CN108997150A - A kind of preparation method of efavirenz intermediate - Google Patents
A kind of preparation method of efavirenz intermediate Download PDFInfo
- Publication number
- CN108997150A CN108997150A CN201811014190.7A CN201811014190A CN108997150A CN 108997150 A CN108997150 A CN 108997150A CN 201811014190 A CN201811014190 A CN 201811014190A CN 108997150 A CN108997150 A CN 108997150A
- Authority
- CN
- China
- Prior art keywords
- aniline
- group
- acyl
- trifluoroacetyl
- trifluoroacetyl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
Abstract
The present invention provides a kind of preparation method of efavirenz intermediate, it is related to compounds process for production thereof technical field, the present invention is with adjacent halobenzene amine (II) for raw material, first amido is protected with acyl chlorides, then N- acyl group -2- halogen-aniline (III) of generation is reacted with magnesium metal generates Grignard Reagent, it reacts to obtain N- acyl group -2- (trifluoroacetyl group) aniline (V) with trifluoroacetyl group aminate (IV) again, then N- acyl group -4- chloro- 2- (trifluoroacetyl group) aniline (VI) is obtained with chlorine reaction under the action of catalyst, using hydrolysis, 4- chloro- 2- (trifluoroacetyl group) anilinechloride hydrate (I) is obtained at salt.Synthesis step of the present invention is short, easy to operate, safety is preferable, and the selectivity of raw material is more, and target product yield is higher, is suitble to large-scale industrial production.
Description
Technical field
The invention belongs to compounds process for production thereof technical fields, and in particular to a kind of preparation side of efavirenz intermediate
Method.
Background technique
With the increase of global aids infection poison crowd, it is more and more that treatment AIDS-treating medicine has obtained medical industry
Concern.Efavirenz is a kind of non-nucleoside reverse transcriptase inhibitor, just starts to list in 1998, is that treatment AIDS most has
The method of effect --- one of most important drug in " cocktail therapy " has the advantages that toxic side effect is small, therapeutic effect is good.
4- chloro- 2- (trifluoroacetyl group) anilinechloride hydrate is the key intermediate for synthesizing big logical sequence drug in accordance with the law,
There is more document to report the synthetic method of the drug, such as document Tetrahedron, 1991,3207;
J.Org.Chem.63(23),1998,8536-8543;US5932726;WO9637457 is anti-using parachloroanilinum and pivaloyl chloride
It answers, obtained intermediate is reacted with Trifluoroacetic Acid Ethyl Ester again after reacting with butyl lithium, then Tudor valeryl in acid condition again
Chlorine obtains 4- chloro- 2- (trifluoroacetyl group) anilinechloride hydrate at salt, but this method needs largely to use butyl lithium,
And butyl lithium is expensive and risk is high.
Therefore, being badly in need of one kind, cost is relatively low, more environmentally-friendly, safety is preferable, is suitble to large-scale industrial production in accordance with the law
The preparation method of Wei Lun intermediate 4- chloro- 2- (trifluoroacetyl group) anilinechloride hydrate.
Summary of the invention
In response to the problems existing in the prior art, the purpose of the present invention is to provide a kind of chloro- 2- (three of efavirenz intermediate 4-
Acetyl fluoride base) anilinechloride hydrate preparation method, this method have preparation cost is lower, more environmentally-friendly, safety compared with
The advantages of good, suitable large-scale industrial production.
The present invention provides the following technical solutions:
A kind of preparation method of efavirenz intermediate, including following synthesis step:
S1, with adjacent halobenzene amine (II) be original raw material, with acyl chlorides occur acylation reaction obtain intermediate N acyl group -2- halogen -
Aniline (III);
S2, intermediate N acyl group -2- halogen-aniline (III) made from step S1 is dissolved in tetrahydrofuran, and in metal
Grignard Reagent is generated under the catalysis of magnesium, then with trifluoroacetyl halogen (IV) or trifluoroacetyl group aminate (IV) or trifluoroacetic acid second
Ester reaction, obtains N- acyl group -2- (trifluoroacetyl group) aniline (V);
S3, N- acyl group -2- (trifluoroacetyl group) aniline (V) made from step S2 and chlorine reaction are obtained into N- acyl group -4-
Chloro- 2- (trifluoroacetyl group) aniline (VI);
S4, N- acyl group -4- chloro- 2- (trifluoroacetyl group) aniline (VI) made from step S3 in acid condition, is passed through
Hydrolysis and salt-forming reaction occur for hydrochloric acid effect, obtain 4- chloro- 2- (trifluoroacetyl group) anilinechloride hydrate (I), institute
The solvent used is glacial acetic acid.
Specific synthetic route are as follows:
Wherein, X is Cl or Br or I, R1For propiono, bytyry, valeryl, isobutyryl, 2- methylbutyryl, isoamyl
One of acyl group and pivaloyl group, R2For Cl, Br, F, piperidyl, diethylin, dimethylamino, morpholinyl and nafoxidine
One of base.
Preferably, acyl chlorides and the molar ratio of adjacent halobenzene amine (II) are 1.02~1.10:1, reaction temperature in S1 step
It is -10~50 DEG C.
Preferably, the quality of tetrahydrofuran is 2~15 times of N- acyl group -2- halogen-aniline (III) quality, N- acyl in S2 step
The reaction temperature that base -2- halogen-aniline (III) generates Grignard Reagent under the catalysis of magnesium metal is 0~80 DEG C.
Preferably, the quality of tetrahydrofuran is 2~4 times of N- acyl group -2- halogen-aniline (III) quality, N- acyl in S2 step
The reaction temperature that base -2- halogen-aniline (III) generates Grignard Reagent under the catalysis of magnesium metal is 30~60 DEG C.
Preferably, Grignard Reagent and trifluoroacetyl halogen (IV) or trifluoroacetyl group aminate (IV) or trifluoro second in S2 step
The reaction temperature of acetoacetic ester is -20~10 DEG C.
Preferably, it is in light that chlorination reaction, which occurs, for N- acyl group -2- (trifluoroacetyl group) aniline (V) and chlorine in S3 step
It is carried out under the initiation in source.
Preferably, reacting for chlorination reaction occurs for N- acyl group -2- (trifluoroacetyl group) aniline (V) and chlorine in S3 step
Temperature is -20~20 DEG C.
Preferably, N- acyl group -2- (trifluoroacetyl group) aniline (V) and chlorine occur what chlorination reaction used in S3 step
Reaction dissolvent is methylene chloride, one of chloroform and carbon tetrachloride.
The beneficial effects of the present invention are:
Synthesis step of the invention is short, and the selectivity of raw material is more, and synthesis cost is lower.Acyl chlorides pair is utilized in the synthesis process
Amido on adjacent halobenzene amine is protected, and is also prepared N- acyl group -2- (trifluoroacetyl group) aniline using grignard reaction, is helped to mention
The yield of high target product, and it is easy to operate, safety is preferable, be suitble to large-scale industrial production.
Specific embodiment
But the scope of the present invention is not limited thereto is further illustrated to the content of present invention below by embodiment:
(1) N- acyl group -2- halogen-aniline (III) synthesis
Embodiment 1:
Blender is being housed, is putting into 80.3g (0.63mol) o-chloraniline, 500mL in the flask of dropping funel and thermometer
Methyl tertiary butyl ether(MTBE), temperature are down to -10~-5 DEG C, and the sodium hydroxide solution of 90.8g (0.68mol) 30% is added, and control temperature
At -10~0 DEG C, it is added dropwise 83.1g (0.69mol) pivaloyl chloride, time for adding 0.5h, in -10~20 DEG C of heat preservation 1h after dripping off,
Layering, organic layer are washed 2 times, and -5 DEG C of heat preservation 2h are cooled to, and are filtered, and filter cake is washed, and are drained, and in vacuum -0.085MPa, 70 DEG C
Drying for 24 hours, obtains 129.5g compound N-pivaloyl group -2- chloroaniline, content 99.2%, yield 97.2% below.
The present embodiment replaces o-chloraniline with o-bromoaniline or adjacent Iodoaniline, with propionyl chloride, butyl chloride, valeric chloride, isobutyl
One of acyl chlorides, 2- methylbutyryl chlorine and isoveryl chloride replace pivaloyl chloride, can also reach same effect.
Embodiment 2:
Blender is being housed, put into the flask of dropping funel and thermometer 108.4g (0.63mol) o-bromoaniline,
500mL methyl tertiary butyl ether(MTBE), temperature are down to 10~15 DEG C, and the sodium hydroxide solution of 90.8g (0.68mol) 30%, control is added
10~20 DEG C of temperature, 83.1g (0.69mol) isoveryl chloride is added dropwise, time for adding 0.5h is kept the temperature after dripping off at 10~30 DEG C
1h, layering, organic layer are washed 2 times, and -5 DEG C of heat preservation 2h are cooled to, and are filtered, and filter cake is washed, and are drained, and in vacuum -0.085MPa,
70 DEG C or less dryings for 24 hours, obtain 155.6g compound N-isovaleryl -2- bromaniline, content 99.4%, yield 96.5%.
(2) synthesis of N- acyl group -2- (trifluoroacetyl group) aniline (V)
Embodiment 3:
Magnesium chips 6g (0.25mol) is added in flask, tetrahydrofuran 40mL is stirred evenly, and weighs N- pivaloyl group -2- chlorobenzene
Amine 43.0g (0.2mol) is dissolved into other 60mL tetrahydrofuran and is added in constant pressure funnel, then adds into flask
Enter 10% this solution, be heated to 40~45 DEG C, then adds 0.5mL 1,2- Bromofume initiation reaction, and temperature herein
N- pivaloyl group -2- chlorobenzene amine aqueous solution is slowly added dropwise under degree and is then cooled to 0 in 40~50 DEG C of insulated and stirred 2h after dripping
It~10 DEG C, is added dropwise trifluoroacetyl group dimethylamine 30.0g (0.21mol), 1h is stirred after being added dropwise to complete, hydrochloric acid 60mL is then added,
Layering, organic layer obtain crude product 56.2g after removing solvent is concentrated under reduced pressure, and crude product is recrystallized to give white with 80mL methyl tertiary butyl ether(MTBE)
Color solid 46.2g is compound N-pivaloyl group -2- (trifluoroacetyl group) aniline, content 99.1%, yield 84.6%.
The present embodiment is with N- propiono (or in bytyry, valeryl, isobutyryl, 2- methylbutyryl, isovaleryl
It is a kind of) 2- bromine (or iodine) aniline is instead of N- pivaloyl group -2- chloroaniline, with Trifluoroacetic Acid Ethyl Ester, trifluoro-acetyl chloride, trifluoroacetyl
Bromine, trifluoro-acetic fluoride, trifluoroacetyl group diethylamine, trifluoroacetyl phenylpiperidines, trifluoroacetyl group morpholine and trifluoroacetyl group tetrahydro
One of pyrroles replaces trifluoroacetyl group dimethylamine, can also reach same effect.
Embodiment 4:
Magnesium chips 6g (0.25mol) is added in flask, tetrahydrofuran 60mL is stirred evenly, and weighs N- isobutyryl -2- bromobenzene
Amine 48.4g (0.2mol) is dissolved into other 150mL tetrahydrofuran and is added in constant pressure funnel, then adds into flask
Enter 10% this solution, addition 0.5mL 1 after being heated to 30-35 DEG C, 2- Bromofume initiation reaction, and it is slow in this temperature
N- isobutyryl -2- bromobenzene amine aqueous solution is added dropwise and is then cooled to -20~-10 in 30~40 DEG C of insulated and stirred 2h after dripping
DEG C, it is added dropwise trifluoroacetyl group diethylamine 32.1g (0.21mol), 1h is stirred after being added dropwise to complete, hydrochloric acid 60mL is then added, be layered,
Organic layer obtains crude product 52.2g after removing solvent is concentrated under reduced pressure, and crude product obtains white solid 42.5g with 80mL recrystallizing methanol,
For compound N-isobutyryl -2- (trifluoroacetyl group) aniline, content 99.0%, yield 82.1%.
(3) synthesis of the chloro- 2- of N- acyl group -4- (trifluoroacetyl group) aniline (VI)
Embodiment 5:
N- pivaloyl group -2- (trifluoroacetyl group) aniline 54.6g (0.2mol) is added in reaction flask, dichloromethane solvent
100mL cools to -15~-10 DEG C, under illumination condition, is slowly introducing chlorine, -15~-5 DEG C of control system temperature, examines
It surveys after completion of the reaction, stopping is passed through chlorine, is washed 3 times with sodium sulfite aqueous solution, and organic layer is concentrated to dryness, crude product 62.2g is obtained,
Crude product obtains white solid 55.6g with 80mL recrystallizing methanol, is compound N-chloro- 2- of pivaloyl group -4- (trifluoroacetyl group)
Aniline, content 99.3%, yield 90.4%.
In the present embodiment with N- propiono (or in bytyry, valeryl, isobutyryl, 2- methylbutyryl, isovaleryl
One kind) -2- (trifluoroacetyl group) aniline replace N- pivaloyl group -2- (trifluoroacetyl group) aniline, with chloroform or carbon tetrachloride
It is solvent instead of methylene chloride, can also reaches same effect.
Embodiment 6:
N- isobutyryl -2- (trifluoroacetyl group) aniline 51.8g (0.2mol) is added in reaction flask, chloroform solvent 100mL,
It cools to -5~0 DEG C, under illumination condition, is slowly introducing chlorine, -5~5 DEG C of control system temperature, detects end of reaction
Afterwards, stop being passed through chlorine, be washed 3 times with sodium sulfite aqueous solution, organic layer is concentrated to dryness, and obtains crude product 61.5g, crude product 80mL
Recrystallizing methanol obtains white solid 49.9g, is compound N-isobutyryl -4- chloro- 2- (trifluoroacetyl group) aniline, content
98.6%, yield 85%.
(4) synthesis of the chloro- 2- of 4- (trifluoroacetyl group) anilinechloride hydrate (I)
Embodiment 7:
N- pivaloyl group -4- chloro- 2- (trifluoroacetyl group) aniline 61.5g (0.2mol) is added in reaction flask, concentrated hydrochloric acid
50mL, glacial acetic acid 60mL are heated to 75~80 DEG C and are stirred to react 4h, and end of reaction cools to 0~5 DEG C, stir 1h, take out
Filter, washs solid with a small amount of ethyl acetate, and decompression drying obtains pale yellow crystals solid 53.6g, is compound 4-chloro -2- (three
Acetyl fluoride base) anilinechloride hydrate, content 99.3%, yield 96.4%.
In this example with N- propiono (or in bytyry, valeryl, isobutyryl, 2- methylbutyryl, isovaleryl
It is a kind of) -4- chloro- 2- (trifluoroacetyl group) aniline replaces N- pivaloyl group -4- chloro- 2- (trifluoroacetyl group) aniline, it can also obtain
Same effect.
Embodiment 8:
N- isobutyryl -4- chloro- 2- (trifluoroacetyl group) aniline 58.7g (0.2mol) is added in reaction flask, concentrated hydrochloric acid
50mL, glacial acetic acid 60mL are heated to 75~80 DEG C and are stirred to react 4h, and end of reaction cools to 0~5 DEG C, stir 1h, take out
Filter, washs solid with a small amount of ethyl acetate, and decompression drying obtains pale yellow crystals solid 52.5g, is compound 4-chloro -2- (three
Acetyl fluoride base) anilinechloride hydrate, content 99.0%, yield 94.4%.
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 (8)
1. a kind of preparation method of efavirenz intermediate, which is characterized in that including following synthesis step:
S1, with adjacent halobenzene amine (II) be original raw material, with acyl chlorides occur acylation reaction obtain intermediate N acyl group -2- halogen-aniline
(Ⅲ);
S2, intermediate N acyl group -2- halogen-aniline (III) made from step S1 is dissolved in tetrahydrofuran, and in magnesium metal
The lower generation Grignard Reagent of catalysis, it is then anti-with trifluoroacetyl halogen (IV) or trifluoroacetyl group aminate (IV) or Trifluoroacetic Acid Ethyl Ester
It answers, obtains N- acyl group -2- (trifluoroacetyl group) aniline (V);
S3, that N- acyl group -2- (trifluoroacetyl group) aniline (V) made from step S2 with chlorine reaction is obtained N- acyl group -4- is chloro-
2- (trifluoroacetyl group) aniline (VI);
S4, N- acyl group -4- chloro- 2- (trifluoroacetyl group) aniline (VI) made from step S3 in acid condition, is passed through into hydrochloric acid
Hydrolysis and salt-forming reaction occur for effect, obtain 4- chloro- 2- (trifluoroacetyl group) anilinechloride hydrate (I), are used
Solvent be glacial acetic acid.
Specific synthetic route are as follows:
Wherein, X is Cl or Br or I, R1For propiono, bytyry, valeryl, isobutyryl, 2- methylbutyryl, isovaleryl
One of with pivaloyl group, R2For in Cl, Br, F, piperidyl, diethylin, dimethylamino, morpholinyl and nafoxidine base
One kind.
2. a kind of preparation method of efavirenz intermediate according to claim 1, which is characterized in that acyl chlorides in S1 step
Molar ratio with adjacent halobenzene amine (II) is 1.02~1.10:1, and reaction temperature is -10~50 DEG C.
3. a kind of preparation method of efavirenz intermediate according to claim 1, which is characterized in that tetrahydro in S2 step
The quality of furans is 2~15 times of N- acyl group -2- halogen-aniline (III) quality, and N- acyl group -2- halogen-aniline (III) is in magnesium metal
The lower reaction temperature for generating Grignard Reagent of catalysis is 0~80 DEG C.
4. a kind of preparation method of efavirenz intermediate according to claim 3, which is characterized in that tetrahydro in S2 step
The quality of furans is 2~4 times of N- acyl group -2- halogen-aniline (III) quality, N- acyl group -2- halogen-aniline (III) urging in magnesium metal
Changing the lower reaction temperature for generating Grignard Reagent is 30~60 DEG C.
5. a kind of preparation method of efavirenz intermediate according to claim 1, which is characterized in that grignard in S2 step
The reaction temperature of reagent and trifluoroacetyl halogen (IV) or trifluoroacetyl group aminate (IV) or Trifluoroacetic Acid Ethyl Ester is -20~10
℃。
6. a kind of preparation method of efavirenz intermediate according to claim 1, which is characterized in that N- acyl in S3 step
With chlorine chlorination reaction, which occurs, for base -2- (trifluoroacetyl group) aniline (V) is carried out under the initiation of light source.
7. a kind of preparation method of efavirenz intermediate according to claim 1, which is characterized in that N- acyl in S3 step
The reaction temperature that chlorination reaction occurs for base -2- (trifluoroacetyl group) aniline (V) and chlorine is -20~20 DEG C.
8. a kind of preparation method of efavirenz intermediate according to claim 1, which is characterized in that N- acyl in S3 step
The reaction dissolvent that base -2- (trifluoroacetyl group) aniline (V) and chlorine generation chlorination reaction use is methylene chloride, chloroform and four
One of chlorination carbon.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811014190.7A CN108997150B (en) | 2018-08-31 | 2018-08-31 | Preparation method of efavirenz intermediate |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811014190.7A CN108997150B (en) | 2018-08-31 | 2018-08-31 | Preparation method of efavirenz intermediate |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108997150A true CN108997150A (en) | 2018-12-14 |
CN108997150B CN108997150B (en) | 2021-01-12 |
Family
ID=64591407
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811014190.7A Active CN108997150B (en) | 2018-08-31 | 2018-08-31 | Preparation method of efavirenz intermediate |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108997150B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998045278A1 (en) * | 1997-04-07 | 1998-10-15 | Du Pont Pharmaceuticals Company | Asymmetric synthesis of benzoxazinones via new intermediates |
CN101844990A (en) * | 2010-05-27 | 2010-09-29 | 浙江沙星医药化工有限公司 | Method for synthesizing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate intermediate |
CN102675125A (en) * | 2011-03-15 | 2012-09-19 | 中国科学院上海有机化学研究所 | Simple, convenient and high-efficiency synthesis method of 4-chloro-2-trifluoroacetylaniline and analogs thereof |
WO2015111004A2 (en) * | 2014-01-24 | 2015-07-30 | Discovery Intermediates Private Limited | Improved process for the preparation of chlorophenyl trifluoroethanone |
CN105777610A (en) * | 2015-10-16 | 2016-07-20 | 浙江沙星医药化工有限公司 | Method for preparing 4-chlorine-2-(trifluoroacetyl) aniline hydrochloride hydrate |
CN105801442A (en) * | 2015-10-16 | 2016-07-27 | 浙江沙星医药化工有限公司 | Preparation method of 4-chloro-2-(trifluoroacetyl) aniline hydrochloride hydrate |
-
2018
- 2018-08-31 CN CN201811014190.7A patent/CN108997150B/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998045278A1 (en) * | 1997-04-07 | 1998-10-15 | Du Pont Pharmaceuticals Company | Asymmetric synthesis of benzoxazinones via new intermediates |
CN101844990A (en) * | 2010-05-27 | 2010-09-29 | 浙江沙星医药化工有限公司 | Method for synthesizing 4-chloro-2-(trifluoroacetyl)aniline hydrochloride hydrate intermediate |
CN102675125A (en) * | 2011-03-15 | 2012-09-19 | 中国科学院上海有机化学研究所 | Simple, convenient and high-efficiency synthesis method of 4-chloro-2-trifluoroacetylaniline and analogs thereof |
WO2015111004A2 (en) * | 2014-01-24 | 2015-07-30 | Discovery Intermediates Private Limited | Improved process for the preparation of chlorophenyl trifluoroethanone |
CN105777610A (en) * | 2015-10-16 | 2016-07-20 | 浙江沙星医药化工有限公司 | Method for preparing 4-chlorine-2-(trifluoroacetyl) aniline hydrochloride hydrate |
CN105801442A (en) * | 2015-10-16 | 2016-07-27 | 浙江沙星医药化工有限公司 | Preparation method of 4-chloro-2-(trifluoroacetyl) aniline hydrochloride hydrate |
Non-Patent Citations (2)
Title |
---|
杜世聪 等: "依法韦仑合成路线图解", 《浙江化工》 * |
胡争朋 等: "依非韦伦关键中间体的合成", 《中国医药工业杂志》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
Also Published As
Publication number | Publication date |
---|---|
CN108997150B (en) | 2021-01-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI669291B (en) | Cyclopropanamine compound and use thereof | |
US20140235862A1 (en) | Method for producing 4, 4-difluoro-3,4-dihydroisoquinoline derivatives | |
CN108440345B (en) | Preparation method of sulfonamide compound | |
CN112707836B (en) | Preparation method of m-diamide compound | |
CN106674069A (en) | GFT505 and preparation method for intermediate thereof | |
ES2732045T3 (en) | Preparation procedure for 3-chloro-2-vinylphenylsulfonates | |
CN108997150A (en) | A kind of preparation method of efavirenz intermediate | |
WO2005007616A1 (en) | Diphenylamino ketone derivatives as mek inhibitors | |
JP6773693B2 (en) | How to prepare Orchipraz | |
CN103588765A (en) | Synthesis method for azilsartan medoxomil or salt thereof, intermediate of azilsartan medoxomil or salt thereof and synthesis method for intermediate | |
CN106565607A (en) | Synthetic method of L-carnosine | |
CN106588925B (en) | It is a kind of to prepare the luxuriant method of the pyridine ring of 1,4,7,10 4 azepine 2,6 | |
CN103755636A (en) | Method for synthesizing Lorcaserin raceme derivative | |
WO2016155596A1 (en) | Method of synthesizing 3-halo-d-alanine methyl ester or acid salt thereof | |
EP2104663B1 (en) | Method for producing substituted pyrazolecarboxylic acid chlorides | |
KR101557702B1 (en) | Method for the preparation of Mitiglinide Calcium Dihydrate | |
US20110137041A1 (en) | Process for preparing atovaquone and associate intermediates | |
KR102210848B1 (en) | Pharmaceutical formulations containing 3-(4-cinnamyl-1-piperazinyl) amino derivatives of 3-formylrifamycin sv and 3-formylrifamycin s and a process of their preparation | |
CN108409550A (en) | A kind of 3-(Rubigan)The synthesis technology of propionic acid | |
KR100881890B1 (en) | Process for preparation of Sarpogrelate HCl salt | |
CN106083564B (en) | A kind of synthesis of 2,6- dimethyl phenoxyacetic acid and purification process | |
RU2448091C1 (en) | METHOD OF PRODUCING ETHYL ETHER OF 6-BROMO-5-HYDROXY-4-DIMETHYL AMINOMETHYL-1-METHYL-2-PHENYLTHIOMETHYLINDOLE-3-CARBOXYLIC ACID HYDROCHLORIDE MONOHYDRATE IN α-CRYSTALLINE FORM | |
DK142767B (en) | Analogous process for the preparation of 1- and dl (racem) forms of derivatives of 6- (m-aminophenyl) -2,3,5,6-tetrahydroimidazo (2,1-b) thiazole. | |
RU2480000C2 (en) | Method of producing 2-dimethylamino-1,3-bis(phenylthiosulphonyl)propane | |
EP3440064B1 (en) | Process for preparing oxathiazin-like compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |