KR102184129B1 - Production method of intermediate compound for synthesizing medicament - Google Patents

Abstract

[화학식 2]

상기 식에서 R1, R2, R3, R4, P₁ 및 P₂는 명세서에 정의되어 있는 바와 같다.The present invention relates to a method for preparing Formula 1, which is an essential intermediate for synthesizing a DPP-IV inhibitory diabetes treatment agent by selectively deprotecting the carboxylic acid protecting group (P ₂ ) of the compound of Formula 2:
[Formula 1]

[Formula 2]

In the above formula, R1, R2, R3, R4, P ₁ and P ₂ are as defined in the specification.

Description

Manufacturing method of intermediate compound for pharmaceutical synthesis TECHNICAL FIELD [PRODUCTION METHOD OF INTERMEDIATE COMPOUND FOR SYNTHESIZING MEDICAMENT}

The present invention relates to a preparation method of Formula 1, which is an essential intermediate for synthesizing dipeptidyl peptidase IV (hereinafter, referred to as'DPP-IV') inhibitory diabetes treatment agent.

A compound useful as a therapeutic agent for inhibiting dipeptidyl peptidase IV (DPP-IV) diabetes disclosed in WO 12/030106 (see compound of formula 1 in WO 12/030106) It is known that it exhibits excellent inhibitory activity against DPP-IV enzyme, and can be effectively used for the treatment and prevention of diseases such as diabetes and obesity caused by the enzyme. In the preparation of such a DPP-IV inhibitor compound, International Patent Publication No. WO 12/030106 discloses a method of preparing a compound of Formula 1 as an essential intermediate.

[Formula 1]

Meanwhile, conventionally, to prepare the compound of Formula 1, the carboxylic acid protecting group (P ₂ ) of the compound of Formula 2 was obtained by performing a deprotection reaction. Specifically, in the case of the compound of Formula 2 in which the protecting group is butyloxycarbonyl (P ₁ , Boc) and the leaving group is t-butyl group (P ₂ ) in the above formula (1) acidic conditions, specifically, a strong acid such as sulfuric acid, and dichloromethane , Deprotection by hydrolysis of the protecting group P ₂ using sodium hydroxide aqueous solution and di-tert-butyl dicarbonate (Boc ₂ O), or (2) basic conditions, specifically sodium hydroxide aqueous solution, ethanol, water reflux conditions It was prepared by hydrolyzing the protecting group P2 and deprotecting it. In particular, in the case of P ₂ being a benzyl group, a methyl group, an ethyl group and an i-propyl group, the hydrolysis conditions using the base specified in (2) were used among the above two conditions.

[Formula 2]

However, the method for preparing the compound of Formula 1 has a disadvantage in that the reaction must proceed under rather severe conditions, a large amount of reaction solvent must be used, and an additional concentration process is required.

Accordingly, the present inventors have conducted intensive research in order to solve the above-described drawbacks of the prior art, and as a result, especially when sodium hydroxide is used in a solid form among the bases, the yield can be remarkably improved even under mild conditions, and a small amount It was confirmed that economical efficiency and productivity were high because it was economical and no additional concentration process was required using the reaction solvent of.

Therefore, in the preparation of the compound of Formula 1, which is an intermediate used for synthesizing a DPP-IV inhibitory diabetes therapeutic agent, unlike the conventional method, sodium hydroxide is used in a basic condition to significantly improve the yield even in mild conditions. It is possible to use a small amount of the reaction solvent, and economical, without the need for an additional concentration process, it is an object to provide a synthesis method with high economic efficiency and high productivity.

As an aspect for solving the above problems, the present invention relates to a method for preparing a compound of Formula 1, wherein the method comprises a carboxylic acid protecting group (P ₂ ) among _two protecting groups P ₁ and P ₂ of the compound of Formula 2 And selectively performing a deprotection reaction, wherein the deprotection reaction is performed using a solid base and a lower alcohol.

The manufacturing method according to the present invention, the compound of Formula 1, which is an intermediate for oral insulin-independent diabetes treatment through inhibition of DPP-IV, 1) can be produced in high yield even under mild conditions, and 2) reduced the amount of reaction solvent to reduce cost. It is economical because it can be done, and 3) it is very useful because it has the advantage of achieving improvement effects such as increase in productivity through removal of the concentration process.

Hereinafter, the present invention will be described in detail.

When the manufacturing method according to the present invention is specifically described, it is shown in Scheme 1 below.

[Scheme 1]

In the above formula, R1, R2, R3 and R4 are each independently hydrogen, halogen, substituted or unsubstituted C ₁ -C ₄ alkyl. P ₁ is a carbonyl group, acyl group, sulfonyl group, acetyl or benzyl group as an amine protecting group, and preferably P ₁ is Boc (butyloxycarbonyl), Cbz (benzyloxycarbonyl) or Fmoc (9-fluorenylmethyloxy Carbonyl), more preferably Boc. P ₂ is a carboxylic acid protecting group, preferably a benzyl group, a methyl group, an ethyl group, an i-propyl group or a t-butyl group, and more preferably a t-butyl group.

In the present invention, when obtaining the compound of Formula 1 through a deprotection reaction of the carboxylic acid protecting group (P ₂ ) of the compound of Formula 2 under conventional basic conditions, the reaction is different from the use of an aqueous solution or a liquid base such as an aqueous sodium hydroxide solution. It is a feature of the invention to use a base in solid form as the base. The solid base used in the present invention may be sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, or a combination thereof, and a sodium hydroxide solid is preferably used to obtain the compound of formula (1).

The amount of the reaction base used is preferably 1 to 4 equivalents, preferably 1 to 2 equivalents based on the compound of Formula 2.

In addition, as the reaction solvent used in the above reaction, a lower alcohol having 1 to 6 carbon atoms and a mixed solvent thereof are used. Specifically, the lower alcohol having 1 to 6 carbon atoms may be at least one selected from the group consisting of methyl alcohol, ethyl alcohol, isopropyl alcohol, and a mixed solvent thereof (Co-solvent), and preferably ethyl alcohol may be used. . The amount of the reaction solvent to be used is preferably 1 fold (mL/g) to 7 fold (mL/g), preferably 2 fold (mL/g) to 3 fold (mL/g) for the compound of Formula 2. The reaction solvent of the present invention is characterized in that a small amount of the reaction solvent is used, unlike the preparation method of Formula 1 according to the conventional basic conditions.

Specifically, the reaction temperature during the deprotection reaction may vary depending on the reaction conditions, but in the case of the present invention, the reaction may be performed at a temperature lower than the reflux condition, for example, 30 to 80°C due to technical characteristics. The reaction time may be preferably 1 to 6 hours, more preferably 3 hours or less, but is not limited thereto.

As a further aspect, the preparation method according to the present invention may further comprise the step of crystallizing the compound of Formula 1 obtained according to the above. The solvent used for crystallization may be one or more solvents selected from the group consisting of water, methyl alcohol, ethyl alcohol, isopropyl alcohol, and a mixed solvent thereof (Co-solvent), but is not limited thereto, and preferably water Or it is a mixed solvent of ethyl alcohol and water. In the crystallization step, an acid can be used to adjust the pH to form crystals, and the preferred pH is 2.5 to 3.0.

[Example]

Hereinafter, the present invention will be described in more detail through Preparation Examples and Examples, but it is only intended to aid understanding of the present invention, and the scope of the present invention is not limited thereto in any sense.

Example 1: (3S)-3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxopiperidino)butanoic acid ((3S)-3-tert-Butoxycarbonylamino- Synthesis of 4-(5,5-difluoro-2-oxopiperidino) butanoic acid)

Starting material t-butyl (3S)-3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxopiperidino butanoate 462.3 kg, ethyl alcohol 729.6 kg, sodium hydroxide 82.2 After adding kg to the reactor at room temperature, the temperature was raised to a range of 40 to 50°C and reacted for 3 hours After completion of the reaction, 3699 kg of water was added, and a 3N hydrochloric acid aqueous solution was added dropwise to adjust the pH to 2.5 to 3.0, followed by crystallization The title compound produced as a solid was filtered, washed with a mixture of water, ethyl alcohol, and t-butyl methyl ether, and dried to prepare 347.6 kg (content: 97.5%, yield: 85.5%) of the title compound.

¹ H NMR (500 MHz, DMSO-d6) δ 1.32 (s, 9H), 2.20-2.43 (m, 6H), 3.26-3.31 (m, 2H), 3.61 (m, 1H), 3.81 (m, 1H) , 4.02 (m, 1H), 6.73 (d, J=8.6 Hz, 1H), 12.16 (s, 1H).

Example 2: (3S)-3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxopiperidino)butanoic acid ((3S)-3-tert-Butoxycarbonylamino- Synthesis of 4-(5,5-difluoro-2-oxopiperidino) butanoic acid)

Starting material t-butyl (3S)-3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxopiperidino butanoate 412.2 kg, ethyl alcohol 2049.0 kg, 6N sodium hydroxide 299.7 kg of aqueous solution was added to the reactor, the temperature was raised to reflux reaction After completion of the reaction, it was concentrated, and 1649 kg of water was added to dissolve the aqueous layer, washed with 1221.8 kg of t-butylmethyl ether, and a 3N aqueous hydrochloric acid solution was added dropwise The resulting solid title compound was filtered, washed with water and t-butyl methyl ether, and dried to obtain 309.8 kg of the title compound (content: 97.4%, yield: 85.4%) was prepared.

Example 3: (3S)-3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxopiperidino)butanoic acid ((3S)-3-tert-Butoxycarbonylamino- Synthesis of 4-(5,5-difluoro-2-oxopiperidino) butanoic acid)

Starting material t-butyl (3S)-3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxopiperidino butanoate 449.2 kg, ethyl alcohol 2033.0 kg, 6N sodium hydroxide 361.9 kg of aqueous solution was added to the reactor, the temperature was raised to reflux reaction, concentrated after the reaction was completed, 1796.9 kg of water was added to dissolve 354.4 kg of ethyl alcohol, and 3N aqueous hydrochloric acid solution was added dropwise to pH 4.1~ The crystallization process was carried out by adjusting to 5.0 and secondly from 2.5 to 3.0 The title compound produced as a solid was filtered, washed with a mixture of water and ethyl alcohol, and dried to obtain 325.0 kg of the title compound (content: 95.5%, yield: 80.6). %) was prepared.

Example 4: (3S)-3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxopiperidino)butanoic acid ((3S)-3-tert-Butoxycarbonylamino- Synthesis of 4-(5,5-difluoro-2-oxopiperidino) butanoic acid)

Starting material t-butyl (3S)-3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxopiperidino butanoate 43.0 g, ethyl alcohol 213.7 g, 6N sodium hydroxide After 8.8 g of aqueous solution was added to the reactor, the temperature was raised for reflux reaction After completion of the reaction, it was concentrated, and 172.0 g of water was added to dissolve it, 33.9 g of ethyl alcohol was added, and 3N aqueous hydrochloric acid solution was added dropwise to pH 4.1~ The crystallization process was carried out by adjusting to 5.0 and secondly from 2.5 to 3.0 The title compound produced as a solid was filtered, washed with a mixture of water and ethyl alcohol, and dried to obtain 35.5 g of the title compound (content: 93.0%, yield: 89.6). %) was prepared.

Example 5: (3S)-3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxopiperidino)butanoic acid ((3S)-3-tert-Butoxycarbonylamino- Synthesis of 4-(5,5-difluoro-2-oxopiperidino) butanoic acid)

Starting material t-butyl (3S)-3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxopiperidino butanoate 43.0 g, ethyl alcohol 67.9 g, sodium hydroxide 8.8 After adding g to the reactor, the reaction was carried out by raising the temperature to 70° C. After the reaction was completed, cooling was performed, and 344.0 g of water was added. 3N aqueous hydrochloric acid solution was added dropwise to adjust the pH to 4.1-5.0 first and 2.5-3.0 secondly. The solid title compound was filtered, washed with a mixture of water and ethyl alcohol, and dried to give 37.7 g (content: 92.4%, yield: 94.4%) of the title compound.

Example 6: (3S)-3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxopiperidino)butanoic acid ((3S)-3-tert-Butoxycarbonylamino- Synthesis of 4-(5,5-difluoro-2-oxopiperidino) butanoic acid)

Starting material t-butyl (3S)-3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxopiperidino butanoate 43.0 g, ethyl alcohol 67.9 g, sodium hydroxide 8.8 After g was added to the reactor, the reaction was carried out by raising the temperature to 30° C. After the reaction was completed, the reaction was cooled, and 344.0 g of water was added. A 3N aqueous hydrochloric acid solution was added dropwise to adjust the pH to 4.1 to 5.0 first and 2.5 to 3.0 secondly. The solid title compound was filtered, washed with a mixture of water and ethyl alcohol, and dried to give 37.7 g (content: 94.1%, yield: 96.2%) of the title compound.

Experimental Example: (3S)-3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxopiperidino)butanoic acid ((3S)-3-tert according to production conditions -Butoxycarbonylamino-4-(5,5-difluoro-2-oxopiperidino) butanoic acid) yield comparison

In order to compare the yield of the compound of Formula 1 according to the base used, the reaction temperature and the reaction solvent, a compound of Formula 1 was prepared from the compound of Formula 2, but was prepared according to the conditions of Table 1, and the results are also shown in Table 1. Shown in.

Comparison of the yield of the compound of Formula 1 according to the base used, the reaction temperature and the reaction solvent entry Base used Formula 2 compound
usage reaction
Temperature Reaction solvent Formula 1
compound
Yield content yield One Sodium hydroxide aqueous solution 43.0 g reflux 271 mL of ethyl alcohol 35.5 g 93.0% 89.6% 2 Sodium hydroxide 43.0 g reflux 43 mL ethyl alcohol, 172 mL water 34.0 g 94.6% 87.2% 3 Lithium hydroxide 43.0 g reflux 43 mL ethyl alcohol, 172 mL water 34.2 g 90.6% 84.1% 4 Sodium hydroxide 43.0 g 70℃ 86 mL ethyl alcohol 37.7 g 92.4% 94.4% 5 Sodium hydroxide 43.0 g 45℃ 86 mL ethyl alcohol 38.5 g 92.8% 96.9% 6 Sodium hydroxide 43.0 g 30℃ 86 mL ethyl alcohol 37.7 g 94.1% 96.2%

As can be seen from the comparative test results shown in Table 1 above, in the case of using a solid base such as sodium hydroxide solid compared to an aqueous base solution such as sodium hydroxide aqueous solution as the base (entry 4 to 6), the amount of the reaction solvent can be reduced. In addition, it was confirmed that the compound of Formula 1 can be obtained in a higher yield by reacting at a lower temperature than the reflux condition. In the case of reducing the reaction solvent, since the compound of Formula 1 can be obtained as a solid by acidification using an acid in a mixed solvent of ethyl alcohol and water without the concentration of the solvent after completion of the reaction, it is preferable to increase productivity.

Claims (9)

It includes the step of selectively deprotecting the carboxylic acid protecting group (P ₂ ) of the P ₁ and P ₂ protecting groups of the following Formula 2 compound, wherein the deprotection reaction includes a solid base as a reaction base, and 1 to carbon atoms as a reaction solvent. The preparation method of the following formula 1, characterized by using a lower alcohol of 6:

[Formula 1]

[Formula 2]

In the above formula,
R1, R2, R3 and R4 are each independently hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl,
P1 is a Boc (butyloxycarbonyl), Cbz (benzyloxycarbonyl) or Fmoc (9-fluorenylmethyloxycarbonyl) group as an amine protecting group,
P2 is a benzyl group, a methyl group, an ethyl group, an i-propyl group or a t-butyl group,
The reaction base is at least one selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide and calcium hydroxide,
The reaction solvent will be used in 1 fold (mL / g) to 7 fold (mL / g) for the compound of formula 2, the method. delete The method of claim 1, wherein the reaction base is used in the amount of 1 to 4 equivalents based on the compound of Formula 2. delete The method of claim 1, wherein the lower alcohol having 1 to 6 carbon atoms is methyl alcohol, ethyl alcohol, or a mixed solvent thereof (Co-solvent). delete The method of claim 1, wherein the deprotection reaction is performed at a reaction temperature of 30 to 80°C. The method of claim 1, further comprising the step of further crystallizing the compound of formula 1 obtained by a deprotection reaction. The method of claim 8, wherein the crystallization uses at least one solvent selected from the group consisting of water, methyl alcohol, ethyl alcohol, isopropyl alcohol, and a mixed solvent thereof (Co-solvent) as the crystallization solvent. Way.