CN108947855A - A kind of synthetic method of efavirenz key intermediate - Google Patents
A kind of synthetic method of efavirenz key intermediate Download PDFInfo
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- CN108947855A CN108947855A CN201810907845.7A CN201810907845A CN108947855A CN 108947855 A CN108947855 A CN 108947855A CN 201810907845 A CN201810907845 A CN 201810907845A CN 108947855 A CN108947855 A CN 108947855A
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- China
- Prior art keywords
- key intermediate
- chloro
- synthetic method
- efavirenz
- chlorphenyl
- Prior art date
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- 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 23
- 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 23
- 229960003804 efavirenz Drugs 0.000 title claims abstract description 23
- 238000010189 synthetic method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- HLLCYQRFEVQMPO-UHFFFAOYSA-N Cl.ClNC1=C(C=CC=C1)C(C(F)(F)F)=O Chemical compound Cl.ClNC1=C(C=CC=C1)C(C(F)(F)F)=O HLLCYQRFEVQMPO-UHFFFAOYSA-N 0.000 claims abstract description 9
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims abstract description 8
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- GMJUEMUDNQJREQ-UHFFFAOYSA-N 1-[2-(chloroamino)phenyl]-2,2,2-trifluoroethanone Chemical compound ClNC1=C(C=CC=C1)C(C(F)(F)F)=O GMJUEMUDNQJREQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 7
- 239000003446 ligand Substances 0.000 claims abstract description 6
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 5
- IZISMXMXCLUHGI-UHFFFAOYSA-N n-(4-chlorophenyl)-2,2-dimethylpropanamide Chemical compound CC(C)(C)C(=O)NC1=CC=C(Cl)C=C1 IZISMXMXCLUHGI-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims abstract description 4
- ABIBCFTYJDONHE-UHFFFAOYSA-N [Mg].C#C Chemical compound [Mg].C#C ABIBCFTYJDONHE-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims abstract description 3
- 238000005844 autocatalytic reaction Methods 0.000 claims abstract description 3
- 230000000694 effects Effects 0.000 claims abstract description 3
- -1 chlorphenyl Chemical group 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 claims 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims 1
- 125000003368 amide group Chemical group 0.000 abstract description 6
- 238000010511 deprotection reaction Methods 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000011084 recovery Methods 0.000 abstract description 4
- 230000001988 toxicity Effects 0.000 abstract description 4
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 239000013110 organic ligand Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- NOKSRMDODJGCPZ-UHFFFAOYSA-N 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone Chemical compound NC1=CC=C(Cl)C=C1C(=O)C(F)(F)F NOKSRMDODJGCPZ-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 101900297506 Human immunodeficiency virus type 1 group M subtype B Reverse transcriptase/ribonuclease H Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical class CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- NPTDXPDGUHAFKC-UHFFFAOYSA-N ethynylcyclopropane Chemical group C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-dimethylbenzene Natural products CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920001084 poly(chloroprene) Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000005583 trifluoroacetylation reaction Methods 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a kind of synthetic method of efavirenz key intermediate, comprising the following steps: parachloroanilinum is reacted protection amino with pivaloyl chloride and obtains N- (4- chlorphenyl) -2,2- dimethylpropionamide；Above-mentioned product and trifluoroacetic anhydride after friedel-crafts acylation reaction, hydrolyze to obtain the chloro- 2- trifluoroacetyl aniline hydrochloride of 4- under alchlor effect in acid condition；Then alkalized to obtain the chloro- 2- trifluoroacetyl aniline of 4-; with ligand (1R; it 2S) is reacted in the catalyst system that -1- phenyl -2- (1- pyrrolidinyl) -1- propyl alcohol is formed with cyclopropyl chlorination of acetylene magnesium, efavirenz key intermediate is made through asymmetric Autocatalysis.The synthetic method of efavirenz key intermediate provided by the invention, raw material is cheap and easy to get, and agents useful for same toxicity is low, and reaction condition is mild, does not need continually to carry out amido protecting and deprotection, and route is succinct, and each reaction yield that walks is excellent, and total recovery is high.
Description
Technical field
The invention belongs to the preparation technical fields of efavirenz, and in particular to a kind of synthesis of efavirenz key intermediate
Method.
Background technique
Efavirenz, chemistry entitled (4S) -6- chloro- 4- (cyclopropyl acethlene base)-Isosorbide-5-Nitrae-dihydro -4- (trifluoromethyl) -2H-
3,1- benzoxazine -2- ketone.Efavirenz is a preferred line anti HIV-1 virus drug, belongs to -1 type (HIV- of human immunodeficiency virus
1) the non-nucleoside reverse transcriptase inhibitors of selectivity pass through noncompetitive combination and inhibit HIV-1 reverse transcriptase active, act on
Template, primer or nucleoside triphosphate have the emulative inhibiting effect of fraction concurrently, to prevent virus transcription and duplication.According to non-
Wei Lun is suitable for adult, teenager and the children infected with other antiviral drugs combination therapy HIV-1.
(S) -1- (2- amino -5- chlorphenyl) -1- trifluoromethyl -3- cyclopropyl -2- propine -1- alcohol is synthesis efavirenz
Key intermediate, existing synthetic method is parachloroanilinum after amido protecting, with n-BuLi and Trifluoroacetic Acid Ethyl Ester into
Trifluoroacetylation on row phenyl ring, then amino is deprotected to obtain the chloro- 2- trifluoroacetyl aniline hydrochloride of 4-, and alkalized to obtain 4-
Chloro- 2- trifluoroacetyl aniline, after 4- methoxyl group benzylalcohol protects amino, n-BuLi, cyclopropyl acetylene and ligand (1R,
2S) under the effect of -1- phenyl -2- (1- pyrrolidinyl) -1- propyl alcohol, in -50 DEG C of asymmetric syntheses (S) -5- chloro- α-(cyclopropyl second
Alkynyl) -2- [(4- methoxy-benzyl) amino]-α-(trifluoromethyl) benzyl alcohol, then through sodium borohydride deamination protect according to
The key intermediate of Fei Weilun, total recovery 62%.Organic ligand high price and dosage is larger in the method；The positive fourth of hazardous agents is used
Base lithium, and asymmetric catalysis synthesis need to carry out under low temperature (- 50 DEG C), severe reaction conditions, need frequent progress amido protecting and
Deprotection, it is cumbersome, be not suitable for industrial production.
Summary of the invention
The object of the present invention is to provide a kind of synthetic methods of efavirenz key intermediate, and raw material is cheap and easy to get, used
Reagent toxicity is low, and reaction condition is mild, does not need continually to carry out amido protecting and deprotection, and route is succinct, and each step reaction is received
Rate is excellent, and total recovery is high.
The present invention provides the following technical solutions:
A kind of synthetic method of efavirenz key intermediate, comprising the following steps:
S1: parachloroanilinum is reacted into protection amino with pivaloyl chloride and obtains N- (4- chlorphenyl) -2,2- dimethylpropionamide；
N- (4- the chlorphenyl) -2,2- dimethylpropionamide and trifluoroacetic anhydride obtained in S2:S1 is acted in alchlor
It is lower after friedel-crafts acylation reaction, hydrolyze to obtain the chloro- 2- trifluoroacetyl aniline hydrochloride of 4- in acid condition；
The chloro- 2- trifluoroacetyl aniline hydrochloride of 4- that S3:S2 is obtained is alkalized to obtain the chloro- 2- trifluoroacetyl aniline of 4-,
The chloro- 2- trifluoroacetyl aniline hydrochloride of 4- is in zinc chloride and ligand (1R, 2S) -1- phenyl -2- (1- pyrrolidinyl) -1- propyl alcohol
It is reacted in the catalyst system of formation with cyclopropyl chlorination of acetylene magnesium, while a small amount of sterling (S) -1- (2- amino -5- chlorphenyl)-is added
Efavirenz key intermediate (S) -1- is made through asymmetric Autocatalysis in 1- trifluoromethyl -3- cyclopropyl -2- propine -1- alcohol
(2- amino -5- chlorphenyl) -1- trifluoromethyl -3- cyclopropyl -2- propine -1- alcohol, reaction equation are as follows:
Preferably, in the S1 parachloroanilinum dissolution solvent be methyl tertiary butyl ether(MTBE) and sodium hydroxide solution mixing
Liquid.
Preferably, the reaction condition in the S1 is that first insulated and stirred reacts 2h at 10~15 DEG C, then is warmed to room temperature and stirs
Mix reaction 4h.
Preferably, the reaction condition in the S2 is to be stirred to react 4h at room temperature.
Preferably, ligand (1R, 2S) -1- phenyl -2- (1- pyrrolidinyl) -1- propyl alcohol and the chloro- 2- trifluoroacetyl group benzene of 4-
The molar ratio of amine is 0.4: 1.
Preferably, sterling (S) -1- (2- amino -5- chlorphenyl) -1- trifluoromethyl -3- cyclopropyl -2- propine -1- alcohol with
The molar ratio of the chloro- 2- trifluoroacetyl aniline of 4- is 0.2: 1.
The beneficial effects of the present invention are: the synthetic method of efavirenz key intermediate provided by the invention, raw material are inexpensive
It is easy to get, agents useful for same toxicity is low, and reaction condition is mild, does not need continually to carry out amido protecting and deprotection, route is succinct, respectively
It is excellent to walk reaction yield, total recovery is high.
Specific embodiment
A kind of synthetic method of efavirenz key intermediate, comprising the following steps:
S1: 25.50g parachloroanilinum is added into 70ml methyl tertiary butyl ether(MTBE) and 24ml sodium hydroxide solution (10mol/L)
In mixed liquor, 10 DEG C are cooled to, the pivaloyl chloride of 25.60g is slowly added dropwise, 40min is dripped off, 10~15 DEG C of insulated and stirred reactions
2h, then be warmed to room temperature and be stirred to react 4h.It is cooled to 0 DEG C, there is white crystal precipitation, is filtered, filter cake is washed with water, dry in 55 DEG C of decompressions
Dry 5h obtains white solid N- (4- chlorphenyl) -2,2- dimethylpropionamide 41.27g；
S2: 60.10g aluminum trichloride (anhydrous) is added in 300ml methylene chloride, is cooled to -20 DEG C, 44.10g is slowly added dropwise
TFAA, temperature control -23~-20 DEG C, 1h are dripped off.Insulation reaction 2h.- 25 DEG C of points of 3 crowdes of addition 38.11g N- (4- chlorphenyl) -2,2-
Dimethylpropionamide adds in 30min, is warmed to room temperature naturally and is stirred to react 3h.Above-mentioned reaction solution is added slowly in ice water, and
Temperature < 15 DEG C are controlled, is finished, is warmed to room temperature and is stirred to react 1h.Above-mentioned reaction solution is extracted with ethyl acetate, merges organic phase, subtracts
Pressure has been concentrated into a small amount of epitaxial and has generated, and the dilution of 100ml glacial acetic acid is added, in 30 DEG C of dropwise addition 70ml hydrochloric acid (3mol/L)；Drop finishes, in
After 30~35 DEG C of stirring 1h, 70~75 DEG C of stirring 4h are heated to, 0~5 DEG C of stirring 2h is then down to again, there is white crystal precipitation,
Centrifugation filters, and filter cake is rinsed with ethyl acetate, 10h is dried under reduced pressure in 50 DEG C and obtains the chloro- 2- trifluoroacetyl of 39.78g white solid 4-
Base anilinechloride；
S3: 0.5L sodium hydroxide solution (1mol/L) is slowly dropped into the chloro- 2- trifluoroacetyl aniline hydrochloric acid of 39.11g4-
In the white opacity liquid of salt and 300ml water, drop finishes, and is adjusted to pH 6~7, is stirred to react 1h.Centrifugation, filtering, filter cake are rinsed with water,
It is recrystallized again with normal heptane, is finally dried under reduced pressure 8h at 45 DEG C and obtains 32.67g faint yellow solid.
3.15g magnesium powder is added in 10ml THF, in 25 DEG C of addition 1ml bromoethanes, reacting liquid temperature rise to 40 DEG C and
Solution is become grey and is had a small amount of bubble to generate from colourless, is then naturally cooling to 20 DEG C.In 20 DEG C of dropwise addition 11.81g1- neoprenes
The mixed liquor of alkane and 45ml THF drips off and is warming up to 50 DEG C and is stirred to react 3h.10~15 DEG C are cooled to, 8.21g cyclopropyl second is added dropwise
Alkynes；Drop finishes, and is stirred to react 2h in 10~20 DEG C, obtains cyclopropyl chlorination of acetylene magnesium.Under the conditions of 15 DEG C, by 8.85g 2,2- dimethyl-
1- propyl alcohol, 5.81g sterling (S) -1- (2- amino -5- chlorphenyl) -1- trifluoromethyl -3- cyclopropyl -2- propine -1- are pure and mild
The 20ml toluene solution of 8.22g organic ligand (1R, 2S) -1- phenyl -2- (1- pyrrolidinyl) -1- propyl alcohol drops to 12.10g hydrogenation
In the 30ml THF supernatant liquid of sodium, drop finishes, and rises to 20~25 DEG C and is stirred to react 2h.- 15 DEG C are cooled to, point 3 batches of addition 18.11g chlorine
Change zinc, 30min is finished；It is warming up to 25~30 DEG C and is stirred to react 3h.15~20 DEG C are cooled to, above-mentioned gained cyclopropyl second is slowly added dropwise
Alkynes magnesium chloride, drop finish, and insulated and stirred reacts 3h.- 10 DEG C are cooled to, the chloro- 2- trifluoroacetyl aniline of 22.50g 4-, room is added
Temperature is stirred to react 2h, is then heated to 40 DEG C, then react 12h.Temperature < 10 DEG C are controlled, above-mentioned reaction solution is added into saturation chlorination
In aqueous ammonium, hydrochloric acid is added to be adjusted to water phase pH 2~3, catalyst (1R, 2S) -1- phenyl -2- (1- pyrrolidinyl) -1- third will be contained
The water phase of alcohol is transferred in returnable bottle, and organic phase is washed with water to neutrality, with being concentrated under reduced pressure after anhydrous magnesium sulfate drying, is obtained faint yellow
Powder；White powder (S) -1- (2- amino -5- chlorphenyl) -1- trifluoromethyl -3- cyclopropyl -2- third is recrystallized to obtain through dimethylbenzene
Alkynes -1- alcohol 30.61g, the 5.81g being added before subtracting, it is practical to obtain product 24.80g, purity 99.1%.
The synthetic method of efavirenz key intermediate provided by the invention, raw material is cheap and easy to get, and agents useful for same toxicity is low,
Reaction condition is mild, does not need continually to carry out amido protecting and deprotection, and route is succinct, and each reaction yield that walks is excellent, total to receive
Rate is high.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, although referring to aforementioned reality
Applying example, invention is explained in detail, for those skilled in the art, still can be to aforementioned each implementation
Technical solution documented by example is modified or equivalent replacement of some of the technical features.It is all in essence of the invention
Within mind and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (6)
1. a kind of synthetic method of efavirenz key intermediate, which comprises the following steps:
S1: parachloroanilinum is reacted into protection amino with pivaloyl chloride and obtains N- (4- chlorphenyl) -2,2- dimethylpropionamide；
N- (4- the chlorphenyl) -2,2- dimethylpropionamide and trifluoroacetic anhydride obtained in S2:S1 passes through under alchlor effect
After friedel-crafts acylation reaction, the chloro- 2- trifluoroacetyl aniline hydrochloride of 4- is hydrolyzed to obtain in acid condition；
S3:S2 obtain the chloro- 2- trifluoroacetyl aniline hydrochloride of 4- alkalized the chloro- 2- trifluoroacetyl aniline of 4-, 4- are chloro-
2- trifluoroacetyl aniline hydrochloride is formed in zinc chloride and ligand (1R, 2S) -1- phenyl -2- (1- pyrrolidinyl) -1- propyl alcohol
Catalyst system in reacted with cyclopropyl chlorination of acetylene magnesium, while a small amount of sterling (S) -1- (2- amino -5- chlorphenyl) -1- three is added
Efavirenz key intermediate (S) -1- (2- is made through asymmetric Autocatalysis in methyl fluoride -3- cyclopropyl -2- propine -1- alcohol
Amino -5- chlorphenyl) -1- trifluoromethyl -3- cyclopropyl -2- propine -1- alcohol, reaction equation are as follows:
2. a kind of synthetic method of efavirenz key intermediate according to claim 1, which is characterized in that in the S1
The dissolution solvent of parachloroanilinum is the mixed liquor of methyl tertiary butyl ether(MTBE) and sodium hydroxide solution.
3. a kind of synthetic method of efavirenz key intermediate according to claim 1, which is characterized in that in the S1
Reaction condition be that first insulated and stirred reacts 2h at 10~15 DEG C, then be warmed to room temperature and be stirred to react 4h.
4. a kind of synthetic method of efavirenz key intermediate according to claim 1, which is characterized in that in the S2
Reaction condition be stirred to react 4h at room temperature.
5. a kind of synthetic method of efavirenz key intermediate according to claim 1, which is characterized in that ligand (1R,
2S) molar ratio of -1- phenyl -2- (1- pyrrolidinyl) -1- propyl alcohol and the chloro- 2- trifluoroacetyl aniline of 4- is 0.4: 1.
6. a kind of synthetic method of efavirenz key intermediate according to claim 1, which is characterized in that sterling (S)-
1- (2- amino -5- chlorphenyl) -1- trifluoromethyl -3- cyclopropyl -2- propine -1- alcohol and the chloro- 2- trifluoroacetyl aniline of 4-
Molar ratio is 0.2: 1.
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Cited By (5)
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| CN111548317A (en) * | 2020-04-28 | 2020-08-18 | 苏州纪元康生物科技有限公司 | Efavirenz synthesis method and method for preparing intermediate thereof |
| CN113717064A (en) * | 2021-09-30 | 2021-11-30 | 浙江工业大学 | Synthesis method of efavirenz intermediate 1- (2-amino-5-chlorphenyl) -2,2, 2-trifluoroacetone |
| CN113979877A (en) * | 2021-10-27 | 2022-01-28 | 盐城迪赛诺制药有限公司 | Refining method for improving purity of 4-chloro-2-trifluoroacetylaniline mother liquor |
| CN115181072A (en) * | 2021-11-18 | 2022-10-14 | 盐城迪赛诺制药有限公司 | Application of novel Effevirgren reaction process technology |
| CN115197075A (en) * | 2021-11-18 | 2022-10-18 | 盐城迪赛诺制药有限公司 | Preparation method of efavirenz key intermediate |
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| CN111548317A (en) * | 2020-04-28 | 2020-08-18 | 苏州纪元康生物科技有限公司 | Efavirenz synthesis method and method for preparing intermediate thereof |
| CN113717064A (en) * | 2021-09-30 | 2021-11-30 | 浙江工业大学 | Synthesis method of efavirenz intermediate 1- (2-amino-5-chlorphenyl) -2,2, 2-trifluoroacetone |
| CN113717064B (en) * | 2021-09-30 | 2024-02-23 | 浙江工业大学 | Synthesis method of efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoro-ethanone |
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| CN115181072A (en) * | 2021-11-18 | 2022-10-14 | 盐城迪赛诺制药有限公司 | Application of novel Effevirgren reaction process technology |
| CN115197075A (en) * | 2021-11-18 | 2022-10-18 | 盐城迪赛诺制药有限公司 | Preparation method of efavirenz key intermediate |
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