CN105272993A - Method for preparing prasugrel intermediate - Google Patents
Method for preparing prasugrel intermediate Download PDFInfo
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- CN105272993A CN105272993A CN201410315254.2A CN201410315254A CN105272993A CN 105272993 A CN105272993 A CN 105272993A CN 201410315254 A CN201410315254 A CN 201410315254A CN 105272993 A CN105272993 A CN 105272993A
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- 0 C*(C)C[C@@]1C(N)=CC=C[C@](C)[C@@]1C Chemical compound C*(C)C[C@@]1C(N)=CC=C[C@](C)[C@@]1C 0.000 description 2
- MQPZKXXMMVLZIX-PLNGDYQASA-N CC(C)/C=C\CC(C)F Chemical compound CC(C)/C=C\CC(C)F MQPZKXXMMVLZIX-PLNGDYQASA-N 0.000 description 1
- QNXGAPIIJSSOOK-HAAWTFQLSA-N CN(CC(C(C1CC1)=[U])c(cccc1)c1F)C/C=C/C(SC)=O Chemical compound CN(CC(C(C1CC1)=[U])c(cccc1)c1F)C/C=C/C(SC)=O QNXGAPIIJSSOOK-HAAWTFQLSA-N 0.000 description 1
- JGJBFLWTFHMNEZ-UHFFFAOYSA-N O=C(CN(CC1)Cc2c1[s]cc2)C1CC1 Chemical compound O=C(CN(CC1)Cc2c1[s]cc2)C1CC1 JGJBFLWTFHMNEZ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a method for preparing a prasugrel intermediate 5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-1,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine. The method comprises a following reaction route. As a result of experiments, the method provided by the invention has the advantages of simple operation, mild reaction conditions, low requirement on equipment, inexpensive and easy-to-obtain raw materials, high yield, and low production cost. An adopted solvent can synchronously recovered. The method can be easily applied in large-scale productions. The method meets the requirements of prasugrel industrialized production, and has industrial application value.
Description
Technical field
The present invention relates to a kind of method preparing prasugrel intermediate, specifically, relate to the key intermediate preparing prasugrel: 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-1,4,5,6,7, the preparation method of 7a-six hydrogen thieno-[3,2-c] pyridine, belongs to technical field of organic chemistry.
Background technology
Platelet aggregation rally causes obstruction of artery and possibility cardiac trigger is sick or apoplexy, and antiplatelet drug is used for preventing platelet aggregation or adhering to each other.Prasugrel (Prasugrel) is the oral anti-diabetic agent being carried out to be total to the first pharmacy three company's joint development by gift, the mechanism of action suppresses platelet activation and concurrent gathering by hindering P2Y12 adenosine diphosphate (ADP) acceptor at platelet surface, get permission listing on February 27th, 2009 in European Union, and start selling in Britain.The tolerance good due to it and security, be expected to become antithrombotic reagent more better than clopidogrel market outlook.
The chemical structural formula of prasugrel is as follows:
5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-Isosorbide-5-Nitrae, 5,6,7,7a-six hydrogen thieno-[3,2-c] pyridine is the key intermediate preparing prasugrel, and its chemical structural formula is as follows:
In prior art, relevant 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-Isosorbide-5-Nitrae, the preparation method of 5,6,7,7a-six hydrogen thieno-[3,2-c] pyridine mainly contains following several:
Following synthetic method is disclosed in method 1:WO2008108291A1:
Itself and cyclopropyl generation grignard reaction for starting raw material, are obtained cyclopropanone compound with adjacent fluorobenzyl bromide by the method, then introduce halogen atom at the ortho position of carbonyl, and then with 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2 (4H)-one carries out condensation, obtains intermediate: 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-1,4,5,6,7,7a-six hydrogen thieno-[3,2-c] pyridine.Because this method uses 5,6,7,7a-tetramethylene sulfide is [3,2-c] pyridine-2 (4H)-one also, and this raw material is difficult to obtain, synthesis condition is harsher, needs to use the not high n-Butyl Lithium of security, so be not suitable for industrialization production requirements in preparation process.
Following synthetic method is disclosed in method 2:WO2009006859A2:
The method take o fluorobenzaldehyde as starting raw material, carries out addition with trimethylammonium itrile group silicon to it, then reacts with the Grignard reagent of cyclopropyl; then methanesulfonates is translated into methylsulfonyl, last and method one is similar, with 5; 6,7,7a-tetramethylene sulfide also [3; 2-c] pyridine-2 (4H)-one carries out condensation reaction, obtains intermediate: 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-Isosorbide-5-Nitrae; 5,6,7; 7a-six hydrogen thieno-[3,2-c] pyridine.Owing to using trimethyl silicane nitrile and 5,6,7,7a-tetramethylene sulfide also [3,2-c] pyridine-2 (4H)-one in this method, not only raw material is difficult to obtain, and expensive, so that cost is higher, is therefore also not suitable for industrialization production requirements.
Summary of the invention
The problems referred to above existed for prior art and defect, the object of this invention is to provide one and prepare prasugrel intermediate: 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-1,4,5,6,7,7a-six hydrogen thieno-[3,2-c] method of pyridine, to meet the requirement of preparation of industrialization prasugrel.
For achieving the above object, the present invention adopts following technical scheme:
One prepares prasugrel intermediate: 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-Isosorbide-5-Nitrae, the method for 5,6,7,7a-six hydrogen thieno-[3,2-c] pyridine, comprises the steps:
A) under the effect of alkali, carry out condensation reaction with compound 1 (that is: adjacent fluorine halogen benzyl) and compound 2, obtain compound 3;
B) under protonic acid effect, carry out ring closure reaction after making compound 3 and paraformaldehyde condensation, obtain compound 4;
C) make compound 4 react with brominated reagent in the basic conditions, obtain compound 5;
D) make compound 5 and magnesium powder generation grignard reaction, obtained Grignard reagent, then drips ring third formonitrile HCN, through saturated ammonium chloride solution process, obtains compound 6;
E) make compound 6 under inorganic salt condition, with hydrogen peroxide generation oxidizing reaction, obtain described intermediate: 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-1,4,5,6,7,7a-six hydrogen thieno-[3,2-c] pyridine (that is: compound 7);
Its reaction scheme is as follows:
Above-mentioned steps a) in, described compound 1 is adjacent fluorobenzyl chloride, adjacent fluorine bromobenzyl, adjacent fluorine fluorine benzyl or adjacent fluorine iodine benzyl, best with adjacent fluorine bromobenzyl; Described alkali can be mineral alkali or organic bases, as salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, triethylamine etc., is preferably sodium carbonate or salt of wormwood.
Above-mentioned steps a) in, described compound 2 is 1:1 ~ 1:2 with the mol ratio of compound 1, best with 1:1.2; Described compound 2 is 1:1 ~ 1:3 with the mol ratio of alkali, best with 1:1.2.
Above-mentioned steps b) in, described protonic acid can be sulfuric acid, hydrochloric acid, phosphoric acid or perchloric acid etc., is preferably sulfuric acid or hydrochloric acid.
Above-mentioned steps c) in, described alkaline condition is formed by organic amine, and described organic amine can be triethylamine, N, N-diethyl ethanamine or N, N-diethyl propylamine, is preferably triethylamine.
Above-mentioned steps c) in, described brominated reagent can be bromine or N-bromo-succinimide (NBS), is preferably bromine.
Above-mentioned steps e) in, described inorganic salt are inorganic metal salt, such as: iron(ic) chloride, ferric sulfate, cupric chloride, copper sulfate, hydrogen sulfate iron, hydrogen sulfate copper etc., are preferably copper sulfate.
Compared with prior art, the present invention has following significance progress:
1, simple to operate, reaction conditions is gentle, equipment requirements is low;
2, not only raw materials used cheap and easy to get, and solvent for use can realize synchronous recovery;
3, production cost is low, is easy to large-scale production;
In a word, adopt the inventive method can meet industrialized mass production 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-Isosorbide-5-Nitrae better, the requirement of 5,6,7,7a-six hydrogen thieno-[3,2-c] pyridine, has significance industrial application value.
Embodiment
Do to illustrate in detail, intactly further to technical scheme provided by the invention below in conjunction with embodiment.
Embodiment 1: the synthesis of compound 3
35.7g (0.189mol) compound 1,20g (0.157mol) compound 2 are dissolved in 100mL tetrahydrofuran (THF), add 20g (0.189mol) sodium carbonate, at room temperature stir 2 hours; React completely, filter, use saturated aqueous common salt wash filtrate, separatory, with 20mL extraction into ethyl acetate aqueous phase, separatory, merges organic phase, uses 10g anhydrous sodium sulfate drying, filters, in 40 DEG C of underpressure distillation, steamed, obtain 33.2g yellow oily compound 3, purity 98.4%, yield 89.7%.
1H-NMR(CDCl
3；TMS)：δ：2.33～2.67(m，4H，CH
2CH
2)，3.81～3.93(m，2H，CH
2)，6.68～7.22(m，7H)。
MS(ESI，m/z)：236[M+H]
+。
Embodiment 2: the synthesis of compound 4
30g (0.121mol) compound 3 is dissolved in 150mL methyl alcohol, add 4g (0.133mol) paraformaldehyde, in stirred at ambient temperature to react completely (about 5 hours), add 10mL concentrated hydrochloric acid, disappear when TLC follows the tracks of raw material point, stopped reaction, revolve and steam removing methyl alcohol, residue 150mL methylene dichloride dissolves, washing, separatory, anhydrous sodium sulfate drying organic phase, filter, filtrate decompression is distilled, steamed, stir with 90mL methyl tertiary butyl ether, filter, in 40 DEG C of forced air dryings to constant weight, obtain 22.5g off-white color solid chemical compound 4, purity 98.6%, yield 71.4%.
1HNMR(CDCl
3；TMS)：δ：2.58～2.64(m，4H，CH
2CH
2)，3.52～3.59(m，2H，CH
2)，3.61～3.72(m，2H，CH
2)，6.33(s，1H，CH)，6.46(s，1H，CH)，7.12～7.52(m，4H，ArH)；
MS(ESI，m/z)：248[M+H]
+。
Embodiment 3: the synthesis of compound 5
20g (0.081mol) compound 4 is dissolved in 100mL methyl alcohol, add 9.8g (0.097mol) triethylamine simultaneously, be cooled to 0 ~ 10 DEG C, drip the mixing solutions of 12.9g (0.081mol) bromine and 20mL methyl alcohol, drip and finish, react 2 hours under room temperature, when TLC follows the tracks of without raw material point, be added dropwise to 10% sodium thiosulfate solution, with 3 × 50mL dichloromethane extraction, merge organic phase, use 50mL water washing, separatory, with anhydrous sodium sulfate drying, filter, filtrate decompression is distilled, steamed, obtain yellow oil, by 60mL methyl tertiary butyl ether stirring and crystallizing, filter, in 40 DEG C of forced air dryings, obtain 19.3g yellow solid compound 5, purity 96.3%, yield 73.1%.
1HNMR(CDCl
3；TMS)：δ：2.42～2.61(m，4H，CH
2CH
2)，3.58(m，2H，CH
2)5.72(s，1H，CH)，6.19(s，H，CH)，6.24(s，H，CH)，6.93～7.15(m，4H，ArH)。
MS(ESI，m/z)：328[M+H]
+。
Embodiment 4: the synthesis of compound 6
15g (0.046mol) compound 5 is dissolved in 45mL tetrahydrofuran (THF) for subsequent use; 1.34g (0.055mol) magnesium powder is added in reaction flask, the compound 5 of 1/10th and the mixing solutions of tetrahydrofuran (THF), heating, after reaction causes, drip the tetrahydrofuran solution containing compound 5, drip Bi Huiliu 30 minutes, in system, drip the tetrahydrofuran (THF) 30mL solution of 3.7g (0.055mol) ring third formonitrile HCN; Dropwise, be heated to backflow; When TLC follows the tracks of without raw material point (about back flow reaction 1.5 hours), in system, add 60mL saturated aqueous ammonium chloride, separate organic phase, aqueous phase is extracted with ethyl acetate 2 times, each 30mL; Separatory, merges organic phase, with the water washing of 30mL saturated common salt, separatory, uses anhydrous sodium sulfate drying organic phase, filters, in 40 DEG C of underpressure distillation filtrates, steamed, stir 30 minutes with 45mL Virahol, filter, in 40 DEG C of forced air drying filter cakes to constant weight, obtain 12.5g light yellow solid Compound 6, purity 97.6%, yield 86.2%.
1HNMR(CDCl
3；TMS)：δ：0.62～0.98(m，4H，CH
2CH
2)，1.87～2.02(s，1H，CH)，2.65～2.92(m，4H，CH
2CH
2)，3.68～3.76(m，2H，CH
2)，4.87(s,1H,CH)，6.21(s，1H，CH)，6.32(s，1H，CH)，6.94～7.23(m，4H，ArH)；
MS(ESI，m/z)：316[M+H]
+。
Embodiment 5: the synthesis of compound 7
10g (0.032mol) compound 6 is dissolved in 150mL methyl alcohol, add 11.9g (0.048mol) copper sulfate and 40mL (0.08mol) 2N sulfuric acid, be cooled to 0 DEG C, drip the hydrogen peroxide of 7.2g (0.063mol) 30wt%, drip and finish, be warming up to room temperature reaction, when TLC follows the tracks of without raw material point (about reacting 16 hours), drip 10wt% sodium thiosulfate solution 30mL, drip and finish, underpressure distillation removing methyl alcohol, steamed, with 3 × 20mL dichloromethane extraction, merge organic phase, use anhydrous sodium sulfate drying organic phase, filter, in 40 DEG C of underpressure distillation filtrates, steamed, stir with 20mL Virahol and separate out solid, filter, in 40 DEG C of forced air dryings to constant weight, obtain 8.1g off-white color solid chemical compound 7, purity 98.4%, yield 77.1%.
1HNMR(CDCl
3；TMS)：δ：0.68～1.03(m，4H，CH
2CH
2)，1.82～1.96(m，1H，CH)，2.09～2.13(m，1H，CH)，2.31～2.43，2.52～2.58(m，2H，CH
2)，2.86～2.93，3.11～3.15(m，2H，CH
2)，3.91～3.99，4.05～4.11(m，2H，CH
2)，4.87,4.90(m，1H，CH)，6.08,6.11(s，1H，CH)，7.16～7.41(m，4H，ArH)。
MS(ESI，m/z)：332[M+H]
+。
Embodiment 6: the synthesis of prasugrel
6g (0.018mol) compound 7 is dissolved in 60mL methylene dichloride, add 2.7g (0.027mol) triethylamine and 1.8g (0.018mol) acetic anhydride, be heated to backflow, when TLC follows the tracks of without raw material point (about back flow reaction 3 hours), cooling, adds 30mL water washing, separatory, use anhydrous sodium sulfate drying organic phase, filter, in 40 DEG C of underpressure distillation, steamed, stir with 20mL methyl alcohol, filter, in 40 DEG C of forced air dryings to constant weight, obtain 6.1g light yellow solid Compound: prasugrel, purity 97.9%, yield 90.2%.
1HNMR(CDCl
3；TMS)：δ：0.80～0.88(m，2H，CH
2)，0.96～1.09(m，2H，CH
2)，2.25(s，3H，CH
3)，2.27～2.31(m，1H，CH)，2.73～2.92(m，4H，CH
2CH
2)，3.45(d，1H，J＝14.4Hz，CH)，3.61(d，1H，J＝14.4Hz，CH)，4.89(s，1H，CH)，6.21(s，1H，ArH)，7.09～7.22(m，2H，ArH)，7.21～7.38(m，1H，ArH)，7.51～7.55(m，1H，ArH)。
MS(ESI，m/z)：374[M+H]
+。
To sum up experiment visible: the method for the invention have simple to operate, reaction conditions is gentle, low for equipment requirements, raw materials used cheap and easy to get, yield is high, solvent for use can realize synchronous recovery, production cost is low, be easy to the plurality of advantages such as large-scale production; meet the production requirement of preparation of industrialization prasugrel, there is industrial application value.
Finally be necessary described herein:
Above embodiment is only for being described in further detail technical scheme of the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.
Claims (10)
1. prepare a method for prasugrel intermediate, it is characterized in that, comprise the steps:
A) under the effect of alkali, carry out condensation reaction with compound 1 and compound 2, obtain compound 3;
B) under protonic acid effect, carry out ring closure reaction after making compound 3 and paraformaldehyde condensation, obtain compound 4;
C) make compound 4 react with brominated reagent in the basic conditions, obtain compound 5;
D) make compound 5 and magnesium powder generation grignard reaction, obtained Grignard reagent, then drips ring third formonitrile HCN, through saturated ammonium chloride solution process, obtains compound 6;
E) make compound 6 under inorganic salt condition, with hydrogen peroxide generation oxidizing reaction, obtain described intermediate: 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-Isosorbide-5-Nitrae, 5,6,7,7a-six hydrogen thieno-[3,2-c] pyridine, that is: compound 7;
Its reaction scheme is as follows:
2. the method for claim 1, is characterized in that: step a) in, described compound 1 is adjacent fluorobenzyl chloride, adjacent fluorine bromobenzyl, adjacent fluorine fluorine benzyl or adjacent fluorine iodine benzyl; Described alkali is mineral alkali or organic bases.
3. method as claimed in claim 2, is characterized in that: described alkali is salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus or organic amine.
4. the method for claim 1, is characterized in that: step a) in, described compound 2 is 1:1 ~ 1:2 with the mol ratio of compound 1, and described compound 2 is 1:1 ~ 1:3 with the mol ratio of alkali.
5. the method for claim 1, is characterized in that: step b) in, described protonic acid is sulfuric acid, hydrochloric acid, phosphoric acid or perchloric acid.
6. the method for claim 1, is characterized in that: step c) in, described alkaline condition is formed by organic amine.
7. the method as described in claim 3 or 6, is characterized in that: described organic amine is triethylamine, N, N-diethyl ethanamine or N, N-diethyl propylamine.
8. the method for claim 1, is characterized in that: step c) in, described brominated reagent is bromine or N-bromo-succinimide.
9. the method for claim 1, is characterized in that: step e) in, described inorganic salt are inorganic metal salt.
10. method as claimed in claim 9, is characterized in that: described inorganic metal salt is iron(ic) chloride, ferric sulfate, cupric chloride, copper sulfate, hydrogen sulfate iron or hydrogen sulfate copper.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009006859A2 (en) * | 2007-07-09 | 2009-01-15 | Zentiva A.S. | A method of manufacturing 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl acetate (prasugrel) |
| CN102056931A (en) * | 2008-06-09 | 2011-05-11 | 安资科技株式会社 | Method for preparing clopidogrel and its derivatives |
| WO2012001486A1 (en) * | 2010-06-28 | 2012-01-05 | Mayuka Labs Pvt. Ltd. | An improved process for the preparation of prasugrel hydrochloride and its intermediates |
-
2014
- 2014-07-03 CN CN201410315254.2A patent/CN105272993A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009006859A2 (en) * | 2007-07-09 | 2009-01-15 | Zentiva A.S. | A method of manufacturing 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl acetate (prasugrel) |
| CN102056931A (en) * | 2008-06-09 | 2011-05-11 | 安资科技株式会社 | Method for preparing clopidogrel and its derivatives |
| WO2012001486A1 (en) * | 2010-06-28 | 2012-01-05 | Mayuka Labs Pvt. Ltd. | An improved process for the preparation of prasugrel hydrochloride and its intermediates |
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