CN104341433B - A kind of preparation method of prasugrel intermediate - Google Patents

Abstract

The invention provides a kind of preparation method of prasugrel intermediate compound, this method includes the following steps：（1）Amido protecting reacts：4; 5,6,7 thiophanes simultaneously [3; 2 c] pyridine hydrochloride is raw material; target compound is obtained by halogenation, alkylated reaction, with sodium alkoxide deprotection reaction and HCl gas acidification reactions, this method is simple, and technique is advanced; the caused three wastes are few in production process; environmental protection pressure is small, and high income, suitable for industrialized production.

Description

A kind of preparation method of prasugrel intermediate

Technical field

A kind of medical synthesis field of the present invention, and in particular to preparation side of anti-platelet aggregation medicine prasugrel intermediate Method.

Background technology

Prasugrel（Prasugrel）, chemical name：2- acetoxyl groups -5-（α-cyclopropyl carbonyl -2- luorobenzyls）- 4,5, 6,7- thiophanes simultaneously [3,2-c] pyridine, structural formula such as following formula（Ⅰ）：

Prasugrel is as a kind of new oral anti-platelet aggregation medicine, by Japanese Sankyo companies and U.S. Eli The joint development development of Lilly companies, and in 2 Yue23Huo European Union approval listing in 2009.Research shows the prevention of prasugrel The effect of thrombus is stronger than the effect of clopidogrel, in experiments it is found that prasugrel can faster work, the trouble of prasugrel group Thrombus after person's medication in blood is fewer than clopidogrel group, and prasugrel is suppressing than the clopidogrel of approval dosage at present Effect in the cohesion of ADP induced platelets is more powerful, and the incidence of prasugrel group ischemic event reduces than clopidogrel group, general The effect that glug thunder antiplatelet is built up is obvious and rapid.And in the code name of prasugrel clinical research it is JUMBO-TIMI26 In second stage research, prasugrel faster and more unified inhibits blood platelet than chlorine Gray really.

Patent US4740510 and EP0542411 disclose a kind of preparation method of prasugrel, and its synthetic route is as follows：

Patent CN101402506 also discloses that a kind of preparation method of prasugrel, and its synthetic route is as follows：

In both the above method, 2- oxygen -2,4,5,6,7,7a- hexahydro thieno [3,2-c] pyridine hydrochloric acid are all employ Salt（Compound 1）Nucleophilic substitution occurs with adjacent luorobenzyl cyclopropyl ketone, is then acylated and obtains 2- acetoxyl groups -5-（a- Cyclopropyl carbonyl -2- luorobenzyls）- 4,5,6,7- thiophanes simultaneously [3,2-c] pyridine（Prasugrel）But the mesh of starting compound 1 Before can not conveniently obtain, can be bought without cheap industrial goods.

Patent US4740510 discloses its a kind of preparation method, and its synthetic route is as follows：

This method be by 4,5,6,7- thiophanes simultaneously [3,2-c] pyridine be initiation material at low temperature with n-BuLi, Butyl borate reacts to obtain 5- trityl -2- oxygen -2,4,5,6,7a- hexahydro thieno [3,2-c] pyridines, finally and formic acid Reaction obtains.Its reaction condition is harsher, it is necessary to -40 DEG C of low temperature, while normal-butyl reason is inflammable and explosive, can give extensive raw Production brings danger.

The system of 2- oxygen -2,4,5,6,7,7a- hexahydros thieno [3,2-c] pyridine hydrochloride is also disclosed that in EP192535 Preparation Method, but the step of patented method synthesis is more, yield is low, and synthesis cost is high, is unfavorable for the big production of lower industryization.

A kind of new intermediate for preparing prasugrel is disclosed in CN101245073A, but it selects benzyl protection, after Continuous deprotection steps will be very difficult.Structural formula is as follows：

For the defects of yield is low, cost is high, environmental protection pressure is big present in synthesis prasugrel at present, further research In high yield, inexpensive, green prasugrel synthetic method has wide market prospects, and this just needs to research and develop newly general Glug thunder intermediate, guarantee is provided to improve the synthetic method of prasugrel.

The content of the invention

It is an object of the invention to overcome the deficiencies of the prior art and provide a kind of prasugrel important intermediate formula (1) Preparation method.The structural formula of the prasugrel intermediate is as follows：

The preparation method of the present invention includes following steps：

1）Amido protecting reacts：Compound 1 and di-tert-butyl dicarbonate（BOC reagents）Reacted in dioxy naphthenic solvent Compound 2

2）Halogenation：Compound 2 occurs halogenation under halogenating agent effect and obtains compound 3

3）Alkylated reaction：Rudimentary sodium alkoxide below the carbon of compound 3 and six reacts to obtain compound 4, wherein R represent six carbon with Lower alkyl

4）Deprotection reaction：Compound 4 obtains compound 1 with HCl gas reactions

Above-mentioned steps 1）, solvent used includes during reaction：Alcohol, esters, dioxy cycloalkanes, dichloromethane, tetrahydrofuran, Benzene, toluene, acetonitrile, DMF etc., preferably dioxy cycloalkanes, 60-100 DEG C of reaction temperature, preferable temperature are 80 DEG C.

Above-mentioned steps 2）, halogenating agent used is CuCl during halogenation₂Or CuBr₂, preferably CuCl₂, solvent for use is methanol.

Above-mentioned steps 3）, sodium alkoxide used is the following sodium alkoxide of six carbon, and preferably sodium methoxide, solvent for use are methanol.

Above-mentioned steps 4）, solvent for use is methanol, and HCl is the saturation methanol solution of the gas, and reaction terminates rear crude product and used Acetone, isopropyl ether are refined to obtain compound 1.

The beneficial effects of the present invention are：

Raw material used in the preparation method of the present invention is easy to get, while this method reaction condition is gentle, it is not necessary to ultralow Reacted under the conditions of temperature, it is safe suitable for large-scale industrial production without using inflammable and explosive reagent, and reaction yield is more Height, cost are lower.

Prasugrel intermediate disclosed by the invention（Compound 1）, its preparation method is simple, and technique is advanced, production process In the caused three wastes it is few, environmental protection pressure is small, and high income, suitable for industrialized production.

Embodiment

Now beneficial effects of the present invention are further described by following examples, it is thus understood that these embodiments are only used for The purpose of illustration, is not limited the scope of the invention, at the same those of ordinary skill in the art according to the present invention done it is apparent Change and modification be also contained within the scope of the invention.

5- tertbutyloxycarbonyl -4,5,6,7- the thiophanes of embodiment 1 simultaneously [3,2-c] pyridine（Compound 2）Preparation：

By 4,5,6,7- thiophanes simultaneously [3,2-c] pyridine hydrochloride（Compound 5）12.6g adds 250ml three-necked flasks In, 150ml dioxane is added into three-necked flask, mechanical agitation is simultaneously dissolved quickly with warming-in-water, raw material, when temperature rises to 80 DEG C when, add 15.2gk₂CO₃0.5h is stirred, di-tert-butyl dicarbonate 16.5g is added dropwise, continues stirring reaction 1h, stops reacting and be down to Room temperature, filtering, filtrate add 200ml ethyl acetate and 200ml ammoniacal liquor to stir, and liquid separation, ethyl acetate layer washing, salt are washed, dried, dense It is reduced to dry that 16.8g had both been compound 2.

The chloro- 5- tertbutyloxycarbonyls -4,5,6,7- thiophanes of the 2- of embodiment 2 simultaneously [3,2-c] pyridine（Compound 3）System It is standby：

Add 15.8g compounds 2 into 250ml three-necked flasks, add 200ml methanol stirring and dissolvings, add 5.6gCuCl₂Continue to stir Reaction 4h is mixed, stops reacting, adds 200ml ethyl acetate and 300ml saturated sodium bicarbonate solutions to stir, liquid separation, ethyl acetate layer water Wash, salt is washed, dry, be concentrated to dryness 18.8g had both been compound 3

2- methoxyl group -5- tertbutyloxycarbonyl -4,5,6,7- the thiophanes of embodiment 3 simultaneously [3,2-c] pyridine（Compound 4） Preparation：

By 18g compounds 3,11.5g sodium methoxides are added in 250ml three-necked flasks, add 150ml methanol, magnetic agitation, in nitrogen 24h is heated to reflux under gas shielded, is cooled down, filtering, filtrate adds 200ml ethyl acetate and 300ml pure water to stir, liquid separation, acetic acid second Ester layer washing, salt are washed, dried, and are concentrated to dryness to obtain crude product, are crossed silicagel column purifying, are obtained 8.4g compounds 4.

Embodiment 4 2- oxygen -2,4,5,6,7,7a- hexahydros thieno [3,2-c] pyridine hydrochloride（Compound 1）System It is standby：

16g compounds 4 are dissolved in the homemade methanol hydrochloride solutions of 300ml, leads to HCl gases, 12h is stirred at room temperature, will Reaction solution is concentrated to dryness, and with 200ml acetone solutions, 400ml isopropyl ethers are added dropwise, has a large amount of crystal to separate out, filters, dries to obtain 6.5g Compound 1.

Claims (5)

1. A kind of 1. preparation of hexahydro thieno [3,2-c] pyridine hydrochlorides of prasugrel intermediate 2- oxygen -2,4,5,6,7,7a one Method, it is characterised in that including following steps：

   1) amido protecting reacts：Compound 5 reacts to obtain chemical combination with di-tert-butyl dicarbonate in 1,4- dioxanes Thing 2

   2) halogenation：Compound 2 occurs halogenation under halogenating agent effect and obtains compound 3

   3) nucleophilic substitution：Compound 3 reacts to obtain compound 4 with sodium methoxide, and wherein R represents methyl

   4) deprotection reaction：Compound 4 leads to HCl gas reactions after dissolving and obtains compound 1

   Halogenating agent used in step 2) is copper chloride；

   Solvent used in step 3) is absolute methanol；

   Solvent used in step 4) is methanol hydrochloride solution.
2. 2. preparation method as claimed in claim 1, it is characterised in that the reaction temperature of step 1) is 60-100 DEG C.
3. 3. preparation method as claimed in claim 1, it is characterised in that the reaction temperature of step 1) is 80 DEG C.
4. 4. preparation method as claimed in claim 1, it is characterised in that the solvent used in step 2) is methanol.
5. 5. preparation method as claimed in claim 1, it is characterised in that step 4) is passed through HCl gases and keeps solution saturation.