KR101744046B1 - Process for preparing an intermediate useful for the synthesis of silodosin - Google Patents

Abstract

The present invention relates to the use of 3- {7-cyano-5 [(2R) -2 - ({2- [2- (2- 2-trifluoroethoxy) phenoxy] ethyl} aminopropyl) -2,3-dihydro-1H-indol-1-yl} propyl benzoate. The present invention also relates to novel acid addition salts of said core intermediates; And a process for preparing silododin using the improved production method.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to a process for preparing an intermediate useful for synthesis of a siloxane,

The present invention relates to a process for the preparation of 3- {7-cyano-5 - [(2R) -2 - ({2- [2- (2,2,2- trifluoroethoxy) Phenoxy] ethyl} aminopropyl) -2,3-dihydro-1H-indol-1-yl} propyl benzoate. The present invention also relates to novel acid addition salts of said core intermediates; And a process for preparing siloxane using the improved process.

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 solve the problems of the conventional silk tricine manufacturing method. As a result, the present inventors have found that when KI or NaI is used as a catalyst to carry out the reaction between the compound of the formula 2 or a salt thereof and the compound of the formula 3 and convert the obtained product into the acid addition salt, . 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, &Lt; / RTI &gt;

Thus, the present invention relates to a process for the preparation of a compound of formula (I) which comprises reacting a compound of formula (II) or a salt thereof with a compound of formula (III) using KI or NaI as catalyst and converting the resulting product It is an object of the present invention to provide an improved method for preparing an acid addition salt of an intermediate (i.e., an acid addition salt of a compound of the formula (IV)) used in the synthesis of Xanthan gum.

It is another object of the present invention to provide a fumaric acid salt of the compound of formula (IV), which is an acid addition salt of the novel compound of formula (4), and a process for producing the same.

It is another object of the present invention to provide a method for producing talc tin by using the above-mentioned production method.

According to one aspect of the present invention there is provided a process for preparing a compound of formula (I), comprising: (a) reacting a compound of formula (II) or a salt thereof with a compound of formula (III) in the presence of KI or NaI as catalyst to form a compound of formula And (b) reacting the compound of formula (4) with an acid to form an acid addition salt of the compound of formula (4): &lt; EMI ID =

(2)

(3)

&Lt; Formula 4 >

According to another aspect of the present invention there is provided a fumarate salt of a compound of formula 4:

&Lt; Formula 4 >

According to a further aspect of the present invention there is provided a process for preparing a compound of formula (I), comprising: (a) reacting a compound of formula (II) or a salt thereof with a compound of formula (III) in the presence of KI or NaI as catalyst to form a compound of formula (b ') Step of reacting fumaric acid with an extract obtained by extracting a reaction mixture containing the compound of formula (4) obtained by performing step (a) with an organic solvent to form an acid addition salt of the compound of formula (4) at 0 to 70 ° C ; And (c ') cooling the reaction mixture obtained in step (b') to room temperature, followed by filtration and drying, to provide a process for preparing a fumaric acid salt of a compound of formula (4)

(2)

(3)

&Lt; Formula 4 >

According to still another aspect of the present invention, there is provided a process for preparing a compound of formula (I), comprising: (i) (ii) hydrolyzing the acid addition salt of the compound of formula (4) with an alkali metal hydroxide to form a compound of formula (5); And (iii) hydrolyzing the compound of formula (5) in the presence of an oxidizing agent to form a compound of formula (1): &lt; EMI ID =

&Lt; Formula 1 >

&Lt; Formula 4 >

&Lt; Formula 5 >

When KI or NaI is used as a catalyst to carry out the reaction of the compound of the formula 2 or a salt thereof with the compound of the formula 3 and convert the obtained product into an acid addition salt, the reaction time is remarkably increased, for example, It can be shortened by time. 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. Therefore, the manufacturing method according to the present invention is suitable for mass production on an industrial scale.

(A) reacting a compound of formula (2) or a salt thereof with a compound of formula (3) in the presence of KI or NaI as catalyst to form a compound of formula (4); And (b) reacting the compound of formula (4) with an acid to form an acid addition salt of the compound of formula (4): &lt; EMI ID =

(2)

(3)

&Lt; Formula 4 >

The production method of the present invention includes using KI or NaI as a catalyst for shortening the reaction time to 6 to 10 hours. 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).

In the process of the present invention, the reaction of step (a) may 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. The reaction of step (a) can be carried out by using the compound of formula (2) in free base form or by using the compound of formula (2) in the form of a salt such as, for example, monotartaric acid salt. Surprisingly, 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 mono-tartarate) 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 of step (a) can be carried out at a temperature of about 80-100 &lt; 0 &gt; C.

In the preparation method of the present invention, step (b) can be carried out by reacting the compound of formula (4) with an acid to form an acid addition salt of the compound of formula (4). The acid includes, for example, oxalic acid, tartaric acid, or fumaric acid, and produces an oxalate, tartrate, or fumarate salt of the compound of Formula 4, respectively. Preferably, the acid is fumaric acid and produces a fumaric acid salt of the compound of formula (4)

On the other hand, WO 2012/147019 has evaluated the possibility of forming various salts including tartarate of the compound of formula (4). It has been disclosed that the salt formation conditions disclosed in WO-A-2012/147019 do not isolate the fumaric acid salt of the compound of formula (4) as a solid. However, according to the preparation method of the present invention, the fumarate salt of the compound of formula (4) is newly isolated, and thus the present invention includes the fumarate salt of the compound of formula (4).

The fumaric acid salt of the compound of formula (4) may be prepared by the steps of: (a) reacting a compound of formula (2) or a salt thereof with a compound of formula (3) in the presence of KI or NaI as catalyst to form a compound of formula (b ') Fumaric acid is added to the extract obtained by extracting the reaction mixture containing the compound of formula (4) obtained by carrying out step (a) with an organic solvent (for example, ethyl acetate) at 0 to 70 ° C, preferably about 50 Lt; 0 &gt; C to form an acid addition salt of the compound of formula 4; And (c ') cooling the reaction mixture obtained in step (b') to room temperature (about 20 to 25 ° C), followed by filtration and drying.

The present invention also encompasses a process for preparing tylosin (compound of formula (I)) using the above process. That is, the present invention provides a process for preparing a compound of formula (I), comprising the steps of: (i) (ii) hydrolyzing the acid addition salt of the compound of formula (4) with an alkali metal hydroxide to form a compound of formula (5); And (iii) hydrolyzing the compound of formula (5) in the presence of an oxidizing agent to form a compound of formula (1): &lt; EMI ID =

&Lt; Formula 1 >

&Lt; Formula 4 >

&Lt; Formula 5 >

The above steps (ii) and (iii) may be carried out according to a known method, for example, the method disclosed in Korean Patent No. 10-1249865, which is incorporated herein by reference in its entirety.

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 3- {7-cyano-5 - [(2R) -2 - ({2- [2- (2,2,2- trifluoroethoxy) phenoxy] ethyl} 2,3-dihydro-1H-indol-1-yl} propyl benzoate fumarate

(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, and then washed again with 200 mL of ethyl acetate.

23 g of fumaric acid was added to the obtained organic layer, and the mixture was heated to 50 DEG C, cooled to room temperature, and stirred for 2 hours. The reaction mixture was filtered, and the resulting solid was washed with 200 mL of ethyl acetate and dried in vacuo to give 113 g of the title compound.

Yield: 85%

Purity: 98%

Impurity (compound of formula 6): not more than 0.1%

^{1 H NMR (DMSO, ppm)} δ 1.08 (3H, d) 2.08 (2H, m) 2.43-2.57 (1H, m) 2.88-3.05 (3H, m) 3.60 (1H, m) 3.70 (2H, t) 4.29 (2H, t), 7.99 (2H, d), 7.99 (2H,

Claims (10)

(a) an organic solvent selected from the group consisting of acetonitrile, dimethylacetamide, dimethylformamide, and mixtures thereof; K ₂ CO ₃ , Na ₂ CO ₃ , KOH, and NaOH; Reacting a mono-tartaric acid salt of a compound of formula (2) with a compound of formula (3) in the presence of KI or NaI as catalyst to form a compound of formula (4); And (b) reacting the compound of formula (4) with an acid to form an acid addition salt of the compound of formula (4).
(2)

(3)

&Lt; Formula 4 >

The process according to claim 1, 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). delete delete delete The process according to claim 1, wherein the organic solvent is a mixed solvent of acetonitrile and dimethylacetamide. The method according to claim 1, wherein the acid is fumaric acid. delete (a) an organic solvent selected from the group consisting of acetonitrile, dimethylacetamide, dimethylformamide, and mixtures thereof; K ₂ CO ₃ , Na ₂ CO ₃ , KOH, and NaOH; Reacting a mono-tartaric acid salt of a compound of formula (2) with a compound of formula (3) in the presence of KI or NaI as catalyst to form a compound of formula (4); (b ') Step of reacting fumaric acid with an extract obtained by extracting a reaction mixture containing the compound of formula (4) obtained by performing step (a) with an organic solvent to form an acid addition salt of the compound of formula (4) at 0 to 70 ° C ; And (c ') cooling the reaction mixture obtained in step (b') to room temperature, followed by filtration and drying, to obtain the fumaric acid salt of the compound of formula (4)
(2)

(3)

&Lt; Formula 4 >

(i) preparing an acid addition salt of a compound of formula (4) according to any one of claims 1, 2, 6 and 7; (ii) hydrolyzing the acid addition salt of the compound of formula (4) with an alkali metal hydroxide to form a compound of formula (5); And (iii) hydrolyzing the compound of formula (5) in the presence of an oxidizing agent to form a compound of formula (1).
&Lt; Formula 1 >

&Lt; Formula 4 >

&Lt; Formula 5 >