KR101184915B1 - Process for preparing high-purity prasugrel - Google Patents

Abstract

The present invention relates to a method for preparing prasugrel or an acid addition salt thereof, and according to the method of the present invention, high purity prasugrel or an acid thereof in which deacetylated 2-oxoprasugrel from prasugrel is minimized. The addition salt can be easily prepared.

Description

Manufacturing method of high purity prasugrel {PROCESS FOR PREPARING HIGH-PURITY PRASUGREL}

The present invention relates to a method for producing a platelet aggregation inhibitor prasugrel or acid addition salt thereof simply.

US for the first time disclosed in the Patent No. 5288726 No. be plastic of the formula geurel is a compound for use in the treatment of the related disease according to platelet aggregation in the US and Europe, particularly EPI gradient (EFFIENT ^®, Eli Lilly and Company Co., Ltd. as a hydrochloride salt form It is marketed under the brand name).

Prasugrel has been disclosed as a free base in U.S. Patent No. 5,288,726, and its hydrochloride and maleate salts, and their crystalline forms, are disclosed in WO 2002/004461, where the acetonitrile solvates of the hydrochloride salts In WO 2008/000418, amorphous and other crystalline forms of the hydrochlorides thereof are disclosed in WO 2009/062044, and various other acid addition salts and their crystal forms are disclosed in WO 2009/098142, WO 2009/066326. No. WO 2009/129983, WO 2009/130289 and Chinese Patent Publication No. 1,255,169 and the like.

The first method for preparing prasugrel disclosed in US Pat. No. 5,288,726, after reacting 2-oxothienopyridine hydrochloride of Formula 2a with 2-bromoethanone derivative of Formula 3a, is shown in Scheme 1 below, From the obtained crude (crude) using silica gel column chromatography to separate the 2-oxothienopyridine derivative of the general formula (4a), it is converted to hydrochloride to prepare a yield of 46%. Thereafter, the compound of formula 4a was acetylated with acetic anhydride (Ac ₂ O) in the presence of a flammable base sodium hydride (NaH), and then the prasugrel of formula 1 was separated again using silica gel column chromatography. Recrystallized in diisopropyl ether (IPE) to give a yield of 64%.

<Reaction Scheme 1>

* DMF = N, N-dimethylformamide

However, the preparation method of prasugrel according to Scheme 1 is difficult to apply industrially since only the simple method of the two reaction steps or the product obtained in each reaction step must be separated by chromatography. In addition, as shown in Scheme 2, the compound of Formula 2 having a 2-oxothienopyridine structure (preform of Formula 2a in Scheme 1) is tautomerized into an enol form of Formula 2 ′, and the like. Not only complicates the crystallization of the obtained product, but also makes the crystallization of the obtained product difficult, and the compounds of Formulas 2a and 3a participating in the reaction are unstable and easily decomposed during the reaction. Since it can be converted to oxoprasugrel (preform of formula 4a in Scheme 1), the overall yield is very low, about 30%.

<Reaction Scheme 2>

An improved method of prasugrel to overcome such problems is disclosed in US Pat. No. 5,874,581 and WO 2002/004461. The method in the U.S. Patent and International Patent Publication discloses the reaction of t-butyldimethylsilyl chloride (TBSCl) with 2-oxothienopyridine p-toluenesulfonate of formula (2b) as shown in Scheme 3. 2-hydroxythienopyridine p-toluenesulfonate of formula (2c) protected with a butyldimethylsilyl group was prepared, and then reacted with a 2-chloroethanone derivative of 3b, and the resulting crude was acetonitrile (MeCN). Crystallization) to prepare 2- (t-butyldimethylsilylhydroxy) thienopyridine derivative of formula 4b in a yield of 79%. Thereafter, the compound of Formula 4b is desilylated and acetylated with acetic anhydride (Ac ₂ O) in the presence of triethylamine (TEA), which is a conventional organic base, and the resulting crude is crystallized in an aqueous solution to give the desired Prasugrel is prepared in a yield of 87%. The overall yield is about 68%.

<Reaction Scheme 3>

* DCM = dichloromethane

However, the method is not only a bypass method using a protecting group such as t-butyldimethylsilyl group, the reaction conditions are very difficult and there are various limitations such as the use of phosphate buffer in the post-reaction treatment. In addition, even prasugrel prepared by this method can be incorporated with deacetylated 2-oxoprasugrel, and thus deacetylated 2-oxopra water according to the method disclosed in WO 2007/114526 or the like. An additional purification process is required to remove grel.

Therefore, there has been a need for the development of a method that can more easily prepare the high purity prasugrel pharmaceutically required.

Accordingly, it is an object of the present invention to provide a convenient method for preparing high purity prasugrel or acid addition salts thereof which are minimally deacetylated 2-oxoprasugrel from prasugrel.

In order to achieve the above object,

1) After reacting p-toluenesulfonate or hydrochloride of 2-oxothienopyridine of formula (2) with 2-bromoethanone derivative of formula (3a) in an inert organic solvent in the presence of an organic base, an organic base and an acetylating agent Adding acetylation in succession and concentrating under reduced pressure, and

2) directly crystallizing prasugrel of the formula (1) in a crystalline mixed solvent containing tetrahydrofuran, isopropanol and water from the residue obtained as a result of the vacuum concentration;

It provides a process for the preparation of prasugrel or acid addition salts of the following formula 1 comprising:

&Lt; Formula 1 >

<Formula 3a>

According to the method of the present invention, high purity prasugrel, which is pharmaceutically required, can be easily produced in high yield.

Hereinafter, the prasugrel manufacturing method according to the present invention will be described in detail step by step.

(Step 1)

First, p-toluenesulfonate or hydrochloride of 2-oxothienopyridine of formula 2 is reacted with 2-bromoethanone derivative of formula 3a in an inert organic solvent in the presence of a base.

In this case, the 2-bromoethanone derivative of Chemical Formula 3a is preferably used in an amount of 1 to 1.5 molar equivalents relative to 1 molar equivalent of 2-oxothienopyridine p-toluenesulfonate or hydrochloride of Formula 2.

It is preferable to use an organic base as the base. When using an organic base, higher purity prasugrel can be obtained in higher yield than when using an inorganic base. Specific examples of the organic base include triethylamine, ethyldimethylamine, ethyldiisopropylamine, and the like, preferably triethylamine.

The base is preferably used in 2 to 5 molar equivalents relative to 1 molar equivalent of 2-oxothienopyridine p-toluenesulfonate or hydrochloride of formula (2).

The inert organic solvent may include aliphatic hydrocarbons such as hexane, cyclohexane, heptane, ligroin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; Ketones such as acetone, methyl ethyl ketone or diethyl ketone; Esters such as ethyl acetate, propyl acetate or butyl acetate; Carboxylic acids such as acetic acid or propionic acid; Or nitriles such as acetonitrile or propionitrile, and the like, preferably dichloromethane or tetrahydrofuran.

At this time, the reaction temperature is -10 ℃ to 60 ℃, preferably 15 ℃ to 30 ℃.

Subsequently, a base and an acetylating agent are added to the reaction mixture to carry out the acetylation reaction continuously.

In this case, the base may be an organic base in the same manner as described above, preferably using triethylamine. The base is preferably used in 1 to 1.5 molar equivalents relative to 1 molar equivalent of 2-oxothienopyridine p-toluenesulfonate or hydrochloride of the formula (2).

As the acetylating agent, acetic anhydride, acetyl chloride, and the like can be used, and preferably acetic anhydride is used. The acetylating agent is preferably used in 1 to 2 molar equivalents to 1 molar equivalent of 2-oxothienopyridine p-toluenesulfonate or hydrochloride of the formula (2).

At this time, the temperature of the acetylation reaction is -10 ℃ to 60 ℃, preferably 15 ℃ to 30 ℃.

The reaction mixture obtained after the acetylation reaction is concentrated under reduced pressure in a conventional manner. The residue obtained as a result of concentration under reduced pressure includes prasugrel or a reactant containing prasugrel.

As described above, the present invention is a reaction of p-toluenesulfonate or hydrochloride of 2-oxothienopyridine of formula (2) with 2-bromoethanone derivative of formula (3a), without separation of the obtained product in each reaction step. The post acetylation reaction is simple because it is continuous.

(Step 2)

The prasugrel of Chemical Formula 1 is directly crystallized in a crystallized mixed solvent from the resulting residue after concentration under reduced pressure in step 2.

As the crystallization mixed solvent, it is preferable to use a crystalline mixed solvent containing tetrahydrofuran, isopropanol and water. The mixing ratio of tetrahydrofuran, isopropanol and water included in the crystallization mixed solvent is preferably 1: 1: 1 to 1: 20: 10 in volume ratio in consideration of yield, purity of prasugrel and content of 2-oxoprasugrel. Do.

The crystallization is carried out by adding tetrahydrofuran to prasugrel or the reactant residue containing prasugrel, further adding isopropanol and water and then stirring at -10 ° C to 40 ° C, preferably 0 ° C to 20 ° C. .

Additionally, the step of recrystallizing the prasugrel of Formula 1 obtained in step 2 in a crystalline mixed solvent of tetrahydrofuran, isopropanol and water. By this process prasugrel can be produced in a more pure state.

Specifically, the prasugrel of Chemical Formula 1 obtained in the present invention generally has a purity of 97.0% or more, preferably 98.0% or more, more preferably 99.0% or more. In addition, the prasugrel of the formula (1) obtained in the present invention is 0.5% by weight or less, preferably 0.3% by weight or less, of the deacetylated compound of the formula (hereinafter referred to as 2-oxoprasugrel) Preferably 0.15% by weight or less.

Prasugrel prepared according to the present invention can be converted into various pharmaceutically acceptable acid addition salts or hydrochlorides thereof, including hydrochloride, according to conventional methods, specifically according to the prior art cited herein. Can be. Specifically, the acid addition salt may be an inorganic acid salt such as sulfate, hydrochloride, nitrate or phosphate; Or organic acid salts such as trifluoroacetate, maleate, methanesulfonate, benzenesulfonate or p-toluenesulfonate, preferably hydrochloride.

Accordingly, the present invention includes pharmaceutically acceptable acid addition salts of prasugrel and various crystalline forms thereof prepared by the process of the present invention.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the invention, the present invention is not limited to the following examples.

<Examples>

The analytical values described in the examples below were determined as follows.

The purity of prasugrel or the content of 2-oxoprasugrel (%) in each obtained product described in the Examples were determined by liquid chromatography (column: Capcell pak MG II C18, inner diameter 4.6 mm × length 150 mm, particle size 5). Μm, detection wavelength: 240 nm, eluent: acetonitrile / 20 mM potassium dihydrogen phosphate solution = 55/45 (V / V%), acetonitrile / 20 mM potassium dihydrogen phosphate solution = 80/20 (V / V%) ), The area of prasugrel peak separated by gradient elution, elution rate: 1.0 ml / min) or the area of 2-oxoprasugrel peak of formula (4) Was calculated:

Example  One

1) p-toluenesulfonate of 5,6,7,7a-tetrahydro-4H-thieno [3,2-c] pyridin-2-one (p-toluenesulfonate of formula 2; 2-oxothiene 35.0 g (0.11 mol) of nopyridine p-toluenesulfonic acid) were dissolved in 130 mL of dichloromethane and cooled to 0 ° C. After slowly adding 32.8 ml (0.24 mol) of triethylamine to the obtained reaction solution, 27.5 g (0.11 of 2-fluoro-?-Cyclopropylcarbonyl benzyl bromide (formula 3a, hereinafter referred to as 2-bromoethanone derivative)) mol) was slowly added dropwise to a solution diluted in 45 mL dichloromethane and stirred for 2 hours at room temperature. The obtained reaction mixture was cooled to 0 ° C., 29.8 ml (0.11 mol) of triethylamine was added thereto, 15.2 ml (0.17 mol) of acetic anhydride was slowly added dropwise, stirred at room temperature for 2 hours, and concentrated under reduced pressure to give a brown residue. Got it.

2) 10 mL of tetrahydrofuran was added to the residue obtained in 1), 100 mL of isopropanol and 70 mL of distilled water were added while stirring at room temperature, followed by stirring for 12 hours. The resulting solid was filtered, washed with 30 ml of isopropanol and dried at 40 ° C. to give 24.6 g of prasugrel (yield 64%, melting point 119-121 ° C., purity of prasugrel 97.9%, 2-oxoprasugrel). Content 0.01%) was obtained as a light white crystalline powder.

3) 10 g of prasugrel obtained in step 2) was added to 40 ml of tetrahydrofuran and warmed to 50 ° C to dissolve, and 40 ml of isopropanol and 40 ml of distilled water were added. The resulting mixture was stirred at 0 ° C. for 2 hours, the resulting solid was filtered, washed with 20 ml of a mixed solvent of pre-cooled isopropanol and distilled water (1: 1, v / v) and dried at 40 ° C. Further purified prasugrel 9.5 g (95% recrystallization yield, 120-122 DEG C of melting point, 99.8% purity of prasugrel, 0.01% or less of oxoprasugrel) were obtained as a white crystalline powder.

¹ H-NMR (CDCl ₃ , ppm): δ 7.5 (m, 1H), 7.3 (m, 1H), 7.1 (m, 2H), 6.3 (s, 1H), 4.8 (s, 1H), 3.5 (q , 2H), 2.9-2.7 (m, 4H), 2.3 (m, 1H), 2.2 (s, 3H), 1.1 (m, 2H), 0.8 (m, 2H).

IR (KBr, cm ^-1 ): 2920, 2815, 2766, 1758, 1704, 1612, 1585, 1493, 1458, 1418, 1368, 1217, 1197, 1127, 1067, 1048, 1010, 888, 7830, 802, 758 , 663.

Example  2 to Example  5

Example 1, except that 35.0 g (0.11 mol) of 2-oxothienopyridine p-toluenesulfonic acid was used, and tetrahydrofuran, isopropanol and distilled water were used as the crystalline mixed solvent in the amounts shown in Table 1 below. Prasugrel was obtained as white to white crystalline powder in the same manner as in steps 1) and 2).

Example THF / IPA / H ₂ O (ml) yield(%) Purity of PRS (%) Content of 2-OPRS (%) 2 10/175/35 60 98.6 <0.01 3 10/100/30 60 98.6 0.01 4 20/175/35 61 98.3 0.01 5 10/10/10 51 98.1 0.01 * THF: Tetrahydrofuran
* IPA: Isopropanol
* PRS: Prasugrel
* 2-OPRS: 2-Oxoprasugrel
* Yield is reaction and crystallization yield from 2-oxothienopyridine p-toluenesulfonic acid

Example  6 to Example  9

Prasugrel (purity 98.0%, 2-oxoprasugrel content 0.01) using the same method as in step 1) and 2) of Example 1 using 75.0 g of 2-oxothienopyridine p-toluenesulfonic acid 0.01 %) Was obtained.

10 g each of the obtained prasugrel, and tetrahydrofuran, isopropanol and distilled water as the crystalline mixed solvent in the same manner as in step 3) of Example 1 except that It was carried out to obtain prasugrel as a white crystalline powder.

Example THF / IPA / H ₂ O (ml) Yield (%) Purity of PRS (%) Content of 2-OPRS (%) 6 40/40/40 95 99.5 <0.01 7 10/10/80 97 99.3 <0.01 8 10/40/20 96 99.5 <0.01 9 20/40/20 95 99.5 <0.01 * THF: Tetrahydrofuran
* IPA: Isopropanol
* PRS: Prasugrel
* 2-OPRS: 2-Oxoprasugrel
* Yield is the recrystallization yield from prasugrel

Example  10

1) Hydrochloride of 5,6,7,7a-tetrahydro-4H-thieno [3,2-c] pyridin-2-one (hydrochloride of Formula 2; hereafter referred to as 2-oxothienopyridine hydrochloric acid) 20.0 g (0.10 mol) was dissolved in 125 mL of tetrahydrofuran and cooled to 0 ° C. After slowly adding 45 ml (0.32 mol) of triethylamine to the obtained reaction solution, a solution of 30.8 g (0.12 mol) of 2-bromoethanone derivative in 25 ml of tetrahydrofuran was slowly added dropwise, and the mixture was stirred at room temperature for 12 hours. Stirred. The resulting reaction mixture was cooled to 0 ° C., 20.9 ml (0.15 mmol) of triethylamine was added, 14.2 ml (0.15 mol) of acetic anhydride was slowly added dropwise, stirred at room temperature for 2 hours, and concentrated under reduced pressure to give a brown color. A residue was obtained.

2) 10 ml of tetrahydrofuran was added to the residue obtained in step 1), 105 ml of isopropanol and 35 ml of distilled water were added while stirring at room temperature, followed by stirring for 12 hours. The resulting solid was filtered and washed with 30 ml of isopropanol and dried at 40 ° C. to give 15.2 g of prasugrel (yield 39%, melting point 119-121 ° C., purity of prasugrel 97.7%, 2-oxoprasugrel). Content 0.03%) was obtained as a light white crystalline powder.

3) 10 g of prasugrel obtained in step 2) was added to 40 ml of tetrahydrofuran and warmed to 50 ° C to dissolve, and 40 ml of isopropanol and 40 ml of distilled water were added. The mixture was stirred at 0 ° C. for 2 hours, the resulting solid was filtered, washed with 20 ml of a pre-cooled mixture of isopropanol and distilled water (1: 1, v / v) and dried at 40 ° C. to further purify the plastic. 9.5 g of sugrel (yield of 95% recrystallization, 120-122 ° C melting point, 99.3% purity of prasugrel, 0.01% or less of oxoprasugrel) were obtained as a white crystalline powder.

Example  11

50 g of prasugrel (purity 99.8%, 2-OPRS <0.01%) obtained in the same manner as in Example 1 were dissolved in 750 ml of acetone, and 36% concentrated hydrochloric acid (6.78 g) was added at room temperature. Slowly added dropwise over minutes. To the resulting reaction mixture, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6, obtained by carrying out the same method as in US Pat. No. 6,693,115, 7-tetrahydrothieno [3,2-c] pyridine hydrochloride (prasugrel B2 crystals) was added and stirred at room temperature for 2 hours. The resulting crystals were filtered off, washed with 100 ml of acetone, and dried at 40 ° C. to give 51.7 g of prasugrel hydrochloride (yield 94%, melting point 180-182 ° C., purity of prasugrel 99.8%, and oxoprasugrel). Content 0.01%) was obtained as a white crystalline powder.

¹ H-NMR (CDCl ₃ , ppm): δ 8.0 (brs, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.3 (m, 1H), 6.4 (brs, 1H), 5.7 (s , 1H), 4.6 (brs, 1H), 4.2 (brs, 1H), 3.8 (brs, 1H), 3.6 (brs, 1H), 3.2 (brs, 1H), 2.9 (brs, 1H), 2.3 (s, 3H), 1.8 (brs, 1H), 1.3 (m, 1H), 1.1 (brs, 1H), 1.0 (m, 1H), 0.9 (brs, 1H)

IR (KBr, cm ⁻¹ ): 3089, 3008, 2956, 2908, 2352, 1760, 1684, 1587, 1503, 1358, 1233, 883, 754, 500.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, It is to be understood that the invention may be practiced within the scope of the appended claims.

Claims (13)

1) p-toluenesulfonate or hydrochloride of 2-oxothienopyridine of formula (2) is reacted with 2-bromoethanone derivative of formula (3a) in dichloromethane or tetrahydrofuran in the presence of triethylamine, and then Adding ethylamine and acetic anhydride to continuously acetylate and concentrate under reduced pressure, and
2) directly crystallizing prasugrel of the formula (1) in a crystalline mixed solvent containing tetrahydrofuran, isopropanol and water from the residue obtained as a result of the vacuum concentration;
Method for producing a prasugrel or acid addition salts of the following formula 1 comprising:
&Lt; Formula 1 >

(2)

<Formula 3a>

The method of claim 1,
The 2-bromoethanone derivative of Formula 3a is used in a 1 to 1.5 molar equivalent to 1 molar equivalent of p-toluenesulfonate or hydrochloride of 2-oxothienopyridine of Formula 2 above. The method of claim 1, wherein
When triethylamine is used in the reaction with 2-bromoethanone derivative of Chemical Formula 3a, it is used in 2 to 5 molar equivalents to 1 molar equivalent of 2-oxothienopyridine p-toluenesulfonate or hydrochloride of Chemical Formula 2 Characterized in the manufacturing method. The method of claim 1,
In the acetylation reaction, triethylamine is used in the amount of 1 to 1.5 molar equivalents to 1 molar equivalent of 2-oxothienopyridine p-toluenesulfonate or hydrochloride of the formula (2). delete delete The method of claim 1,
The acetic anhydride is a production method, characterized in that used in 1 to 2 molar equivalents to 1 molar equivalent of 2-oxothienopyridine p-toluenesulfonate or hydrochloride of the formula (2). delete The method of claim 1, wherein
The method according to claim 2, further comprising crystallizing prasugrel of Formula 1 obtained after crystallization in crystalline mixed solvent comprising tetrahydrofuran, isopropanol and water. The method according to claim 1 or 9
Said crystalline mixed solvent comprises tetrahydrofuran, isopropanol and water in a mixing volume ratio of 1: 1: 1 to 1:20:10. The method of claim 1,
Prasugrel of the formula (1) is characterized in that it comprises less than 0.5% by weight of 2-oxoprasugrel of the formula (4).
&Lt; Formula 4 >

The method of claim 11,
Prasugrel of the formula (1) is characterized in that it comprises less than 0.3% by weight of 2-oxo prasugrel of formula (4). The method of claim 12,
Prasugrel of the formula (1) is characterized in that it comprises less than 0.15% by weight of 2-oxoprasugrel of formula (4).