CN109503416A - A kind of miscellaneous Shandong amine intermediate synthetic method of grace - Google Patents
A kind of miscellaneous Shandong amine intermediate synthetic method of grace Download PDFInfo
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- CN109503416A CN109503416A CN201811588915.3A CN201811588915A CN109503416A CN 109503416 A CN109503416 A CN 109503416A CN 201811588915 A CN201811588915 A CN 201811588915A CN 109503416 A CN109503416 A CN 109503416A
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- bromo
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
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Abstract
The invention discloses a kind of miscellaneous Shandong amine intermediate synthetic methods of grace, characterized by the following steps: the bromo- 2- fluobenzoic acid of 4- and thionyl chloride is added in organic solvent, evacuation is changed nitrogen and reacted at 80-100 degrees Celsius.After reaction, solvent evaporated obtains the bromo- 2- fluorobenzoyl chloride of 4-, adds organic solvents into the bromo- 4- fluorobenzoyl chloride of 2-, and being slowly added to methylamine water solution adjusting reaction solution pH=8~9, the reaction was continued.It to the end of reacting, is extracted with organic solvent, yield organic phase, solvent evaporated obtains the fluoro- N-methyl-benzamide of the bromo- 2- of 4-.The present invention is using the bromo- 2- fluobenzoic acid of 4-, 2- aminoisobutyric acid as raw material, it is prepared under the action of cuprous halide catalysis and ligand auxiliary and acid binding agent by substitution reaction, yield is 75%, but pass through optimal conditions, cheaper acetylacetone,2,4-pentanedione has been filtered out as ligand, has greatly reduced cost.
Description
Technical field
The invention belongs to the miscellaneous Shandong amine intermediate 2- of grace (the fluoro- 4- of 3- (methyl-carbamoyl)-phenyl amino)-neopentanoic acids
Synthesis technical field, specially a kind of miscellaneous Shandong amine intermediate synthetic method of grace.
Background technique
The miscellaneous Shandong amine (enzalutamide) of grace is cooperated out by Medivation company and Astellas (Astellas) company
Hair is resistant to prostate cancer (castration-resistant in advanced stage male's castration that treatment has been spread or recurred
prostate cancer).Compound chemical formula is 4- [3- [4- cyano -3- (trifluoromethyl) phenyl] -5,5- dimethyl -4- oxygen
Generation -2- thioketones -1- imidazolidinyl] the fluoro- N-methyl-benzamide of -2-.Synthesize intermediate 2- (the fluoro- 4- of 3- of Enzalutamide
(methyl-carbamoyl)-phenyl amino)-neopentanoic acid is having many patents and document report before this, but used 2-
Acetyl cyclohexanone is as ligand, and ultimate yield is 75% or so, and 2- acetyl cyclohexanone is more expensive, this is for advising greatly
The industrialization of mould has very big limitation.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the existing defects, provides a kind of miscellaneous Shandong amine intermediate synthesis side of grace
Method can effectively solve the problems in background technique.
To achieve the above object, the invention provides the following technical scheme:
A kind of miscellaneous Shandong amine intermediate synthetic method of grace, characterized by the following steps:
S1: the bromo- 2- fluobenzoic acid of 4- and thionyl chloride are added in organic solvent, and it is Celsius in 80-100 that nitrogen is changed in evacuation
Degree reaction.After reaction, solvent evaporated obtains the bromo- 2- fluorobenzoyl chloride of 4-；
S2: it adds organic solvents into the bromo- 4- fluorobenzoyl chloride of 2- and is slowly added to methylamine water solution under condition of ice bath
Adjusting reaction solution pH=8~9, the reaction was continued.It to the end of reacting, is extracted with organic solvent, yield organic phase, solvent evaporated obtains
The fluoro- N-methyl-benzamide of the bromo- 2- of 4-；
S3: the fluoro- N-methyl-benzamide of the bromo- 2- of 4- and 2- aminoisobutyric acid are dissolved in organic solvent, is then added and urges
Agent, ligand, acid binding agent and water, nitrogen protection item add lower 100-120 degrees Celsius of reaction；
S4:TLC detection, after reaction, is first evaporated organic solvent, then under condition of ice bath, with certain density lemon
Lemon acid for adjusting pH=1~2, filtering, dry cake is target product；
As a preferred technical solution of the present invention, the organic solvent is ethyl acetate, N, N- dimethyl formyl
Amine (DMF), one of Isosorbide-5-Nitrae-dioxane, dimethyl sulfoxide, t-butyl methyl ether.
As a preferred technical solution of the present invention, the catalyst is stannous chloride.
As a preferred technical solution of the present invention, the ligand is L-PROLINE, acetylacetone,2,4-pentanedione, 2- acetyl basic ring
Hexanone, 1,3- diphenyl -1,3- propanedione, dipivaloylmethane.
As a preferred technical solution of the present invention, the acid binding agent is potassium carbonate, sodium carbonate, one in triethylamine
Kind.
As a preferred technical solution of the present invention, the extractant is selected from methylene chloride, chloroform, tert-butyl first
One of base ether.
As a preferred technical solution of the present invention, the concentration of the citric acid is 0.1mol/L~5mol/L.
As a preferred technical solution of the present invention, the fluoro- N-methyl-benzamide of the bromo- 2- of the 4-: 2- amino is different
Butyric acid: catalyst: ligand: acid binding agent: the molar ratio of water is 1:(1~3): (0.1~0.25): (0.2~0.5): (1~3):
(0.01~0.03).
As a preferred technical solution of the present invention, the reaction temperature is 80~120 degrees Celsius.Reaction time is
12~24 hours.
Beneficial effects of the present invention: the present invention is using the bromo- 2- fluobenzoic acid of 4-, 2- aminoisobutyric acid as raw material, in halogenation Asia
It is prepared under the action of copper catalysis and ligand auxiliary and acid binding agent by substitution reaction, yield 75%, but passes through optimization item
Part has filtered out cheaper acetylacetone,2,4-pentanedione as ligand, greatly reduces cost, this method is easy to operate, it is safe, at
This is cheap, has the value of amplification production.
Specific embodiment
The present invention is further illustrated by the following examples, but these embodiments must not be used to explain to the present invention
The limitation of protection scope.
Embodiment:
A kind of miscellaneous Shandong amine intermediate synthetic method of grace, characterized by the following steps:
S1: the bromo- 2- fluobenzoic acid of 10g4- is entered into dry 100ml three-necked flask, and 50ml anhydrous acetic acid second is added
Ester, evacuation are changed nitrogen and are reacted at 80 degrees Celsius.After reaction, solvent evaporated obtains the bromo- 2- fluorobenzoyl chloride of 4-.
S2: it adds organic solvents into the bromo- 4- fluorobenzoyl chloride of 2- and is slowly added to methylamine water solution under condition of ice bath
Adjusting reaction solution pH=8~9, the reaction was continued, continues stirring 12 hours.TLC thirty, which detects reaction, to be terminated, with 40ml tert-butyl first
Organic phase is collected in the extraction of base ether, and anhydrous sodium sulfate is dried to obtain the fluoro- N-methyl-benzamide 10.4g of the bromo- 2- of 4-, yield 98%.
S3: being dissolved in organic solvent for the fluoro- N-methyl-benzamide of the bromo- 2- of 9.2g 4- and 6.18g2- aminoisobutyric acid,
Then stannous chloride 792mg, acetylacetone,2,4-pentanedione 1.6g, potassium carbonate 13.8g and water 1ml, nitrogen protection item is added and adds lower 110 degrees Celsius
Reaction 24 hours.
S4:TLC detection, after reaction, is first evaporated organic solvent, then under condition of ice bath, is slowly added to 0.1mol/
The citric acid of L adjusts pH=1~2, and filtering, dry cake is target product, and solid washs three with ethyl alcohol (100:1) with water
Time, it is then washed one time with ethyl acetate again, obtains solid 8g,
Yield 75%, HPLC purity 99%.
Synthetic route of the invention is as follows:
It although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
A variety of variations, modification, replacement can be carried out to these embodiments without departing from the principles and spirit of the present invention by understanding
And modification, the scope of the present invention is defined by the appended.
Claims (9)
1. a kind of miscellaneous Shandong amine intermediate synthetic method of grace, characterized by the following steps: S1: by the bromo- 2- fluobenzoic acid of 4-
It being added in organic solvent with thionyl chloride, evacuation is changed nitrogen and is reacted at 80-100 degrees Celsius, after reaction, solvent evaporated,
Obtain the bromo- 2- fluorobenzoyl chloride of 4-；S2: the bromo- 4- fluorobenzoyl chloride of 2- is added organic solvents into, under condition of ice bath, slowly
Methylamine water solution is added and adjusts reaction solution pH=8~9 continuation instead, to the end of reacting, is extracted, yield organic phase, is steamed with organic solvent
Dry solvent obtains the fluoro- N-methyl-benzamide of the bromo- 2- of 4-；
S3: being dissolved in organic solvent for the fluoro- N-methyl-benzamide of the bromo- 2- of 4- and 2- aminoisobutyric acid, be then added catalyst,
Ligand, acid binding agent and water, nitrogen protection item add lower 100-120 degrees Celsius of reaction；
S4:TLC detection, after reaction, is first evaporated organic solvent, then under condition of ice bath, with certain density citric acid
PH=1~2 are adjusted, filtering, dry cake is target product.
2. the miscellaneous Shandong amine intermediate synthetic method of a kind of grace according to claim 1, it is characterized in that: the organic solvent is
Ethyl acetate, n,N-Dimethylformamide (DMF), one of Isosorbide-5-Nitrae-dioxane, dimethyl sulfoxide, t-butyl methyl ether.
3. the miscellaneous Shandong amine intermediate synthetic method of a kind of grace according to claim 1, it is characterized in that: the catalyst is chlorine
Change cuprous.
4. the miscellaneous Shandong amine intermediate synthetic method of a kind of grace according to claim 1, it is characterized in that: the ligand is L- dried meat
Propylhomoserin, acetylacetone,2,4-pentanedione, 2- acetyl cyclohexanone, 1,3- diphenyl -1,3- propanedione, dipivaloylmethane.
5. the miscellaneous Shandong amine intermediate synthetic method of a kind of grace according to claim 1, it is characterized in that: the acid binding agent is carbon
One of sour potassium, sodium carbonate, triethylamine.
6. the miscellaneous Shandong amine intermediate synthetic method of a kind of grace according to claim 1, it is characterized in that: the extractant selects
From one of methylene chloride, chloroform, t-butyl methyl ether.
7. the miscellaneous Shandong amine intermediate synthetic method of a kind of grace according to claim 1, it is characterized in that: the citric acid is dense
Degree is 0.1mol/L~5mol/L.
8. the miscellaneous Shandong amine intermediate synthetic method of a kind of grace according to claim 1, it is characterized in that: the bromo- 2- of the 4- is fluoro-
N-methyl-benzamide: 2- aminoisobutyric acid: catalyst: ligand: acid binding agent: the molar ratio of water is 1:(1~3): (0.1~
0.25): (0.2~0.5): (1~3): (0.01~0.03).
9. the miscellaneous Shandong amine intermediate synthetic method of a kind of grace according to claim 1, it is characterized in that: the reaction temperature is
80~120 degrees Celsius, the reaction time is 12~24 hours.
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| CN201811588915.3A CN109503416A (en) | 2018-12-24 | 2018-12-24 | A kind of miscellaneous Shandong amine intermediate synthetic method of grace |
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| CN201811588915.3A CN109503416A (en) | 2018-12-24 | 2018-12-24 | A kind of miscellaneous Shandong amine intermediate synthetic method of grace |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011044327A1 (en) * | 2009-10-07 | 2011-04-14 | Medivation Prostate Therapeutics, Inc. | Substituted phenylcarbamoyl alkylamino arene compounds and n,n'-bis-arylurea compounds |
| CN103108549A (en) * | 2010-02-24 | 2013-05-15 | 梅迪维新前列腺医疗股份有限公司 | Processes for the synthesis of diarylthiohydantoin and diarylhydantoin compounds |
| US20150210649A1 (en) * | 2014-01-27 | 2015-07-30 | Cadila Healthcare Limited | Process for preparation of androgen receptor antagonist |
| CN105330560A (en) * | 2015-10-13 | 2016-02-17 | 福格森（武汉）生物科技股份有限公司 | Enzalutamide intermediate preparation method |
| CN105985258A (en) * | 2015-01-29 | 2016-10-05 | 上海彩迩文生化科技有限公司 | Method for preparing benzamide compound and its intermediate |
| CN106164052A (en) * | 2014-04-07 | 2016-11-23 | 赞蒂瓦有限合伙公司 | For the method preparing grace miscellaneous Shandong amine |
| CN108976171A (en) * | 2018-08-27 | 2018-12-11 | 长沙泽达医药科技有限公司 | Compound, composition and its purposes in medicine preparation |
-
2018
- 2018-12-24 CN CN201811588915.3A patent/CN109503416A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011044327A1 (en) * | 2009-10-07 | 2011-04-14 | Medivation Prostate Therapeutics, Inc. | Substituted phenylcarbamoyl alkylamino arene compounds and n,n'-bis-arylurea compounds |
| CN103108549A (en) * | 2010-02-24 | 2013-05-15 | 梅迪维新前列腺医疗股份有限公司 | Processes for the synthesis of diarylthiohydantoin and diarylhydantoin compounds |
| US20150210649A1 (en) * | 2014-01-27 | 2015-07-30 | Cadila Healthcare Limited | Process for preparation of androgen receptor antagonist |
| CN106164052A (en) * | 2014-04-07 | 2016-11-23 | 赞蒂瓦有限合伙公司 | For the method preparing grace miscellaneous Shandong amine |
| CN105985258A (en) * | 2015-01-29 | 2016-10-05 | 上海彩迩文生化科技有限公司 | Method for preparing benzamide compound and its intermediate |
| CN105330560A (en) * | 2015-10-13 | 2016-02-17 | 福格森（武汉）生物科技股份有限公司 | Enzalutamide intermediate preparation method |
| CN108976171A (en) * | 2018-08-27 | 2018-12-11 | 长沙泽达医药科技有限公司 | Compound, composition and its purposes in medicine preparation |
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Application publication date: 20190322 |