KR20160027537A - Process for preparing silodosin - Google Patents

Abstract

The present invention provides a method for producing silodosin through a novel synthesis pathway, wherein the silodosin is a therapeutic agent of urinary disturbances by benign prostatic hyperplasia. In addition, the present invention provides a method for producing a beta crystal form and/or a gamma crystal form of the silodosin using a crystallization solvent with excellent stability.

Description

{Process for preparing silodosin}

The present invention relates to a process for the preparation of cilostazol via a novel synthetic route. Further, the present invention relates to a process for producing a crystalline β and / or a crystalline γ of siloxane using a crystallization solvent excellent in safety.

The silodosin has selective urethral smooth muscle contraction inhibitory activity, thus reducing the urethral pressure without significantly affecting blood pressure and selectively acting on the a-adrenergic receptor subtype, And the like. Wherein the chemical structure of the spiroglycine is represented by the following Chemical Formula 1.

≪ Formula 1 >

The prior art process for preparing gadoline ghrelin comprises converting the mono-tartaric acid salt of the compound of formula 2 into the compound of formula 2 in free base form and then reacting it with the compound of formula 3, 4, preparing a compound represented by the formula (5) by hydrolyzing the compound represented by the formula (4), and further hydrolyzing the compound represented by the formula (5) to prepare a compound represented by the formula (1) do.

<Reaction Scheme 1>

In the above conventional preparation method, by-products of the following general formula (6) are produced in the process of preparing the compound of general formula (4), for example, WO 2011/247404 and WO 2012/131710, To remove the by-product.

(6)

Further, Korean Patent No. 10-1249865 discloses a method for avoiding the column chromatography process which is not suitable for an industrial production method by converting the compound of Chemical Formula 4 into an oxalate salt to remove the by-product And WO No. 2012/147019 discloses the conversion of a compound of formula 4 to a tartaric acid salt to remove the by-product.

In addition, Korean Patent No. 10-0670592 discloses three crystal forms of gypsum-like crystalline type?, Crystalline type? And crystalline type?, And a method of producing the same. The crystalline α, crystalline β and crystalline γ are obtained using ethyl acetate, petroleum ether, and toluene as the crystallization solvents, respectively.

On the other hand, the conventional process requires a step of converting the mono-tartaric acid salt of the compound of formula (2) into the compound of formula (2) in the free base form, which leads to a problem that the reaction process is unnecessarily prolonged. In addition, the reaction of the compound of formula (II) with the compound of formula (III) in the free base form takes a long period of time from 24 to 34 hours, so that it is not suitable for industrial mass production. In addition, since the conventional method for preparing gypsum crystal β and crystalline γ requires the use of a toxic organic solvent such as petroleum ether and toluene, the resulting product, ie, the solvent remaining in crystalline β and crystalline γ of siloxane There is a problem that must be adjusted very strictly.

The present inventors have conducted various studies in order to develop a new pathway method of producing a roving rope. As a result, the present inventors have found that it is possible to avoid the production of dimeric form by-products even when a step of converting the compound of the formula (5), which is not the compound of the formula (4), into the acid addition salt form is introduced. Further, it has been found that by using isopropyl alcohol, which is much more safe than petroleum ether and toluene, as a crystallization solvent, it is possible to effectively produce crystal form β and crystalline form γ of xylose.

Accordingly, it is an object of the present invention to provide a method for producing silododin through a novel synthetic route.

The present invention also aims to provide an intermediate useful as a compound for the synthesis of tautosaccharides, that is, a compound of the formula (5).

It is another object of the present invention to provide a process for preparing crystalline β and crystalline γ of siloxane using isopropyl alcohol as a crystallization solvent.

According to one aspect of the present invention there is provided a process for the preparation of a compound of formula (I), comprising: (a) hydrolyzing a compound of formula (4) with an alkali metal hydroxide to form a compound of formula (b) reacting the compound of formula (5) with an acid to form an acid addition salt of the compound of formula (5); And (c) reacting the acid addition salt of the compound of formula (5) with a base, followed by hydrolysis in the presence of an oxidizing agent to form a compound of formula (1):

&Lt; Formula 1 >

&Lt; Formula 4 >

&Lt; Formula 5 >

According to another aspect of the present invention there is provided an oxalate, succinate, or fumarate salt of a compound of formula 5:

&Lt; Formula 5 >

According to a further aspect of the present invention there is provided a process for the preparation of a compound of formula (I), comprising: (i) refluxing a compound of formula 1 in isopropyl alcohol and cooling to 5-10 캜; And (ii) seeding the crystalline form beta of the compound of formula (1), stirring and filtering the reaction mixture of step (i), to form a crystalline form of the compound of formula (1)

&Lt; Formula 1 >

According to a further aspect of the present invention there is provided a process for the preparation of a compound of formula (I '), comprising: (i') refluxing a compound of formula 1 in isopropyl alcohol and cooling to 5-10 캜; There is provided a process for the preparation of a crystalline form of a compound of formula (1), comprising the step of: (i) seeding a crystalline form of the compound of formula (1), stirring and filtering the reaction mixture of step (i)

&Lt; Formula 1 >

It has been found by the present invention that by introducing a step of converting the compound of formula (5), which is not the compound of formula (4), into the acid addition salt form, it is possible to avoid generation of the by-product in the form of a dimer. Further, it has been found by the present invention that by using isopropyl alcohol, which is much more safe than petroleum ether and toluene, as a crystallization solvent, it is possible to effectively produce crystalline β and crystalline γ of siloxane. Therefore, the manufacturing method according to the present invention is suitable for mass production on an industrial scale.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is an XRD difracogram of a crystalline form of gamma globin obtained according to the present invention. Fig. The crystalline form? Has peaks at the 2? Values of 6.26, 7.95, 10.89, 11.25, 12.82, 13.9, 15.4, 17.3, 18.17, 19.17, 19.9, 20.9, 21.6, 22.3, 23.2, 23.9 and 24.6.
Fig. 2 is an XRD difractogram of a crystalline form β of spodum sinus obtained according to the present invention. The crystalline form β has peaks at 2θ values of 5.68, 6.23, 7.34, 7.85, 8.13, 10.00, 10.73, 11.25, 12.33, 12.73, 15.51, 16.02, 20.09, 20.84, 21.39 and 28.18.

(A) hydrolyzing a compound of formula (4) using an alkali metal hydroxide to form a compound of formula (5); (b) reacting the compound of formula (5) with an acid to form an acid addition salt of the compound of formula (5); And (c) reacting the acid addition salt of the compound of formula (5) with a base, followed by hydrolysis in the presence of an oxidizing agent to form a compound of formula (1):

&Lt; Formula 1 >

&Lt; Formula 4 >

&Lt; Formula 5 >

In step (a), the alkali metal hydroxide may be selected from the group consisting of KOH, NaOH, and LiOH. The hydrolysis of step (a) can be carried out in water, methanol, ethanol, or a mixed solvent thereof, preferably in a mixed solvent of water and methanol. The hydrolysis of step (a) can be carried out, for example, at room temperature for about 10 hours.

In step (b), the acid may be oxalic acid, succinic acid, or fumaric acid to produce the oxalate, succinate, or fumarate salt of the compound of formula (5), respectively. The amount of the acid used may be in the range of 1 to 2 equivalents based on 1 equivalent of the compound of formula (5). The acid addition reaction of step (b) can be carried out in a solvent such as ethyl acetate, isopropanol or acetone, preferably in ethyl acetate. The resulting acid addition salt of the compound of formula (5) can be isolated using a semi-solvent such as isopropyl ether. By forming the acid addition salt of the compound of the general formula (5) as described above, it is possible to effectively remove impurities in the form of a dimer.

In step (c), the acid addition salt of the compound of formula (5) is reacted with a base to give the free base form of the compound of formula (5). At this time, usable bases can be selected from the group consisting of K ₂ CO ₃ , NaOH, NaHCO ₃ , and Na ₂ CO ₃ . The oxidizing agent used in step (c) may be selected from the group consisting of H ₂ O ₂ , NaClO, and H ₂ SO ₅ . The hydrolysis of step (c) can be preferably carried out in the presence of one or more selected bases from the group consisting of KOH, NaOH, and LiOH. In addition, the hydrolysis of step (c) can be carried out in an organic solvent such as a mixed solvent of dimethylsulfoxide and water.

The compound of Formula 4 used as a starting material of the present invention can be obtained by reacting a compound of Formula 2 or a salt thereof with a compound of Formula 3 below.

(2)

(3)

When the reaction of the compound of the above formula 2 or a salt thereof with the compound of the formula 3 is carried out as a catalyst in the presence of KI or NaI, the reaction time can be shortened remarkably, for example, 6 to 10 hours It turned out. Therefore, it is preferable that the reaction of the compound of the formula 2 or the salt thereof with the compound of the formula 3 is carried out in the presence of KI or NaI as a catalyst. The KI or NaI may be used in a proportion of 0.1 to 1.0 equivalent, preferably 0.1 to 0.5 equivalent, more preferably 0.1 to 0.3 equivalent based on 1 equivalent of the compound of formula (2). The reaction of the compound of formula 2 or a salt thereof with the compound of formula 3 may also be carried out in the presence of a base selected from the group consisting of K ₂ CO ₃ , Na ₂ CO ₃ , KOH, and NaOH.

In addition, when the reaction is carried out in the presence of a specific solvent and base, it is possible to avoid the step of converting the salt of the compound of formula (2) (for example, monotartaric acid salt) into the free base form, Thus reducing manufacturing costs. Thus, in one embodiment, the reaction of a salt of a compound of formula 2 with a compound of formula 3 is carried out in an organic solvent selected from the group consisting of acetonitrile, dimethylacetamide, dimethylformamide, and mixtures thereof; And in the presence of a base selected from the group consisting of K ₂ CO ₃ , Na ₂ CO ₃ , KOH, and NaOH. Preferably, the organic solvent may be a mixed solvent of acetonitrile and dimethylacetamide, for example, 1: 1 (by volume) of acetonitrile and dimethylacetamide. The reaction may be carried out at a temperature of about 80-100 &lt; 0 &gt; C.

The present invention also provides an oxalate, succinate, or fumarate salt of a compound of formula 5 useful for the synthesis of xanthine ginsenoside:

&Lt; Formula 5 >

The present invention also includes a process for preparing crystalline β and / or crystalline γ of siloxane using isopropyl alcohol, which is far superior to petroleum ether and toluene, as a crystallization solvent. (I) refluxing the compound of formula (1) in isopropyl alcohol and cooling to 5 to 10 占 폚; And (ii) seeding the crystalline form beta of the compound of formula (I) with the reaction mixture of step (i), stirring and filtering the compound of formula (I). (I ') refluxing the compound of formula (1) in isopropyl alcohol and cooling to 5-10 캜; And (ii ') a step of seeding the crystalline form y of the compound of formula (I) in a reaction mixture of step (i'), stirring and filtering the compound of formula (1). In the process for producing the crystalline Form β and the crystalline Form γ of the compound of Chemical Formula 1 of the present invention, the compound of Chemical Formula 1 may be obtained by the above-described production method.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the following examples are intended to illustrate the present invention, and the scope of the present invention is not limited thereto.

Example 1: Preparation of 1- (3-hydroxypropyl) -5 - [(2R) -2 - ({2- [2- (2,2,2- trifluoroethoxy) phenoxy] -2,3-dihydro-1H-indole-7-carbonitrile oxalate

(2R, 3R) -monotartaric acid salt (formula (2)) was obtained in the same manner as in (2) (80 g) and a mixed solvent of acetonitrile and dimethylacetamide (ACN / DMAC = 500 mL / 500 mL) was heated to 80 DEG C and stirred for 30 minutes Respectively. To the reaction mixture, 70 g of 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl methanesulfonate (compound of formula (III)) and 9.70 g of KI were added and the mixture was stirred at the same temperature for 10 hours Lt; / RTI &gt; The reaction mixture was cooled to room temperature and extracted with 1 L of ethyl acetate and 1.5 L of water. The organic layer obtained by layer separation was washed with 1 L of brine, dried over 40 g of anhydrous MgSO ₄ for 30 minutes, washed again with 200 mL of ethyl acetate, and the solvent was distilled off.

400 mL of methanol, 100 mL of water and 20 g of KOH were added to the obtained residue. The mixture was stirred at room temperature for 10 hours, then extracted with 1 L of ethyl acetate and 1 L of water for 10 minutes. The organic layer obtained by layer separation was washed sequentially with 1 L of saturated aqueous solution and 1 L of saturated brine, dried over 40 g of anhydrous MgSO ₄ for 30 minutes, washed with 200 mL of ethyl acetate, and then 18 g of oxalic acid was added. The reaction mixture was stirred at 50 &lt; 0 &gt; C for 30 minutes and then cooled to room temperature. 600 mL of isopropyl ether was added to the reaction mixture, stirred for 2 hours, and then filtered. The obtained crystals were washed with 200 mL of isopropyl ether and vacuum-dried at 40 DEG C for 10 hours to obtain 88 g of the title compound.

Yield: 82%

Purity: 99.5%

Impurities (dimer): not more than 0.1%

^{1 H NMR (DMSO, ppm)} δ 1.02 (3H, d) 1.75-1.85 (2H, m) 2.30-2.40 (4H, s) 2.63 (1H, dd) 2.80-2.90 (2H, m) 3.10-3.20 (3H , bs) 3.50-3.60 (6H, m) 4.05-4.15 (2H, m) 4.30 (2H, m) 6.80-7.10 (5H, m)

Example 2: Synthesis of 1- (3-hydroxypropyl) -5 - [(2R) -2 - ({2- [2- (2,2,2- trifluoroethoxy) phenoxy] -2,3-dihydro-1H-indole-7-carbonitrile succinate

The reaction was carried out in the same manner as in Example 1, except that 23 g of succinic acid was used instead of oxalic acid to obtain 92 g of the title compound.

Yield: 81%

Purity: 99.5%

Impurities (dimer): not more than 0.1%

^{1 H NMR (DMSO, ppm)} δ 0.98 (3H, d) 1.75-1.85 (2H, m) 2.30-2.40 (4H, s) 2.63 (1H, dd) 2.80-2.90 (2H, m) 3.10-3.20 (3H m) 6.50 (2H, s), 6.80-7.10 (5H, m), 3.50-3.60 (6H, m) 4.05-4.15

Example 3: Synthesis of 1- (3-hydroxypropyl) -5 - [(2R) -2 - ({2- [2- (2,2,2- trifluoroethoxy) phenoxy] -2,3-dihydro-1H-indole-7-carbonitrile fumarate

The reaction was carried out in the same manner as in Example 1, except that 23.5 g of fumaric acid was used instead of oxalic acid to obtain 92 g of the title compound.

Yield: 81%

Purity: 99.5%

Impurities (dimer): not more than 0.1%

^{1 H NMR (DMSO, ppm)} δ 1.08 (3H, d) 1.75-1.85 (2H, m) 2.43 (1H, dd) 2.80-2.90 (2H, m) 3.10-3.20 (3H, bs) 3.50-3.60 (6H m) 4.05-4.15 (2H, m) 4.30 (2H, m) 6.50 (2H, s) 6.80-7.10 (5H, m)

Example 4: Synthesis of 1- (3-hydroxypropyl) -5 - [(2R) -2 - ({2- [2- (2,2,2- trifluoroethoxy) -2,3-dihydro-1H-indole-7-carboxamide (crystal form y of Chen Rodin Shin)

To a solution of 122 g of K ₂ CO _{3 in} 500 mL of water was added 350 mL of ethyl acetate and then 1- (3-hydroxypropyl) -5 - [(2R) -2 - ({2- [2- , 2,2-trifluoroethoxy) phenoxy] ethyl} aminopropyl-2,3-dihydro-1H-indole-7-carbonitrile oxalate was added and stirred for 30 minutes. The organic layer was dried over 10 g of anhydrous MgSO ₄ , washed with 100 mL of ethyl acetate, and then distilled to remove the solvent. To the obtained residue, 422 mL of dimethylsulfoxide was added, and 5M The temperature of the reaction mixture was cooled to 5-10 ° C, 38.2 mL of H ₂ O ₂ (35%) was slowly added, and the mixture was stirred for 5-6 hours at 20 ° C. 1055 mL A solution of 16.95 g of Na ₂ SO ₃ in water was added to the reaction solution at 20 to 25 ° C to quench the remaining H ₂ O _{2. The} reaction mixture was extracted with 600 mL of ethyl acetate 500 mL of isopropyl alcohol was added to the obtained residue, and the mixture was refluxed for 10 minutes and then cooled to 5 to 10 DEG C. To the reaction mixture was added dropwise a solution of The crude product was seeded with 0.5 g of a crystalline form of γ and stirred for 2 to 3 hours, followed by filtration and vacuum drying at 40 ° C. for 9 hours to obtain 35 g of the title compound. The obtained product was purified with D8 Advance (Bruker ) Analysis Conditions 3-50 XRD was measured under conditions of 40 kV and 40 mA, and the obtained XRD difractogram is shown in FIG.

Yield: 80%

^{1 H NMR (DMSO, ppm)} δ 1.08 (3H, d) 1.75-1.85 (2H, m) 2.53 (1H, dd) 2.68 (1H, dd) 2.90-3.10 (5H, m) 3.19 (2H, t) 3.41 (1H, bs), 6.65 (1H, b), 6.85-7.05 (5H, m), 7.16 (1H, )

Example 5: Synthesis of 1- (3-hydroxypropyl) -5 - [(2R) -2 - ({2- [2- (2,2,2- trifluoroethoxy) phenoxy] -2,3-dihydro-1H-indole-7-carboxamide (crystal form β of silododosin)

The reaction was carried out in the same manner as in Example 4, except that the crystal form of β-glucoside was actually seeded instead of the crystalline form of γ, to obtain 35 g of the title compound. The obtained product was subjected to XRD measurement under the same conditions as in Example 4, and the obtained XRD difractogram is shown in FIG.

Yield: 80%

^{1 H NMR (DMSO, ppm)} δ 1.08 (3H, d) 1.75-1.85 (2H, m) 2.53 (1H, dd) 2.68 (1H, dd) 2.90-3.10 (5H, m) 3.19 (2H, t) 3.41 (1H, bs), 6.65 (1H, b), 6.85-7.05 (5H, m), 7.16 (1H, )

Claims (16)

(a) hydrolyzing a compound of formula (4) using an alkali metal hydroxide to form a compound of formula (5);
(b) reacting the compound of formula (5) with an acid to form an acid addition salt of the compound of formula (5); And
(c) reacting the acid addition salt of the compound of formula (5) with a base and then hydrolyzing in the presence of an oxidizing agent to form a compound of formula
: &Lt; EMI ID =
&Lt; Formula 1 &gt;

&Lt; Formula 4 &gt;

&Lt; Formula 5 &gt;

The method according to claim 1, wherein the alkali metal hydroxide is selected from the group consisting of KOH, NaOH, and LiOH. The process according to claim 1, wherein the acid is oxalic acid, succinic acid, or fumaric acid. The method according to claim 1, wherein the oxidizing agent is selected from the group consisting of H ₂ O ₂ , NaClO, and H ₂ SO ₅ . 5. The process according to any one of claims 1 to 4, wherein the compound of formula (4) is obtained by reacting a compound of formula (2) or a salt thereof with a compound of formula (3)
(2)

(3)

The process according to claim 5, wherein the reaction is carried out in the presence of KI or NaI as a catalyst. 6. The process according to claim 5, wherein KI or NaI is used in a proportion of 0.1 to 1.0 equivalent based on 1 equivalent of the compound of formula (2). The method of claim 5, wherein the production method which is characterized in that the reaction is carried out in the presence of a base selected from the group consisting of _{K 2 CO 3, Na 2 CO} 3, KOH, and NaOH. 6. The process according to claim 5, wherein the salt of the compound of formula (2) is mono-tartaric acid salt. 10. The method of claim 9, wherein the reaction is an organic solvent selected from the group consisting of acetonitrile, dimethylacetamide, dimethylformamide, and mixtures thereof; And in the presence of a base selected from the group consisting of K ₂ CO ₃ , Na ₂ CO ₃ , KOH, and NaOH. 11. The method according to claim 10, wherein the organic solvent is a mixed solvent of acetonitrile and dimethylacetamide. Oxalate, succinate, or fumarate salt of a compound of formula 5:
&Lt; Formula 5 >

(i) refluxing the compound of formula (1) in isopropyl alcohol and cooling to 5-10 占 폚; And (ii) seeding the crystalline form beta of the compound of formula (1), stirring and filtering the compound of formula (1) to the reaction mixture of step (i)
&Lt; Formula 1 >

The process according to claim 13, wherein the compound of formula (1) is obtained according to the process of any one of claims 1 to 4. (i ') refluxing the compound of formula (1) in isopropyl alcohol and cooling to 5-10 캜; And (ii ') seeding the crystalline form of the compound of formula (1) to the reaction mixture of step (i'), stirring and filtering the compound of formula (1)
&Lt; Formula 1 >

The process according to claim 15, wherein the compound of formula (1) is obtained according to the process of any one of claims 1 to 4.

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