CN102659811A - Method for preparing prasugrel - Google Patents
Method for preparing prasugrel Download PDFInfo
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- CN102659811A CN102659811A CN2012101482765A CN201210148276A CN102659811A CN 102659811 A CN102659811 A CN 102659811A CN 2012101482765 A CN2012101482765 A CN 2012101482765A CN 201210148276 A CN201210148276 A CN 201210148276A CN 102659811 A CN102659811 A CN 102659811A
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- DTGLZDAWLRGWQN-UHFFFAOYSA-N CC(Oc1cc(CN(CC2)C(C(C3CC3)=O)c3ccccc3F)c2[s]1)=O Chemical compound CC(Oc1cc(CN(CC2)C(C(C3CC3)=O)c3ccccc3F)c2[s]1)=O DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a method for preparing prasugrel (I). The method comprises the following steps: performing addition reaction of a Grignard reagent prepared from fluorobenzyl bromide and cyclopropanecarbonitrile to obtain cyclopropyl-2-fluorobenzyl ketone; performing chlorination to obtain a main intermediate, namely alpha-cyclopropyl carbonyl-2-fluorobenzyl chloride (II); performing condensation reaction of (II) and 2-oxo-2,4,5,6,7,7alpha-hexahydrothieno[3,2-c]pyridine 4-methylbenzenesulfonate to obtain an intermediate, namely 5-(alpha-cyclopropyl carbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7alpha-hexahydrothieno[3,2-c]pyridine (IV); and performing acetic anhydride esterification on the (IV) to obtain the prasugrel (I).
Description
Technical field
The present invention relates to antiplatelet drug prasugrel (2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the 7-THTP is [3,2-c] pyridine also) preparation method (I).
Background technology
The hydrogenated pyridine verivate like ticlopidine and clopidogrel, has been widely used in treating thrombosis and relative disease.And prasugrel (I) is follow-on hydrogenated pyridine verivate, and research shows to have good platelet aggregation restraining effect.Its acid addition salt (particularly hydrochloric acid or PHENRAMINE MALEATE) has good oral absorption property, a little less than metabolic activity and the toxicity, is a kind of rising anti-freezing medicine therefore.
U.S. Pat 5874581 has been reported a kind of method for preparing prasugrel: through 2-siloxy-4,5,6; The 7-THTP also coupling of [3,2-c] pyridine tosilate and cyclopropyl-(α-chloro-2-luorobenzyl) ketone obtains 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-siloxy-4,5; 6; The 7-THTP is [3,2-c] pyridine also, and then esterification obtains (I) under the aceticanhydride effect.This method need experience the silylation protection process of a hydroxyl, has not only increased the step of reaction, has also increased industrialized cost.
U.S. Pat 5288726 has been reported and has been utilized α-cyclopropyl carbonyl-2-luorobenzyl bromination thing and 2-oxygen-2,4,5,6 in addition; 7,7 α-six hydrogen thieno-[3,2-c] pyridine hydrochloride coupling obtains midbody 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2; 4,5,6; 7,7 α-six hydrogen thieno-[3,2-c] pyridines (IV), then (IV) in the presence of sodium hydride, obtain the method for title product (I) with aceticanhydride reaction.The linked reaction yield of this method very low (32%), and when carrying out bromo, to use the bigger solvent-tetracol phenixin of toxicity; In this step reaction of acylations, need to use dangerous highly basic---sodium hydride, this is unfavorable for unsettled title product; And the amount ratio of aceticanhydride is bigger.
Summary of the invention
For solving the defective that exists in the above-mentioned prior art, the present invention aim to provide a kind of new simple to operate, reaction conditions is gentle, step is less, be fit to the method for mass preparation prasugrel (I).
The preparation method of prasugrel of the present invention (I) comprises following process:
(a) addition reaction generation midbody cyclopropyl-2-luorobenzyl ketone (VII) takes place with Grignard reagent and the cyclopropylniitrile (VI) that magnesium makes in adjacent fluorobenzyl bromide (V);
(b) midbody (VII) generates midbody cyclopropyl-(α-chloro-2-luorobenzyl) ketone (II) with chlorination reagent generation chlorination;
(c) midbody (II) and 2-oxo-2,4,5,6; Condensation reaction takes place and obtains midbody 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2 in the hydrochlorate (III) of 7,7 α-six hydrogen thieno-[3,2-c] pyridine under the effect of additive and alkali; 4,5,6; 7,7 α-six hydrogen thieno-[3,2-c] pyridines (IV);
(d) acylation reaction takes place with acylating reagent in midbody (IV) under the effect of alkali, generates prasugrel (I).
Above-mentioned each reaction process can be represented by the reactions formula:
The specific operation process and the condition of each step reaction are following among the above-mentioned preparation method:
Step (a): adjacent fluorobenzyl bromide (V) reacts in organic solvent with MAGNESIUM METAL 99 and generates Grignard reagent; Described organic solvent is for to be selected from: the ether of THF, ether, 2-methyltetrahydrofuran, positive propyl ether, isopropyl ether, MTBE, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether; The consumption of MAGNESIUM METAL 99 is 1～10 equivalent of substrate; Temperature of reaction is 0～80 ℃, and the reaction times is 1～12 hour; Then addition reaction is taken place for grignard reaction liquid that makes and ring third cyanogen (VI), the amount of wherein encircling third cyanogen is 0.1～10 equivalent of adjacent fluorobenzyl bromide (V), and temperature of reaction is 0～100 ℃, and the reaction times is 1～24 hour; Reaction finishes the back reacts with the saturated aqueous ammonium chloride cancellation, carries out purifying through vacuum fractionation or column chromatography and obtains compound (VII), also can not purifiedly directly be used for next step reaction.
Step (b): chlorination takes place with chlorinating agent in compound (VII) in organic solvent; Described chlorinating agent is for being selected from: SULPHURYL CHLORIDE, sulfur oxychloride, phosphorus pentachloride; Temperature of reaction is-20～60 ℃; Reaction times is 1～24 hour, carries out purifying through underpressure distillation or column chromatography after reaction is accomplished and obtains compound (II), also can not purifiedly directly be used for next step reaction.
Step (c): compound (II) and (III) linked reaction takes place under the effect of additive and alkali and generate compound (IV); This linked reaction solvent for use is one or more the combination that is selected from following: benzene,toluene,xylene, methylene dichloride, chloroform, ethylene dichloride, tetracol phenixin, THF, ether, 2-methyltetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, N; Dinethylformamide, N; N-N,N-DIMETHYLACETAMIDE, HMPA, DMSO 99.8MIN., acetone or acetonitrile, the concentration of reaction are 0.01～10 mol.
The salt of compound (III) is for being selected from described in the step (c): vitriol, hydrochloride, mesylate, tosilate.
Additive described in the step (c) is the combination of following one or more: Soiodin, potassiumiodide, lithium iodide, cesium iodide, Sodium Bromide, Potassium Bromide, lithiumbromide, cesium bromide, sodium-chlor, Repone K, lithium chloride, cesium chloride, sodium pyrosulfate, sal enixum, sodium hydrogen phosphate, SODIUM PHOSPHATE, MONOBASIC, potassium hydrogen phosphate, potassium primary phosphate, tetramethyl ammonium chloride, tetramethyl-ammonia bromide, tetramethyl-iodate ammonia, TEA chloride, tetraethyl-ammonia bromide, tetraethyl-iodate ammonia, tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetrabutylammonium iodide, trimethyl benzyl ammonia chloride, triethyl benzyl ammonia chloride etc., the consumption of additive is 0.1～10 equivalent of substrate.
Alkali is for being selected from described in the step (c): yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus, cesium carbonate, sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, calcium hydroxide, quicklime, sodium hydride etc., triethylamine, diisopropyl ethyl amine, pyridine, 4-N; N-dimethyl aminopyridines etc., the consumption of alkali is 0.5～10 equivalent of substrate.
The temperature of reaction of step (c) is 0～100 ℃, and the time of reaction is 1～24 hour.
The reaction of step (c) can obtain compound (IV) through crystallization, also can not purifiedly directly be used for next step reaction.
Step (d): acylation reaction takes place and generates compound (I) in compound (IV); The solvent of this acylation reaction is for being selected from: methylene dichloride, chloroform, THF, ether, dioxane, N; Dinethylformamide, N; N-N,N-DIMETHYLACETAMIDE, DMSO 99.8MIN., acetone or acetonitrile, the concentration of reaction are 0.01～10 mol.
Acylating reagent in the step (d) is for being selected from: acetic acid, aceticanhydride, Acetyl Chloride 98Min., acetyl bromide, vinyl acetic monomer etc., the consumption of acylating reagent is 0.5～10 equivalent of substrate.
Alkali used in the step (d) is for being selected from: yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus, sodium hydroxide, Pottasium Hydroxide etc., triethylamine, diisopropyl ethyl amine, pyridine, 4-N; N-dimethyl aminopyridine, the consumption of alkali are 0.5～10 equivalent of substrate.
The temperature of reaction of step (d) is-20～60 ℃, and the reaction times is 0.5～12 hour, and reaction finishes the back and obtains compound (I) through crystallization.
Compare with the existing method for preparing prasugrel (I), the invention has the advantages that: reagent that reaction conditions is gentle, step is short, use toxicity is little and solvent, high, the suitable suitability for industrialized production of yield; Can improve the yield and the final product quality of linked reaction through adding the mode of additive especially; And in acylation reaction, only need to use general alkali and acylating reagent, and effectively prevented the decomposition of this unstable compound, improved the yield of reaction.
Specific embodiment
Pass through embodiment further explain technical scheme of the present invention below, but protection scope of the present invention is not limited thereto.
Embodiment one
In the 1L there-necked flask, add magnesium (9.6g, 0.4mol) and MTBE (40mL) in three neck bottles, at room temperature, be added dropwise to adjacent fluorobenzyl bromide (75.6g, MTBE 0.4mol) (300mL) solution.After dropwising, in reaction system, be added dropwise to cyclopropylniitrile (26.8g, MTBE 0.4mol) (300mL) solution.After dropwising, reflux 2 hours.In system, add saturated aqueous ammonium chloride (300mL), tell organic layer, water layer merges organic layer with ETHYLE ACETATE (300mL) extraction, anhydrous sodium sulfate drying, and underpressure distillation obtains oily matter 3 (49.9g, 70%).
1H?NMR(CDCl
3)δ：0.88～0.93(m，2H，CH
2)，1.07～1.11(m，2H，CH
2)，2.00～2.04(m，1H，CH)，3.90(s，2H，CH
2)，7.07～7.29(m，4H，ArH)。
Embodiment two
(131g, 0.74mol) and methylene dichloride (500mL), (99.4g, methylene dichloride 0.74mol) (1000mL) solution drip Bi Jixu and stirred 1 hour at room temperature to drip SULPHURYL CHLORIDE in the 5L there-necked flask, to add 3.Add saturated sodium bicarbonate aqueous solution (1500mL), tell organic layer, water layer merges organic layer, anhydrous sodium sulfate drying with methylene dichloride (1500mL) extraction, and filtration, underpressure distillation obtain oily matter 4 (125g, 82%).
1H?NMR(CDCl
3)δ：0.94～1.20(m，4H，CH
2CH
2)，2.09～2.13(m，1H，CH)，5.91(s，1H，CH)，7.12～7.48(m，4H，ArH)。
Embodiment three
In the 5L there-necked flask, add 4 (106g, 0.5mol), 5,6,7; 7 α-THTP also [3,2-c] pyridines-2 (4H)-ketone tosilate (163g, 0.5mol), salt of wormwood (138g; 1mol), (75g 0.5mol), DMSO 99.8MIN. (2500mL), heats 60 ℃ and stirred 14 hours down Soiodin.Add water, ethyl acetate extraction (2L).Merge organic layer, the saturated sodium-chloride washing, anhydrous sodium sulfate drying, pressure reducing and steaming solvent, resistates obtain light yellow solid 5 (116g, 70%) with isopropyl ether (1L) crystallization.
1H?NMR(CDCl
3)δ：0.70～1.08(m，4H，CH
2CH
2)，1.86～2.02(m，1H，CH)，2.07～2.14(m，1H，CH)，2.29～2.43，2.52～2.58(m，2H，CH
2)，2.85～2.88，3.08～3.15(m，2H，CH
2)，3.93～4.00，4.10～4.14(m，2H，CH
2)，4.87，4.90(s，s，1H)，6.06，6.08(s，s，1H)，7.15～7.38(m，4H，ArH)。
Embodiment four
In the 1L there-necked flask, add 5 (80g, 0.24mol), (24g, 0.24mol), DMSO 99.8MIN. (400mL), (25g, DMSO 99.8MIN. 0.25mol) (100mL) solution stirred 6 hours down at 60 ℃ triethylamine to drip aceticanhydride.Add water, use ethyl acetate extraction.Organic layer with the saturated common salt water washing after, anhydrous sodium sulfate drying, removal of solvent under reduced pressure, the gained resistates obtains white solid 1 (73g, 81%) with isopropyl ether (500mL) crystallization.
1H?NMR(CDCl
3)δ：0.82～0.88(m，2H，CH
2)，0.99～1.09(m，2H，CH
2)，2.25(s，3H，CH
3)，2.23-2.30(m，1H，CH)，2.73-2.92(m，4H，CH
2CH
2)，3.47(d，1H，J＝14.4Hz，CH)，3.56(d，1H，J＝14.4Hz，CH)，4.83(s，1H，CH)，6.26(s，1H，ArH)，7.09～7.20(m，2H，ArH)，7.26-7.34(m，1H，ArH)，7.44～7.49(m，1H，ArH).MS(ESI，m/z)：374[M+H]
+。
Claims (10)
- One kind prepare prasugrel (2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the 7-THTP is the method for [3,2-c] pyridines (I) also, its characteristic comprises:
(a) addition reaction generation midbody cyclopropyl-2-luorobenzyl ketone (VII) takes place with cyclopropyl cyanogen (VI) after generating Grignard reagent with magnesium in adjacent fluorobenzyl bromide (V) in organic solvent,
(b) midbody (VII) generates midbody cyclopropyl-(α-chloro-2-luorobenzyl) ketone (II) with chlorination reagent generation chlorination,
(c) midbody (II) and 2-oxo-2,4,5,6; Condensation reaction takes place and obtains midbody 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4 in 7,7 α-six hydrogen thieno-[3,2-c] pyridinium salts (III) under the effect of additive and alkali; 5,6,7; 7 α-six hydrogen thieno-[3,2-c] pyridines (IV)(d) acylation reaction takes place with acylating reagent in midbody (IV) under the effect of alkali, generates prasugrel (I),
- 2. preparation method according to claim 1, the used solvent of the preparation of the Grignard reagent of wherein said reaction process (a) is for being selected from: THF, ether, 2-methyltetrahydrofuran, positive propyl ether, isopropyl ether, MTBE, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether etc.
- 3. preparation method according to claim 1, the used chlorination reagent of wherein said reaction process (b) is for being selected from: SULPHURYL CHLORIDE, thionyl chloride, phosphorus pentachloride.
- 4. preparation method according to claim 1; Wherein said reaction process (c) solvent for use is to be selected from following one or more combination: benzene,toluene,xylene, methylene dichloride, chloroform, ethylene dichloride, tetracol phenixin, THF, ether, 2-methyltetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, N; Dinethylformamide, DMAC N,N, HMPA, DMSO 99.8MIN., acetone, acetonitrile.
- 5. preparation method according to claim 1, the salt of the compound (III) that wherein said reaction process (c) is used is for being selected from: vitriol, hydrochloride, mesylate, tosilate.
- 6. preparation method according to claim 1, the used additive of wherein said reaction process (c) is to be selected from following one or more combination: Soiodin, potassiumiodide, lithium iodide, cesium iodide, Sodium Bromide, Potassium Bromide, lithiumbromide, cesium bromide, sodium-chlor, Repone K, lithium chloride, cesium chloride, sodium pyrosulfate, sal enixum, sodium hydrogen phosphate, SODIUM PHOSPHATE, MONOBASIC, potassium hydrogen phosphate, potassium primary phosphate etc., tetramethyl ammonium chloride, tetramethyl-ammonia bromide, tetramethyl-iodate ammonia, TEA chloride, tetraethyl-ammonia bromide, tetraethyl-iodate ammonia, tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetrabutylammonium iodide, trimethyl benzyl ammonia chloride, triethyl benzyl ammonia chloride.
- 7. preparation method according to claim 1; The used alkali of wherein said reaction process (c) is for being selected from: yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus, cesium carbonate, sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, calcium hydroxide, quicklime, sodium hydride, triethylamine, diisopropyl ethyl amine, pyridine, 4-N, N-dimethyl aminopyridine.
- 8. preparation method according to claim 1; The used solvent of wherein said reaction process (d) is for being selected from: methylene dichloride, chloroform, THF, ether, dioxane, N; Dinethylformamide, DMAC N,N, DMSO 99.8MIN., acetone or acetonitrile.
- 9. preparation method according to claim 1, the used acylating reagent of wherein said reaction process (d) is for being selected from: acetic acid, aceticanhydride, Acetyl Chloride 98Min., acetyl bromide, vinyl acetic monomer.
- 10. preparation method according to claim 1; Alkali used in the wherein said reaction process (d) is for being selected from: yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus, sodium hydroxide, Pottasium Hydroxide, triethylamine, diisopropyl ethyl amine, pyridine, 4-N, N-dimethyl aminopyridine.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103739614A (en) * | 2013-12-31 | 2014-04-23 | 成都百裕科技制药有限公司 | Hydrogenated pyridine derivative and preparation method thereof |
| CN103923101A (en) * | 2014-04-29 | 2014-07-16 | 湖南方盛制药股份有限公司 | Synthetic method of prasugrel |
| CN104592250A (en) * | 2015-01-15 | 2015-05-06 | 新发药业有限公司 | Low-cost environment-friendly preparation method of prasugrel |
| CN107056803A (en) * | 2017-05-19 | 2017-08-18 | 兰州大学 | The method for synthesizing intermediate of prasugrel and preparation method thereof and synthesis prasugrel |
-
2012
- 2012-05-11 CN CN2012101482765A patent/CN102659811A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103739614A (en) * | 2013-12-31 | 2014-04-23 | 成都百裕科技制药有限公司 | Hydrogenated pyridine derivative and preparation method thereof |
| CN103923101A (en) * | 2014-04-29 | 2014-07-16 | 湖南方盛制药股份有限公司 | Synthetic method of prasugrel |
| CN103923101B (en) * | 2014-04-29 | 2017-05-03 | 湖南方盛制药股份有限公司 | Synthetic method of prasugrel |
| CN104592250A (en) * | 2015-01-15 | 2015-05-06 | 新发药业有限公司 | Low-cost environment-friendly preparation method of prasugrel |
| CN104592250B (en) * | 2015-01-15 | 2016-05-11 | 新发药业有限公司 | A kind of environment-friendly preparation method of prasugrel cheaply |
| CN107056803A (en) * | 2017-05-19 | 2017-08-18 | 兰州大学 | The method for synthesizing intermediate of prasugrel and preparation method thereof and synthesis prasugrel |
| CN107056803B (en) * | 2017-05-19 | 2019-06-11 | 兰州大学 | The method for synthesizing intermediate of prasugrel and preparation method thereof and synthesis prasugrel |
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Application publication date: 20120912 |