CN111909040A - Preparation method of Elagolix intermediate 2-fluoro-6-trifluoromethylbenzylamine - Google Patents
Preparation method of Elagolix intermediate 2-fluoro-6-trifluoromethylbenzylamine Download PDFInfo
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- CN111909040A CN111909040A CN201910386580.5A CN201910386580A CN111909040A CN 111909040 A CN111909040 A CN 111909040A CN 201910386580 A CN201910386580 A CN 201910386580A CN 111909040 A CN111909040 A CN 111909040A
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- C07C51/15—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction of organic compounds with carbon dioxide, e.g. Kolbe-Schmitt synthesis
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- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
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- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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Abstract
The invention discloses a preparation method of an Elagolix intermediate 2-fluoro-6-trifluoromethylbenzylamine, belonging to the technical field of medical intermediates. It comprises the following steps: (1) synthesizing 2-fluoro-6- (trifluoromethyl) benzoic acid; (2) synthesizing 2-fluoro-6- (trifluoromethyl) benzyl alcohol; (3) synthesizing 2-fluoro-6- (trifluoromethyl) benzene methane sulfonate and phthalimide compound; (4) directly synthesizing a phthalimide compound; (5) synthesis of 2-fluoro-6-trifluoromethylbenzylamine. The preparation method optimizes factors such as reaction reagents, reaction solvents and the like, so that the reaction condition is mild, the process flow is simple and convenient, the requirement on equipment is low, the raw materials are cheaper, the obtained product has high purity, and the industrial production is facilitated.
Description
Technical Field
The invention relates to a preparation method of an Elagolix intermediate 2-fluoro-6-trifluoromethylbenzylamine, belonging to the technical field of medical intermediates.
Background
Albervib, english name Elagolix, CAS: 834153-87-6, having the chemical name of (R) -4- ((2- (5- (2-fluoro-3-methoxyphenyl) -3- (2-fluoro-6- (trifluoromethyl) benzyl) -4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H) -yl) -1-phenylethyl) amino) butanoid acid, which was granted NDA priority qualification by the FDA for treatment of endometriosis in 10 months in 2017 and is expected to be the first approved drug by the FDA for treatment of endometriosis.
Regarding the synthesis of the elbowei Elagolix intermediate 2-fluoro-6-trifluoromethylbenzylamine, the synthesis method disclosed in world patent wo 2007134862 is to use 2-fluoro-6- (trifluoromethyl) benzonitrile as a starting material and reduce with borane tetrahydrofuran complex to obtain 2-fluoro-6-trifluoromethylbenzylamine. However, the raw materials adopted by the method are expensive, and the cost of the raw materials is greatly increased.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provides a preparation method of an Elagolix intermediate 2-fluoro-6-trifluoromethylbenzylamine, which solves the problem that the raw materials for synthesizing the 2-fluoro-6-trifluoromethylbenzylamine are expensive.
The technical problem to be solved by the invention is realized by adopting the following technical scheme:
a preparation method of an Elagolix intermediate 2-fluoro-6-trifluoromethylbenzylamine comprises the following steps:
(1) taking 3-fluorotrifluorotoluene as a raw material and THF as a solvent, cooling, dropwise adding n-butyllithium, introducing carbon dioxide gas, and reacting to generate 2-fluoro-6- (trifluoromethyl) benzoic acid;
(2) reducing 2-fluoro-6- (trifluoromethyl) benzoic acid at the temperature of 0-10 ℃ by borane or boron trifluoride ethyl ether and sodium borohydride to obtain 2-fluoro-6- (trifluoromethyl) benzyl alcohol;
(3) reacting 2-fluoro-6- (trifluoromethyl) benzyl alcohol with methylsulfonyl chloride to obtain methanesulfonate, 2- (chloromethyl) -1-fluoro-3- (trifluoromethyl) benzene, and reacting the methanesulfonate and 2- (chloromethyl) -1-fluoro-3- (trifluoromethyl) benzene with phthalimide under the action of alkali to obtain phthalimide compound;
(4) reacting the 2-fluoro-6- (trifluoromethyl) benzyl alcohol generated in the step (2) with phthalimide under the action of DIAD and triphenylphosphine to directly obtain a phthalimide compound;
(5) and (4) reacting the phthalimide compound generated in the step (3) or (4) with hydrazine hydrate to generate the 2-fluoro-6-trifluoromethylbenzylamine.
As a preferred example, n-butyllithium is added dropwise with cooling to-78 ℃ in the step (1).
As a preferred example, the molar ratio of 3-fluorotrifluorotoluene to n-butyllithium in the step (1) is: 1.0: 1.0-1.0: 2.0.
As a preferred example, the base in said step (3) is K2CO3、Na2CO3、NaH。
As a preferable example, the molar ratio of 2-fluoro-6- (trifluoromethyl) benzyl alcohol to phthalimide in the step (3) is 1.0:1.0 to 1.0: 1.5.
As a preferred example, the molar ratio of 2-fluoro-6- (trifluoromethyl) benzyl alcohol to DIAD and triphenylphosphine in step (4) is 1.0:1.0: 1.0-1.0: 3.0: 3.0.
As a preferable example, the molar ratio of the phthalimide compound to the hydrazine hydrate in the step (5) is 1.0:2.0 to 1.0: 10.0.
As a preferred example, in the step (3), 2-fluoro-6- (trifluoromethyl) benzyl alcohol is reacted with phosphorus tribromide to give 2- (bromomethyl) -1-fluoro-3- (trifluoromethyl) benzene, and methanesulfonate, 2- (bromomethyl) -1-fluoro-3- (trifluoromethyl) benzene are reacted with phthalimide under the action of a base to give a phthalimide compound. 2- (bromomethyl) -1-fluoro-3- (trifluoromethyl) benzene and 2- (chloromethyl) -1-fluoro-3- (trifluoromethyl) benzene can be substituted for each other.
The invention has the beneficial effects that: the preparation method optimizes factors such as reaction reagents, reaction solvents and the like, so that the reaction condition is mild, the process flow is simple and convenient, the requirement on equipment is low, the raw materials are cheaper, the obtained product has high purity, and the industrial production is facilitated.
Drawings
FIG. 1 shows two parallel preparation paths involved in the present preparation method;
FIG. 2 is a structural formula of 2-fluoro-6- (trifluoromethyl) benzoic acid;
FIG. 3 is a structural formula of 2-fluoro-6- (trifluoromethyl) benzyl alcohol;
FIG. 4 is a structural formula of 2-fluoro-6- (trifluoromethyl) benzenemethansulfonate;
FIG. 5 is a structural formula of phthalimide compound;
FIG. 6 shows the structural formula of 2-fluoro-6-trifluoromethylbenzylamine.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further explained below.
As shown in FIG. 1, the present production method comprises two parallel production routes.
Example (b):
(1) synthesis of 2-fluoro-6- (trifluoromethyl) benzoic acid (see FIG. 2).
50g (0.3mol) of 3-fluorotrifluorotoluene and 500ml of anhydrous tetrahydrofuran are added into a 2L four-mouth bottle provided with a thermometer, a mechanical stirring and constant pressure dropping funnel device under the protection of nitrogen, liquid nitrogen is cooled to-78 ℃, 190.5ml (1.6M) of n-butyl lithium is dropwise added, the temperature is controlled to be-60 to-65 ℃, after the dropwise addition is finished, the temperature is controlled to be-60 to-65 ℃, the stirring is continued for 5 hours, and carbon dioxide gas is introduced until the reaction is complete; adding a small amount of water to quench the reaction, and heating to room temperature; adjusting pH to 2 with hydrochloric acid, adding 500ml ethyl acetate, and separating an organic layer; the organic layer was concentrated under reduced pressure to give 53 g of a white solid in 85% yield and 98% purity.
(2) Synthesis of 2-fluoro-6- (trifluoromethyl) benzyl alcohol (see FIG. 3).
Under the protection of nitrogen, adding 52 g (0.25mol) of 2-fluoro-6- (trifluoromethyl) benzoic acid and 520ml of THF (tetrahydrofuran) into a 2L three-necked bottle, mechanically stirring, cooling to 0-10 ℃, adding 28.5 g (0.75mol) of sodium borohydride in batches, and controlling the temperature to be 0-10 ℃; dropping BF3-OEt2106ml, and controlling the temperature to be 0-10 ℃; after the dropwise addition, the temperature is raised to the room temperature, and the mixture is stirred for reaction overnight; 600 g of water is added dropwise to quench the reaction; adding sodium carbonate solid in batches, and adjusting the pH to about 9; extracting with MTBE (500ml × 3); liquid separation; organic compoundsWashing with phase saturated sodium chloride; the solvent was removed under reduced pressure to give 47 g of a viscous liquid with a purity of 98% and a yield of 97%.
(3) 2-fluoro-6- (trifluoromethyl) benzene sulfonic acid ester (as shown in figure 4) and synthesis of phthalimide compound (as shown in figure 5).
Under the protection of nitrogen, adding 20ml of dichloromethane, 2.0 g (10mmol) of 2-fluoro-6- (trifluoromethyl) benzyl alcohol and 2.0 g (20mmol) of triethylamine into a 250ml three-neck flask, mechanically stirring, cooling to 0 ℃ in an ice bath, controlling the temperature to be 0-10 ℃, and dropwise adding 1.3 g (11mmol) of methanesulfonyl chloride MsCl1; after the dropwise addition, the temperature is raised to the room temperature, and the stirring is continued for 1 hour; the reaction solution was washed with a saturated sodium bicarbonate solution (20 ml. times.3), with a saturated sodium chloride solution (20 ml. times.3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give 2.6 g of a viscous oil as a mixture of methanesulfonate and chloromethyl compound (2-fluoro-6- (trifluoromethyl) benzenemethansulfonate) which was used in the next step without purification. The chloromethyl compound can be replaced by a bromomethyl compound.
Under the protection of nitrogen, 20ml of DMF, 2.6 g (10mmol) of mesylate and 2.0 g (20mmol) of triethylamine are added into a 250ml three-necked flask, and then the mixture is mechanically stirred and 2.95 g (20mmol) of phthalimide is added; heating to 80 ℃, and reacting for 8 hours; the reaction was cooled to room temperature, 60ml of water was added, extracted with methyl tert-ether (20 ml. times.3), the organic layer was washed with saturated sodium chloride solution (20 ml. times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was freed of solvent under reduced pressure to give an off-white solid (or slightly yellow viscous liquid) which was used in the next step without purification.
(4) The phthalimide compound (as shown in figure 5) is directly synthesized.
Adding 39 g (200mmol) of 2-fluoro-6- (trifluoromethyl) benzyl alcohol and THF390ml into a 1L three-necked bottle under the protection of nitrogen, mechanically stirring, cooling to 0-10 ℃, adding 40g (276mmol) of phthalimide and PPh3120.5g (460mmol), controlling the temperature to 0-10 ℃, dropwise adding 90ml (460mmol) of DIAD, heating to room temperature after dropwise adding, reacting for 2h, dropwise adding 50ml of water, quenching (controlling the temperature to 0-10 ℃), removing the solvent (THF) under reduced pressure, adding 400ml of MTBE and 60ml of water, stirring for 30min, separating an organic layer, drying by anhydrous sodium sulfate, and removing the solvent by organic phase decompression to obtain 200 g of off-white solid (or yellowish viscous liquid) which is directly used in the next step without purification.
(5) Synthesis of 2-fluoro-6-trifluoromethylbenzylamine (see FIG. 6).
Adding 200 g of phthalimide compound and 1600ml of ethanol into a 1L three-necked flask under the protection of nitrogen, heating to 80-85 ℃, dropwise adding 86g (80%) of hydrazine hydrate (a large amount of solid is separated) to react, continuously stirring for 1.5h, cooling to room temperature, filtering, removing the solvent from the filtrate under reduced pressure, adding 500ml of water and 600ml of MTBE into the MTBE, stirring for 15min, separating, extracting the aqueous phase with MTBE600ml, combining MTBE phases, filtering to remove insoluble substances, adding 5L of water into the filtrate, adjusting the pH of the filtrate to about 5-6 with 1N hydrochloric acid (1.4L), extracting the MTBE (300ml x 2), adjusting the pH of the aqueous phase to 9 with sodium carbonate solid, extracting the MTBE (500ml x 2) product, adding saturated sodium chloride into the MTBE phase to wash, and removing the solvent under reduced pressure to obtain 32g of yellow liquid with purity of 98% and yield of 85% in two steps.
The preparation method optimizes factors such as reaction reagents, reaction solvents and the like, so that the reaction condition is mild, the process flow is simple and convenient, the requirement on equipment is low, the raw materials are cheaper, the obtained product has high purity, and the industrial production is facilitated.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (8)
1. A preparation method of an Elagolix intermediate 2-fluoro-6-trifluoromethylbenzylamine is characterized by comprising the following steps:
(1) taking 3-fluorotrifluorotoluene as a raw material and THF as a solvent, cooling, dropwise adding n-butyllithium, introducing carbon dioxide gas, and reacting to generate 2-fluoro-6- (trifluoromethyl) benzoic acid;
(2) reducing 2-fluoro-6- (trifluoromethyl) benzoic acid at the temperature of 0-10 ℃ by borane or boron trifluoride ethyl ether and sodium borohydride to obtain 2-fluoro-6- (trifluoromethyl) benzyl alcohol;
(3) reacting 2-fluoro-6- (trifluoromethyl) benzyl alcohol with methylsulfonyl chloride to obtain methanesulfonate, 2- (chloromethyl) -1-fluoro-3- (trifluoromethyl) benzene, and reacting the methanesulfonate and 2- (chloromethyl) -1-fluoro-3- (trifluoromethyl) benzene with phthalimide under the action of alkali to obtain phthalimide compound;
(4) reacting the 2-fluoro-6- (trifluoromethyl) benzyl alcohol generated in the step (2) with phthalimide under the action of DIAD and triphenylphosphine to directly obtain a phthalimide compound;
(5) and (4) reacting the phthalimide compound generated in the step (3) or (4) with hydrazine hydrate to generate the 2-fluoro-6-trifluoromethylbenzylamine.
2. The process for preparing 2-fluoro-6-trifluoromethylbenzylamine, an Elagolix intermediate, according to claim 1, wherein n-butyllithium is added dropwise during the cooling to-78 ℃ in step (1).
3. The method for preparing 2-fluoro-6-trifluoromethylbenzylamine as an Elagolix intermediate according to claim 1, wherein the molar ratio of 3-fluorotrifluorotoluene to n-butyllithium in step (1) is: 1.0: 1.0-1.0: 2.0.
4. The process for preparing 2-fluoro-6-trifluoromethylbenzylamine as an Elagolix intermediate according to claim 1, wherein the base in step (3) is K2CO3、Na2CO3、NaH。
5. The method for preparing Elagolix intermediate 2-fluoro-6-trifluoromethylbenzylamine according to claim 1, wherein the molar ratio of 2-fluoro-6- (trifluoromethyl) benzyl alcohol to phthalimide in step (3) is 1.0: 1.0-1.0: 1.5.
6. The method for preparing Elagolix intermediate 2-fluoro-6-trifluoromethylbenzylamine according to claim 1, wherein the molar ratio of 2-fluoro-6- (trifluoromethyl) benzyl alcohol to DIAD and triphenylphosphine in step (4) is 1.0:1.0: 1.0-1.0: 3.0: 3.0.
7. The method for preparing Elagolix intermediate 2-fluoro-6-trifluoromethylbenzylamine according to claim 1, wherein the molar ratio of the phthalimide compound to the hydrazine hydrate in step (5) is 1.0:2.0 to 1.0: 10.0.
8. The method for preparing Elagolix intermediate 2-fluoro-6-trifluoromethylbenzylamine according to claim 1, wherein in step (3), 2-fluoro-6- (trifluoromethyl) benzyl alcohol is reacted with phosphorus tribromide to obtain 2- (bromomethyl) -1-fluoro-3- (trifluoromethyl) benzene, and the mesylate and 2- (bromomethyl) -1-fluoro-3- (trifluoromethyl) benzene are reacted with phthalimide under the action of alkali to obtain the phthalimide compound.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006257042A (en) * | 2005-03-18 | 2006-09-28 | Central Glass Co Ltd | Method for producing 2-fluoro-6-(trifluoromethyl)benzyl bromide and 2-fluoro-6-(trifluoromethyl)benzylamine |
| WO2017156179A1 (en) * | 2016-03-09 | 2017-09-14 | Raze Therapeutics, Inc. | 3-phosphoglycerate dehydrogenase inhibitors and uses thereof |
| CN107935863A (en) * | 2017-11-30 | 2018-04-20 | 厦门海乐景生化有限公司 | The synthetic method of the critical materials compound C of Elagolix |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006257042A (en) * | 2005-03-18 | 2006-09-28 | Central Glass Co Ltd | Method for producing 2-fluoro-6-(trifluoromethyl)benzyl bromide and 2-fluoro-6-(trifluoromethyl)benzylamine |
| WO2017156179A1 (en) * | 2016-03-09 | 2017-09-14 | Raze Therapeutics, Inc. | 3-phosphoglycerate dehydrogenase inhibitors and uses thereof |
| CN107935863A (en) * | 2017-11-30 | 2018-04-20 | 厦门海乐景生化有限公司 | The synthetic method of the critical materials compound C of Elagolix |
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Application publication date: 20201110 |