CN107033010A - A kind of method of asymmetric syntheses anti-AIDS drug efavirenz key intermediate - Google Patents
A kind of method of asymmetric syntheses anti-AIDS drug efavirenz key intermediate Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 15
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 title claims abstract description 11
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 title claims abstract description 11
- 229960003804 efavirenz Drugs 0.000 title claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 8
- 229940124321 AIDS medicine Drugs 0.000 title claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- -1 alcohol compound Chemical class 0.000 claims abstract description 13
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 6
- 239000007787 solid Substances 0.000 claims description 10
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical group [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 10
- 239000012044 organic layer Substances 0.000 claims description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 6
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 claims description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- 238000013517 stratification Methods 0.000 claims description 5
- 238000010792 warming Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 235000005074 zinc chloride Nutrition 0.000 claims description 5
- 239000011592 zinc chloride Substances 0.000 claims description 5
- FMCGSUUBYTWNDP-ONGXEEELSA-N (1R,2S)-2-(dimethylamino)-1-phenyl-1-propanol Chemical compound CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 FMCGSUUBYTWNDP-ONGXEEELSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- FMCGSUUBYTWNDP-UHFFFAOYSA-N N-Methylephedrine Natural products CN(C)C(C)C(O)C1=CC=CC=C1 FMCGSUUBYTWNDP-UHFFFAOYSA-N 0.000 claims description 4
- 229960002221 methylephedrine Drugs 0.000 claims description 4
- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 claims description 4
- 150000003751 zinc Chemical class 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical group [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 229940102001 zinc bromide Drugs 0.000 claims description 3
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- LZTRCELOJRDYMQ-UHFFFAOYSA-N triphenylmethanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1=CC=CC=C1 LZTRCELOJRDYMQ-UHFFFAOYSA-N 0.000 claims description 2
- 244000248349 Citrus limon Species 0.000 claims 2
- 235000005979 Citrus limon Nutrition 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical class CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 abstract description 11
- 235000019445 benzyl alcohol Nutrition 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000007259 addition reaction Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 229910003002 lithium salt Inorganic materials 0.000 abstract description 2
- 159000000002 lithium salts Chemical class 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 159000000000 sodium salts Chemical class 0.000 abstract description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 2
- 239000000460 chlorine Substances 0.000 abstract 2
- 229910052801 chlorine Inorganic materials 0.000 abstract 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 abstract 1
- 125000006493 trifluoromethyl benzyl group Chemical group 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 239000003579 shift reagent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of method of asymmetric syntheses anti-AIDS drug efavirenz key intermediate, belong to medical synthesis technical field.Including 2 methyltetrahydrofurans, alkaline reagent, alcohol compound, chiral aminoalcohol solution, cyclopropyl acethlene are reacted, after add the amino trifluoro-benzene ketone of 5 chlorine 2 occur addition reaction, again by terminating reaction liquid terminating reaction, the chlorine a cyclopropyl acethlene a trifluoromethyl benzyl alcohols of key intermediate (S) 2 amino 5 of efavirenz are obtained.Avoiding needs the operating process of the lithium salts, sodium salt or its RMgBr that first prepare cyclopropyl acethlene in industrial production, significantly reduce the operation difficulty and cost of reaction, is adapted to industrialized production.
Description
Technical field
The invention belongs to medical synthesis technical field, and in particular to a kind of synthetic method of efavirenz.
Background technology
Entitled (the S) -6- of efavirenz chemistry chloro- 4- (cyclopropyl acethlene base) -1,4- dihydros -4- (trifluoromethyl) -2H-
3,1- benzoxazine -2- ketone, its structure is as follows：
Efavirenz, which obtains U.S. FDA for 1998, to be ratified to be used for anti human immune deficiency virus (HIV) infection, is existing international AIDS
Treat non-core former times class RTI (NNRTI) class choice drug that guilding principle is recommended.Efavirenz combines 2 core former times
The first-line treatment scheme that class RTI (NRTI) class medicine can infect as AntiHIV1 RT activity.
(S) the chloro- a- cyclopropyl acethlenes-a- trifluoromethyl benzyl alcohols of -2- amino -5- are a keys for synthesizing efavirenz
Intermediate, its synthetic method reported at present mainly has two kinds：A kind of is first to protect the amino of the chloro- 2- amino trifluoro-benzene ketones of 5-
Shield is got up, then in the presence of chiral shift reagent, is reacted with cyclopropyl alkynes lithium, amido protecting group is then sloughed again and is somebody's turn to do
Intermediate, is shown in J. Org. Chem., 1998,63:Its synthetic route of 8536-8543. is as follows：
Another method is the chloro- 2- amino trifluoromethyl benzonitriles of 5- in the presence of zinc chloride and chiral ligand and auxiliary reagent
The directly reaction of the RMgBr of ketone and cyclopropyl acethlene obtains the intermediate, sees that its synthetic route of the A. of CN 101786959 is as follows
It is shown：
First method is related to the protection and deprotection of amino；Second method needs to prepare ring the third acetylene grignard reagent.They
Both increase the synthesis cost of the chloro- a- cyclopropyl acethlenes-a- trifluoromethyl benzyl alcohols of (S) -2- amino -5-.
The content of the invention
In view of the above-mentioned problems, the invention discloses a kind of asymmetric syntheses anti-AIDS drug efavirenz key intermediate
Method, preparation process is simple, cost-effective.
It is described to comprise the following steps：
（1）2- methyltetrahydrofurans and 4.0 ~ 8.0mol alkaline reagents are added to reaction bulb, 5 ~ 10 DEG C are cooled to, it is added dropwise 0.9 ~
Temperature is within 35 DEG C in 1.1mol alcohol compounds, control；
（2）10 DEG C are cooled to after dripping, temperature in 1.1 ~ 1.5mol chiral aminoalcohol solution, control is added dropwise and within 35 DEG C, is added dropwise
5 DEG C are cooled to after complete；Temperature in 1.1 ~ 1.4mol n-butyl chloride base magnesium, control is added dropwise within 20 DEG C, 0 is cooled to after dripping
℃；1.0 ~ 1.3mol cyclopropyl acethlenes are added dropwise, 1h is stirred at 25 DEG C, 1.2 ~ 1.5mol inorganic zinc salts are added, 3h is stirred at 25 DEG C；
（3）- 10 DEG C are cooled to, the chloro- 2- amino trifluoro-benzene ketones of 1mol 5- are added, 3 ~ 3.5h is reacted, 5 DEG C of reactions 2.5 are warming up to
~ 3.5h, then 20 DEG C of 3 ~ 5h of reaction are to slowly warm up to, 5 ~ 10 DEG C are cooled to after having reacted；
（4）Terminating reaction liquid terminating reaction is added dropwise, stratification after 1 ~ 2h is stirred at room temperature；Organic layer with saturated common salt water washing extremely
Neutrality, anhydrous magnesium sulfate is dried；Organic layer is evaporated, and adds normal heptane, there is white solid precipitation, filters and dry to constant weight and obtain white
Color solid.
The alkaline reagent is Sodamide, butyl lithium, sodium hydride.
The alcohol compound is selected from trifluoroethanol, ethapon, the tert-butyl alcohol, neopentyl alcohol, triphenylcarbinol, methanol.
The chiral aminoalcohol is (1R, 2S)-N- pyrrolidinyls norephedrine, (+)-N, N- dimethyl-a- (hydroxyls
Methyl)-R- hydroxyls-p-nitrophenyl ethamine.
The inorganic zinc salt is zinc chloride, zinc bromide.
The terminating reaction liquid is one or more mixing in ammonium chloride, hydrochloric acid, sulfuric acid and citric acid.
The present invention is anti-by 2- methyltetrahydrofurans, alkaline reagent, alcohol compound, chiral aminoalcohol solution, cyclopropyl acethlene
Should, addition reaction occurs for the rear chloro- 2- amino trifluoro-benzene ketones of 5- that add, then by terminating reaction liquid terminating reaction, obtains according to non-
The Wei Lun chloro- a- cyclopropyl acethlenes-a- trifluoromethyl benzyl alcohols of key intermediate (S) -2- amino -5-.Avoid industrial production
The middle operating process for needing first to prepare the lithium salts, sodium salt or its RMgBr of cyclopropyl acethlene, significantly reduces reaction
Operation difficulty and cost, are adapted to industrialized production.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1
Dry 2- methyltetrahydrofurans 90m1 and Sodamide (0.42mol) is added to reaction bulb, 5 DEG C are cooled to, trifluoro is added dropwise
Temperature is within 35 DEG C in ethanol (0.09mol), control.10 DEG C are cooled to after dripping, (1R, 2S)-N- pyrrolidinyls are added dropwise and go
The 2- methyltetrahydrofurans of methylephedrine (0.12mol)（60ml）, the interior temperature of control is within 35 DEG C.5 DEG C are cooled to after dripping,
The 2- methyltetrahydrofuran solution of n-butyl chloride base magnesium is added dropwise（65ml, 1.8mol/L）, the interior temperature of control is within 20 DEG C.It is added dropwise
0 DEG C is cooled to after complete, cyclopropyl acethlene (0.11mol) is added dropwise, is stirred 1 hour at 25 DEG C, zinc chloride (0.14mol) is added,
25 DEG C are stirred 3 hours.Then it is cooled to -10 DEG C of addition chloro- 2- amino trifluoro-benzene ketones of 5-（20.0g, 0.09mol), at a temperature of this
React 3.5 hours, be warming up to 5 DEG C and react 3.5 hours, then be to slowly warm up to 20 DEG C and react 5 hours.5 DEG C are cooled to after having reacted
Left and right, is added dropwise to citric acid solution (150m1) terminating reaction of weight concentration 30%, stratification after 1 hour is stirred at room temperature.Have
Machine layer is again with saturated common salt water washing to neutrality, anhydrous magnesium sulfate drying.Organic layer is evaporated, and adds normal heptane 150m1, there is white
Solid is separated out, and is filtered and is dried to constant weight and obtains white solid 25.2g, HPLC purity 99.3%, and ee values are 99.5 %.
Embodiment 2
Dry 2- methyltetrahydrofurans 90m1 and sodium hydride (0.55mol) is added to reaction bulb, 5 DEG C are cooled to, trifluoro is added dropwise
Temperature is within 35 DEG C in ethanol (0.10mol), control.10 DEG C are cooled to after dripping, (1R, 2S)-N- pyrrolidinyls are added dropwise and go
The 2- methyltetrahydrofurans of methylephedrine (0.11mol)（60ml）, the interior temperature of control is within 35 DEG C.5 DEG C are cooled to after dripping,
The 2- methyltetrahydrofuran solution of n-butyl chloride base magnesium is added dropwise（65ml, 1.8mol/L）, the interior temperature of control is within 20 DEG C.It is added dropwise
0 DEG C is cooled to after complete, cyclopropyl acethlene (0.11mol) is added dropwise, is stirred 1 hour at 25 DEG C, zinc chloride (0.14mol) is added,
25 DEG C are stirred 3 hours.Then it is cooled to -10 DEG C of addition chloro- 2- amino trifluoro-benzene ketones of 5-（20.0g, 0.09mol), at a temperature of this
React 3.5 hours, be warming up to 5 DEG C and react 3.5 hours, then be to slowly warm up to 20 DEG C and react 5 hours.5 DEG C are cooled to after having reacted
Left and right, is added dropwise to sulfuric acid solution (100m1) terminating reaction of weight concentration 20%, stratification after 2 hours is stirred at room temperature.It is organic
Layer is again with saturated common salt water washing to neutrality, anhydrous magnesium sulfate drying.Organic layer is evaporated, and adds normal heptane 150m1, has white solid
Body is separated out, and is filtered and is dried to constant weight and obtains white solid 22.2g, HPLC purity 98.5%, and ee values are 99.3 %.
Embodiment 3
Dry 2- methyltetrahydrofurans 90m1 and butyl lithium (0.43mol) is added to reaction bulb, 10 DEG C are cooled to, trifluoro is added dropwise
Temperature is within 35 DEG C in ethanol (0.09mol), control.10 DEG C are cooled to after dripping, (1R, 2S)-N- pyrrolidinyls are added dropwise and go
The 2- methyltetrahydrofurans of methylephedrine (0.11mol)（60ml）, the interior temperature of control is within 35 DEG C.5 DEG C are cooled to after dripping,
The 2- methyltetrahydrofuran solution of n-butyl chloride base magnesium is added dropwise（65ml, 1.8mol/L）, the interior temperature of control is within 20 DEG C.It is added dropwise
0 DEG C is cooled to after complete, cyclopropyl acethlene (0.10mol) is added dropwise, is stirred 1 hour at 25 DEG C, zinc bromide (0.14mol) is added,
25 DEG C are stirred 3 hours.Then it is cooled to -10 DEG C of addition chloro- 2- amino trifluoro-benzene ketones of 5-（20.0g, 0.09mol), at a temperature of this
React 3.0 hours, be warming up to 5 DEG C and react 2.5 hours, then be to slowly warm up to 20 DEG C and react 3 hours.10 DEG C are cooled to after having reacted
Left and right, is added dropwise to ammonium chloride solution (200m1) terminating reaction of weight concentration 15%, stratification after 2 hours is stirred at room temperature.Have
Machine layer is again with saturated common salt water washing to neutrality, anhydrous magnesium sulfate drying.Organic layer is evaporated, and adds normal heptane 150m1, there is white
Solid is separated out, and is filtered and is dried to constant weight and obtains white solid 24.2g, HPLC purity 99.5%, and ee values are 99.7 %.
Claims (6)
1. a kind of method of asymmetric syntheses anti-AIDS drug efavirenz key intermediate, it is characterised in that step is as follows：
（1）2- methyltetrahydrofurans and 4.0 ~ 8.0mol alkaline reagents are added to reaction bulb, 5 ~ 10 DEG C are cooled to, it is added dropwise 0.9 ~
Temperature is within 35 DEG C in 1.1mol alcohol compounds, control；
（2）10 DEG C are cooled to after dripping, temperature in 1.1 ~ 1.5mol chiral aminoalcohol solution, control is added dropwise and within 35 DEG C, is added dropwise
5 DEG C are cooled to after complete；Temperature in 1.1 ~ 1.4mol n-butyl chloride base magnesium, control is added dropwise within 20 DEG C, 0 is cooled to after dripping
℃；1.0 ~ 1.3mol cyclopropyl acethlenes are added dropwise, 1h is stirred at 25 DEG C, 1.2 ~ 1.5mol inorganic zinc salts are added, 3h is stirred at 25 DEG C；
（3）- 10 DEG C are cooled to, the chloro- 2- amino trifluoro-benzene ketones of 1mol 5- are added, 3 ~ 3.5h is reacted, 5 DEG C of reactions 2.5 are warming up to
~ 3.5h, then 20 DEG C of 3 ~ 5h of reaction are to slowly warm up to, 5 ~ 10 DEG C are cooled to after having reacted；
（4）Terminating reaction liquid terminating reaction is added dropwise, stratification after 1 ~ 2h is stirred at room temperature；Organic layer with saturated common salt water washing extremely
Neutrality, anhydrous magnesium sulfate is dried；Organic layer is evaporated, and adds normal heptane, there is white solid precipitation, filters and dry to constant weight and obtain white
Color solid.
2. according to the method described in claim 1, it is characterised in that the alkaline reagent is Sodamide, butyl lithium, sodium hydride.
3. according to the method described in claim 1, it is characterised in that the alcohol compound be selected from trifluoroethanol, ethapon,
The tert-butyl alcohol, neopentyl alcohol, triphenylcarbinol, methanol.
4. according to the method described in claim 1, it is characterised in that the chiral aminoalcohol is that (1R, 2S)-N- pyrrolidinyls are gone
Methylephedrine, (+)-N, N- dimethyl-a- (hydroxymethyl)-R- hydroxyls-p-nitrophenyl ethamine.
5. according to the method described in claim 1, it is characterised in that the inorganic zinc salt is zinc chloride, zinc bromide.
6. according to the method described in claim 1, it is characterised in that the terminating reaction liquid is ammonium chloride, hydrochloric acid, sulfuric acid and lemon
One or more mixing in lemon acid.
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| CN201710313357.9A CN107033010A (en) | 2017-05-05 | 2017-05-05 | A kind of method of asymmetric syntheses anti-AIDS drug efavirenz key intermediate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113880693A (en) * | 2021-11-12 | 2022-01-04 | 盐城迪赛诺制药有限公司 | Method for recovering trifluoroethanol in multi-component solvent |
| CN114920268A (en) * | 2022-06-27 | 2022-08-19 | 盐城迪赛诺制药有限公司 | Method for separating metal salts from mixed salts in efavirenz intermediate production wastewater |
-
2017
- 2017-05-05 CN CN201710313357.9A patent/CN107033010A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113880693A (en) * | 2021-11-12 | 2022-01-04 | 盐城迪赛诺制药有限公司 | Method for recovering trifluoroethanol in multi-component solvent |
| CN113880693B (en) * | 2021-11-12 | 2022-08-23 | 盐城迪赛诺制药有限公司 | Method for recovering trifluoroethanol in multi-component solvent |
| CN114920268A (en) * | 2022-06-27 | 2022-08-19 | 盐城迪赛诺制药有限公司 | Method for separating metal salts from mixed salts in efavirenz intermediate production wastewater |
| CN114920268B (en) * | 2022-06-27 | 2023-09-05 | 盐城迪赛诺制药有限公司 | Method for separating metal salts from mixed salts of wastewater from production of efavirenz intermediates |
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