JPWO2006062063A1 - Piperidine derivatives and process for producing the same - Google Patents

Abstract

By employing a piperidine derivative represented by the formula (I) or a salt thereof as an intermediate, a 2-cyano-4-fluoropyrrolidine derivative useful as a pharmaceutical, particularly a DPP-IV inhibitor, can be efficiently produced. . In particular, by employing the intermediate, the total number of steps can be reduced as compared with known production methods, and the overall yield is improved. Further, the 2-cyano-4-fluoropyrrolidine derivative can be produced without using a cryogenic reaction that is not suitable for industrial production or a reaction that requires strict water management in the reaction system. [Wherein, Ms represents methanesulfonyl, Me represents methyl, R1 represents —H, halogen, or —OH. ]

Description

  The present invention relates to a process for producing 2-cyano-4-fluoropyrrolidine derivatives known as pharmaceuticals, particularly dipeptidyl peptidase-IV (hereinafter referred to as DPP-IV) inhibitors, and intermediates thereof, and intermediates thereof. It relates to the manufacturing method of the body.

4-fluoro-1-({[4-methyl-1- (methanesulfonyl) piperidin-4-yl] amino} acetyl) pyrrolidine-2-carbonitrile represented by the following formula (IV) (hereinafter referred to as Compound A) Is a compound known as a DPP-IV inhibitor (Patent Document 1) and is a compound useful for the treatment and / or prevention of type 1 diabetes, type 2 diabetes, insulin resistance disease, obesity and the like. It has been known.

  Regarding Compound A, the following production method X using 4-methyl-1- (methanesulfonyl) piperidin-4-amine (hereinafter referred to as Compound B) or its hydrochloride as a raw material compound is specifically known. (Patent Document 1).

［式中、Msはメタンスルホニルを、Meはメチルを示す。以下同様。］(A) Compound A Production Method “Production Method X”

[Wherein, Ms represents methanesulfonyl, and Me represents methyl. The same applies hereinafter. ]

  Further, it is known that Compound B or its hydrochloride, which is a raw material compound in Production Method X, is produced by the following Production Method Y or Production Method Z (Patent Document 1).

［式中、Bocはtert-ブチルオキシカルボニルを、Et₃Nはトリエチルアミンを、MsClはメタンスルホニルクロリドを、CH₂Cl₂は塩化メチレンを、DMFはN,N-ジメチルホルムアミドを、4M HCl-EtOAcは4 mol/L塩酸の酢酸エチル溶液を、EtOAcは酢酸エチルを示す。以下同様。］(B) Production Method “Production Method Y” of Compound B Hydrochloride

[Where Boc is tert-butyloxycarbonyl, Et ₃ N is triethylamine, MsCl is methanesulfonyl chloride, CH ₂ Cl ₂ is methylene chloride, DMF is N, N-dimethylformamide, 4M HCl-EtOAc Indicates 4 mol / L hydrochloric acid in ethyl acetate, and EtOAc indicates ethyl acetate. The same applies hereinafter. ]

［式中、Cbzはベンジルオキシカルボニルを、10% Pd/Cは10%パラジウム担持炭素を、MeOHはメタノールを示す。以下同様。］(C) Production method “Production method Z” of compound B

[Wherein Cbz represents benzyloxycarbonyl, 10% Pd / C represents 10% palladium-supported carbon, and MeOH represents methanol. The same applies hereinafter. ]

  However, although the raw material compounds used in the above production method Y and production method Z are known compounds, they are not commercially cheap and easily obtainable compounds. In order to obtain these raw material compounds, the following compounds are used. It is necessary to manufacture separately with a well-known manufacturing method, and the manufacturing process is as follows.

［式中、Bnはベンジルを、BnNH₂はベンジルアミンを、Acはアセチルを示す。以下同様。］(D) Production method of compound Y-1 (Patent Document 2, Non-Patent Document 1, Non-Patent Document 2)

[Wherein, Bn represents benzyl, BnNH ₂ represents benzylamine, and Ac represents acetyl. The same applies hereinafter. ]

［式中、CO₂Etはエトキシカルボニルを示す。以下同様。］(E) Production method of compound Z-1 (Patent Document 3)

[Wherein, CO ₂ Et represents ethoxycarbonyl. The same applies hereinafter. ]

That is, the following method (A), (B) or (C) is used to produce compound B, which is a useful intermediate in producing compound A, using a cheap and readily available compound as a starting material. The total number of steps and the total yield in each method are as shown below.
(A) Method for producing B or a salt thereof via Y-5 and Y-1 using Y-8 as a starting material Total number of steps: 9 steps Total yield: Of all 9 steps, The yield can be specifically derived from the four steps from the description, but the total yield is 30.0% even if only these four steps are included, and if the remaining five specific steps are not included, it should be 30.0% or less. Is clear.
(B) Method for producing B or a salt thereof via Y-5 and Y-1 using Y-9 as a starting material Total number of steps: 7 steps Total yield: Of all 7 steps, The yield can be specifically derived from the five steps from the description, but the total yield is 17.7% even if only these five steps are included, and if the remaining two specific steps are unknown, it is 17.7% or less. Is clear.
(C) Method for producing B or a salt thereof via Z-1 using Z-6 as a starting material Total number of steps: 7 steps Total yield: Of all 7 steps, specific from the description in the prior art document The yield can be derived in 4 steps, but the total yield is 47.6% even with these 4 steps alone, and it is clear that it is 47.6% or less if the remaining 3 specific steps are unknown. .

International Publication No. WO 2004/009544 Pamphlet Japanese Patent Application Publication No. 7-165754 International Publication No. WO 99/40070 pamphlet Journal of American Chemical Society, 1985, 107, pp. 1768-1769 Tetrahedron, 1970, Volume 26, pp.5519-5527

  Accordingly, it has been desired to develop a method for producing Compound B or a salt thereof with a reduced total number of steps and an improved overall yield, starting from an inexpensive and readily available compound for industrial production.

  As a result of diligent investigation on a method for separately producing Compound A useful for the treatment and / or prevention of type 1 diabetes, type 2 diabetes, insulin resistance disease, and obesity as DPP-IV inhibitors, It was found that the compound A can be efficiently produced by the production method 1 and the production method 2 shown in the following, and the present invention was completed.

  That is, according to the present invention, a piperidine derivative represented by the following formula (I) or a salt thereof, which is a useful intermediate when employing the production method of Compound A shown in Production Method 2 described later, is provided.

［式中、R¹は-H、ハロゲン又は-OHを示す。］
なお、R¹として好ましくはハロゲンであり；さらに好ましくはクロロ又はブロモである。

[Wherein, R ¹ represents —H, halogen or —OH. ]
R ¹ is preferably halogen; more preferably chloro or bromo.

なお、この製造法において、R¹を有するアセチル基を脱離させる反応としては、酸を用いた加水分解反応が好ましく、その中でも塩酸、臭化水素酸、トリフルオロ酢酸、硫酸、メタンスルホン酸、並びにp-トルエンスルホン酸及びその水和物からなる群より選択される１種若しくは２種以上の酸を用いた加水分解反応が好ましい。Also provided is a method for producing compound B represented by formula (II), which comprises removing an acetyl group having R ¹ from a piperidine derivative represented by the above formula (I) or a salt thereof.

In this production method, the reaction for removing the acetyl group having R ¹ is preferably a hydrolysis reaction using an acid, among which hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid, In addition, a hydrolysis reaction using one or more acids selected from the group consisting of p-toluenesulfonic acid and hydrates thereof is preferable.

なお、この製造法において適用される反応としては、クロロアセトニトリル、ブロモアセトニトリル、アセトニトリル、シアン化水素及びグリコロニトリルからなる群より選択されるシアノ基を有する化合物を、酸性条件下に作用させる反応を用いることが好ましく、特にクロロアセトニトリル、ブロモアセトニトリル及びアセトニトリルからなる群より選択されるアセトニトリル誘導体と式（ＩＩＩ）の化合物を、メタンスルホン酸及び硫酸からなる群より選択される酸の存在下に反応させることが好ましい。Moreover, the manufacturing method of the piperidine derivative or its salt shown by the formula (I) which is this invention compound using the 4-hydroxy piperidine derivative or its salt shown by Formula (III) is provided.

The reaction applied in this production method is a reaction in which a compound having a cyano group selected from the group consisting of chloroacetonitrile, bromoacetonitrile, acetonitrile, hydrogen cyanide and glycolonitrile is allowed to act under acidic conditions. In particular, an acetonitrile derivative selected from the group consisting of chloroacetonitrile, bromoacetonitrile and acetonitrile and a compound of formula (III) are reacted in the presence of an acid selected from the group consisting of methanesulfonic acid and sulfuric acid. preferable.

In addition, a compound represented by the formula (IV) using a compound B produced by a production method including removing an acetyl group having R ¹ from a piperidine derivative represented by the above formula (I) or a salt thereof. A manufacturing method of A is provided.

(1) Production method 1

This production method is a method for producing a compound represented by the formula (I), which is a compound of the present invention, via a compound represented by the formula (III).
(First step)
This step is a step of adding a methanesulfonyl group to the amino group of compound 1-2.
The reaction can be carried out by a method obvious to those skilled in the art or by the method described in “Protective Groups in Organic Synthesis (third edition)” by Greene and Wuts.
Compound 1-1 can also be produced by the method described in WO 98/57862 pamphlet.
(Second step)
This step is a step of adding a methyl group to the carbonyl group of compound 1-1.
Examples of the reaction reagent include methylmagnesium halides such as methylmagnesium chloride and methylmagnesium bromide, methyllithium, trimethylaluminum, lithium dimethylcouprate, and methyltrichlorotitanium. In addition, when methyl magnesium halide or methyl lithium is used, the addition of cerium trichloride or the like can suppress the enolization of compound 1-1 and can be expected to improve the yield. The reaction varies depending on the reaction reagent used, but aromatic hydrocarbons such as toluene and xylene; ethers such as ethyl ether, isopropyl ether, di-n-butyl ether, tetrahydrofuran (THF), and dioxane; dichloromethylene, chloroform, Halogenated hydrocarbons such as dichloroethane, trichloroethane, and carbon tetrachloride; or a solvent inert to the reaction such as a mixed solvent thereof, under cooling, under cooling to room temperature, or under room temperature to heating, The reaction temperature can be appropriately selected according to the reaction conditions.
(Third step)
This step is a step of adding a compound having a cyano group to compound (III) under acidic conditions.
Examples of the reaction reagent include chloroacetonitrile, bromoacetonitrile, acetonitrile, hydrogen cyanide, and glycolonitrile. Examples of acids used include sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid or hydrates thereof; sulfuric acid; trifluoroacetic acid; perchloric acid; phosphoric acid; polyphosphoric acid; formic acid; boron trifluoride etherate. And Lewis acids such as trimerylsilyl triflate. Although the reaction varies depending on the reaction reagent used, it can be carried out without solvent or in a solvent inert to the reaction. Examples of the solvent inert to the reaction include acetic acid; acetic anhydride; ethers; hexane, pentane, heptane, etc. Aliphatic hydrocarbons; halogenated hydrocarbons; nitrobenzene and the like. The reaction temperature can be appropriately selected depending on the reaction conditions, but can be performed under cooling, under cooling to room temperature, or under room temperature to heating.

(2) Production method 2

This production method is a production method of the compound B represented by the formula (II) and the production method of the compound A represented by the formula (IV) using the compound of the present invention represented by the formula (I).
(First step)
This step is a step of removing the acetyl group having R ¹ from the compound (I) of the present invention.
Preferably, a hydrolysis reaction using an acid can be mentioned. Examples of the acid include hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid, and p-toluenesulfonic acid or a hydrate thereof. Of these, one acid can be used, or two or more acids can be used. The reaction varies depending on the group represented by R ¹ in compound (I), but alcohols such as methanol (MeOH), ethanol (EtOH), 1-propanol, 2-propanol (iPrOH), and 1-butanol (nBuOH) In a mixed solvent of water and water (in addition, water can be substituted with water originally contained in concentrated hydrochloric acid, sulfuric acid, etc.), under cooling, under cooling to room temperature or under room temperature to heating, The temperature can be appropriately selected according to the reaction conditions.
(Second step)
This step comprises compound (II), 1-chloroacetyl-4-fluoropyrrolidine-2-carbonitrile produced by the method described in International Publication No. WO 2004/009544 pamphlet, or a method analogous thereto, or its This is a step of condensing an analog (for example, 1-bromoacetyl-4-fluoropyrrolidine-2-carbonitrile).
The reaction can be advantageously carried out by adding a base or using an excess of compound (II). Examples of the base include organic bases such as triethylamine, N-ethyldiisopropylamine, and pyridine; potassium carbonate, cesium carbonate And inorganic bases such as sodium hydrogen carbonate and potassium hydroxide. The reaction varies depending on the reactivity of the compound to be condensed with the compound (II), but the reaction can be carried out without solvent or using a solvent. Examples of the solvent used include acetonitrile, N, N-dimethylformamide, dimethyl Examples thereof include sulfoxides, aromatic hydrocarbons, ethers, alcohols, halogenated hydrocarbons, ketones such as methyl ethyl ketone and acetone, water, and mixed solvents thereof. The reaction can be performed under cooling, under cooling to room temperature, or under room temperature to heating, and the reaction temperature can be appropriately selected according to the reaction conditions.

That is, according to the production method of the present invention, the compound (II) can be produced from piperidin-4-one hydrochloride hydrate, which is an inexpensive and easily available raw material compound, in only 4 steps. Further, as shown in Examples 4 to 6 described later, the total yield is 43.7%.
On the other hand, in producing compound (II), the known production methods are as described in (A), (B) and (C) above. In terms of the total number of steps, 9 steps were required in the known production method (A), and 7 steps were required in the known production methods (B) and (C), but according to the production method of the present invention, it can be produced in 4 steps. . It is well known that this reduction in the total number of processes brings very advantageous effects in terms of industrial production, such as economy and efficiency, and stable supply.
Moreover, in terms of the total yield, the known production methods (A), (B), and (C) each have a process whose yield is unknown, but in the known production process (A), there are five processes whose yield is unknown. Even if all the yields are assumed to be 100%, it is 30.0%. In the known production method (B), the yields of the two steps whose yields are unknown are all assumed to be 17.7%. In addition, with regard to the known production method (C), there are three steps with unknown yield. Of these, three additional tests were conducted on the step of producing Z-0 from Z-1, and the average yield was It was 68.7%, and when the process for producing B from Z-0 was conducted twice, the average yield was 98.5%. Therefore, with regard to the total yield of the known production method (C), if these additional test results are taken into consideration, one process with an unknown yield remains, but even if the yield of the process is assumed to be 100%, The yield is 32.2%. Since the overall yield of the production method of the present invention is 43.7%, the overall yield of the production method of the present invention is significantly improved over the known production methods (A), (B) and (C). It can be said. It is well known that the improvement of the overall yield brings about advantageous effects from the viewpoint of economic efficiency, efficiency, and stable supply in industrial production.
In addition, in the known production method (C), lithium diisopropylamide is used to introduce the methyl group at the 4-position of piperidine, but this reagent requires a reaction at a very low temperature. Needs as low as -78 ° C. In industrial production, it is often difficult to control such a very low temperature, which is not suitable for industrial production in terms of economy and efficiency. Furthermore, in the known production method (C), a so-called Curtius rearrangement reaction is used to convert the carboxyl group at the 4-position of piperidine into a benzyloxycarbonylamino group. This reaction is an intermediate generated in the reaction system. Since it is easily decomposed by water, it is necessary to strictly control the water content in the reaction system, and this reaction is not suitable in terms of economy and efficiency in industrial production.

  Therefore, the production method of the present invention has (1) the total number of steps is remarkably shortened and (2) the overall yield is greatly improved, compared with the known production methods, and ( 3) Reactions that require very low temperatures and reactions that are not suitable for industrial production, such as reactions that may hinder the progress of the reaction due to the presence of moisture, are unnecessary, and only reactions that are suitable for industrial production. It is an excellent production method in that it is constituted by, and is a very useful and simple production method. That is, in the production of compound (II), and further in the production of compound (IV), it is extremely advantageous to employ the compound (I) of the present invention as a production intermediate, and the effect is as described above.

The present invention will be further described as follows.
In the present specification, “halogen” includes chloro, bromo, iodo and fluoro, preferably chloro or bromo.
Further, “a piperidine derivative represented by formula (I) or a salt thereof”, “a 4-aminopiperidine derivative represented by formula (II) or a salt thereof”, “a 4-hydroxypiperidine derivative represented by formula (III) or a salt thereof The salt in “salt” or “2-cyano-4-fluoropyrrolidine derivative or salt thereof” is a piperidine derivative represented by formula (I), a 4-aminopiperidine derivative represented by formula (II), or a formula (III) It means an acid addition salt of the 4-hydroxypiperidine derivative or 2-cyano-4-fluoropyrrolidine derivative shown, and the acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Mineral acids of methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid and other sulfonic acids; formic acid, acetic acid, propionic acid, oxalic acid And the like can be given; aspartic acid, acidic amino acids glutamic acid and the like; malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, organic acids such as citric acid. The “salts” also include various hydrates, solvates and crystalline polymorphs of the respective compounds and salts thereof.
In addition, since compound (IV) has an asymmetric carbon, the following four optical isomers exist, and (2S, 4S) -form represented by (IV-1) is preferable.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not restrict | limited at all by these Examples.

Example 1
A solution of 150.0 g of 4- [1- (methanesulfonyl)] piperidone in 1950 mL of THF in 847.0 g of a 2 mol / L THF solution of methylmagnesium chloride was added with stirring at 10 ° C. or less, and 75 mL of THF was added. I washed it in. After stirring for 4 hours, 75 mL of water, 1000 mL of 20% (w / v) ammonium chloride aqueous solution and 750 mL of toluene were added, and the organic layer was separated. The organic layer was washed with 900 mL of 20% (w / v) brine, this solution was concentrated under reduced pressure, and the operation of adding 1050 mL of toluene and concentrating under reduced pressure was repeated twice more. To the residue, 450 mL of toluene was added and dissolved by heating at 80 ° C. The mixture was cooled to 0 ° C. with stirring, and the precipitated crystals were collected by filtration, washed with toluene, and dried under reduced pressure to give 127.1 g of 4-methyl-1- (methanesulfonyl) piperidin-4-ol as white. Obtained as crystals.
¹ H-NMR (DMSO-d ₆ ): 1.14 (s, 3H), 1.47-1.58 (m, 4H), 2.83 (s, 3H), 3.00 (dt, 2H), 3.25 (dt, 2H), 4.37 ( s, 1H).
FAB-MS m / z: 194 (M + 1).

Example 2
200.0 g of 4-methyl-1- (methanesulfonyl) piperidin-4-ol was added to 740.5 g of methanesulfonic acid and washed with 148.1 g of methanesulfonic acid. To the obtained mixture, 78.1 g of chloroacetonitrile was added, and the mixture was stirred overnight at room temperature. To the reaction solution, 1200 mL of ethyl acetate (EtOAc) was added, and the mixture was gradually added dropwise to 2700 mL of 27% (w / v) aqueous potassium carbonate solution with stirring. The organic layer was separated and washed with 600 mL of 10% (w / v) aqueous potassium hydrogen carbonate solution and 600 mL of water. The solvent was distilled off under reduced pressure to obtain 264.7 g of 2-chloro-N- [4-methyl-1- (methanesulfonyl) piperidin-4-yl] acetamide as pale yellow crystals.
¹ H-NMR (CDCl ₃ ): 1.45 (s, 3H), 1.74-1.81 (m, 2H), 2.25-2.29 (m, 2H), 2.81 (s, 3H), 2.97-3.04 (m, 2H), 3.47-3.52 (m, 2H), 4.00 (s, 2H), 6.27 (brs, 1H).
FAB-MS m / z: 269 (M + 1).

Example 3
To 15 mL of acetic acid, 10.00 g of 4-methyl-1- (methanesulfonyl) piperidin-4-ol was added and cooled to 10 ° C. 10 mL of sulfuric acid and 5.08 g of chloroacetonitrile were added with stirring at 20 ° C., and then stirred for 9 hours. The reaction solution was added to a mixed solution of 150 mL of water, 22.00 g of lithium carbonate, and 100 mL of isopropyl acetate at 35 ° C. or lower. The organic layer was separated and washed with 20 mL of water, and the solvent was distilled off under reduced pressure.
To a concentrated residue containing 2-chloro-N- [4-methyl-1- (methanesulfonyl) piperidin-4-yl] acetamide were added 8 mL of water and 8 mL of concentrated hydrochloric acid, and the mixture was stirred at 100 ° C. for 24 hours. After cooling at room temperature, 50 mL of 2-propanol was added to precipitate crystals. The mixture was cooled to 0 ° C. with stirring, the crystals were collected by filtration, washed with 2-propanol, and dried under reduced pressure to give 4-methyl-1- (methanesulfonyl) piperidin-4-amine monohydrochloride monohydrochloride. Hydrates were obtained as white crystals.

Example 4
Piperidin-4-one monohydrochloride monohydrate 500.0 g, potassium carbonate 674.8 g, and acetonitrile 2400 mL were added to 2500 mL of water, and the mixture was cooled to 10 ° C. or lower. Methanesulfonyl chloride (559.3 g) was added with stirring at 35 ° C. or lower and washed with 100 mL of acetonitrile. After stirring for 24 hours, 45.0 g of potassium carbonate was added for neutralization, and 2500 mL of toluene was added for extraction. The aqueous layer was separated, and further extracted with 500 mL of acetonitrile and 1500 mL of toluene. The organic layers were mixed and the solvent was distilled off under reduced pressure. Furthermore, 2500 mL of toluene was added, and the solvent was distilled off under reduced pressure. To the resulting residue, 2500 mL of toluene was added and dissolved by heating at 85 ° C. The mixture was cooled to 0 ° C. with stirring, and the precipitated crystals were collected by filtration, washed with toluene, and dried under reduced pressure to give 488.7 g of 4- [1- (methanesulfonyl)] piperidone (yield 84.7%) Was obtained as white crystals.
¹ H-NMR (DMSO-d ₆ ): 2.46 (t, 4H), 2.97 (s, 3H), 3.49 (t, 4H).
FAB-MS m / z: 178 (M + 1).

Example 5
A solution of 2.00 g of 4- [1- (methanesulfonyl)] piperidone in 26 mL of THF was added to 21.02 g of a 1 mol / L THF solution of methylmagnesium chloride with stirring at 10 ° C. or less, and 1 mL of THF was added. I washed it in. After stirring at room temperature for 2 hours, 1 mL of water and 13 mL of 20% (w / v) aqueous ammonium chloride solution were added, and the organic layer was separated. The organic layer was washed with 11 mL of 20% (w / v) brine. This organic layer was concentrated under reduced pressure to 10 mL, 14 mL of toluene was added, and the operation of concentration under reduced pressure to a total volume of 14 mL was repeated 4 times. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 1.84 g (yield 84.4%) of 4-methyl-1- (methanesulfonyl) piperidin-4-ol as white crystals.

Example 6
To 15 mL of acetic acid, 10.00 g of 4-methyl-1- (methanesulfonyl) piperidin-4-ol was added and cooled to 10 ° C. 10 mL of sulfuric acid and 5.08 g of chloroacetonitrile were added with stirring at 20 ° C. or lower, and then stirred for 3 days. The reaction solution was added to a mixed solution of 150 mL of water, 21.00 g of lithium carbonate, and 100 mL of isopropyl acetate at 30 ° C. or lower. The organic layer was separated and washed with 20 mL of water, and the solvent was distilled off under reduced pressure.
To the concentrated residue containing 2-chloro-N- [4-methyl-1- (methanesulfonyl) piperidin-4-yl] acetamide was added 60 mL of nBuOH, 10 mL of water, and 10 mL of concentrated hydrochloric acid, and the mixture was stirred at 100 ° C. for 13 hours. . After cooling at room temperature, 200 mL of iPrOH was added. The white crystals of Example 3 were inoculated to precipitate crystals, and then cooled to 0 ° C. with stirring. The crystals were collected by filtration, washed with iPrOH, and then dried under reduced pressure to give 7.81 g (yield 61.2%) of 4-methyl-1- (methanesulfonyl) piperidin-4-amine monohydrochloride monohydrate Was obtained as white crystals.

  That is, if the compound of the present invention is employed as a production intermediate and compound (II) is produced by the production method of the present invention, piperidine-4 which is an inexpensive and readily available starting compound is obtained from the results of Examples 4 to 6. Compound (II) can be produced with only 4 steps and an overall yield of 43.7%, starting from -one hydrochloride hydrate.

Example 7
8.5 mL of acetonitrile was added to 2.85 g of 4-methyl-1- (methanesulfonyl) piperidin-4-ol and cooled to 10 ° C. or lower. 5.7 mL of sulfuric acid was added with stirring at 20 ° C. or lower, and then stirred for 3 hours. The reaction solution was poured into 100 mL of ice-cold water and neutralized by adding 12.7 g of sodium carbonate. Extraction was performed with 80 mL of EtOAc and 50 mL of EtOAc, the organic layer was concentrated under reduced pressure, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform: MeOH = 50: 1) to give 3.56 g of N- [4-methyl-1- (methanesulfonyl) piperidin-4-yl] acetamide as a yellow oil Got as.
¹ H-NMR (DMSO-d ₆ ): 1.27 (s, 3H), 1.45-1.52 (m, 2H), 1.81 (s, 3H), 2.15-2.18 (m, 2H), 2.85 (s, 3H), 2.88-2.97 (m, 2H), 3.20-3.27 (m, 2H), 7.36 (brs, 1H).
FAB-MS m / z: 235 (M + 1).

Example 8
The reaction was conducted in the same manner as in Example 6 except that chloroacetonitrile was replaced with bromoacetonitrile, to give 4-methyl-1- (methanesulfonyl) piperidin-4-amine monohydrochloride monohydrate.
¹ H-NMR (DMSO-d ₆ ): 1.33 (s, 3H), 1.73-1.77 (m, 2H), 1.81-1.84 (m, 2H), 2.90 (s, 3H), 3.03-3.09 (m, 2H ), 3.39-3.45 (m, 2H), 8.33 (brs, 3H).
ESI-MS m / z: 193 (M + 1).

Example 9
2.00 g of (2S, 4S) -1- (chloroacetyl) -4-fluoropyrrolidine-2-carbonitrile prepared by the method described in International Publication No. WO 2004/009544, 14 mL of acetonitrile, 4-methyl-1- (methane (Sulfonyl) piperidin-4-amine monohydrochloride monohydrate (2.88 g) and N-ethyldiisopropylamine (5.4 mL) were added, and the mixture was heated with stirring at 80 ° C. for 14 hours. The solvent was distilled off under reduced pressure, EtOH 14 mL was added, and the solvent was further distilled off. Water (2 mL), EtOH (50 mL), and N-ethyldiisopropylamine (0.54 mL) were added and dissolved by heating, and the mixture was cooled with stirring to precipitate crystals. After cooling to 0 ° C., the crystals were collected by filtration, washed with EtOH, and then dried under reduced pressure to give (2S, 4S) -4-fluoro-1-({[4-methyl-1- (methanesulfonyl ) Piperidin-4-yl] amino} acetyl) pyrrolidine-2-carbonitrile (3.04 g) was obtained as white crystals.
¹ H-NMR (CDCl ₃ ): 1.12, 1.14 (s, 3H), 1.66 (brs, 4H), 2.26-2.72 (m, 2H), 2.78 (s, 3H), 3.16-4.05 (m, 6H), 3.33 (ABq, 2H), 4.89, 4.95 (d, 1H), 5.36, 5.44 (dt, 1H).
FAB-MS m / z: 347 (M + 1).

  According to the present invention, an efficient production method of a compound A or a salt thereof useful as a pharmaceutical, particularly a DPP-IV inhibitor, particularly a compound B or a salt thereof as an intermediate when the production method is employed, and A method for its manufacture is provided.

Claims (4)

Formula (I)

[The symbols in the formula have the following meanings.
Ms: Methanesulfonyl.
Me: methyl.
R ¹ : —H, halogen or —OH. ]
And removing the acetyl group having R ¹ from the piperidine derivative represented by the formula (II) or a salt thereof:

[The symbols in the formula have the following meanings.
Ms: Methanesulfonyl.
Me: methyl. ]
A process for producing a 4-aminopiperidine derivative represented by the formula: A piperidine derivative represented by the formula (I) or a salt thereof.

[The symbols in the formula have the following meanings.
Ms: Methanesulfonyl.
Me: methyl.
R ¹ : —H, halogen or —OH. ] Formula (III)

[The symbols in the formula have the following meanings.
Ms: Methanesulfonyl.
Me: methyl. ]
The manufacturing method of the compound of Claim 2 using the 4-hydroxy piperidine derivative or its salt shown by these. A 4-aminopiperidine derivative represented by the formula (II) according to claim 1, which is produced by the method according to claim 1, or a salt thereof,

[The symbols in the formula have the following meanings.
Ms: Methanesulfonyl.
Me: methyl. ]
A process for producing a 2-cyano-4-fluoropyrrolidine derivative represented by the formula: