KR20180118054A - Production Method of Intermediate Compound for Synthesizing Medicament - Google Patents

Abstract

The present invention relates to a manufacturing method which produces chemical formula 1 with ultimately high yield and purity by manufacturing a compound of chemical formula 2 under a mild condition, wherein the compound of chemical formula 2 is necessarily used to manufacture a compound of chemical formula 1, intermediate, used to synthesize a treatment for diabetes inhibiting dipeptidyl peptidase IV enzymes. In above formulas, R1, R2, R3, R4, R5 and P_1 are defined in the specification.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for preparing an intermediate compound for synthesis of a medicament,

The present invention relates to a method for efficiently producing an amidine compound which is essentially used for preparing a dihydropyridopyrimidine intermediate compound used for synthesizing a dipeptidyl peptidase IV (hereinafter also referred to as "DPP-IV") inhibiting diabetes therapeutic agent .

Compounds useful as therapeutic agents for the inhibition of dipeptidyl peptidase IV (DPP-IV) inhibition of diabetes mellitus as disclosed in International Application Publication No. WO 06/104356 (see the compound of formula 1 of WO 06/104356) DPP-IV enzyme, and is known to be effectively used for the treatment and prevention of diabetes, obesity and the like caused by the enzyme. In the preparation of such DPP-IV inhibitor compounds, International Publication WO 06/104356 discloses a process for the preparation of compounds of formula (I) as core intermediates (see International Application Publication No. WO 06/104356, Scheme 1) This method has a problem that a substance of the following formula (2), which is essentially used for preparing the compound of formula (1), is an expensive substance. In addition, various methods for converting amide to amidine are known in the literature and can be roughly divided into two methods. One is by the condensation of amides and amines in the presence of a dehydrating reagent (such as phosphorus pentoxide) and the other is by adding amines to the activated amides using strong electrophiles such as trifluoromethanesulfonic anhydride (triflic anhydride) , There is a disadvantage that these reactions are mostly undesirable in terms of production since they occur under vigorous conditions.

Disclosure of the Invention The present invention has been made in order to solve the above-mentioned problems, and it is an object of the present invention to provide a compound of formula (2), which is an essential intermediate for preparing a compound of formula (1) The present invention provides a method for providing a plurality of data streams.

In one aspect for solving the above object, the present invention provides a DPP-IV inhibitor, which is essentially used to prepare the compound of formula (I) used as a core intermediate of the compound disclosed in WO 06/104356, Lt; RTI ID = 0.0 > formula:

[Chemical Formula 1]

(2)

In this formula,

R1 is hydrogen or CF ₃ and;

R2 is hydrogen, a substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₈ aryl And substituted and unsubstituted C ₃ -C ₇ heteroaryl;

R3, R4 and R5 each independently represent hydrogen, substituted or unsubstituted C ₁ -C ₄ alkyl;

P ₁ represents an amine protecting group, preferably t-butyloxycarbonyl.

When C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl and C ₃ -C ₇ heteroaryl are substituted, those substituted with a halo group or a hydroxy group are preferred, and C ₄ -C ₈ aryl Is substituted with a halo group, a hydroxy group, or a substituted or unsubstituted C ₁ -C ₄ alkyl group (which may be substituted with a halo group or a hydroxy group).

The heteroaryl may include one or more hetero atoms selected from the group consisting of N, O and S, and preferable examples thereof include 2-furan, 3-furan, 2-thiophene, Pyridine, 3-pyridine, 4-pyridine, 2-pyrrole, 3-pyrrole and the like, which may be substituted as defined above.

The process for preparing the compound of formula (2) is carried out by converting the compound of formula (4) into the compound of formula (3) and then continuously producing the compound of formula (2) under ammonia conditions.

Specifically, in the production process according to the present invention, the conversion of the compound of formula (4) to the compound of formula (3) (step 1) can be carried out by reacting the compound of formula (4) with pyridine and / or dichloromethane, methanesulfonyl chloride ) And trifluoroacetic anhydride (TFAA), and then reacting the compound of formula (III), which is produced in gaseous form, with an ammonia solution in succession to produce the compound of formula (Step 2). The reaction in each of these steps is as shown in Scheme 1.

[Reaction Scheme 1]

In this formula,

R2 is hydrogen, a substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₈ aryl, and substituted and unsubstituted C ₃ -C ₇ heteroaryl. ≪ / RTI >

Hereinafter, the production method of the present invention according to Reaction Scheme 1 will be described in more detail.

In the first step of Reaction Scheme 1, the compound of Formula 4 used in the preparation of the compound of Formula 3 may be, for example, trifluoroacetamide. Compounds of formula 4, such as trifluoroacetamide, may be reacted with methanesulfonyl chloride (MsCl), trifluoromethanesulfonyl chloride (TfCl), toluenesulfonyl chloride (TsCl) and the like, in the presence of pyridine and / or dichloromethane Bromo benzene sulfonyl chloride (BsCl), preferably methanesulfonyl chloride, and trifluoroacetic anhydride (TFAA), to form trifluoroacetamide trifluoromethyl acetonitrile is replaced with (CF ₃ CN) the amide group of the formula (4) produced in the nitrile compound of formula (3) is generated;

In the second step of preparing the compound of formula 2, the ammonia solution is preferably an ammonia solution contained in a solvent selected from the group consisting of isopropyl alcohol, ethyl alcohol and methyl alcohol, preferably ammonia isopropyl alcohol Is reacted with a compound of the formula (3) prepared in the first step to obtain a compound of the formula (2). In a preferred embodiment, in the second step, the compound of Formula 3 prepared in the first step may be in the form of a gas, and a compound of Formula 3 (e.g., trifluoronitrile gas (CF ₃ CN, gas) is bubbled into the ammonia solution and reacted to obtain the compound of formula (2). In the case of using ammonia isopropyl alcohol, especially ammonia solution, there is a problem that the yield of the reaction is lowered when the compound of the formula (1) is subsequently reacted with the compound of the formula (5) continuously without going through the purification process The compound of formula (1) can be prepared at an excellent reaction yield.

In another aspect, the present invention relates to a process for the preparation of a compound of formula (1) comprising the following steps:

(a) converting the compound of formula 4 into a compound of formula 3;

(b) reacting the compound of formula (3) prepared in step (a) with an ammonia solution to prepare the compound of formula (2); And

(c) cyclizing the compound of formula (5) and the compound of formula (2) prepared in step (b) to prepare a compound of formula (1).

The above steps (a) and (b) are as shown in Reaction Scheme 1, and Step (c) is as shown in Reaction Scheme 2 below.

[Reaction Scheme 2]

In this formula,

R1 is hydrogen or CF ₃ and;

R2 is hydrogen, a substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₈ aryl, and substituted and unsubstituted C ₃ -C ₇ heteroaryl;

R3, R4 and R5 each independently represent hydrogen, substituted or unsubstituted C ₁ -C ₄ alkyl;

P ₁ represents an amine protecting group, preferably t-butyloxycarbonyl.

Each step will be described in detail below.

The above steps (a) and (b) are all the steps of preparing the compound of formula (2), which can be carried out by applying the same method as the compound of formula (2).

Step (c) is a step of reacting the compound of the formula (5) with the compound of the formula (2) to obtain the compound of the formula (1). Specifically, the compound of the formula (5) Is used singly or in combination, or under a condition that does not include all of the above-mentioned substances, a cyclization reaction is carried out to obtain a compound of formula (1). In this case, it is preferable that the base is composed of C ₁ -C ₄ trialkylamine, diisopropylethylenediamine (DIPEA, Hunig's base), pyridine, K ₂ CO ₃ , KOH, NaOH, NaOMe, NaOEt, Cs ₂ CO ₃ and LiOH In addition, the material selected from the group consisting of TsOH and AcOH can be used singly or in combination, and Cu, In, Mn, Zn and Al Can be used singly or in combination, and as the organic catalyst, a substance selected from the group consisting of NaOAc and BF ₃ OEt ₂ can be used singly or in combination, and preferably, pyridine is used .

As the reaction solvent, it is possible to use isopropyl alcohol (IPA), ethyl alcohol, methyl alcohol, n-butyl alcohol, t-butyl alcohol, sec-butyl alcohol, toluene and ethyl acetate as a single solvent or a mixed solvent, Isopropyl alcohol can be used. The reaction temperature may be any temperature ranging from room temperature to reflux temperature , Preferably at 70 to 90 < 0 > C.

The process for preparing the compound of formula (2) of the present invention has an advantage that the compound of formula (2) can be easily produced by mild reaction conditions, unlike the case of using amide, which is undesirable in terms of production, . Further, the compound of formula (II) dissolved in the solution is suitable for producing the compound of formula (1) with high yield and purity by continuously reacting with the compound of formula (5) without a separate purification process.

Accordingly, in another aspect, the present invention provides a method for producing a compound exhibiting dipeptidyl peptidase IV (hereinafter, also referred to as 'DPP-IV') inhibitory activity of the following formula (8)

(a) converting the compound of formula 4 into a compound of formula 3;

(b) reacting the compound of formula (3) prepared in step (a) with an ammonia solution to prepare the compound of formula (2);

(c) cyclizing the compound of formula (5) and the compound of formula (2) prepared in step (b) to prepare a compound of formula (1);

(d) deprotecting the compound of formula (1) and introducing it into a compound of formula (6) to prepare a compound of formula (7); And

(e) deprotecting the compound of formula (7) to produce a compound of formula (8).

The above steps (a) to (c) are as shown in Reaction Schemes 1 and 2, and Steps (d) to (e)

[Reaction Scheme 3]

In this formula,

이고,A is

ego,

이며,B is

Lt;

P ₂ is preferably an amine protecting group such as Boc (t-butyloxycarbonyl), Fmoc (fluorenylmethyloxycarbonyl chloride) or Cbz (carbamazepine)

Gt; to R < 5 > are as defined above,

R6, R7, R8 and R9 are each independently hydrogen, halogen or substituted or unsubstituted C1-C4 alkyl.

Specifically, the above reaction scheme 3 is a process for preparing a compound 7, which is an amide having an amine group A, by introducing a compound of the formula 1 into the compound of the formula 6 and introducing it through a coupling reaction, removing the amine protecting group P ₂ , Compound 8 having an effect can be obtained.

In one specific example, the coupling reaction of the compound of Formula 6 with the compound of Formula 1 can be carried out by introducing EDC or HOBT. In the deprotection of the amine protecting group P2, when P2 is Boc, Can be performed by removing H ₂ / Pd / C or TMSI in the case of strong acid, Cbz and Et ₂ NH in case of Fmoc.

The compound of formula (6) may be prepared by the following reaction scheme (4).

[Reaction Scheme 4]

In this formula,

P < ₂ > is as defined above as an amine protecting group,

P ₃ and P ₄ are each independently a benzyl group, a methyl group, an ethyl group, an i-propyl group or a t-butyl group,

G ₁ functions as a good leaving group with oxygen. G ₁ O is trifluoromethanesulfonate, mesylate, tosylate, besylate or nonafluorobutanesulfonate, preferably triflate or nonaplate.

Specifically, Scheme 4

(i) subjecting a compound of formula (9) and a compound of formula (10) to a coupling reaction by adding a base;

(ii) adding an acid to perform a cyclization reaction to obtain a compound of Formula 11; And

(iii) hydrolyzing the obtained compound of formula (11) to remove the carboxylic acid protecting group to obtain the compound of formula (6).

In Scheme 4, a) is a base such as Hunig's base; b) is an acid such as AcOH and an organic solvent such as CH ₂ Cl ₂ ; c is different depending on the protecting group, but typically, when P ₂ is Boc and P ₃ is a t-butyl group, (1) a strong acid such as H ₂ SO ₄ and CH ₂ Cl ₂ , aq. (2) in the case where P ₂ is Boc and P ₃ is a benzyl group, a methyl group, an ethyl group and an i-propyl group, and the other is selected from the group consisting of NaOH, Boc ₂ O or (2) NaOH, EtOH, H ₂ O, Is used as the hydrolysis condition. R6, R7, R8, R9, P 2, P 3, P 4 and G ₁ are the same as defined above. Specifically, in step (a), the unprotected primary amine of the compound of the formula (9) and the carbon having the leaving group of the compound of the formula (10) react with each other under basic conditions, and -OG ₁ is eliminated. As the base, a C1 to C4 trialkylamine is used, preferably triethylamine or diisopropylethylamine. As the reaction solvent, a common organic solvent such as dichloroethane or dichloromethane or a cyclized ether (e.g., tetrahydrofuran (THF), dioxane) is used. Solvents can be substituted for the base used for a smooth reaction. The reaction may be carried out at any temperature ranging from 0 < 0 > C to reflux temperature. In step (b), the compound of formula (11) is synthesized through cyclization of the secondary amine group of the compound produced in step (a) with an internal ester group under acidic conditions. At this time, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as formic acid, acetic acid and tartaric acid can be used as acid, and acetic acid is particularly preferable. can be carried out under the conditions of the solvent and the temperature described in step (a). The steps (a) and (b) are performed continuously. In step (c), the compound of formula (11) obtained in step (b) is hydrolyzed to obtain the compound of formula (6). Specifically, in the case of the compound of formula (11) wherein P ₂ is Boc and P ₃ is a t-butyl group, all of the two protecting groups are removed by first using strong acid such as sulfuric acid, hydrochloric acid, phosphoric acid, and TFA (trifluoroacetic acid) , The Boc protecting group can be attached to the amine again under basic conditions to give the desired compound of formula (6). Or, by hydrolysis under basic conditions a non-acid conditions, P ₃ man selectively removing of the protecting group P ₂ and P ₃ can give a compound of formula (6), this method is more efficient. Preferably, a sodium hydroxide solution is used as a base. After completion of the reaction, the compound of formula (6) can be obtained as a solid through acidification using an acid. When P ₂ is Boc and P ₃ is a benzyl group, a methyl group, an ethyl group and an i-propyl group, hydrolysis is carried out using a base. When P ₂ is Cbz, the deprotection reaction is carried out using H ₂ / Pd-C. When P ₂ is Fmoc, the deprotection reaction is carried out using Bu ₄ N + F-. Preferably, when P ₃ is a t-butyl group or an i-propyl group, more preferably a t-butyl group, and P ₄ is a methyl group or an ethyl group, a high yield of the compound of formula 6 is obtained.

The preparation method of the DPP-IV inhibitor compound of the formula (8) is described in detail in International Patent Publication Nos. WO 2006/104356 and Korean Patent Registration No. 10-1378984 in addition to the above-mentioned method. The above document is included in the present invention as a reference material of the present invention.

According to the present invention, 2,2,2-trifluoro-1-imino-1-ethanamine (2,2,2-trifluoro-1-imino- 2-trifluoro-1-imino-1-ethanamine) can be efficiently produced under mild conditions, and the compound of formula (I) can be produced with high yield and purity by using it.

Hereinafter, the constitution and effects of the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.

Example 1 Synthesis of 2,2,2-trifluoro-1-imino-1-ethanamine (2,2,2-trifluoro-1-imino-1-ethanamine)

2,2,2-Trifluoroacetamide (200.1 g) was added to a mixed solution of dichloromethane (1325.8 g) and pyridine (420.1 g) and stirred at 20 ° C. A mixed solution of methanesulfonyl chloride (243.4 g) and trifluoroacetic anhydride (37.2 g) was slowly added dropwise. The trifluoroacetonitrile gas generated at this time was bubbled into an ammonia isopropyl alcohol solution having a concentration of 1.7 to 1.9 mol. When the reaction was completed, about 10 to 20% of the reaction mixture solution was distilled under reduced pressure to obtain 158.7 g of the title compound in an isopropyl alcohol solution.

_{1H NMR (500 MHz, CDCl 3} ) δ 8.51 (s, 2H)

Example 2: Preparation of tert-butyl 2,4, -di (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] Pyrimidine-7-carboxylate ( tert -Butyl 2,4-di (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] pyrimidine-7-carboxylate)

(2,2,2-trifluoroacetyl) -1-piperidinecarboxylate (8.4 g) was added to tert -butyl 3-oxo-4- trifluoromethyl-1-imino-1-ethanamine (4.7 g) and stirred for 1 hour at room temperature and then added dropwise to the starting material, tert - butyl 3-oxo-4- (2,2,2-trifluoro-acetyl ) -1-piperidinecarboxylate was removed, pyridine (6.8 g) was added dropwise, and the mixture was heated under reflux for 6 hours or more. When the reaction was completed, purified water (40 g) was added thereto and slowly cooled to obtain a solid Respectively. The reaction mixture was aged at about 5 to 10 ° C for at least 1 hour, filtered, and the resulting solid compound was washed with a mixture of ethyl alcohol and purified water and dried under nitrogen to obtain the title compound (8.6 g) in 81% yield.

_{1H NMR (500 MHz, CDCl 3} ) δ 1.50 (s, 9H), 3.12 (bt, 2H), 3.78 (t, 2H, J = 5.8 Hz), 4.85 (s, 2H)

Claims (19)

A process for the preparation of a compound of formula (2), which comprises converting a compound of formula (4) to a compound of formula (3) and subsequently obtaining a compound of formula (2)

(2)

(3)

[Chemical Formula 4]

In this formula,
R2 is hydrogen, a substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₈ aryl, and substituted and unsubstituted C ₃ -C ₇ heteroaryl. ≪ / RTI > The method of claim 1 wherein, R2 is a method of manufacturing, characterized in that CF _3. The process according to claim 1, wherein the compound of formula (IV) is converted to a compound of formula (III) in the presence of pyridine, dichloromethane, methanesulfonyl chloride (MsCl) and trifluoroacetic anhydride (TFAA). 2. The process according to claim 1, wherein Trifluoroacetamide is reacted with (i) methanesulfonyl chloride (MsCl), trifluoromethanesulfonyl chloride (TfCl), toluenesulfonyl chloride (TsCl) in the presence of pyridine, dichloromethane ) And bromobenzene sulfonyl chloride (BsCl) with a mixture of trifluoroacetic anhydride (TFAA) to produce a compound of formula (III) in gaseous form. . 2. The process according to claim 1, wherein, when converting the compound of formula (3) into the compound of formula (2), the compound of formula (3) in gaseous form is reacted with a compound of formula ≪ / RTI > is bubbled into an ammonia solution to convert to the compound of formula (2). (a) converting a compound of formula (4) to a compound of formula (3);
(b) reacting the compound of formula (3) prepared in step (a) with an ammonia solution to prepare a compound of formula (2); And
(c) cyclizing the compound of formula (5) and the compound of formula (2) prepared in step (b) to prepare a compound of formula (1)
≪ RTI ID = 0.0 > 1 < / RTI >

[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

In this formula,
R1 is hydrogen or CF ₃ and;
R2 is hydrogen, a substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₈ aryl, and substituted and unsubstituted C ₃ -C ₇ heteroaryl;
R3, R4 and R5 each independently represent hydrogen, substituted or unsubstituted C ₁ -C ₄ alkyl;
P ₁ represents t-butyloxycarbonyl as an amine protecting group. 7. The process according to claim 6, wherein the two compounds of the formula obtained in the step (b) are subjected to a cyclization reaction with the compound of the formula (5) continuously in the step (c) without separation and purification. The method of claim 6 wherein the method for manufacturing the R1 and R2 may be each independently CF _3. 7. The process according to claim 6, wherein R3, R4 and R5 are each independently hydrogen. The method according to claim 6,
Wherein the cyclization of step (c) is carried out by adding at least one material selected from the group consisting of a base, an acid catalyst, a metal catalyst and an organic catalyst to the compound of formula (5) and the compound of formula (2). 11. The method of claim 10, wherein the base is selected from the group consisting of C ₁ -C ₄ trialkylamines, Hunig's base, pyridine, K ₂ CO ₃ , KOH, NaOH, NaOMe, NaOEt, Cs ₂ CO _3, ≪ RTI ID = 0.0 > and / or < / RTI > 11. The method of claim 10, wherein the method is at least one selected from the group consisting of acid catalysts TsOH-H ₂ O and AcOH. 11. The method according to claim 10, wherein the metal catalyst is at least one selected from the group consisting of Cu, In, Mn, Zn and Al. 11. The method of claim 10, the method of manufacturing the organic catalyst is at least one selected from the group consisting of NaOAc, and BF ₃ OEt _2. 11. The process according to claim 10, wherein the cyclization of step (c) is carried out in the presence of pyridine. The process according to claim 6, wherein the cyclization reaction of step (c) is carried out without using any base, acid catalyst or metal catalyst. The method according to claim 6, wherein the reaction solvent used in the cyclization reaction of step (c) is selected from the group consisting of isopropyl alcohol, ethyl alcohol, methyl alcohol, n-butyl alcohol, t-butyl alcohol, sec-butyl alcohol, ≪ / RTI > is at least one solvent selected from the group consisting of: 7. The process according to claim 6, wherein the cyclization of step (c) is carried out at 70 to 90 < 0 > C. (a) converting the compound of formula (4) to a compound of formula (3);
(b) reacting the compound of formula (3) prepared in step (a) with an ammonia solution to prepare a compound of formula (2);
(c) cyclizing the compound of formula (5) and the compound of formula (2) prepared in step (b) to prepare a compound of formula (1);
(d) deprotecting the compound of Formula 1 and introducing the compound of Formula 6 into the compound of Formula 6 to prepare a compound of Formula 7; And
(e) deprotecting the compound of formula (VII) to produce a compound of formula (VIII).
[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 8]

In this formula,
A is

ego,
B is

Lt;
P ₂ represents Boc (t-butyloxycarbonyl), Fmoc (fluorenylmethyloxycarbonyl chloride) or Cbz (carbamazepine) as an amine protecting group;
R1 is hydrogen or CF ₃ and;
R2 is hydrogen, a substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₄ -C ₈ aryl, and substituted and unsubstituted C ₃ -C ₇ heteroaryl;
R3, R4 and R5 each independently represent hydrogen, substituted or unsubstituted C ₁ -C ₄ alkyl;
R6, R7, R8 and R9 are each independently hydrogen, halogen or substituted or unsubstituted C1-C4 alkyl.