C, stirring and dissolving keeps the temperature 30min after Fei Weilun crude intermediate whole dissolved clarification；
Step (2): it is kept for 50~55 DEG C, 104.52g normal heptane is slowly dropped in the dissolution system of step (1), body
Tying up to dropwise addition process just has a large amount of solids to be precipitated；
Step (3): being added dropwise, and cools the temperature to 32 DEG C, keeps negative pressure -0.01~-0.09MPa, and 30~32 DEG C of temperature,
The mixing organic solvent of 31.68g is concentrated under reduced pressure；
Step (4): slow cooling keeps the temperature crystallization 1h, filtering to 15 DEG C, and normal heptane washing is dried, obtained in efavirenz
Mesosome 12.81g, chiral purity 99.96%, yield 82.12%.
Embodiment 3
A kind of preparation method of high chiral purity efavirenz intermediate provided in this embodiment, specifically includes following step
It is rapid:
Step (1): by 15.64g efavirenz intermediate crude product (chiral purity 97.6%) and 9.85g methyl tertiary butyl ether(MTBE)
It is added in reaction flask, is warming up to 55 DEG C, stirring and dissolving keeps the temperature 30min after Fei Weilun crude intermediate whole dissolved clarification；
Step (2): it is kept for 50~55 DEG C, 104.79g normal heptane is slowly dropped in the dissolution system of step (1), body
Tying up to dropwise addition process just has a large amount of solids to be precipitated；
Step (3): being added dropwise, and cools the temperature to 32 DEG C, keeps negative pressure -0.01~-0.09MPa, and 30~32 DEG C of temperature,
The mixing organic solvent of 31.72g is concentrated under reduced pressure；
Step (4): 30~32 DEG C of crystallization 1h of heat preservation degree, filtering, normal heptane washing, drying obtain efavirenz intermediate
12.53g, chiral purity 100%, yield 80.12%.
Embodiment 4
A kind of preparation method of high chiral purity efavirenz intermediate provided in this embodiment, specifically includes following step
It is rapid:
Step (1): by 15.67g efavirenz intermediate crude product (chiral purity 97.6%) and 9.87g methyl tertiary butyl ether(MTBE)
It is added in reaction flask, is warming up to 55 DEG C, stirring and dissolving keeps the temperature 30min after Fei Weilun crude intermediate whole dissolved clarification；
Step (2): it is kept for 50~55 DEG C, 104.99g normal heptane is slowly dropped in the dissolution system of step (1), body
Tying up to dropwise addition process just has a large amount of solids to be precipitated；
Step (3): being added dropwise, and cools the temperature to 45 DEG C, keeps negative pressure -0.01~-0.09MPa, and 40~45 DEG C of temperature,
The mixing organic solvent of 31.78g is concentrated under reduced pressure；
Step (4): slow cooling keeps the temperature crystallization 1h, filtering to 15 DEG C, and normal heptane washing is dried, obtained in efavirenz
Mesosome 12.86g, chiral purity 100%, yield 82.07%.
Embodiment 5
A kind of preparation method of high chiral purity efavirenz intermediate provided in this embodiment, specifically includes following step
It is rapid:
Step (1): by 15.74g efavirenz intermediate crude product (chiral purity 97.6%) and 9.92g methyl tertiary butyl ether(MTBE)
It is added in reaction flask, is warming up to 55 DEG C, stirring and dissolving keeps the temperature 30min after Fei Weilun crude intermediate whole dissolved clarification；
Step (2): it is kept for 50~55 DEG C, 105.46g normal heptane is slowly dropped in the dissolution system of step (1), body
Tying up to dropwise addition process just has a large amount of solids to be precipitated；
Step (3): being added dropwise, and cools the temperature to 45 DEG C, keeps negative pressure -0.01~-0.09MPa, and 40~45 DEG C of temperature,
The mixing organic solvent of 31.71g is concentrated under reduced pressure；
Step (4): 30~32 DEG C of crystallization 1h of heat preservation degree, filtering, normal heptane washing, drying obtain efavirenz intermediate
12.60g, chiral purity 100%, yield 80.05%.
Embodiment 6
A kind of preparation method of high chiral purity efavirenz intermediate provided in this embodiment, specifically includes following step
It is rapid:
Step (1): by 15.68g efavirenz intermediate crude product (chiral purity 95.2%) and 9.88g methyl tertiary butyl ether(MTBE)
It is added in reaction flask, is warming up to 55 DEG C, stirring and dissolving keeps the temperature 30min after Fei Weilun crude intermediate whole dissolved clarification；
Step (2): it is kept for 50~55 DEG C, 105.06g normal heptane is slowly dropped in the dissolution system of step (1), body
Tying up to dropwise addition process just has a large amount of solids to be precipitated；
Step (3): being added dropwise, and slow cooling keeps the temperature crystallization 1h, filtering to 15 DEG C, and normal heptane washing is dried, obtained
Efavirenz intermediate 10.73g, chiral purity 100%, yield 68.43%.
Embodiment 7
A kind of preparation method of high chiral purity efavirenz intermediate provided in this embodiment, specifically includes following step
It is rapid:
Step (1): by 15.81g efavirenz intermediate crude product (chiral purity 95.2%) and 9.96g methyl tertiary butyl ether(MTBE)
It is added in reaction flask, is warming up to 55 DEG C, stirring and dissolving keeps the temperature 30min after Fei Weilun crude intermediate whole dissolved clarification；
Step (2): it is kept for 50~55 DEG C, 104.93g normal heptane is slowly dropped in the dissolution system of step (1), body
Tying up to dropwise addition process just has a large amount of solids to be precipitated；
Step (3): being added dropwise, and cools the temperature to 32 DEG C, keeps negative pressure -0.01~-0.09MPa, and 30~32 DEG C of temperature,
The mixing organic solvent of 32.25g is concentrated under reduced pressure；
Step (4): slow cooling keeps the temperature crystallization 1h, filtering to 15 DEG C, and normal heptane washing is dried, obtained in efavirenz
Mesosome 12.61g, chiral purity 99.90%, yield 79.76%.
Embodiment 8
A kind of preparation method of high chiral purity efavirenz intermediate provided in this embodiment, specifically includes following step
It is rapid:
Step (1): by 15.86g efavirenz intermediate crude product (chiral purity 95.2%) and 9.99g methyl tertiary butyl ether(MTBE)
It is added in reaction flask, is warming up to 55 DEG C, stirring and dissolving keeps the temperature 30min after Fei Weilun crude intermediate whole dissolved clarification；
Step (2): it is kept for 50~55 DEG C, 106.26g normal heptane is slowly dropped in the dissolution system of step (1), body
Tying up to dropwise addition process just has a large amount of solids to be precipitated；
Step (3): being added dropwise, and cools the temperature to 32 DEG C, keeps negative pressure -0.01~-0.09MPa, and 30~32 DEG C of temperature,
The mixing organic solvent of 31.64g is concentrated under reduced pressure；
Step (4): 30~32 DEG C of crystallization 1h of heat preservation degree, filtering, normal heptane washing, drying obtain efavirenz intermediate
12.12g, chiral purity 100%, yield 76.42%.
Embodiment 9
A kind of preparation method of high chiral purity efavirenz intermediate provided in this embodiment, specifically includes following step
It is rapid:
Step (1): by 15.84g efavirenz intermediate crude product (chiral purity 95.2%) and 9.98g methyl tertiary butyl ether(MTBE)
It is added in reaction flask, is warming up to 55 DEG C, stirring and dissolving keeps the temperature 30min after Fei Weilun crude intermediate whole dissolved clarification；
Step (2): it is kept for 50~55 DEG C, 106.13g normal heptane is slowly dropped in the dissolution system of step (1), body
Tying up to dropwise addition process just has a large amount of solids to be precipitated；
Step (3): being added dropwise, and cools the temperature to 45 DEG C, keeps negative pressure -0.01~-0.09MPa, and 40~45 DEG C of temperature,
The mixing organic solvent of 31.91g is concentrated under reduced pressure；
Step (4): slow cooling keeps the temperature crystallization 1h, filtering to 15 DEG C, and normal heptane washing is dried, obtained in efavirenz
Mesosome 12.68g, chiral purity 99.92%, yield 80.05%.
Embodiment 10
A kind of preparation method of high chiral purity efavirenz intermediate provided in this embodiment, specifically includes following step
It is rapid:
Step (1): by 15.77g efavirenz intermediate crude product (chiral purity 95.2%) and 9.94g methyl tertiary butyl ether(MTBE)
It is added in reaction flask, is warming up to 55 DEG C, stirring and dissolving keeps the temperature 30min after Fei Weilun crude intermediate whole dissolved clarification；
Step (2): it is kept for 50~55 DEG C, 105.66g normal heptane is slowly dropped in the dissolution system of step (1), body
Tying up to dropwise addition process just has a large amount of solids to be precipitated；
Step (3): being added dropwise, and cools the temperature to 45 DEG C, keeps negative pressure -0.01~-0.09MPa, and 40~45 DEG C of temperature,
The mixing organic solvent of 31.57g is concentrated under reduced pressure；
Step (4): 30~32 DEG C of crystallization 1h of heat preservation degree, filtering, normal heptane washing, drying obtain efavirenz intermediate
12.08g, chiral purity 100%, yield 76.60%.
Embodiment 11
A kind of preparation method of high chiral purity efavirenz intermediate provided in this embodiment, specifically includes following step
It is rapid:
Step (1): by 15.62g efavirenz intermediate crude product (chiral purity 97.6%) and 9.84g methyl tertiary butyl ether(MTBE)
It is added in reaction flask, is warming up to 55 DEG C, stirring and dissolving keeps the temperature 30min after Fei Weilun crude intermediate whole dissolved clarification；
Step (2): it is kept for 50~55 DEG C, 104.65g normal heptane is slowly dropped in the dissolution system of step (1), body
Tying up to dropwise addition process just has a large amount of solids to be precipitated；
Step (3): being added dropwise, and slow cooling keeps the temperature crystallization 1h, filtering to 15 DEG C, and normal heptane washing is dried, obtained
Efavirenz intermediate 11.28g, chiral purity 100%, yield 72.22%.
Embodiment 12
A kind of preparation method of high chiral purity efavirenz intermediate provided in this embodiment, specifically includes following step
It is rapid:
Step (1): by 15.73g efavirenz intermediate crude product (chiral purity 97.6%) and 9.91g methyl tertiary butyl ether(MTBE)
It is added in reaction flask, is warming up to 55 DEG C, stirring and dissolving keeps the temperature 30min after Fei Weilun crude intermediate whole dissolved clarification；
Step (2): it is kept for 50~55 DEG C, 105.39g normal heptane is slowly dropped in the dissolution system of step (1), body
Tying up to dropwise addition process just has a large amount of solids to be precipitated；
Step (3): being added dropwise, and cools the temperature to 32 DEG C, keeps negative pressure -0.01~-0.09MPa, and 30~32 DEG C of temperature,
The mixing organic solvent of 37.84g is concentrated under reduced pressure；
Step (4): slow cooling keeps the temperature crystallization 1h, filtering to 15 DEG C, and normal heptane washing is dried, obtained in efavirenz
Mesosome 13.09g, chiral purity 99.66%, yield 83.28%.
Embodiment 13
A kind of preparation method of high chiral purity efavirenz intermediate provided in this embodiment, specifically includes following step
It is rapid:
Step (1): by 15.67g efavirenz intermediate crude product (chiral purity 97.6%) and 9.87g methyl tertiary butyl ether(MTBE)
It is added in reaction flask, is warming up to 55 DEG C, stirring and dissolving keeps the temperature 30min after Fei Weilun crude intermediate whole dissolved clarification；
Step (2): it is kept for 50~55 DEG C, 104.98g normal heptane is slowly dropped in the dissolution system of step (1), body
Tying up to dropwise addition process just has a large amount of solids to be precipitated；
Step (3): being added dropwise, and cools the temperature to 32 DEG C, keeps negative pressure -0.01~-0.09MPa, and 30~32 DEG C of temperature,
The mixing organic solvent of 37.64g is concentrated under reduced pressure；
Step (4): 30~32 DEG C of crystallization 1h of heat preservation degree, filtering, normal heptane washing, drying obtain efavirenz intermediate
12.73g, chiral purity 99.80%, yield 81.24%.
Embodiment 14
A kind of preparation method of high chiral purity efavirenz intermediate provided in this embodiment, specifically includes following step
It is rapid:
Step (1): by 15.66g efavirenz intermediate crude product (chiral purity 97.6%) and 9.87g methyl tertiary butyl ether(MTBE)
It is added in reaction flask, is warming up to 55 DEG C, stirring and dissolving keeps the temperature 30min after Fei Weilun crude intermediate whole dissolved clarification；
Step (2): it is kept for 50~55 DEG C, 104.94g normal heptane is slowly dropped in the dissolution system of step (1), body
Tying up to dropwise addition process just has a large amount of solids to be precipitated；
Step (3): being added dropwise, and cools the temperature to 45 DEG C, keeps negative pressure -0.01~-0.09MPa, and 40~45 DEG C of temperature,
The mixing organic solvent of 37.57g is concentrated under reduced pressure；
Step (4): slow cooling keeps the temperature crystallization 1h, filtering to 15 DEG C, and normal heptane washing is dried, obtained in efavirenz
Mesosome 13.01g, chiral purity 99.72%, yield 83.08%.
Embodiment 15
A kind of preparation method of high chiral purity efavirenz intermediate provided in this embodiment, specifically includes following step
It is rapid:
Step (1): by 15.71g efavirenz intermediate crude product (chiral purity 97.6%) and 9.90g methyl tertiary butyl ether(MTBE)
It is added in reaction flask, is warming up to 55 DEG C, stirring and dissolving keeps the temperature 30min after Fei Weilun crude intermediate whole dissolved clarification；
Step (2): it is kept for 50~55 DEG C, 105.27g normal heptane is slowly dropped in the dissolution system of step (1), body
Tying up to dropwise addition process just has a large amount of solids to be precipitated；
Step (3): being added dropwise, and cools the temperature to 45 DEG C, keeps negative pressure -0.01~-0.09MPa, and 40~45 DEG C of temperature,
The mixing organic solvent of 37.73g is concentrated under reduced pressure；
Step (4): 30~32 DEG C of crystallization 1h of heat preservation degree, filtering, normal heptane washing, drying obtain efavirenz intermediate
12.78g, chiral purity 99.85%, yield 81.35%.
In embodiment 1-15, efavirenz intermediate crude product is 1- (2- amino -5- chlorphenyl) -2,2,2- trifluoroethanones
It with cyclopropyl chlorination of acetylene magnesium grignard reagent through asymmetric syntheses, is quenched, washs, organic layer is directly concentrated under reduced pressure obtained to dry
Object；
In embodiment 1-10, the efavirenz intermediate chiral purity that is obtained after efavirenz intermediate crude product refining >=
99.90%, even as high as 100%.
In embodiment 11-15, the efavirenz intermediate chiral purity that is obtained after efavirenz intermediate crude product refining
>=99.6%, still<99.90%, the embodiment 11 (referred to as control batch) not being concentrated under reduced pressure only reaches 100%.
The investigation that temperature is concentrated under reduced pressure, is depressured concentration amount and crystallization temperature, mode of operation: takes in a certain amount of efavirenz
Mesosome crude product is dissolved by heating with the methyl tertiary butyl ether(MTBE) of 0.63 weight ratio, the normal heptane of 6.7 weight ratios is added dropwise, and is controlled interior temperature, is opened
Begin the mixing organic solvent for being concentrated under reduced pressure into a certain amount of ratio, and cool down crystallization, and filtering obtains efavirenz intermediate finished product, investigates
Product chiral purity and yield.
(remarks: amounting to the statistics for listing 15 experimental programs, the embodiment 1-15 in corresponding patent)
A pair of investigation that temperature is concentrated under reduced pressure, is depressured concentration amount and crystallization temperature of experiment is specifically shown in Table 1；
Table 1: fixed organic solvent concentration amount is the crude product weight of 2 times of amounts, investigates and temperature and crystallization temperature pair is concentrated under reduced pressure
The influence of product quality and yield
Remarks: control batch is the crystallization technique not being concentrated under reduced pressure, investigates and criticizes as crystallization technique is concentrated under reduced pressure.
Brief summary:
1. organic solvent concentration amount is the chiral purity of investigation four batches of products of batch under conditions of the crude product weight of 2 times of amounts
99.9% or more is entirely reached, wherein three batches of chiral purities reach 100%, only (30 DEG C are concentrated under reduced pressure, then for investigation batch 2
15 DEG C of crystallizations) purity be 99.96%.
2. the yield 82.07%-82.12% of 15 DEG C of crystallization batches, relatively control batch yield improves 10% or so；30 DEG C of analysis
The yield 80.05-80.12% of brilliant batch, relatively control batch yield improve 8% or so.
It tests the investigation that two pairs are concentrated under reduced pressure temperature, decompression concentration amount and crystallization temperature and is specifically shown in Table 2；
Table 2: fixed organic solvent concentration amount is the crude product weight of 2 times of amounts, investigates and temperature and crystallization temperature pair is concentrated under reduced pressure
The influence of product quality and yield
Remarks: control batch is the crystallization technique not being concentrated under reduced pressure, investigates and criticizes as crystallization technique is concentrated under reduced pressure.
Brief summary:
1. organic solvent concentration amount is the chiral purity of investigation four batches of products of batch under conditions of the crude product weight of 2 times of amounts
Entirely reach 99.9% or more, control batch and the investigation of two 30 DEG C of crystallizations batch chiral purity are 100%, two 15 DEG C of crystallizations
Investigating batch chiral purity is 99.90%-99.92%.
2. the yield 79.76%-80.05% of 15 DEG C of crystallization batches, relatively control batch yield improves 11.5% or so；30℃
The yield 76.42-76.60% of crystallization batch, relatively control batch yield improve 8% or so.
It tests the investigation that three pairs are concentrated under reduced pressure temperature, decompression concentration amount and crystallization temperature and is specifically shown in Table 3；
Table 3: fixed organic solvent concentration amount is the crude product weight of 2.4 times of amounts, investigates and temperature and crystallization temperature is concentrated under reduced pressure
Influence to product quality and yield
Remarks: control batch is the crystallization technique not being concentrated under reduced pressure, investigates and criticizes as crystallization technique is concentrated under reduced pressure.
Brief summary:
1. organic solvent concentration amount is the chiral purity of investigation four batches of products of batch under conditions of the crude product weight of 2 times of amounts
Between 99.66%-99.85%, all < 99.9%.
2. the yield 83.08%-83.28% of 15 DEG C of crystallization batches, relatively control batch yield improves 11% or so；30 DEG C of analysis
The yield 81.24-81.35% of brilliant batch, relatively control batch yield improve 8% or so.
Easy to operate using the method for the present invention preparation efavirenz intermediate, high income, cost is relatively low, is suitble to industry metaplasia
It produces, and obtained efavirenz intermediate chiral purity >=99.90%, even as high as 100%.
In addition to the implementation, the present invention can also have other embodiments.It is all to use equivalent substitution or equivalent transformation shape
At technical solution, fall within the scope of protection required by the present invention.
Claims (10)
1. a kind of preparation method of high chiral purity efavirenz intermediate, it is characterised in that: specifically includes the following steps:
Step (1): efavirenz intermediate crude product is mixed with benign organic solvent, heating, to efavirenz intermediate
Crude product all after dissolution, is kept the temperature；
Step (2): certain temperature is kept, bad organic solvent is slowly dropped in the dissolution system of step (1)；
Step (3): after being added dropwise, certain temperature is kept, a certain amount of mixing organic solvent is concentrated under reduced pressure；
Step (4): cooling crystallization is filtered, is washed, and drying obtains the efavirenz intermediate of high chiral purity.
2. the preparation method of high chiral purity efavirenz intermediate according to claim 1, it is characterised in that: it is described according to
Fei Weilun crude intermediate is 1- (2- amino -5- chlorphenyl) -2,2,2- trifluoroethanone and cyclopropyl chlorination of acetylene magnesium grignard reagent
It through asymmetric syntheses, is quenched, washs, organic layer is directly concentrated under reduced pressure obtained to dry.
3. the preparation method of high chiral purity efavirenz intermediate according to claim 1, it is characterised in that: it is described according to
The chiral purity of Fei Weilun crude intermediate is 95.0-99.0%.
4. the preparation method of high chiral purity efavirenz intermediate according to claim 1, it is characterised in that:
Benign organic solvent as described in step (1) is selected from one of methyl tertiary butyl ether(MTBE), tetrahydrofuran, acetone, preferably first
Base tertbutyl ether；
Bad organic solvent described in step (2) is selected from one of normal heptane, n-hexane, petroleum ether, preferably normal heptane.
5. the preparation method of high chiral purity efavirenz intermediate according to claim 1, it is characterised in that:
The weight ratio of the efavirenz intermediate crude product and benign organic solvent is 1:(0.5-5)；
The weight ratio of the efavirenz intermediate crude product and bad organic solvent is 1:(5-100).
6. the preparation method of high chiral purity efavirenz intermediate according to claim 1, it is characterised in that: the step
Suddenly the dropping temperature range of (2) is 25-80 DEG C, preferably 50-55 DEG C.
7. the preparation method of high chiral purity efavirenz intermediate according to claim 1, it is characterised in that: the step
Suddenly the negative pressure concentration vacuum degree of (3) is -0.01 ~ -0.09Mpa, and thickening temperature is 25 ~ 80 DEG C, preferably 30-50 DEG C.
8. the preparation method of high chiral purity efavirenz intermediate according to claim 1, it is characterised in that: it is described according to
Fei Weilun crude intermediate is 1:(1- with a certain amount of weight ratio for mixing organic solvent of reduced pressure described in step (3)
100).
9. the preparation method of high chiral purity efavirenz intermediate according to claim 1, it is characterised in that: the step
Suddenly the cooling crystallization temperature of (4) is 0-40 DEG C, preferably 15-30 DEG C.
10. the preparation method of high chiral purity efavirenz intermediate according to claim 1, it is characterised in that: described
Chiral purity degree >=99.90% of the efavirenz intermediate for the high chiral purity that step (4) obtains.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114044759A (en) * | 2021-11-18 | 2022-02-15 | 盐城迪赛诺制药有限公司 | Application of novel Effevirgren reaction process technology |
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| CN101786959A (en) * | 2009-01-23 | 2010-07-28 | 上海迪赛诺医药发展有限公司 | Method for preparing chiral cylopropyl acetenyl tertiary alcohol compound |
| WO2011000532A2 (en) * | 2009-07-03 | 2011-01-06 | Archimica Gmbh | Method for the enantioselective addition of organometallic carbon nucleophiles to trifluoromethyl ketones and use of the method in the synthesis of hiv reverse transcriptase inhibitors |
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| CN1276781A (en) * | 1997-09-03 | 2000-12-13 | 麦克公司 | Process for enhancing optical purity of 2R-[1-hydroxy-1-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline |
| CN101786959A (en) * | 2009-01-23 | 2010-07-28 | 上海迪赛诺医药发展有限公司 | Method for preparing chiral cylopropyl acetenyl tertiary alcohol compound |
| WO2011000532A2 (en) * | 2009-07-03 | 2011-01-06 | Archimica Gmbh | Method for the enantioselective addition of organometallic carbon nucleophiles to trifluoromethyl ketones and use of the method in the synthesis of hiv reverse transcriptase inhibitors |
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| CN114044759A (en) * | 2021-11-18 | 2022-02-15 | 盐城迪赛诺制药有限公司 | Application of novel Effevirgren reaction process technology |
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