KR102152445B1 - Production method of intermediate compound for synthesizing medicament - Google Patents

Abstract

상기 식에서 P₁은 아민 보호기로서 카르보닐기, 아실기, 술포닐기, 아세틸 또는 벤질기이고, P₂는 카르복시산 보호기이다.The present invention can be produced in high purity through 1) oxazolidinone cyclization reaction and decyclization reaction to convert to amide, an intermediate used to synthesize dipeptidyl peptidase IV enzyme inhibitory diabetes therapeutic agent, 2) It is possible to increase the yield and increase the productivity through stabilization of the manufacturing process, and 3) It relates to a manufacturing method that can achieve improvement effects such as reduction of raw material cost by using a cheap starting material.
[Formula 2]

In the above formula, P ₁ is a carbonyl group, an acyl group, a sulfonyl group, an acetyl or benzyl group as an amine protecting group, and P ₂ is a carboxylic acid protecting group.

Description

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

The present invention is a method for preparing a compound of the following formula (2) used in the preparation of the following formula (1), which is an essential intermediate for synthesizing dipeptidyl peptidase IV (hereinafter, referred to as'DPP-IV') inhibitory diabetes treatment, and to carry out the method. It relates to the following novel compounds of formulas 3 and 4, which are produced as intermediates.

A compound useful as a therapeutic agent for dipeptidyl peptidase IV (DPP-IV) inhibiting diabetes disclosed in WO 06/104356 (see the compound of formula 1 in WO 06/104356) 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 Application Publication No. WO 06/104356 discloses a method for preparing a compound of the following formula (1) as an essential intermediate.

[Formula 1]

Meanwhile, the compound of Formula 2 is used to prepare the compound of Formula 1, and generally, 4- tert- Butyl (2 S )-2- tert- butoxycarbonylamino-butanedioate, which is commercially useful for preparing the compound of Formula 2, is used as a starting material. The method of manufacturing with is disclosed in Korean Patent Application No. 10-2010-0086619, but 1) the manufacturing process is not suitable for commercial mass production, and 2) the high cost and low yield are a major factor in increasing the production cost. There was a problem.

Accordingly, the present inventors intensively conducted research in order to solve the above-described disadvantages of the prior art, and developed a technology for introducing a protecting group (P ₂ ) to a carboxylic acid group through introduction of an amine protecting group (P ₁ ) and cyclization reaction. In addition, the intermediates produced in the manufacturing process were found to be novel compounds by themselves, and the present invention was completed.

Specifically, it is shown in Scheme 1 below:

[Scheme 1]

In order to solve the aforementioned problems in the prior art, the present inventors attempted to synthesize the compound of Formula 2 from the compound of Formula 6, which is inexpensive.

In the case of Pathway 1 ( Chem . Commun ., 2001, 1710-1711) of Scheme 1 according to the prior art, 1) a low yield of 30 to 34% and 2) raw materials such as toxic thionyl chloride and ammonia While the use of gas 3) low-temperature reaction is required, in the case of Pathway 2 corresponding to the manufacturing method according to the present invention, the compound of Formula 2 can be obtained with mild reaction conditions and a high yield of 57 to 61%. Advantages can be secured.

Accordingly, the present invention provides a method for preparing a compound of Formula 2, which is essential for preparing the compound of Formula 1, which is an intermediate used for synthesizing a therapeutic agent for DPP-IV inhibition diabetes, that is suitable for commercial mass production, while being economical and in high yield. It aims to provide.

In order to solve the above problems, the present invention:

1) obtaining a compound of Formula 5 in which the amine group is protected by introducing a P ₁ group into the amine group of the compound of Formula 6 below;

2) obtaining a compound of formula 4 through a cyclization reaction through a condensation reaction under an acid catalyst to the compound of formula 5 produced in step 1);

3) converting the carboxylic acid group into an ester group by introducing a P ₂ group into the carboxylic acid group of the compound of Formula 4 produced in step 2) to obtain a compound of Formula 3; And

4) obtaining an amide compound of Formula 2 through oxazolidinone decyclization by reacting with a nitrogen raw material compound of the compound of Formula 3 produced in step 3),

It relates to a method for preparing a compound of the following formula 2 comprising:

[Formula 6]

[Formula 5]

[Formula 4]

[Formula 3]

[Formula 2]

In the above formula, P ₁ is an amine protecting group that may be selected from a carbonyl group, an acyl group, a sulfonyl group, an acetyl or benzyl group, and preferably P ₁ is Boc (butyloxycarbonyl), Cbz (benzyloxycarbonyl) or Fmoc ( 9-fluorenylmethyloxycarbonyl), more preferably Boc.

P ₂ is a carboxylic acid protecting group. Preferably, they are a benzyl group, a methyl group, an ethyl group, an i-propyl group or an i-butyl group, more preferably a t-butyl group.

Hereinafter, the present invention will be described in detail based on the reaction formula. However, the following reaction scheme is only intended to aid understanding of the present invention, and is not intended to limit the present invention in any sense.

A detailed description of the manufacturing method according to the present invention is shown in Scheme 2 below:

[Scheme 2]

The reaction base used in the protective vaporization reaction of the first step of Scheme 2 is triethylamine, N,N-diisopropylethylamine (Hunig's base), lithium t-butoxide, potassium t-butoxide, sodium t- It may be one or more selected from the group consisting of butoxide and sodium hydroxide. Preferably, it is good to use triethylamine. The amount of the reaction base used is preferably 1.0 equivalent or more, particularly preferably 2.0 to 3.0 equivalents, based on the compound of formula (6).

In addition, as the reaction solvent, one or more organic solvents that can be commonly used in organic reactions such as isopropyl alcohol, ethyl alcohol, dichloroethane, dichloromethane, tetrahydrofuran, acetone and dioxane can be selected and used. Together with, a mixed solvent (Co-solvent), etc. may be used. In particular, a mixed solvent of isopropyl alcohol and water is preferable.

In a specific embodiment, 1) When introducing a butyloxycarbonyl or acetyl group as P ₁ , di-tert-butyldicarbonate (Boc anhydride) or acetic anhydride (Acetic anhydride); Bases such as triethylamine (TEA) and N,N-diisopropylethylamine (Hunig's base); As the reaction solvent, dichloroethane, dichloromethane, cyclized ether (e.g., tetrahydrofuran (THF), dioxane), isopropanol (IPA)/H ₂ O mixed solvent or THF/H ₂ O mixed solvent may be used. And 2) Fmoc-Cl when introducing a Fmoc (9-Fluorenylmethoxycarbonyl) group as P ₁ ; Sodium carbonate (aq Na ₂ CO ₃ ) as base; Dioxane may be used as the reaction solvent, and 3) 4-nitrobenzenesulfonyl chloride (Ns-Cl) when P ₁ is 4-nitrobenzenesulfonyl (Ns); Bases such as triethylamine or N,N-diisopropylethylamine and sodium hydroxide; Acetone may be used as the reaction solvent, and 4) benzyl chloroformate when P ₁ is carboxylbenzyl (Cbz); Sodium hydrogen carbonate (NaHCO ₃ ) as base; Tetrahydrofuran/water can be used as the reaction solvent.

Preferably, the case of using di-tert-butyldicarbonate to protect with bunyloxycarbonyl as P ₁ is preferable in terms of yield, and the amount used is 1.0 equivalent or more, particularly preferably 1.0 to 1.3 equivalent, based on the compound of Formula 6 Do. In addition, the above equivalents apply equally to compounds for introducing other protecting groups, ie, acetic anhydride, Fmoc-Cl, acetylanhydride and benzylchloropermates.

The cyclization reaction of the second step is carried out through a condensation reaction by reacting with paraformaldehyde under an acid catalyst. Specifically, 1) paraformaldehyde, paratoloenesulfonic acid (p-TsOH)-water, toluene Or ethyl acetate-benzene, or 2) paraformaldehyde, pyridinium-p-toluenesulfonate (PPTS, Pyridium- p- toluenesulfonate), and toluene-ethylacetate The compound of formula 4 can be obtained under conditions. In terms of safety and economy, it is preferable to use a mixed solvent of pyridine-p-toluenesulfonate as an acid catalyst and a toluene-ethylacetate as the reaction solvent. In particular, the amount of pyridinium-p-toluenesulfonate is used in the amount of 0.005 equivalents or more based on the compound of Formula 5, and preferably 0.01 to 0.02 equivalents. The compound of Formula 4 produced as a result of the reaction in the second step can be obtained as a high-purity solid compound when recrystallized in an ethyl acetate/toluene mixed solvent. Regarding the mixing ratio of the recrystallization solvent, ethyl acetate and toluene may be mixed in a volume ratio of 1:7 to 1:10 with respect to the resultant Formula 4 compound, and preferably 1:8 to 1:9 Recrystallization can be carried out in a mixed solvent mixed in a volume ratio.

In the esterification reaction of the third step, the carboxylic acid group is converted into an ester group while P ₂ is introduced into the compound of Formula 4 to produce the compound of Formula 3. At this time, a single solvent such as t-butyl alcohol, isopropyl alcohol, ethyl alcohol, methyl alcohol or tetrahydrofuran, or a mixed solvent obtained by mixing them is used, and the catalytic amount (with respect to the compound of Formula 4 is in the range of 0.05 to 0.2 equivalent, Preferably, 0.1 equivalent) of 4-di(methylamino)pyridine can be used. Depending on P ₂ to be introduced, the reaction solvent, reagent, temperature conditions, etc. may be different. For example, when P ₂ is a t-butyl group, 1.0 to 2.0 equivalents of di-tert-butyldicarbonate is used, and the third step is performed in a temperature range of about room temperature to 60°C, preferably 40°C to 50°C. Can be done.

In the oxazolidinone decyclization reaction of the fourth step, the compound of Formula 3 having the oxazolidinone structure and the nitrogen raw material compound are reacted and decyclized to obtain the compound of Formula 2 as an amide compound. At this time, as the reaction solvent, a solvent selected from the group consisting of t-butyl alcohol, methyl alcohol, ethyl alcohol, n-butyl alcohol and n-propanol may be used, and preferably, the reaction rate is shortened and the generation of impurities is minimized. Isopropyl alcohol can be used. It is preferable to use ammonia water (25% to 30% concentration) as the nitrogen raw material compound, and the amount used is 1.0 fold (fold: ml/g) or more, preferably 1.2 to 1.5 folds for the compound of Formula 2 In addition, ammonia gas may be used, and in this case, the amount used is preferably 1.0 to 2.0 equivalents based on the compound of Formula 2. The reaction temperature is in the range of reflux at room temperature, and is preferably 60°C to 80°C in consideration of the generation of impurities and reaction rate. After completion of the reaction, the reaction solvent may be removed by distillation under reduced pressure, and extraction may be performed using toluene or ethyl acetate as an extraction solvent. Thereafter, after washing in an aqueous sodium hydroxide solution and an aqueous hydrochloric acid solution, the extraction solvent is distilled under reduced pressure to obtain a high purity compound of Formula 2.

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.

The preparation method according to the present invention provides the compound of Formula 2, which is an intermediate for oral insulin-independent diabetes treatment through inhibition of DPP-IV, 1) high purity through oxazolidinone cyclization reaction and decyclization reaction to convert to amide. It is very useful because it has the advantage of being able to achieve improvement effects such as reduction of raw material costs by using 2) increased yield and productivity through stabilization of the manufacturing process, and 3) using cheap starting materials for samples. .

Example 1: Synthesis of N-(t-butoxycarbonyl)-L-aspartic acid (N-(tert-butoxycarbonyl)-L-aspartic acid)

500 kg of starting material L-aspartic acid, 785 kg of isopropyl alcohol, 250 kg of H ₂ O, and 760.3 kg of triethylamine were added to the reactor at room temperature, and then di-tert-butyldicarbonate while maintaining the reaction temperature at 40 ^o C. 901.9 kg was slowly added dropwise. After the reaction was completed, it was cooled to room temperature, and 740 kg of methyl tert-butylmethyl ether (MTBE), 19.7% NaOH aqueous solution was added dropwise while maintaining a temperature of 20° C. or less so that the pH was 9, followed by stirring and layer separation. The aqueous layer was washed once more with 1110 kg of tert-butylmethyl ether and the layers were separated. A 17.9% aqueous hydrochloric acid solution was added dropwise while maintaining a temperature of 20 ^o C or less so that the pH was about 3, stirred, and the layers were separated, and the organic layer was distilled under reduced pressure to prepare 832.3 kg of the title compound. (Yield: 95%)

¹ H NMR (DMSO-d6, 300 MHz) δ 12.5 (br, 2 H), 6.97 (d, J = 8.4 Hz, 1 H), 4.24 (m, 1 H), 2.65 (dd, J = 16.3,5.6 Hz, 1 H), 2.50 (dd, J = 16.0, 7.9 Hz, 1 H), 1.36 (s, 9 H)

Example 2: 2-[(4S)-3-(t-butyloxycarbonyl)-5-oxo-1,3-oxazolan-4-yl]acetic acid (2-[(4S)-3-(tert Synthesis of -butyloxycarbonyl)-5-oxo-1,3-oxazolan-4-yl]acetic acid)

The starting material prepared in Example 1 N-(t-butoxycarbonyl)-L-aspartic acid 832.3 kg, toluene 3294.6 kg, ethyl acetate 2118.2 kg, formaldehyde 214.3 kg, pyridinium-p-toluenesulfonate (PPTS ) 9.44 kg and 217.2 kg of magnesium sulfate (MgSO ₄ ) were added at room temperature, the temperature was raised, and the reaction was carried out under reflux. At this time, the water generated during the reaction affects the completion of the reaction and the yield, so it was carried out with a Dean-stark facility. After completion of the reaction, magnesium sulfate was removed by filtration, and the filtrate was washed with 762.5 kg of ethyl acetate and 879.8 kg of a 15.5% aqueous ammonium chloride solution to separate layers. The organic layer was washed and layered with 737 kg of water, and the organic layer was distilled under reduced pressure and recrystallized in a toluene/ethyl acetate mixed solvent ratio of 8 to 9/1 (v/v) in consideration of the ethyl acetate content of the concentrate. Thus, the title compound formed as a solid was filtered, washed with toluene, and dried to prepare 673.9 kg of the title compound. (Yield: 77%)

¹ H NMR (DMSO-d6, 500 MHz) δ 12.8 (br, 2 H), 5.42 (s, J = 1 H), 5.16 (s, 1 H), 4.41 (s, 1 H), 2.79 (m, 1H), 1.47 (s, 9H)

Example 3: t-butyl (4S)-4-(t-butyloxycarbonylmethyl)-5-oxo-1,3-oxazolane-3-carboxylate (tert-butyl (4S)-4-( Synthesis of tert-butyloxycarbonylmethyl)-5-oxo-1,3-oxazolane-3-carboxylate)

In the reactor, 650 kg of 2-[(4S)-3-(t-butyloxycarbonyl)-5-oxo-1,3-oxazolan-4-yl]acetic acid prepared in Example 2, t-butyl alcohol 906.8 kg and 32.4 kg of 4-dimethylaminopyridine (DMAP) were added, and 578.5 kg of di-tert-butyldicarbonate was slowly added dropwise at 40 ^° C., and the temperature was raised to a range of 45 to 55 ^° C. and stirred for 1 hour or more. After performing the analysis to confirm the completion of the reaction, if not completed, di-tert-butyldicarbonate was additionally added to complete the reaction. After completion of the reaction, distillation under reduced pressure to remove t-butyl alcohol, and to prevent formation of t-butyl alcohol crystals in the cooling condenser as t-butyl alcohol is distilled, add 350 kg of ethyl acetate and complete the distillation under reduced pressure, and then ethyl acetate 1750. kg was added and a 5.3% aqueous ammonium chloride solution was added at 25 ^o C or less, followed by stirring, layer separation, and distillation under reduced pressure of the organic layer. The title compound obtained was immediately used in the next reaction step.

DP09: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.44 (s, 9H), 1.54 (s, 9H), 2.96 (m, 1H), 4.41 (s, 1H), 5.27, (d, J = 4.0 Hz, 1H), 5.41 (d, J =4.0 Hz, 1H).

Example 4: Synthesis of t-butyl (3S)-3-butoxycarbonylamino-3-carbonylpropaneoate

T-butyl (4S)-4-(t-butyloxycarbonylmethyl)-5-oxo-1,3-oxazolane-3-carboxylate and isopropyl alcohol 2824.4 kg and 28% ammonia obtained in Example 3 After adding 719.6 kg of aqueous solution, the mixture was stirred at 70 ^o C for at least 5 hours. After completion of the reaction, distillation was performed under reduced pressure, 2075.5 kg of ethyl acetate was added to the concentrate, stirred, and 650 kg of purified water, 125 kg of ethyl acetate, and 325 kg of a 3.84% sodium hydroxide aqueous solution were added/stirred/settled and the layers were separated, and the organic layer was 650 purified water. kg, after washing with 324.7 kg of 3.6% aqueous hydrochloric acid solution, layer separation and concentration were performed to obtain 580.8 kg of the title compound. (Final Yield: 76%)

DP56: ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.29 (s, 18H), 2.64 (dd, J =6.0, 16.8 Hz, 1H), 2.83 (dd, J =5.2, 16.4 Hz, 1H), 4.48 ( bs, 1H), 5.79 (br d, J =7.6 Hz, 1H), 6.06 (bs, 1H), 6.63 (bs, 1H).

Claims (17)

1) introducing a protecting group P ₁ to the amine group of the compound of Formula 6 to obtain a compound of Formula 5 in which the amine group is protected;
2) obtaining a compound of formula 4 through a cyclization reaction through a condensation reaction under an acid catalyst to the compound of formula 5 produced in step 1);
3) converting the carboxylic acid group into an ester group by introducing a protecting group P ₂ to the carboxylic acid group of the compound of Formula 4 produced in step 2) to obtain a compound of Formula 3; And
4) obtaining an amide compound of Formula 2 through oxazolidinone decyclization by reacting with a nitrogen raw material compound of the compound of Formula 3 produced in step 3),
Method for preparing a compound of Formula 2 comprising:

[Formula 6]

[Formula 5]

[Formula 4]

[Formula 3]

[Formula 2]

In the above formula,
P ₁ is an amine protecting group, which is a carbonyl group, an acyl group, a sulfonyl group, an acetyl or benzyl group,
P ₂ is a carboxylic acid protecting group. The method of claim 1, wherein P ₁ is Boc (butyloxycarbonyl), Cbz (benzyloxycarbonyl) or Fmoc (9-fluorenylmethyloxycarbonyl). The method of claim 1, wherein the P ₂ group is a benzyl group, a methyl group, an ethyl group, an i-propyl group or an i-butyl group. The method of claim 1, wherein step 1) is one selected from triethylamine, N,N-diisopropylethylamine, lithium t-butoxide, potassium t-butoxide, sodium t-butoxide, and sodium hydroxide. To use the above reaction base, the production method. The method of claim 4, wherein the reaction base is used in the amount of 2 to 3 equivalents based on the compound of Formula 6. The method of claim 1, wherein the step 1) comprises at least one organic solvent selected from the group consisting of isopropyl alcohol, ethyl alcohol, dichloroethane, dichloromethane, tetrahydrofuran, and dioxane, or a mixed solvent of the organic solvent and water. To use a reaction solvent, the production method. The method according to claim 1, wherein step 2) is performed through a condensation reaction by reacting paraformaldehyde with a compound of Formula 5 under an acid catalyst. The method of claim 1, wherein step 2),
(1) paraformaldehyde; Paratoloenesulfonic acid (p-TsOH)-H ₂ O as an acid catalyst; And toluene or ethyl acetate-benzene as a reaction solvent, or
(2) paraformaldehyde; Pyridium- p -toluenesulfonate (PPTS, Pyridium- p- toluenesulfonate) as an acid catalyst; And toluene-ethylacetate as a reaction solvent. The method of claim 1, further comprising obtaining a solid compound of Formula 4 by recrystallization in a mixed solvent of ethyl acetate and toluene after completion of the reaction in step 2). The method of claim 1, wherein the step 3) uses a single solvent of t-butyl alcohol, isopropyl alcohol, ethyl alcohol, methyl alcohol or tetrahydrofuran, or a mixed solvent obtained by mixing two or more of the solvents as the reaction solvent. Phosphorus, manufacturing method. The method of claim 1, wherein the step 3) uses 4-dimethylaminopyridine (DMAP) as a catalyst. The method of claim 11, wherein the catalyst is used in an amount of 0.05 to 0.2 equivalents based on the compound of Formula 4. The method of claim 1, wherein step 3) is performed at a reaction temperature of room temperature to 60°C. The method of claim 1, wherein the step 4) uses at least one reaction solvent selected from the group consisting of t-butyl alcohol, methyl alcohol, ethyl alcohol, n-butyl alcohol, n-propanol and i-propanol. , Manufacturing method. The method of claim 1, wherein step 4) is performed at a reaction temperature in the range of 60 to 80°C. Compounds of Formula 4:

[Formula 4]

In the above formula,
P ₁ represents an acyl group, a sulfonyl group, an acetyl or benzyl group. Compounds of Formula 3:

[Formula 3]

In the above formula.
P ₁ is an acyl group, a sulfonyl group, an acetyl or benzyl group;
P ₂ represents a benzyl group, a methyl group, an ethyl group, an i-propyl group or a t-butyl group.