KR101628946B1 - Improved Process of Silodosin - Google Patents

Abstract

More particularly, the present invention relates to an improved process for the preparation of 3-hydroxypropyl group at the N1 position of indoline by conducting an N -alkylation reaction using oxetane under Lewis acid catalyst, To an improved production process capable of maintaining a shortened manufacturing process and mild reaction conditions, thereby obtaining tacrolimus in high purity and high yield. Further, the present invention relates to a method for easily obtaining β-form crystals of pristine ginseng by selectively using a good solvent and an anti-solvent as an amorphous chamber.

Description

Improved Process of Silodosin < RTI ID = 0.0 >

More particularly, the present invention relates to an improved process for the preparation of 3-hydroxypropyl group at the N1 position of indoline by conducting an N -alkylation reaction using oxetane under Lewis acid catalyst, To an improved production process capable of maintaining a shortened manufacturing process and mild reaction conditions, thereby obtaining tacrolimus in high purity and high yield.

Silodosin is an indoline-based compound represented by the following formula (1), which is disclosed in European Patent Registration No. 600,675, and the compound is 1- (3-hydroxypropyl) -5 - [(2R) -2- 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl} amino) propyl] -7-indolecarboxamide.

[Chemical Formula 1]

On the basis of the selective action of urethral smooth muscle contraction on urethral smooth muscle contraction, the urethral pressure is lowered without significantly affecting blood pressure, and selectively inhibiting the? -Adrenergic receptor, .

The process for preparing siloxane disclosed in EP 600,675 is as shown in the following Reaction Scheme 1 and is synthesized by performing a multistage production process.

[Reaction Scheme 1]

(In the above Reaction Scheme 1, Boc represents a tert -butoxycarbonyl group)

In the production method shown in Scheme 1 a pointed portion with the problems is the method comprising: introducing a 3-hydroxypropyl the N1 position of the indoline, tert represented by Formula 4 - protected-butyl-dimethyl-silyl (TBDMS) Hydroxypropyl < / RTI > p -nitrobenzenesulfonate. The TBDMS used as an alcohol protecting agent is expensive and low in reactivity, which causes a decrease in yield. Further, there is a problem that a deprotection process for removing TBDMS must be added. In the above reaction scheme 1, tetra ( n -butyl) ammonium fluoride (TBAF) is used for the deprotection of TBDMS. TBAF is also a high-priced compound, but is highly corrosive. In fact, the yield of the hydroxypropyl group introduction reaction and the deprotection reaction according to Reaction Scheme 1 is as low as about 30%, which limits its commercial use.

In addition, Chinese Patent Registration No. 101,302,183 proposes a method for N -alkylation using 3-halopropyl alcohol represented by the following general formula (7) in order to improve the production method according to Reaction Scheme 1.

[Reaction Scheme 2]

(In the above Reaction Scheme 2, Boc represents a tert -butoxycarbonyl group and X represents a halogen atom)

The production method according to Reaction Scheme 2 excludes the use of an expensive TBDMS-protected alcohol compound, which was pointed out in European Patent Registration No. 600,675, and the production process is shortened, and the yield of the step of introducing 3-hydroxypropyl is And 65%, respectively.

However, the production method according to the reaction scheme 2 has a problem that the purity and yield of the object are lowered because the reaction temperature is as high as about 100 ° C. and the reaction time is as long as 12 hours or more to generate a large amount of reaction byproducts.

As described above, the step of introducing the 3-hydroxypropyl group at the N1 position of indolin in the production method of xanthan gum is an important step that determines the purity and yield of xanthan gum. Economically and efficiently, it can have the greatest impact on price competitiveness and high purity product production. Therefore, there is a desperate need to develop an improved preparation method which is suitable for mass production of xylose by efficiently carrying out a step of introducing a 3-hydroxypropyl group.

On the other hand, in International Patent Publication No. WO2004-022538, three crystalline forms of alpha, beta, and gamma are disclosed as polymorphs of Shadrosine. A manufacturing method of each of the crystalline polymorphs is proposed as follows. That is, the crude crystals are added to ethyl acetate and dissolved by warming, and then left at room temperature to obtain alpha-form crystals; The crude crystals are added to methanol and dissolved by heating, followed by addition of petroleum ether to obtain a beta-form crystal; The crude crystals are added to toluene and dissolved by heating, and then left at room temperature to obtain gamma-type crystals.

However, in the above-mentioned crystallization method, it is difficult to obtain a uniform yield and purity with the possibility of mixing different types of crystal form due to difference in temperature and stirring degree in the actual mass production process, and as a result of quenching, . Accordingly, there is a desperate need for an improved crystallization method capable of more easily precipitating a crystalline polymorphism in a high purity and a high yield.

It is an object of the present invention to provide an improved method for producing industrially produced starch and its crystalline polymorph with high yield and high purity.

In order to solve the above-mentioned problems, the process for producing siloxane according to the present invention is characterized in that,

(a) reacting a compound represented by the following formula (2) with oxetane represented by the following formula (8) by N -alkylation to prepare a compound represented by the following formula (9) wherein a 3-hydroxypropyl group is introduced at the N- ;

b) hydrolyzing a compound represented by the following formula (9) to prepare a compound represented by the following formula (10) wherein the cyano group at the C7 position of the indoline is converted to a carbamoyl group; And

(c) deprotecting a compound represented by the following formula (10) to prepare an amorphous silicate of formula (1); And the like.

[Reaction Scheme 3]

(In the above scheme 3, Boc represents a tert -butoxycarbonyl group)

Also, the process for preparing siloxane according to the present invention comprises

d) dissolving the tarsin in an amorphous gel in a good solvent, and then adding an anti-solvent to precipitate the tarsonate crystals in a beta-form yarn.

The production process of the present invention is characterized in that the step of introducing a 3-hydroxypropyl group at the N1 position of indoline is carried out by performing an N -alkylation reaction using oxetane to omit the step of introducing and deprotecting an alcohol protecting group The effect of shortening and maintaining mild reaction conditions using Lewis acid are effective in increasing the reaction yield and purity of the target.

In addition, in the N -alkylation reaction, the generation of impurities is minimized, so that the intermediate can be easily separated and purified. Thus, the purity of the final product can be improved.

The process of the present invention was able to minimize the generation of side reactions by improving the process to convert the cyano group at the C7 position to a carbamoyl group after N -alkylation of the indoline to the N1 position, The yield is improved by 5% or more.

According to the production method of the present invention, there is an effect of obtaining crystals that are stably grafted into a beta-type yarn in a stable and high yield by suitably selecting a good solvent and a semi-solvent as an amorphous yarn.

The present invention relates to a series of manufacturing methods for synthesizing crystals which are toughened to a yarn or a beta type yarn. The process of the present invention is particularly advantageous in that 1) N -alkylation reaction using oxetane is carried out under mild conditions during the introduction of 3-hydroxypropyl group at the N1 position of indolin, 2) 3) a specific positive solvent and an anti-solvent are selectively used in order to efficiently obtain crystals trisubstituted by a beta-form siloxane, and the like. have.

The manufacturing method according to the present invention will be described in more detail as follows.

The first preparation step is a step of introducing a 3-hydroxypropyl group into the indoline N1 position in the compound represented by the above formula (2).

In the present invention, the N -alkylation reaction is carried out using oxetane for the introduction of the 3-hydroxypropyl group, and the introduction of the alcohol protecting group and the deprotection are not required. In the present invention, a Lewis acid catalyst is used so that the N -alkylation reaction proceeds under mild reaction conditions. The Lewis acid catalyst may be at least one selected from the group consisting of lithium boron tetrafluoride, lithium perchlorate, ytterbium (III) triflate, and bismuth (III) chloride. Examples of the N -alkylation reaction solvent include water, methanol, ethanol, isopropanol, butanol, diethyl ether, isopropyl ether, chloroform, dichloromethane, acetonitrile, Tetrahydrofuran and the like, or a mixed solvent thereof may be used.

As a result, the N - alkylation reaction can be completed within a short time (about 3 to 5 hours) even at a temperature around room temperature, specifically, a low temperature of 15 to 30 ° C. According to the N -alkylation reaction according to the present invention, the compound represented by the above formula (9) can be synthesized at a high yield of 90% or more, and the production of by-products is extremely low. After completion of the reaction, Lt; / RTI > can be obtained.

In addition, according to the N -alkylation reaction according to the present invention, the conventional production method shown in the above reaction formula 2 has a high reaction temperature and a long reaction time to produce a large amount of impurities. The alkylation yield of sec- It is possible to solve problems such as performing an inadequate refining process industrially at once. Therefore, the production method of the present invention can make a significant contribution to the economical, efficient and industrially utilizable synthesis of spiroglycine through the improvement of the N -alkylation step.

The second manufacturing step is a step of converting a cyano group (-CN) of indoline in the C7 position of the compound represented by the above formula (9) with a carbamoyl group _{(-C (O) NH 2)} .

In the present invention, the cyano group at the C7 position is converted to a carbamoyl group after the N -alkylation of the indoline to the N1 position, since the cyano group has less reactivity than the carbamoyl group, It is an idea. That is, when the N -alkylation reaction using oxetane is carried out in the state where a carbamoyl group is present at the C7 position, more impurities are produced and the purity of the final product is lowered, so that a multi-step purification process is inevitably required Which in turn leads to a lower yield of silodic acid.

In the present invention, a hydrolysis reaction is carried out in order to convert a cyano group to a carbamoyl group. The hydrolysis is carried out in the presence of an oxidizing agent and an alkalizing agent. Specific examples of the oxidizing agent include hydrogen peroxide, percarbonate, and peroxodisulfate, and hydrogen peroxide may be preferably used. The alkalizing agent may be at least one selected from the group consisting of alkali metal hydroxides and alkali metal carbonates. Specifically, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or a mixture thereof may be used. As the hydrolysis reaction solvent, water, a water-soluble organic solvent, or a mixed solvent thereof may be used as a conventional solvent used in the art. The water-soluble organic solvent may be at least one selected from the group consisting of alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol and isopropyl alcohol, acetone, tetrahydrofuran, dioxane, dimethylsulfoxide (DMSO) . A mixed solvent of methanol and dimethylsulfoxide is preferably used. The hydrolysis is carried out at a temperature ranging from 0 ° C to room temperature for 1 to 12 hours, specifically at a temperature range of 0 to 30 ° C, preferably at a temperature range of 0 to 10 ° C.

The compound represented by the formula (10) prepared by the hydrolysis described above is prepared in high purity and high yield, and can be used immediately for the next reaction without any special purification process. Further, a simple solvent crystallization may be carried out as necessary to obtain a high-purity product, which may be used for the next reaction. At this time, the crystallization solvent may be easily crystallized through a conventional crystallization process using a single solvent or a mixed solvent selected from ether-based solvents such as ethyl ether, isopropyl ether and petroleum ether.

The third preparation step is a deprotection step for removing the Boc protecting group in the compound represented by the above formula (10).

The deprotection can be carried out using a suitable solvent and a conventional deprotecting agent. The deprotecting agent may be at least one selected from hydrochloric acid, hydrobromic acid (HBr), sulfuric acid, nitric acid, trifluoroacetic acid (TFA), trimethylsilyl chloride (TMSCl) The deprotecting reaction solvent may be appropriately selected from conventional solvents, and specifically, it may be used in a single solvent selected from water, methanol, ethanol, isopropanol, butanol, ethyl acetate, chloroform, dichloromethane, acetone, Or a mixed solvent thereof may be used. The deprotection is carried out at a temperature ranging from 0 ° C to room temperature for 1 to 24 hours, specifically at a temperature range of 0 to 30 ° C, preferably at a temperature range of 20 to 25 ° C.

Since the siloxane dyes represented by the formula (1) prepared through deprotection as described above are produced in high purity and high yield, they need not be subjected to a special purification process (for example, column chromatography, distillation, etc.). The crystallization solvent used may be an ether solvent such as ethyl ether, isopropyl ether or petroleum ether, a single solvent selected from ethyl acetate, toluene, hexane, heptane and the like. A solvent or a mixed solvent may be used.

The fourth manufacturing step is a step of obtaining a filamentous cord represented by the formula (1) as a beta- type crystal.

That is, the production method of the present invention may further include a step of precipitating crystals that are grafted from the sieve into the amorphous sieve to the beta type sieve. In the present invention, in order to obtain beta-form crystals obtained by the present invention, the amorphous silica is dissolved in a halogenated hydrocarbon solvent, which is a good solvent, and then an aliphatic hydrocarbon solvent having 6 to 8 carbon atoms To obtain beta-form crystals. The aliphatic hydrocarbon solvent used as the anti-solvent may include at least one selected from the group consisting of hexane, cyclohexane, heptane, cycloheptane, and octane. Preferably, chloroform is used as the good solvent and n-heptane is used as the anti-solvent.

The method for producing the tridododinose according to the present invention as described above will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

[Example]

Example 1: Preparation of (R) -tert -Butyl-1- [7-cyano-1- (3- hydroxypropyl) indol- , 2,2-trifluoroethoxy) phenoxy] ethyl} carbamate (Formula 9)

To the reactor were added 100 mL of acetonitrile and 100 mL of (R) -tert -butyl-1- (7- cyanoindolin -5-yl) propan-2-yl- {2- [2- (2,2,2- (38.49 mmol), oxetane (2.6 g, 44.77 mmol) and lithium boron tetrafluoride (7.2 g, 76.80 mmol) were charged and stirred at 20 to 25 ° C for 2 hours Respectively. After completion of the reaction, the reaction mixture was neutralized by adding an aqueous ammonia solution (60 mL), and 100 mL of chloroform and 100 mL of distilled water were added thereto, followed by stirring and layer separation. The organic layer was washed with a saturated sodium chloride aqueous solution, and activated carbon and anhydrous sodium sulfate were added thereto. The mixture was stirred for 30 minutes, filtered, and concentrated under reduced pressure to obtain 20.46 g (92%) of the title compound.

_{^{1 H NMR (CDCl 3) δ}} 7.02-6.92 (m, 6H), 4.32 (q, J = 8.4 Hz, 2H), 4.11-3.88 (m, 3H), 3.75 (t, J = 6.0 Hz, 2H), 3.67 (t, J = 7.3 Hz , 2H), 3.56 (t, J = 8.6 Hz, 2H), 3.42 (dd, J = 23.2, 7.3 Hz, 2H), 2.91 (t, J = 8.6 Hz, 2H), 2.78-2.68 (m, 1H), 2.51 (dd, J = 13.9, 6.7 HZ, 1H), 1.91 (p, J = 7.0 Hz, 2H), 1.40 (s, 9H), 1.23 (d, J = 7.0 HZ , 3H)

Example 2: Preparation of (R) -tert -Butyl-1- [7-carbamoyl-1- (3- hydroxypropyl) indol- , 2,2-trifluoroethoxy) phenoxy] ethyl} carbamate

To a mixed solution of 30 mL of dimethylsulfoxide (DMSO) and 50 mL of methanol was added (R) -tert -butyl-1- [7-cyano-1- (3- hydroxypropyl) Yl] propan-2-yl- {2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl} carbamate was added to the solution and dissolved. After the temperature of the reaction solution was cooled to 0 to 5 캜, 30% aqueous hydrogen peroxide 4.08 g (51.90 mmol) was added dropwise. After stirring for 30 minutes while maintaining the temperature at 0 to 5 캜, 17.26 mL (51.90 mmol) of 5N sodium hydroxide was added dropwise while maintaining the temperature below 15 캜, and the mixture was stirred at 20 to 25 캜 for 5 hours. After completion of the reaction, acetic acid was added to neutralize the mixture, and then 90 mL of purified water and 90 mL of ethyl acetate were added thereto, followed by stirring and layer separation. The organic layer was concentrated under reduced pressure, and 100 mL of isopropyl ether was added thereto, followed by stirring at 0? 5 占 폚 for 3 hours, followed by filtration and drying to obtain 9.6 g (93.1%) of the title compound.

_{^{1 H NMR (CDCl 3) δ}} 7.21-6.83 (6H, m), 4.37 (q, J = 8.3 Hz, 2H), 4.12-3.59 (m, 5H), 3.62-3.02 (m, 6H), 2.91 (t , J = 8.4 Hz, 2H) , 2.89-2.48 (m, 2H), 1.89-1.77 (m, 2H), 1.35 (s, 9H), 1.30-1.17 (m, 3H),

Example 3: Preparation of siloxane

To 48 mL of methanol was added (R) -tert-butyl-1- [7-carbamoyl-1- (3- hydroxypropyl) indolin- Phenoxy] ethyl} carbamate (8.0 g, 13.42 mmol) was added to the solution and dissolved in the flask. After cooling to 0 to 5 캜, 5.10 g (47.00 mmol) of trimethylsilyl chloride (TMSCl) was added dropwise and the mixture was stirred at 5 to 10 캜 for 30 minutes and then at 20 to 25 캜 for 7 hours. After completion of the reaction, the reaction mixture was neutralized by adding a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. Activated carbon and anhydrous sodium sulfate were added to the organic layer, stirred for 30 minutes, and then filtered. 80 mL of ethyl acetate was added to the residue, which was dissolved by heating. The solution was slowly cooled to 20 to 25 DEG C, and the resultant solid was filtered and dried at 40 DEG C for 40 hours to obtain 5.65 g (84.9%) of the title compound.

_{^{1 H NMR (CDCl 3) δ}} 7.14 (s, 1H), 7.02-6.85 (m, 5H), 4.27 (q, J = 8.4 Hz, 2H), 4.08-4.04 (m, 2H), 3.69 (t, J = 5.6 Hz, 2H), 3.36 (t, J = 8.5 Hz, 3H), 3.15 (t, J = 5.6 Hz, 2H), 3.03-2.87 (m, 5H), 2.65 (dd, J = 13.6, 6.4 Hz 2H), 1.03 (d, J = 6.2 Hz, 3H), 2.48 (dd, J = 13.6,6.8 Hz,

Example 4: Preparation of beta-

5.0 g of tylosin prepared in Example 3 was dissolved in 25 g of chloroform. The resultant crystals were filtered and dried at 30 DEG C for 12 hours to obtain 4.8 g of the title compound (yield: 96%, HPLC purity: 99.97%). ).

The results of the X-ray diffraction analysis of the obtained crystals are shown in Table 1 below, and it was confirmed that the crystals obtained in this Example were β-type crystals of Shadrosine.

No. 2θ (°) century(%) One 7.108 42.78 2 8.810 23.08 3 10.438 22.35 4 12.022 43.27 5 12.518 51.01 6 13.065 46.16 7 15.862 30.29 8 17.920 54.82 9 18.647 31.60 10 19.543 48.70 11 20.768 100.00 12 21.133 58.22 13 23.900 21.34

Claims (9)

(a) reacting a compound represented by the following formula (2) with oxetane represented by the following formula (8) by N -alkylation to prepare a compound represented by the following formula (9) wherein a 3-hydroxypropyl group is introduced at the N- ;

(In the above reaction scheme, Boc represents a tert -butoxycarbonyl group)
b) hydrolyzing a compound represented by the following formula (9) to prepare a compound represented by the following formula (10) wherein the cyano group at the C7 position of the indoline is converted to a carbamoyl group; And

(In the above reaction scheme, Boc represents a tert -butoxycarbonyl group)
(c) deprotecting a compound represented by the following formula (10) to prepare an amorphous silicate of formula (1);

(In the above reaction scheme, Boc represents a tert -butoxycarbonyl group)
≪ / RTI >
The method according to claim 1,
d) dissolving tarsin in an amorphous silicate in a good solvent, and then adding an anti-solvent of an aliphatic hydrocarbon to precipitate the tarsonate crystals in a beta-form siloxane. Manufacturing method of God.
The method according to claim 1,
Wherein the N -alkylation reaction in step a) is carried out in the presence of a Lewis acid catalyst.
The method of claim 3,
Wherein the Lewis acid catalyst is selected from the group consisting of lithium boron tetrafluoride, lithium perchlorate, ytterbium (III) triflate, and bismuth (III) chloride.
The method according to claim 1,
Wherein the hydrolysis in step b) is carried out using hydrogen peroxide water and an alkalizing agent.
6. The method of claim 5,
Wherein the hydrolysis in step b) is carried out in the presence of a single solvent or a mixed solvent selected from the group consisting of dimethylsulfoxide (DMSO) and alcohols having 1 to 4 carbon atoms.
6. The method of claim 5,
Wherein the alkalizing agent is at least one selected from the group consisting of alkali metal hydroxides and alkali metal carbonates.
The method according to claim 1,
Wherein the deprotection of step c) is carried out using trimethylsilyl chloride (TMSCl).
3. The method of claim 2,
Wherein the two solvents in step d) are chloroform, and the semi-solvent is a single solvent selected from the group consisting of hexane, cyclohexane, heptane, cycloheptane and octane, or a mixed solvent thereof.