WO2019066578A1

WO2019066578A1 - Process for preparing intermediate compound for pharmaceutical synthesis

Info

Publication number: WO2019066578A1
Application number: PCT/KR2018/011565
Authority: WO
Inventors: 이석주; 김봉찬; 박애리; 류인애; 박종원
Original assignee: 주식회사 엘지화학
Priority date: 2017-09-28
Filing date: 2018-09-28
Publication date: 2019-04-04
Also published as: MX2020003543A

Abstract

The present invention relates to a process for preparing a compound of formula 2 that is an intermediate used to synthesize a dipeptidyl peptidase IV enzyme-inhibiting therapeutic agent for treating diabetes mellitus, which (1) can be produced in high purity through an oxazolidinone cyclization reaction and a decyclization reaction of converting the same into amide, (2) can lead to an increase in yield and productivity through stabilization of a production process, and (3) can achieve an improved effect, such as reduction of raw material costs, by using an inexpensive material as a starting material.

Description

DESCRIPTION OF THE INVENTION

Title of the Invention

Method for producing intermediate compound for pharmaceutical synthesis

TECHNICAL FIELD

Cross-reference with related application (s)

This application claims the benefit of priority based on Korean Patent Application No. 10-2017-0126119 filed on September 28, 2017, and Korean Patent Application No. 10-2018-0115838 filed on September 28, 2018, The entire contents of which are incorporated herein by reference.

The present invention relates to a method for producing a compound represented by the following formula (2), which is an essential intermediate for synthesizing a therapeutic agent for inhibiting dipeptidyl peptidase IV (hereinafter also referred to as 'DPP-IV'), The present invention relates to novel compounds of formula (III) and (IV) which are produced as adenosine. TECHNICAL BACKGROUND OF THE INVENTION

The dipeptidyl peptidases disclosed in WO < RTI ID = 0.0 > 06/104356 &

IV (DPP-IV) inhibitory compounds (see the compound of formula (1) of WO 06/104356) exhibit excellent inhibitory activity against DPP-IV enzyme and are useful for the treatment of diabetes, Obesity and the like can be effectively used for treatment and prevention. In the preparation of such DPP-IV inhibitor compounds, International Publication WO010 / 104356 discloses a process for preparing from compounds of formula 1 as essential intermediates.

4-ieri-Buty 1 (25) 1-2-feri-butoxycarbony 1 amino-2-carbaldehyde, which is commercially available for the preparation of the compound of formula (2) butaned ioate is disclosed in Korean Patent Application No. 10-2010-0086619, but it has been found that 1) the production process is not suitable for commercial mass production, 2) the production cost due to the high unit price and low yield, There was a problem that became the main factor of the rise. DISCLOSURE OF THE INVENTION

[Problem to be solved]

The present inventors have intensively studied to solve the above-mentioned disadvantages of the prior art, and developed a technique of introducing a protecting group (P ₂ ) into a carboxylic acid group through the introduction of an amine protecting group () and a cyclization reaction. In addition, o ^'l These were the intermediates were found to complete the present invention that a new compound per se produced in the manufacturing process. Specifically, the following reaction formula 1 is given:

However,

2

In order to solve the above-mentioned problems in the prior art, the present inventors attempted to synthesize the compound of the formula (2) from the compound of the formula (6) which is inexpensive.

The route pathway 1) {Chem. Co Hidden. , 2001, 1710-1711), 1) a low yield of 30 to 34%, 2) the use of raw materials such as thionyl chloride and ammonia gas, 3) low temperature reaction, (Pathway 2), the advantage of being able to obtain the compound of Formula 2 with a mild reaction condition and a high yield of 57 to 61% can be obtained.

Accordingly, the present invention provides a method for preparing a compound of formula (2), which is an essential intermediate for preparing a compound of formula (1), which is an intermediate used for synthesizing a therapeutic agent for DPP-IV inhibiting diabetes, in an economical and high yield, The purpose is to provide.

MEANS FOR SOLVING THE PROBLEMS In order to solve the above problems, the present invention provides:

1) introducing a Pi group to an amine group of the following formula 6 compound to obtain a compound of formula 5 wherein the amine group is protected;

2) obtaining a compound of formula (IV) via cyclization reaction via condensation reaction under acid catalysis to the compound of formula (5) produced in step 1);

3) introducing a P ₂ group to the carboxylic acid group of the compound of formula 4 produced in step 2) to convert the carboxylic acid group to an ester group to obtain a compound of formula 3; And

4) reacting with the nitrogen source compound of the compound of formula 3 produced in step 3) to obtain the amide compound of formula 2 via oxazolidinone decarboxylation,

It relates to a process for the preparation of ⁷ and formula (2) compound comprising:

[Chemical Formula

Wherein Pi is a carbonyl group as an amine protecting group. (Butyloxycarbonyl), cbz (benzyloxycarbonyl) or Fmoc (9-fluorenylmethyloxycarbonyl), which may be selected from an acyl group, a sulfonyl group, an acetyl group or a benzyl group, 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 an i - butyl group, more preferably a t - butyl group.

【Effects of the Invention】

The preparation method according to the present invention is a process for preparing a compound of the formula (2), which is an intermediate for the treatment of non-insulin-dependent diabetes mellitus through DPP-IV inhibition, through a decarboxylation reaction which converts 1) an oxazolidinone cyclization counterpart and an amide, Can produce. 2) it is possible to increase the yield and productivity by stabilizing the manufacturing process, and 3) to use the starting material of the inexpensive sample to reduce the raw material cost.

DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, the present invention will be described in detail based on the reaction formula. It should be understood, however, that the following description is intended to assist the understanding of the present invention, and is not intended to limit the invention in any way. The preparation method according to the present invention will be described in detail as follows.

[Reaction Scheme 2]

The antimony base used in the first stage of the protective vaporization reaction of the above-mentioned Biological Formula 2 is triethylamine, N, Hunig's base, lithium t-appendoxal potassium t-appendicide sodium t-appendix Sodium hydroxide and sodium hydroxide. Preferably, triethylamine is used. The amount of the reaction base to be used is preferably 1.0 equivalents or more, particularly 2.0 to 3.0 equivalents relative to the compound of formula (VI). In addition, as the anti-humectant solvent, one or more kinds of organic solvents which can be commonly used in organic solvents such as isopropyl alcohol, ethyl alcohol, dichloroethane, dichloromethane, tetrahydrofuran acetone and dioxane can be selected and used. Co-solvent and the like can be used. Especially preferred are isopropyl alcohol and water miscible solvents. In a specific embodiment, 1) when introducing a butyloxycarbonyl or an acetyl group as Pi, di-tert-butyl dicarbonate (Boc anhydride) or acetic anhydride; Bases such as triethylamine (TEA), N, N-diisopropylethylamine (Hunig's base); As banung solvent dichloroethane, dichloromethane, cyclization ether (e.g., tetrahydrofuran (THF), dioxane (dioxane)), isopropanol (IPA) / H ₂ 0 heunhap solvent or in THF / H ₂ 0 heunhap solvent can be used When Fmoc (9-Fluorenylmethoxycarbonyl) group is introduced as Fmoc-Cl as a base, sodium carbonate (aq Na ₂ CO ₃ ) as a base; Dioxane can be used as a vanoy solvent, and 3) P l 4-Nitrobenzenesulfonyl chloride (Ns-Cl) when it is 4-nitrobenzenesulfonyl (Ns); Bases such as triethylamine or N, N-diisopropylethylamine, sodium hydroxide and the like; Acetone may be used as an anti-solvent; 4) benzyl chloroformate when P 1 is carboxyl benzyl (Cbz); sodium bicarbonate (NaHCO ₃ ) as a base; Tetrahydrofuran / water can be used as an anti-solvent.

Preferably, the use of di-tert-butyl dicarbonate for protecting with < RTI ID = 0.0 > nubyloxycarbonyl < / RTI > as is preferable from the viewpoint of yield and the amount used is 1.0 equivalent or more, particularly 1.0 to 1.3 equivalent desirable. In addition, the equivalents apply equally to compounds for introducing other protecting groups, i.e., acetic anhydride, Fnioc-Cl, acetyl anhydride and benzyl chloropermates.

The second step of the cyclization reaction is carried out by condensation with paraformaldehyde in the presence of an acid catalyst. Specifically, 1) paraformaldehyde, para-toluenesulfonic acid (p-TsOH) (2) paraformaldehyde, pyridium-P-, or rubenesulfonate (PPTS, Pyr idi Lim-1 toenesu 1 plantate) under the conditions of Compound can be obtained. From the viewpoint of safety and economical efficiency, it is preferable to use pyruvate-P- as the acid catalyst and ruben-ethylacetate co-solvent as the vanoy solvent. In particular, rhythm-P- and rubenesulfonate are used in an amount of 0.005 equivalent or more, preferably 0.01 to 0.02 equivalents, based on the compound of formula (5). The resulting compound of formula (IV) as a result of the reaction of step 2 can be obtained in the form of a solid compound of high purity by recrystallization of ethyl acetate / in a racemate solvent. Regarding the blending ratio of the recrystallization solvent, the resulting compound of formula (IV) can be carried out in a mixed solvent of ethyl acetate and rubrene in a volume ratio of 1: 7 to 1:10, preferably 1: 8 to 1: 9 < / RTI > volume ratio.

In the esterification reaction of the third step, P ₂ is introduced into the compound of formula (4), and the carboxylic acid group is converted to the ester group to produce the compound of formula (3). In this case, a single solvent such as t-butyl alcohol isopropyl alcohol, ethyl alcohol, methyl alcohol or tetrahydrofuran, or a common solvent thereof, is used, and the amount of the catalyst (0.05 to 0.2 equivalent weight, 0.1 equivalents) of 4-di (methylamino) pyridine can be used. Depending on the p ₂ to be introduced, the solvent, reagent, and temperature conditions may be different. For example, when P ₂ is a t-butyl group, 1.0 to 2.0 equivalents of di-tert-butyl dicarbonate are used, and the temperature is in the range of about room temperature to about 60 ^° C, preferably in the range of 4 rc to 5 In the oxazolidinone decarboxylation reaction of the fourth step, the compound of Formula 3 of the oxazolidinone structure and the nitrogen source compound are deblocked to yield the compound of Formula 2, which is an amide compound. , A solvent selected from the group consisting of t-butyl alcohol, methyl alcohol, ethyl alcohol, n-butyl alcohol and n-propanol may be used as the anti-Wong solvent, and preferably, the reaction rate is shortened and the generation of impurities is minimized It is preferable to use ammonia water (25% to 30% concentration) as the nitrogen source compound and the amount of the nitrogen source compound used is 1.0 Preferably, 1.2 to 1.5 folds is used, and ammonia gas may be used. In this case, the amount to be used is preferably 1.0 to 2.0 equivalents relative to the compound of formula (2) The reaction temperature is preferably in the range of reflux at room temperature and is preferably between 60 ^° C and 80 ^° C in consideration of the formation of impurities and the reaction rate. After completion of the reaction, the reaction mixture is distilled off under reduced pressure, After washing in an aqueous sodium hydroxide solution and an aqueous hydrochloric acid solution, a high-purity compound of formula (2) can be obtained by distilling off the extraction solvent under reduced pressure. It is to be understood, however, that the scope of the invention is not limited in any way to the understanding of the invention.

EXAMPLES Example 1 Synthesis of N- (t-butoxycarbonyl) -L-aspartic acid (N- (tert-butoxycarbonyl) -L-aspart ic acid)

HO ₂ --CO ₂ H

0 NHBoc

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 at room temperature to the semi-annular stage, 901.9 kg of di-tert-butyl dicarbonate was slowly added dropwise while maintaining the temperature. After completion of the reaction, the mixture was stirred at room temperature and 740 kg of methyl tert-butyl methyl ether (MTBE) and 19.7% NaOH aqueous solution were added dropwise while maintaining the temperature below 20 ^° C so that the pH became 9, followed by layer separation . The aqueous layer was washed once with 1110 kg of tert-butyl methyl ether and layered. A 17.9% hydrochloric acid aqueous solution was added dropwise while maintaining the temperature below 20 ^° C so that the pH was about 3, and the mixture was stirred. The organic layer was separated by vacuum distillation to obtain 832.3 kg of the title compound. (Yield: 95%).

J = 8.4 Hz, 1H), 4.24 (m, 1H), 2.65 (dd, J = 16.3, 5.6 Hz, 1H) , 2.50 (dd, J = 16.0, 7.9 Hz, 1H), 1.36 (s, 9H). Example 2: Synthesis of 2 - [(4S) -3- (tert- butyloxycarbonyl) -5 -Oxo-1,3-oxazolan-4-yl] acetic acid (2 - [(4S) -3- (tert- butyloxycarbonyl) -5-oxo-1,3-oxazo lan- synthesis

832.3 kg of the starting material N- (t -exocycarbonyl) -L-aspartic acid prepared in Example 1, 3294.6 kg of ruben, 2118.2 kg of ethyl acetate, 214.3 kg of formaldehyde, (PPTS) to the elevated temperature and then added to 9.44 kg and a magnesium sulfate (MgS0 ₄₎ 217.2 kg at room temperature to proceed the reaction under reflux. At this time, the water produced in the reaction was subjected to the Dean-stark facility because it affects the completion of the reaction and the yield. After completion of the reaction, the magnesium sulfate was removed by filtration, and the filtrate was separated by washing with 762.5 kg of ethyl acetate and 879.8 kg of 15.5% ammonium chloride aqueous solution. The organic layer was washed and layered using 737 kg of water and the organic layer was subjected to a recrystallization process at a ratio of 8 to 9/1 (v / v) of toluene / ethylacetate free solvent in consideration of the ethyl acetate content of the concentrate after distillation under reduced pressure The title compound was isolated by filtration, washed with toluene and dried to give 673.9 kg of the title compound. (Yield: 77%)

1 H NMR (DMSO-d 6, 500 MHz)? 12.8 (br, 2 H), 5.42 (s, J = Example 3 Synthesis of t-butyl (4S) -4- (t-butyloxycarb) 2, (4S) -4- (tert-butyloxycarbonylmethyl) -5-oxo-1,3-oxazo 1 ane-3- carboxy 1 at e) synthesis

650 kg of 2 - [(4S) -3- (t-butyloxycarbonyl) -5-oxo-1,3-oxazolan-4-yl] acetic acid prepared in Example 2, 906.8 kg of alcohol and 32.4 kg of 4-dimethylaminopyridine (DMAP) were added. 578.5 kg of di-tert-butyl dicarbonate was slowly added dropwise at 40 ^° C, and the mixture was heated to 45 to 55 ^° C and stirred for 1 hour or more. Analysis was performed to confirm the end of the reaction. When the reaction was not completed, di-tert-butyl dicarbonate was added to complete the reaction. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove t-butyl alcohol. In order to prevent t-butyl alcohol from being distilled off and t-butyl alcohol crystals from being formed in the condenser, 350 kg of ethyl acetate was added, kg, and 5.3% ammonium chloride aqueous solution was added thereto at 25 ^° C or lower. The mixture was stirred and separated, and the organic layer was subjected to vacuum distillation. The resulting compound was used in the next reaction step.

DP09: ¾隱(400 MHz, DMS0-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, 1 H), 5.41 (d, J = 4.0 Hz, 1 H). Example 4: Synthesis of t-butyl (3S) -3-butoxycarbonylamino-3-carbonylpropanoate (tert-butyl (3S) -3-butoxycarbonylamino-3-carbonylpropaneoate).

T-butyl (4S) -4- (t-butyloxycarbonylmethyl) -5-oxo- 1, 3-oxazolane-3-carboxylate, 2824.4 kg of isopropyl alcohol and 719.6 kg of 28% ammonia aqueous solution, and the mixture was stirred at 70 ^° C for 5 hours or longer. After the reaction was completed, distillation under reduced pressure was carried out. 2075.5 kg of ethyl acetate was added to the concentrate and stirred. Then, 650 kg of purified water, 125 kg of ethyl acetate, and 325 kg of 3.84% aqueous sodium hydroxide solution were added thereto / stirred / kg, 3.6% aqueous hydrochloric acid solution (324.7 kg), followed by layer separation and concentration to obtain 580.8 kg of the title compound. (Final yield: 76%)

DP56: ¾ NMR (400丽z , CDC1 3) δ 1.29 (s, 18H), 2.64 (dd, /=6.0,

1H), 6.63 (bs, 1H), 4.79 (bs, 1H), 2.83 (dd, J = 5.2,16.4 Hz, 1H).

Claims

Claims:

Claim 11

1) introducing a protecting group ^ to the amine group of the compound of Formula 6 to obtain a compound of Formula 5 wherein the amine group is protected;

3) introducing a protecting group P ₂ into the carboxylic acid group of the compound of formula 4 produced in step 2) to convert the carboxylic acid group into an ester group to obtain a compound of formula 3; And

4) reacting with the nitrogen source compound of the compound of formula 3 produced in step 3) to obtain an amide compound of formula 2 via oxazolidonate cyclization,

: &Lt; / RTI >

(3)

In this formula,

Pi is an amine protecting group such as a carbonyl group, an acyl group, a sulfonyl group, an acetyl or benzyl group _,

P ₂ is a carboxylic acid protecting group.

[Claim 2]

The method of claim 1, wherein Pi is Boc (butyloxycarbonyl), Cbz

(Benzyloxycarbonyl) or Fnioc (9-fluorenylmethyloxycarbonyl).

[3]

The production method according to 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.

Claim 4

The method of claim 1, wherein the step 1) is one or more selected from the group consisting of triethylamine, N, N-diisopropylethylamine, lithium t-heptoxide, potassium t -specificide, sodium t- By weight, based on the total weight of the composition.

[Claim 5]

The process according to claim 4, wherein said base is used in an amount of 2 to 3 equivalents based on the compound of formula (VI).

[Claim 6]

The method according to claim 1, wherein the step 1) is carried out by using one or more organic solvents selected from the group consisting of isopropyl alcohol, ethyl alcohol, dichloroethane, dichloromethane, tetrahydrofuran and dioxane, Wherein the solvent is an organic solvent.

[7]

The process according to claim 1, wherein the step 2) is carried out through condensation reaction by reacting paraformaldehyde with the compound of formula (5) under an acid catalyst.

8.

The method of claim 1, wherein step (2)

(1) paraformaldehyde; Para-toluenesulfonic acid (p-TsOH) -H ₂ O as an acid catalyst; And < RTI ID = 0.0 > ethane < / RTI > acetate-

(2) paraformaldehyde; As an acid catalyst, pyridyl-p-toluenesulphonate (PPTS, Pyridinium-toluenesulphonate); And ruben-ethylacetate as an anti-solvent.

9]

^3. The process according to claim 1, further comprising recrystallizing ethyl acetate and an enantiomeric solvent after completion of the reaction in step 2) to obtain the solid compound of formula (4).

[Claim 10]

[2] The method according to claim 1, wherein the step 3) comprises using a single solvent of t-butyl alcohol, isopropyl alcohol, ethyl alcohol, methyl alcohol or tetrahydrofuran, Lt; / RTI >

Claim 11

The process according to claim 1, wherein said step 3) uses 4-dimethylaminopyridine (DMAP) as a catalyst.

Claim 12

12. The process according to claim 11, wherein the catalyst is used in an amount of 0.05 to 0.2 equivalents based on the compound of formula (IV).

Claim 13

2. The method of claim 1, wherein step (3) is carried out at room temperature to 60 ^° C.

14.

The method according to claim 1, wherein said step (4) is one using at least one unoccurring solvent selected from the group consisting of t-butyl alcohol, methyl alcohol, ethyl alcohol, n-butyl alcohol, n-propane and i- .

[15] 2. The method of claim 1, wherein step 4) is a method of manufacturing is performed in banung temperature of 60 to 80 ^o C range.

16. The method of claim 16,

A compound of formula 4:

In this formula,

A Pr carbonyl group, an acyl group, a sulfonyl group, an acetyl group or a benzyl group. 17.

A compound of formula (3)

Gt;

Pr & is a carbonyl group, an acyl group, a sulfonyl group, an acetyl or benzyl group; And

P2 represents a benzyl group, a methyl group, an ethyl group, an i-propyl group or a t-butyl group.