CN102786437A - Preparation method of teriflunomide - Google Patents
Preparation method of teriflunomide Download PDFInfo
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- CN102786437A CN102786437A CN2012103254655A CN201210325465A CN102786437A CN 102786437 A CN102786437 A CN 102786437A CN 2012103254655 A CN2012103254655 A CN 2012103254655A CN 201210325465 A CN201210325465 A CN 201210325465A CN 102786437 A CN102786437 A CN 102786437A
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Abstract
The invention relates to a preparation method of (Z)-2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-butenamide (I). The preparation method is characterized in that cyanoacetic acid (I) is dehydrated and condensed to obtain cyan acetic anhydride (III), the cyan acetic anhydride (III) reacts with trifluoromethyl phenyl under the action of catalyst to obtain 2-cyano-N-(4-trifluoromethyl-phenyl)-ethanamide (IV), and the 2-cyano-N-(4-trifluoromethyl-phenyl)-ethanamide (IV) reacts with the acetylchloride in the presence of sodium hydride to obtain teriflunomide (I).
Description
Technical field
The present invention relates to a kind of preparation method of Teriflunomide.
Background technology
Teriflunomide (teriflunomide); Chemical name: (Z)-2-cyano-3-hydroxy N-[4-(trifluoromethyl) phenyl]-2-butylene acid amides, structural formula is following, is a kind of dihydroorate dehydrogenase (DHODH) suppressor factor; Active metabolite for leflunomide; By the exploitation of Sanofi-Aventis company, in II phase clinical study, be used for the treatment of recurrence type multiple sclerosis, carrying out III phase clinical study at present.Domesticly also Teriflunomide is conducted a research, be mainly used in treating for skin disease.
Teriflunomide synthetic mainly contains two reaction schemes:
(1) by methyl aceto acetate and triethyl orthoformate condensation; Generate ethoxy methyne methyl aceto acetate; Generate 5-methyl-isoxazole-4-ethyl formate with the azanol cyclization, generate 5-methyl-isoxazole-4-formic acid through hydrolysis again, generate corresponding acyl chlorides with the sulfur oxychloride reaction then; Get leflunomide with the p-trifluoromethylaniline condensation again, the isoxazole open loop gets Teriflunomide (EP0257882A1) under alkaline condition at last.This route is long, and yield is low, and cost is high, is unfavorable for suitability for industrialized production.
(2) process ethyl cyanoacetate or cyanogen Acetyl Chloride 98Min. and p-trifluoromethylaniline reaction through cyanoacetic acid and make 2-cyanic acid-N-(4-trifluoromethyl-phenyl)-ethanamide (IV), in the presence of sodium hydride, obtain Teriflunomide at last with excess acetyl chloride.
1. with ethyl cyanoacetate preparation (IV), see patent US5700823, be reflected under the hot conditions and carry out that the reaction products therefrom is complicated, need column chromatography to separate, yield low (49.8%) is not suitable for suitability for industrialized production.
2. with cyanogen Acetyl Chloride 98Min. preparation (IV), see document J.Med.Chem.2009,52,2683-2693, used sulfur oxychloride is seriously polluted, cyanogen Acetyl Chloride 98Min. poor stability, the reaction needs strictness is anhydrous, and yield low (57%).
Summary of the invention
The present invention is variation route, the novel method of a kind of preparation Teriflunomide (I), and synthetic route of the present invention is following:
The present invention gets cyanoacetic acid acid anhydride (III) by cyanoacetic acid (II) self dehydrating condensation, and is easy and simple to handle, and the products therefrom water stability, is high; (III) under catalyst action with p-trifluoromethylaniline react 2-cyanic acid-N-(4-trifluoromethyl-phenyl)-ethanamide (IV), yield reaches 73.1%; (IV) under the sodium hydride existence condition, get Teriflunomide (I) with excess acetyl chloride.Reactions step is short, and reaction conditions is gentle, and aftertreatment is simple, and cost is low, can successfully realize suitability for industrialized production, is a kind of economy, efficient, environmental protection, has the preparation method that good suitability for industrialized production is worth.
Synthesis step of the present invention:
(1) preparation of cyanoacetic acid acid anhydride (III)
1. toluene divides the water preparation
The preparation of cyanoacetic acid acid anhydride (III) is a raw material with cyanoacetic acid (II), divides water to make with toluene, and temperature of reaction is 90～110 ℃.
Toluene divides cyanoacetic acid acid anhydride (III) that water makes with the big solvent extraction of polarity, and solvent for use is selected from water, DMSO, acetonitrile, DMF, dioxane, THF, Pyrrolidine, piperidines, pyridine or N-Methyl pyrrolidone.
2. Vanadium Pentoxide in FLAKES dehydration preparation
The preparation of cyanoacetic acid acid anhydride (III) is a raw material with cyanoacetic acid (II), is the dewatering agent preparation with the Vanadium Pentoxide in FLAKES, and temperature of reaction is 20～120 ℃.
Among the preparation method of cyanoacetic acid acid anhydride (III); Solvent is a non-protonic solvent, and solvent for use is selected from DMSO, acetonitrile, DMF, ETHYLE ACETATE, acetone, THF, ether, isopropyl ether, methylene dichloride, chloroform, tetracol phenixin, toluene, benzene or YLENE.
Among the preparation method of cyanoacetic acid acid anhydride (III), cyanoacetic acid (II) is 1: 0.5～10 with the mol ratio of Vanadium Pentoxide in FLAKES, preferred 1: 0.5～1.5.
Among the preparation method of cyanoacetic acid acid anhydride (III), cyanoacetic acid (II) is 1: 5～15 with the weightmeasurement ratio of solvent.
(2) preparation of 2-cyanic acid-N-(4-trifluoromethyl-phenyl)-ethanamide (IV)
Cyanoacetic acid acid anhydride (III) is 1.05～3.5: 1 with the reaction mol ratio of p-trifluoromethylaniline, preferred 1.5～2.5: 1.
Cyanoacetic acid acid anhydride (III) is AlCl with the catalyst for reaction of p-trifluoromethylaniline
3, AlBr
3, ZnCl
2, ZnBr
2, SnCl
4, SnBr
4, BF
3Deng Lewis acid, or protonic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, methylsulfonic acid, or organic bases such as pyridine, triethylamine, diisopropylethylamine, tri-n-butylamine, lutidine, DMAP, DBU.
During cyanoacetic acid acid anhydride (III) reacted with p-trifluoromethylaniline, the mol ratio of p-trifluoromethylaniline and catalyzer was 1: 0.05%～2%, preferred 1: 0.5～1.5%.
Cyanoacetic acid acid anhydride (III) is reflected in the non-protonic solvent with p-trifluoromethylaniline and carries out, and solvent for use is selected from DMSO, acetonitrile, DMF, ETHYLE ACETATE, acetone, THF, ether, isopropyl ether, methylene dichloride, chloroform, tetracol phenixin, toluene, benzene or YLENE.Preferentially select solvent good to cyanoacetic acid acid anhydride (III) solvability and that remove easily for use, like acetonitrile.
The weightmeasurement ratio of p-trifluoromethylaniline and solvent was 1: 5～12 during cyanoacetic acid acid anhydride (III) reacted with p-trifluoromethylaniline.
Cyanoacetic acid acid anhydride (III) is 20～120 ℃ with the p-trifluoromethylaniline temperature of reaction.
(3) preparation of Teriflunomide (I)
Among the preparation method of Teriflunomide (I), solvent is a non-protonic solvent, and solvent for use is selected from THF, DMF, ether.
Among the preparation method of Teriflunomide (I), temperature of reaction is 0～25 ℃
Among the preparation method of Teriflunomide (I), used highly basic is sodium hydride, potassium hydride KH.
Among the preparation method of Teriflunomide (I), 2-cyanic acid-N-(4-trifluoromethyl-phenyl)-ethanamide (IV) is 1: 1～3 with the alkaline mol ratio.
Among the preparation method of Teriflunomide (I), 2-cyanic acid-N-(4-trifluoromethyl-phenyl)-ethanamide (IV) is 1: 1.1～2 with the mol ratio of Acetyl Chloride 98Min..
Embodiment
Embodiment:
Embodiment 1, the preparation of cyanoacetic acid acid anhydride (III)
1. toluene divides the water preparation
Add cyanoacetic acid (II) 34.0g in the reaction flask, toluene 200ml stirs, reflux water-dividing, reaction 16h, concentrating under reduced pressure adds acetonitrile 500ml, stir, suction filtration, filtrate decompression concentrate brown liquid (III) 25.2g, yield 82.9%.
2. Vanadium Pentoxide in FLAKES dehydration preparation
Add cyanoacetic acid (II) 34.0g in the reaction flask, Vanadium Pentoxide in FLAKES 35.5g, anhydrous tetrahydro furan 200ml is warming up to 65 ℃, stirs 24h, suction filtration while hot, filter cake use minor amounts of acetonitrile drip washing, filtrate decompression concentrated brown liquid 27.3g, yield 89.8%.
Embodiment 2, the preparation of 2-cyanic acid-N-(4-trifluoromethyl-phenyl)-ethanamide (IV)
Add cyanoacetic acid acid anhydride (III) 22.8g, p-trifluoromethylaniline 12.08g, acetonitrile 120ml, vitriol oil 0.075g in the reaction flask; Be warming up to 81 ℃, stir 36h, concentrating under reduced pressure adds ETHYLE ACETATE 300ml; Stir, gained solution is used saturated sodium-chloride water solution 150ml * 3 washings, the organic layer concentrating under reduced pressure afterwards with 2.7mol/L hydrochloric acid soln 150ml * 3 washings; Residue is used ethyl alcohol recrystallization, pale yellow powder solid (IV) 12.5g, mp191～193 ℃, yield 73.1%.
MS(m/z)：227(M
+)。
Embodiment 3, the preparation of Teriflunomide (I)
Add sodium hydride 6.0g in the reaction flask, dry tetrahydrofuran 100ml drips the tetrahydrofuran solution 25ml that contains 2-cyanic acid-N-(4-trifluoromethyl-phenyl)-ethanamide (IV) 11.4g under the condition of ice bath, stir 1h; Dripping acetyl chloride 4.3g, room temperature reaction 24h, acetate cancellation, concentrating under reduced pressure; Add entry 200ml, stir, solution is with methylene dichloride 100ml * 3 washings, and water layer is transferred pH=2 with 10% hydrochloric acid; Separate out a large amount of solids, suction filtration, filter cake is used recrystallizing methanol; White solid (I) 10.6g, mp228～230 ℃, yield 78.5%.
1H-NMR(DMSO-d
6)δ：7.72(d，2H)，7.59(d，2H)，2.13(s，3H)，11.67(s，1H)。
MS(m/z)：269(M
+)。
Claims (10)
1. the preparation method of a Teriflunomide; It is characterized in that cyanoacetic acid (II) self dehydrating condensation gets cyanoacetic acid acid anhydride (III); (III) under catalyst action with p-trifluoromethylaniline react 2-cyanic acid-N-(4-trifluoromethyl-phenyl)-ethanamide (IV), (IV) under the sodium hydride existence condition and excess acetyl chloride get Teriflunomide (I).
2. the preparation method of Teriflunomide according to claim 1 (I), the preparation of cyanoacetic acid acid anhydride (III) is to be raw material with cyanoacetic acid (II), divides water to make with toluene, temperature of reaction is 90～110 ℃.
3. according to claim 2, toluene divides cyanoacetic acid acid anhydride (III) that water makes with the big solvent extraction of polarity, and solvent for use is selected from water, DMSO, acetonitrile, DMF, dioxane, THF, Pyrrolidine, piperidines, pyridine or N-Methyl pyrrolidone.
4. the preparation method of Teriflunomide according to claim 1 (I), the preparation of cyanoacetic acid acid anhydride (III) is a raw material with cyanoacetic acid (II), is the dewatering agent preparation with the Vanadium Pentoxide in FLAKES, temperature of reaction is 20～120 ℃.
5. according to claim 4; The preparation method of cyanoacetic acid acid anhydride (III); Solvent is a non-protonic solvent, and solvent for use is selected from DMSO, acetonitrile, DMF, ETHYLE ACETATE, acetone, THF, ether, isopropyl ether, methylene dichloride, chloroform, tetracol phenixin, toluene, benzene or YLENE.
6. according to claim 4,5 said, among the preparation method of cyanoacetic acid acid anhydride (III), cyanoacetic acid (II) is 1: 0.5～10 with the mol ratio of Vanadium Pentoxide in FLAKES; Cyanoacetic acid (II) is 1: 5～15 with the weightmeasurement ratio of solvent.
7. the preparation method of Teriflunomide according to claim 1 (I); Cyanoacetic acid acid anhydride (III) is reflected in the non-protonic solvent with p-trifluoromethylaniline and carries out, and solvent for use is selected from DMSO, acetonitrile, DMF, ETHYLE ACETATE, acetone, THF, ether, isopropyl ether, methylene dichloride, chloroform, tetracol phenixin, toluene, benzene or YLENE.
8. according to the preparation method of claim 1,7 described Teriflunomides (I), during cyanoacetic acid acid anhydride (III) reacted with p-trifluoromethylaniline, the weightmeasurement ratio of p-trifluoromethylaniline and solvent was 1: 5～12; Temperature of reaction is 20～120 ℃.
9. the preparation method of Teriflunomide according to claim 1 (I), cyanoacetic acid acid anhydride (III) is AlCl with the catalyst for reaction of p-trifluoromethylaniline
3, AlBr
3, ZnCl
2, ZnBr
2, SnCl
4, SnBr
4, BF
3Deng Lewis acid, or protonic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, methylsulfonic acid, or organic bases such as pyridine, triethylamine, diisopropylethylamine, tri-n-butylamine, lutidine, DMAP, DBU.
10. according to the preparation method of claim 1,9 described Teriflunomides (I), cyanoacetic acid acid anhydride (III) is 1.05～3.5: 1 with the reaction mol ratio of p-trifluoromethylaniline; The mol ratio of p-trifluoromethylaniline and catalyzer is 1: 0.05%～2%.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103709068A (en) * | 2013-12-26 | 2014-04-09 | 武汉工程大学 | Preparation method of teriflunomide |
| CN103848756A (en) * | 2014-03-28 | 2014-06-11 | 翰宇药业（武汉）有限公司 | Preparation method of teriflunomide and intermediate thereof |
| CN113666842A (en) * | 2021-09-23 | 2021-11-19 | 河北凯威恒诚制药有限公司 | Continuous flow teriflunomide preparation process |
| CN114736154A (en) * | 2022-03-15 | 2022-07-12 | 安庆朗坤药业有限公司 | Preparation method of N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide |
| CN115838340A (en) * | 2022-12-31 | 2023-03-24 | 辰欣药业股份有限公司 | Preparation method of teriflunomide |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103709068A (en) * | 2013-12-26 | 2014-04-09 | 武汉工程大学 | Preparation method of teriflunomide |
| CN103709068B (en) * | 2013-12-26 | 2015-12-02 | 武汉工程大学 | Fluorine founds the preparation method of special amine |
| CN103848756A (en) * | 2014-03-28 | 2014-06-11 | 翰宇药业（武汉）有限公司 | Preparation method of teriflunomide and intermediate thereof |
| CN103848756B (en) * | 2014-03-28 | 2015-04-22 | 翰宇药业（武汉）有限公司 | Preparation method of teriflunomide and intermediate thereof |
| CN113666842A (en) * | 2021-09-23 | 2021-11-19 | 河北凯威恒诚制药有限公司 | Continuous flow teriflunomide preparation process |
| CN114736154A (en) * | 2022-03-15 | 2022-07-12 | 安庆朗坤药业有限公司 | Preparation method of N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide |
| CN114736154B (en) * | 2022-03-15 | 2023-07-21 | 安庆朗坤药业有限公司 | Process for preparing N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide |
| CN115838340A (en) * | 2022-12-31 | 2023-03-24 | 辰欣药业股份有限公司 | Preparation method of teriflunomide |
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