CN113717064B - Synthesis method of efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoro-ethanone - Google Patents
Synthesis method of efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoro-ethanone Download PDFInfo
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- CN113717064B CN113717064B CN202111162140.5A CN202111162140A CN113717064B CN 113717064 B CN113717064 B CN 113717064B CN 202111162140 A CN202111162140 A CN 202111162140A CN 113717064 B CN113717064 B CN 113717064B
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- -1 2-amino-5-chlorophenyl Chemical group 0.000 title claims abstract description 51
- 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
- 229960003804 efavirenz Drugs 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
- 238000001308 synthesis method Methods 0.000 title claims description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 239000003054 catalyst Substances 0.000 claims abstract description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 10
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000008569 process Effects 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 45
- 239000003960 organic solvent Substances 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 239000007818 Grignard reagent Substances 0.000 claims description 9
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 7
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- 150000004795 grignard reagents Chemical class 0.000 claims description 4
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 4
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 238000011068 loading method Methods 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 5
- 230000009471 action Effects 0.000 abstract description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000005660 chlorination reaction Methods 0.000 abstract description 4
- 239000007868 Raney catalyst Substances 0.000 abstract description 2
- 229910000564 Raney nickel Inorganic materials 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000013076 target substance Substances 0.000 description 3
- BCJUMGSHTLYECD-UHFFFAOYSA-N 2,2,2-trifluoro-1-piperidin-1-ylethanone Chemical compound FC(F)(F)C(=O)N1CCCCC1 BCJUMGSHTLYECD-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical group [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JRGGUPZKKTVKOV-UHFFFAOYSA-N 1-bromo-3-chlorobenzene Chemical compound ClC1=CC=CC(Br)=C1 JRGGUPZKKTVKOV-UHFFFAOYSA-N 0.000 description 1
- JXMZUNPWVXQADG-UHFFFAOYSA-N 1-iodo-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1I JXMZUNPWVXQADG-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 description 1
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229910052740 iodine Chemical group 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- VMVNZNXAVJHNDJ-UHFFFAOYSA-N methyl 2,2,2-trifluoroacetate Chemical compound COC(=O)C(F)(F)F VMVNZNXAVJHNDJ-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a synthetic method of an efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoro-ethanone. The method takes o-halonitrobenzene as an initial raw material, firstly reacts with trifluoroacetyl compound to obtain an intermediate compound, then the intermediate compound is catalyzed and reduced by Raney nickel under the action of hydrogen to obtain a reduced compound, and finally the reduced compound reacts with N-chlorosuccinimide under the catalysis of dimethyl sulfoxide as a catalyst to obtain a target product 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethanone. The method has the characteristics of short steps, simple process, simple and convenient operation, mild aniline chlorination reaction conditions, high total yield and the like, thereby having great implementation value and social and economic benefits.
Description
Technical Field
The invention relates to the technical field of synthesis of pharmaceutical and chemical intermediates, in particular to a method for preparing an anti-AIDS drug Efeveren key intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethanone (I) by taking o-halonitrobenzene (II) as a starting material.
Background
Efavirenz (Efavirenz) is a non-nucleoside reverse transcriptase inhibitor developed by Merck corporation in America at the earliest time, and is marketed in the United states for the first time in 2 months in 1992, and is clinically used as one of important drug varieties for treating AIDS, and has the characteristics of long half-life period, good tolerance, high selectivity, good treatment effect, small adverse reaction and the like. At present, the traditional Chinese medicine has become a first-line medicine for treating AIDS in China, and has great prospect. Therefore, the research on the synthesis method of the key intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethanone (I) has theoretical research value and certain economic benefit.
The structural formula of the efavirenz key intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoro-ethanone (I) is shown as follows:
before the present invention is presented, the main synthesis method of 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethanone (I) is as follows:
1) In 2020, patent US2020062722A1 reports that p-chloroaniline is used as a raw material, firstly reacts with di-tert-butyl dicarbonate to perform amino protection, then reacts with trifluoroacetyl piperidine under the action of butyl lithium, and is introduced with trifluoroacetyl at the ortho position of amino, finally removes the protecting group under an acidic condition to obtain hydrochloride thereof, and then alkalizes to obtain a target substance. The synthetic route is as follows:
the route has four steps, wherein the second step needs to use trifluoroacetyl piperidine as a raw material, is expensive, requires the use of equivalent butyl lithium (anhydrous and oxygen-free reaction is required at the temperature of minus 40 ℃), has strict reaction conditions, and is not easy to realize industrial production.
2) In 2018, patent CN108997150a reports that o-chloroaniline is taken as a raw material, firstly reacts with pivaloyl chloride to perform amino protection, then reacts with a grignard reagent prepared from magnesium powder to perform nucleophilic substitution reaction, then performs chlorination reaction under the action of chlorine, finally removes a protecting group under the system of hydrochloric acid and glacial acetic acid to obtain hydrochloride thereof, and then alkalizes the hydrochloride to obtain a target substance. The synthetic route is as follows:
the route has five steps, the initiation of the second-step format reaction is difficult, the raw materials of trifluoroacetyl chloride for the Grignard reaction and the raw material of chlorine for the third-step chlorination reaction are gases, the requirements on reaction equipment are high, the toxicity is high, and the large-scale production is not easy to realize.
3) In 2016, patent CN106518636a reported that m-bromochlorobenzene was used as a starting material, and (a) was subjected to grignard exchange reaction with isopropyl magnesium chloride, respectively; (b) Lithium bromide exchange occurs under the action of butyl lithium, nucleophilic substitution reaction occurs, nitric acid is used for nitration, 5% Pd/C is used for catalysis, target substances are obtained through reduction under the action of hydrogen, and the synthetic route is as follows:
the method has three steps, the price of isopropyl magnesium bromide and equivalent butyl lithium used in the Grignard exchange reaction is high, the corresponding harsh reaction conditions are difficult to industrialize, and the use of concentrated sulfuric acid and concentrated nitric acid causes more three wastes and does not meet the green chemical requirements.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a synthesis method of an efavirenz key intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethanone, which has the advantages of simple operation, low cost and mild reaction conditions and is suitable for industrial production.
In order to solve the technical problems, the technical ideas of the invention are as follows:
the invention discloses a synthesis method of an efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoro-ethanone, which is characterized by comprising the following steps:
(A) O-halonitrobenzene shown in a formula (II) is used as a raw material, freshly prepared phenylmagnesium bromide or magnesium chloride is used as a Grignard reagent, an organic solvent A and a trifluoroacetyl compound shown in a formula (III) are added, and stirring reaction is carried out for 2-8 hours at a temperature of minus 40-25 ℃ to obtain a compound (IV) shown in a formula (IV);
(B) Dissolving the compound (IV) obtained in the step (A) in an organic solvent B, introducing hydrogen in the presence of a catalyst A, and stirring and reacting for 8-26 hours at the temperature of 20-80 ℃ under the pressure of 0.1-1.5 Mpa to obtain a compound (V) shown in the formula (V);
(C) Dissolving the compound (V) obtained in the step (B) in an organic solvent C, reacting with a chloro reagent N-chlorosuccinimide at 0-60 ℃ for 8-20 hours in the presence of a catalyst dimethyl sulfoxide, obtaining a target product 1- (2-amino-5-chlorophenyl) -2, 2-trifluoro-ethanone shown in the formula (I),
in o-halonitrobenzene shown in a formula (II), a substituent X is chlorine, bromine or iodine; in the trifluoroacetyl compound shown in the formula (III), the substituent R is chlorine, bromine, piperidyl, N-methyl, methoxy, dimethylamino, methoxy, diethylamino or ethoxy.
In the step (A) of the invention, the preparation method of the phenylmagnesium bromide or magnesium chloride Grignard reagent is a conventional method.
Further, the invention also defines that the solvent A in the step (A) is one or more of ether solvents and alkane solvents, and the ether solvents are one or more of tetrahydrofuran, methyl tertiary butyl ether, diethyl ether or petroleum ether; the alkane solvent is one or more of pentane, hexane or heptane, preferably tetrahydrofuran, and the volume amount of the organic solvent A is 1-12 mL/g, preferably 3-6mL/g, based on the mass of the o-halonitrobenzene shown in the formula (II); the reaction temperature in the step (A) is preferably-10-0 ℃;
further, the present invention defines that the trifluoroacetyl compound in step (a) is ethyl trifluoroacetate.
Further, the invention defines that the mass ratio of o-halonitrobenzene shown in the formula (II), the format reagent phenylmagnesium chloride or phenylmagnesium bromide and the trifluoroacetyl compound shown in the formula (III) is 1:1-1.6:1-1.8, preferably 1:1.1-1.4:1.1-1.5.
Further, the invention defines that catalyst a in step (B) is selected from 5% pd/C, 10% pd/C catalyst or Raney Ni, preferably Raney Ni; the mass dosage of the catalyst A is 0.5-12% of the mass of the compound (IV), and is preferably 1-5%.
Further, the invention defines that the organic solvent B in the step (B) is selected from one or more of toluene, ethanol and tetrahydrofuran, preferably ethanol; the volume amount of the organic solvent B is 1-12 mL/g, preferably 3-7mL/g, based on the mass of the compound (IV).
Further, the invention defines that the reaction temperature in the step (B) is 45-65 ℃ and the reaction pressure is 0.6-1.0 Mpa.
Further, the invention defines that the organic solvent C in the step (C) is selected from one or more of toluene, methylene dichloride, chloroform, 1, 2-dichloroethane and N, N-dimethylformamide, preferably chloroform; the volume amount of the organic solvent C is 1 to 10mL/g, preferably 3 to 6mL/g, based on the mass of the compound (V).
Further, the invention defines that the ratio of the amounts of the compound (V), N-chlorosuccinimide and the catalyst dimethyl sulfoxide in the step (C) is 1:1-2.1:0.01-0.8, preferably 1:1.2-1.6:0.08-0.3.
The reaction process of the invention is as follows:
by adopting the technology, compared with the prior art, the invention has the advantages that:
1) In the reaction process of reducing the nitro into amino, the invention adopts the catalytic amount of Raney nickel or Pd/C catalyst to finish the reaction with high yield, and the catalyst can be recycled, thereby reducing the raw material cost of production;
2) According to the invention, N-chlorosuccinimide is used as a chloro reagent, dimethyl sulfoxide is used as a catalyst, and the intermediate compound (V) is directly chlorinated to obtain a target compound, so that the amino protection and deprotection processes are avoided, the reaction steps are shortened, and the three-waste generation amount is reduced;
3) The invention designs and opens up a new process route for preparing 1- (2-amino-5-chlorophenyl) -2, 2-trifluoro-ethanone by taking o-halogen nitrobenzene as a raw material and carrying out Grignard exchange reaction, hydrogenation catalytic nitro reduction and chlorination of aniline in 3 steps.
Detailed Description
The invention will be further illustrated with reference to specific examples, but the scope of the invention is not limited thereto.
Embodiment one: preparation of 1- (2-nitrophenyl) -2, 2-trifluoroethanone (IV)
Taking a 500mL four-port bottle with a condenser tube, a mechanical stirring device, a dropping funnel and a thermometer, adding 7.6g (320 mmol) of magnesium chips, 1.79g of bromobenzene (11 mmol) serving as an initiator, 52mL of tetrahydrofuran, heating to 65 ℃ for reflux, initiating Grignard reagent, dropwise adding bromobenzene (40.8 g,260mmol diluted by 180mL of tetrahydrofuran) in a reflux state, and continuing reflux reaction for 4 hours after dropwise adding for 1-2 hours to prepare a phenylmagnesium bromide Grignard reagent, wherein the preparation method of the phenylmagnesium chloride Grignard reagent is the same as that of the phenylmagnesium bromide Grignard reagent; after the reaction system is cooled to minus 20 ℃, o-iodonitrobenzene (200 mmol,49.8 g) is dissolved in 40mL of tetrahydrofuran and is added dropwise, the temperature is controlled not to exceed minus 10 ℃ in the dropping process, the dropwise reaction is completed for 30min, ethyl trifluoroacetate (240 mmol,34.2 g) is added for 30min, the mixture is heated to room temperature and stirred, after the reaction is completed, tetrahydrofuran is recovered by decompression concentration to obtain residue, dichloromethane (80 mL) is added for dissolution, a small amount of water is added for washing, and the dichloromethane is recovered by decompression concentration to obtain brown oily liquid product, namely the compound (IV) (29.8 g, yield 68%).
Profile characterization of compound (iv):
1 H NMR(400MHz,CDCl 3 )δ＝8.32(d,J＝6.9Hz,1H),7.90(t,J＝8.0Hz,1H),7.82(t,J＝8.0Hz,1H),7.56(d,J＝6.0Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ184.1(q,J C-F ＝38Hz),146.1,135.2,132.8,130.2,128.6,124.4,115.4(q,J C-F ＝289Hz),77.3,77.0,76.7.
embodiment two: preparation of 1- (2-aminophenyl) -2, 2-trifluoroethanone (V)
Taking 500mL autoclave, sequentially adding 1- (2-nitrophenyl) -2, 2-trifluoroethanone (100 mmol,21.9 g), 95% ethanol (140 mL), raney Ni catalyst (1.3 g), introducing hydrogen, pressure to 0.6-0.7 MPa, heating to 50-60 ℃, keeping the temperature and stirring, completely reacting, filtering and recovering the catalyst, concentrating the organic phase under reduced pressure to recover ethanol until the organic phase is dry, recrystallizing the residue by n-octanol (60 mL) to obtain a compound (V), wherein the product is a dark yellow solid (17.4 g, yield 92%) and melting point is 51-52 ℃.
Profile characterization of compound (iv):
1 H NMR(400MHz,CDCl 3 )δ＝7.75(d,J＝8.4Hz,1H),7.38(t,J＝7.8Hz,1H),6.71(dd,J＝13.8,8.2Hz,2H),6.41(s,2H). 13 C NMR(100MHz,CDCl 3 )δ＝180.8(q,J C-F ＝30Hz),153.1,136.6,131.3,117.4,117.0(q,J C-F ＝289Hz),116.3,111.0,77.3,77.0,76.7.
embodiment III: preparation of 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethanone (I)
A500 mL two port round bottom flask was charged with 1- (2-aminophenyl) -2, 2-trifluoroethanone (100 mmol,19.2 g), N-chlorosuccinimide (15.8 g,120 mmol), 150mL of chloroform, catalyst dimethyl sulfoxide (0.71 g,10 mmol), stirred at room temperature, the reaction was completed, the solvent recovered by concentrating under reduced pressure, and the residue was recrystallized from N-hexane (80 mL) to give compound (I) (19.3 g, yield 86%) as a bright yellow solid with a melting point of 90-91℃and a purity of 98.5% as measured by HPLC (mobile phase acetonitrile: water=70:30, V/V).
Profile characterization of compound (I):
1 H NMR(400MHz,DMSO-d 6 )δ＝7.86(s,2H),7.45(d,J＝2.8Hz,2H),6.98(d,J＝8.4Hz,1H). 19 F NMR(376MHz,DMSO-d 6 )δ＝-68.90,-83.12. 13 C NMR(100MHz,DMSO-d 6 )δ＝178.2(q,J C-F ＝30Hz),153.7,137.2,128.6,120.7,118.6,117.2(q,J C-F ＝289Hz),109.6,40.6,40.4,40.2,40.0,39.8,39.6,39.4.HRMS(ESI):m/z calcd for C 8 H 5 ClF 3 NO[M+H] + 224.0089,found 224.0085
fourth to fifteen examples:
preparation of 1- (2-nitrophenyl) -2, 2-trifluoroethanone (IV) the preparation method of each example is shown in example I, except that certain reaction conditions (such as the type of solvent, the amount of fed trifluoroacetyl compound (III), the temperature, the type of o-halonitrobenzene (II), the molar ratio of o-halonitrobenzene (II) to phenylmagnesium bromide or magnesium chloride (a) and fed trifluoroacetyl compound (III)) are changed, and the specific changed conditions and corresponding reaction effects of each example are shown in tables 1-2 below.
TABLE 1
TABLE 2
In combination with table 1, the reaction conditions changed in example four are the type of solvent; in the fifth and sixth examples, the reaction conditions were changed to the type of formula III, methyl trifluoroacetate and trifluoroacetic anhydride, respectively; in the seventh and eighth examples, the reaction conditions were changed to the molar ratio of o-halonitrobenzene (II) to phenyl Grignard reagent (a); in the ninth and tenth examples, the reaction conditions were changed to the o-halonitrobenzene (II) as the starting material.
In combination with Table 2, examples eleven, twelve and thirteenth, the reaction conditions were varied by the molar ratio of o-halonitrobenzene (II) to the compound of formula (III); example fourteen, example fifteen, example sixteen, example seventeen, the changed reaction conditions are the format reaction temperatures.
Seventeenth to twenty-eighth examples:
preparation of 1- (2-aminophenyl) -2, 2-trifluoroethyl ketone (V), the preparation method of each example is repeated in example two, except that certain reaction conditions (such as the type of the solvent B, the type of the catalyst A, the catalyst amount, the pressure of the reaction kettle, the temperature and the like) are changed, and the specific changed reaction conditions and the corresponding reaction effects of each example are shown in tables 3 to 4 below.
TABLE 3 Table 3
TABLE 4 Table 4
In Table 3, 10% Pd/C and 5% Pd/C represent Pd/C catalysts having Pd loadings of 10% Pd/C and 5% Pd/C, respectively. Examples eighteen and nineteenth, with the type of reaction solvent being changed; example twenty, example twenty one, with the change of the catalyst type; in the second and third examples, the amount of the catalyst added was changed.
Referring to table 4, the temperature of the reaction kettle was changed according to twenty-four examples, twenty-five examples, twenty-six examples, and twenty-seven examples; the pressure of the reaction kettle is changed in the twenty-eighth embodiment, the twenty-ninth embodiment and the thirty-eighth embodiment.
Examples twenty-nine to forty-one:
preparation of 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethanone (I), the preparation process of each example was repeated for example III, except that certain reaction conditions (such as the type of solvent C, the amount of dimethyl sulfoxide (DMSO), the temperature, the molar ratio of 1- (2-aminophenyl) -2, 2-trifluoroethanone (V) to the addition of the chlorinating agent NCS, etc.) were changed, and the specific changed reaction conditions and the corresponding reaction effects of each example are shown in tables 5 to 6 below.
TABLE 5
TABLE 6
In combination with Table 5, examples thirty-one and thirty-two, the types of reaction solvents were changed; examples thirty-three, thirty-four, thirty-five and thirty-six, the amount of catalyst dimethyl sulfoxide (DMSO) added was varied.
In Table 6, the reaction temperatures were changed by examples thirty-seven, thirty-eight, thirty-nine and forty; the molar ratio of 1- (2-aminophenyl) -2, 2-trifluoroethanone (V) to the chlorinating agent NCS was varied from example forty-one, example forty-two, example forty-three.
What has been described in this specification is merely an enumeration of possible forms of implementation for the inventive concept and may not be considered limiting of the scope of the present invention to the specific forms set forth in the examples.
Claims (15)
1. The synthesis method of the efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethyl ketone is characterized by comprising the following steps:
(A) O-halonitrobenzene shown in a formula (II) is used as a raw material, freshly prepared phenylmagnesium bromide or magnesium chloride is used as a Grignard reagent, an organic solvent A and a trifluoroacetyl compound shown in a formula (III) are added, and stirring reaction is carried out for 2-8 hours at-40-25 ℃ to obtain a compound (IV) shown in a formula (IV), wherein the solvent A is one or more of an ether solvent and an alkane solvent;
(B) Dissolving the compound (IV) obtained in the step (A) in an organic solvent B, introducing hydrogen in the presence of a catalyst A, and stirring and reacting for 8-26 hours at the temperature of 20-80 ℃ under the pressure of 0.1-1.5 Mpa to obtain the compound (V) shown in the formula (V), wherein the organic solvent B is one or more of the following: toluene, ethanol, tetrahydrofuran;
(C) Dissolving the compound (V) obtained in the step (B) in an organic solvent C, and reacting with a chloro reagent N-chlorosuccinimide at 0-60 ℃ for 8-20 hours under stirring in the presence of a catalyst dimethyl sulfoxide to obtain a target product 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethanone shown in a formula (I), wherein the organic solvent C is one or more of the following: toluene, methylene chloride, chloroform, 1, 2-dichloroethane, N-dimethylformamide,
。
2. the synthesis method of the efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethanone (i) according to claim 1, wherein the ethereal solvent in the step (a) is one or more of tetrahydrofuran, methyl tertiary butyl ether, diethyl ether or petroleum ether; the alkane solvent is one or more of pentane, hexane or heptane, and the volume dosage of the organic solvent A is 1-12 mL/g based on the mass of o-halonitrobenzene shown in the formula (II); the reaction temperature in the step (A) is preferably-10-0 ℃.
3. The synthesis method of the efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethyl ketone (I) according to claim 2, wherein the alkane solvent in the step (A) is tetrahydrofuran, and the volume amount of the organic solvent A is 3-6mL/g based on the mass of o-halonitrobenzene shown in a formula (II).
4. The synthesis method of the efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethyl ketone according to claim 1, wherein in the step (a), the trifluoroacetyl compound (iii) is ethyl trifluoroacetate.
5. The method for synthesizing the efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethyl ketone according to claim 1, wherein in the step (A), the ratio of the o-halonitrobenzene shown in the formula (II), the format reagent phenylmagnesium chloride or phenylmagnesium bromide and the trifluoroacetyl compound shown in the formula (III) is 1:1-1.6:1-1.8.
6. The method for synthesizing the efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethyl ketone according to claim 5, wherein in the step (A), the ratio of the amounts of o-halonitrobenzene represented by the formula (II), the formative reagent phenylmagnesium chloride or phenylmagnesium bromide and the trifluoroacetyl compound represented by the structure of the formula (III) is 1:1.1-1.4:1.1-1.5.
7. The synthesis method of the efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethyl ketone according to claim 1, wherein in the step (B), the catalyst a is selected from one of 5% Pd/C or 10% Pd/C catalyst or Raney Ni, and the Pd loading in the Pd/C catalyst is 5% or 10%; the mass dosage of the catalyst A is 0.5-12% of the mass of the compound (IV).
8. The synthesis method of the efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethyl ketone according to claim 7, wherein in step (B), the catalyst a is Raney Ni; the mass dosage of the catalyst A is 1% -5% of the mass of the compound (IV).
9. The synthesis method of the efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethanone according to claim 1, wherein in step (B), the organic solvent B is ethanol; the volume consumption of the organic solvent B is 1-12 mL/g based on the mass of the compound (IV).
10. The process for the synthesis of the efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethyl ketone according to claim 9, wherein in step (B), the volume amount of the organic solvent B is 3 to 7mL/g based on the mass of the compound (iv).
11. The method for synthesizing the efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethyl ketone according to claim 1, wherein in the step (B), the reaction temperature is 45-65 ℃ and the pressure of a reaction kettle is 0.6-1.0 Mpa.
12. The synthesis method of the efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethanone according to claim 1, wherein in step (C), the organic solvent C is chloroform; the volume amount of the organic solvent C is 1-10 mL/g based on the mass of the compound (V).
13. The process for the synthesis of the efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethyl ketone according to claim 12, wherein in step (C), the volume amount of the organic solvent C is 3 to 6mL/g based on the mass of the compound (V).
14. The method for synthesizing the efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethyl ketone according to claim 1, wherein in the step (C), the amount ratio of the compound (V) represented by the formula (V), N-chlorosuccinimide and dimethyl sulfoxide serving as a catalyst is 1:1-2.1:0.01-0.8.
15. The method for synthesizing efavirenz intermediate 1- (2-amino-5-chlorophenyl) -2, 2-trifluoroethyl ketone according to claim 14, wherein in the step (C), the ratio of the amounts of the compound (V), N-chlorosuccinimide and dimethyl sulfoxide catalyst is 1:1.2-1.5:0.08-0.3.
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| CN106496051A (en) * | 2016-08-31 | 2017-03-15 | 浙江沙星药业有限公司 | A kind of synthetic method of 4 chlorine, 2 trifluoroacetyl aniline hydrochloride hydrate |
| CN106518636A (en) * | 2016-10-18 | 2017-03-22 | 浙江天宇药业股份有限公司 | Method for preparing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate and free alkalis thereof |
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