JPH10101649A - Manufacture of n2-arylsulfonyl-l-arginine amides - Google Patents

Abstract

PROBLEM TO BE SOLVED: To effectively obtain the subject compound in industrial scale useful for medicine such as an antithrombotic agent, etc., by carrying out a reaction of pyperizine-2-carboxylic acid derivatives and (α-amino group of L-arginine, etc., after the initial condensation, under the presence of a specific compound. SOLUTION: The object compounds are the prescribed compounds such as N<2> -arylsulfonyl-L-arginie amides, e.g.; N<2> -(3-methyl-8quinolinsulfonyl)-NG-nitro-L- arginine. A condensation of (A) NG-nitrol-arginine with (B) 3-(H or lower alkyl)-8-quinolinesulfonylchloride is carried out. Normally, the condensation is carried out by dissolving (B) in a water miscible organic solvent (e.g.: acetone, etc.) and mixing with nitroarginine dissolved in aqueous solution of a base (e.g.: NaOH, etc.), under cooling at about 0-10 deg.C. N<2> -arylsulfonyl-L-arginine amides useful for medicine are effectively manufactured.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an N ² -arylsulfonyl-L- useful as an active ingredient of a drug such as an antithrombotic drug.
The present invention relates to a method for producing argininamides.

[0002]

BACKGROUND OF THE INVENTION (2R, 4R) -4- methyl -1- [N ² - (3- methyl-1,
2,3,4-Tetrahydro-8-quinolinesulfonyl) -L-arginyl] -2-piperidinecarboxylic acid is a mammal as described in Table 1 of JP-B-61-48829 as Compound No. 6. It is a compound that has a highly specific inhibitory effect on thrombin in the body and is useful for treating and preventing thrombosis or as an inhibitor of platelet aggregation. The monohydrate of this compound is used as a selective antithrombin agent for the treatment of chronic arterial occlusion and cerebral thrombosis.

Conventionally, such N ² -arylsulfonyl
-L- Arginine amides can be produced by
No. 35000, pages 2-3, and Japanese Patent Publication No. 2-31055, No. 3
The method of the following scheme shown on the page is known (in the scheme, Ar is substituted at a 3-position with a methyl group or an ethyl group).
Represents a 1,2,3,4-tetrahydro-8-quinolyl group; Q represents an 8-quinolyl group substituted at the 3-position with a methyl group or an ethyl group; R ¹ is a hydrogen atom or C _1-5 alkyl X represents a halogen atom; R ² represents a hydrogen atom, a C _1-10 alkyl group or a C _7-15 aralkyl group; at least one of R ′ and R ″ is a guanidino protecting group And R ″ ′ represents a protecting group for the α-amino group).

[0004]

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In this method, an arginine derivative (compound (III) in the scheme) in which a guanidino group and an amino group on the α-carbon are appropriately protected is compared with a piperidine-2-carboxylic acid derivative (compound (IV) in the scheme). ), The protecting group on the amino group on the α-carbon of the obtained condensate (compound (V) in the scheme) is deprotected, and the amino group is quinoline sulfonyl halide (compound in the scheme). (VII)) to remove the substituent (eg, nitro group) on the guanidino group, reduce the quinolyl group, and deprotect the carboxyl group to produce the desired product (compound (I) in the scheme). Is the way.

According to Example 2 on page 7 of JP-B-61-48829, (2R, 4R) -4-methyl-1- [N ^2- (3-methyl-1,2,3, 4-tetrahydro-8-quinolinesulfonyl)-
A specific method for producing [L-arginyl] -2-piperidinecarboxylic acid is disclosed, and the raw material ^NG -nitro-N ^2-
(tert-butoxycarbonyl) -L-arginine in 3 steps
(2R, 4R) -1- [N G - nitro -N ² - (3- methyl-8-quinoline-sulfonyl) -L- arginyl] -4 that prepared methyl 2-piperidinecarboxylic acid ethyl ester, and Process (A)
Was reported to be 74.5%.

In addition, the scheme on pages 4 to 5 of Japanese Patent Publication No. 1-35000 discloses that an unprotected L-arginine (compound (II) in the scheme) is converted to a quinoline sulfonyl halide having a molar equivalent of about one equivalent. To produce N ² -quinoline sulfonyl-L-arginine (compound (IX) in the scheme), and then piperidine-2-carboxylic acid derivative (compound (IV) in the scheme) There is disclosed a method of the following scheme for reacting and reducing the quinolyl group and deprotecting the carboxyl group to produce the desired product. However, this method is not specifically shown by the Examples, or does not describe means for controlling a sulfonylation reaction on an unprotected guanidino group, which is a parallel side reaction which is naturally expected, so that the target compound is not described. It is impossible to obtain high selectivity, and it cannot be said that it is an industrially significant method.
Furthermore, there is no suggestion or teaching in this publication to react an arginine with a protected guanidino group (eg, compound (III) shown in the above scheme) with a quinoline sulfonyl halide according to this method.

[0008]

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[0009]

An object of the present invention is to provide a method for efficiently producing N ² -arylsulfonyl-L-argininamides on an industrial scale. Another object of the present invention is to provide N ² -arylsulfonyl-L-
It is to provide an intermediate compound useful for efficiently producing argininamides.

[0010]

DISCLOSURE OF THE INVENTION The present inventors have been diligently searching for a method for producing N ² -arylsulfonyl-L-argininamides which is more efficient than the production method described in the above-mentioned gazette. By first condensing L-arginine, whose group is protected with a nitro group, with quinoline sulfonyl halide, then reacting the piperidine-2-carboxylic acid derivative with an α-amino group in the presence of a certain compound, Each reaction can proceed very efficiently,
It has been found that the process can be simplified and the overall yield can be greatly improved.

[0011] The present invention, N ^G - nitro -L- arginine and 3- (a hydrogen atom or a lower alkyl) -8-quinolinesulfonyl chloride containing chloride and a step of condensing the N ² - (3- (
Hydrogen atom or lower alkyl) -8-quinolinesulfonyl) -N
It is intended to provide a method for producing ^G -nitro-L-arginine. According to another aspect of the present invention, N ² is a novel compound useful as active ingredients of medicaments - (3- (a hydrogen atom or a lower alkyl) -8-quinolinesulfonyl) -N ^G - nitro -L
-Arginine (preferably (2R, 4R) -4-methyl-1- [N ^2- (3-
N ^2- (3-Methyl-8-quinolinsulfonyl)-useful as an intermediate for the production of methyl-1,2,3,4-tetrahydro-8-quinolinsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid) ^NG -nitro-L-arginine is provided.

According to another aspect of the present invention, N ^2- (3-
(Hydrogen atom or lower alkyl) -8-quinolinesulfonyl)
-N ^G -Nitro-L-arginine and 4-methylpiperidine-2-
A carboxylic acid lower alkyl ester comprising the step of condensing 1- [N ^G - nitro -N ² - (3- (a hydrogen atom or a lower alkyl) -8-quinolinesulfonyl) -L- arginyl] -4-methyl-2
-A process for producing a lower alkyl ester of piperidine carboxylic acid is provided. According to yet another aspect: (a) ^NG −
Nitro-L-arginine is reacted with 3- (hydrogen atom or lower alkyl) -8-quinoline sulfonyl chloride to give N ²
- (3- (a hydrogen atom or a lower alkyl) -8-quinolinesulfonyl) -N ^G - process for producing a nitro -L- arginine; and
(b) the step is obtained N ² - (3- (a hydrogen atom or a lower alkyl) -8-quinolinesulfonyl) -N ^G - nitro -L- arginine 4-methyl-piperidine-2-carboxylic acid lower alkyl esters 1- [N ^G -nitro-N
^A process for producing a lower alkyl ester of 2- (3- (hydrogen atom or lower alkyl) -8-quinoline sulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid is provided.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, the notation 3- (hydrogen atom or lower alkyl) shown in a compound name means that the substituent at the 3-position is either a hydrogen atom or a lower alkyl group. Means that. Novel compound provided by the present invention: N ^2- (3- (hydrogen atom or lower alkyl) -8-
Quinoline sulfonyl) -N ^G - In nitro -L- arginine, the 3-position of the substituents are a linear or branched C _1-4 alkyl group, preferably a methyl group or an ethyl group, particularly preferably a methyl group Can be used.

N ^2- (3- (hydrogen atom or lower alkyl) -8-quinolinsulfonyl) -N ^G -nitro-L-arginine is represented by N
^It can be produced by condensing ^G -nitro-L-arginine with 3- (hydrogen atom or lower alkyl) -8-quinoline sulfonyl chloride. An example of the method is described in detail in the examples of the present specification. Usually, the reaction is performed by dissolving nitroarginine in an aqueous solution of a base such as sodium hydroxide, and then dissolving 3- (hydrogen atom or lower alkyl) -8 in an organic solvent that can be mixed with water (for example, tetrahydrofuran or acetone). -By mixing quinoline sulfonyl chloride with the above aqueous solution of nitroarginine. During the reaction, a base such as sodium carbonate may be further added.

The above reaction is preferably carried out under cooling, for example, at a temperature of about 0 to 10 ° C. ^NG used as raw material
-Nitro-L-arginine, and 3- (hydrogen atom or lower alkyl) -8-quinoline sulfonyl chloride (for example, 3-methyl-8-quinoline sulfonyl chloride, 3-ethyl-8-
Quinoline sulfonyl chloride) is a known compound, and can be produced, for example, by the method described in Japanese Patent Publication No. 4-984, or a commercially available product can be easily obtained. After completion of the reaction subjected to ordinary post-treatments, by performing purification such as chromatography or recrystallization as necessary, N ² - (3- (a hydrogen atom or a lower alkyl) -8-quinolinesulfonyl) -N ^G - Nitro-L-arginine can be isolated and purified. However, the above-mentioned reaction proceeds in extremely good yield and has few by-products, so that it is contained in an extract or the like obtained by ordinary post-treatment without isolating and purifying the target product in the usual case. The crude product can be used as it is in the next step.

[0016] The N ² - using nitro -L- arginine, useful as active ingredients of medicaments N ² - - (3- (a hydrogen atom or a lower alkyl) -8-quinolinesulfonyl) -N ^G arylsulfonyl - L-argininamides (preferably, 4-methyl-1- [N ^2- (3- (hydrogen atom or lower alkyl) -1,2,3,4-
Tetrahydro-8-quinolinesulfonyl) -L-arginyl]-
2-piperidinecarboxylic acid) can be produced efficiently. For example, N ² - (3- (a hydrogen atom or a lower alkyl) -8-quinolinesulfonyl) -N ^G - nitro -L- arginine 4-methyl-2-piperidinecarboxylic acid lower alkyl ester and condensed l- [ N ^G -nitro-N ^2- (3- (hydrogen atom or lower alkyl) -8-quinolinesulfonyl) -L-arginyl] -4-methyl-2-piperidinecarboxylic acid lower alkyl ester was produced, and the lower After hydrolyzing the alkyl ester, the obtained carboxylic acid derivative is subjected to catalytic reduction to obtain 4-methyl-1- [N ^2- (3- (hydrogen atom or lower alkyl) -1,2 with high yield. , 3,4-Tetrahydro-8-quinolinesulfonyl) -L-arginyl] -2-piperidinecarboxylic acid.

The lower alkyl ester of 4-methyl-2-piperidinecarboxylic acid lower alkyl ester used in the above reaction includes, for example, a linear or branched C _1-4 alkyl group, preferably a methyl or ethyl group, Particularly preferably, an ethyl group can be used. Further, since the piperidine derivative has two asymmetric carbons, there are optical isomers and diastereoisomers. These pure isomers may be used in the process of the present invention, but any mixtures thereof may be used. When using an optically active substance, its configuration is not particularly limited, for example,
It is preferable to use (2R, 4R) -4-methyl-2-piperidinecarboxylic acid lower alkyl ester. It is particularly preferable to use (2R, 4R) -4-methyl-2-piperidinecarboxylic acid ethyl ester as the ester compound. These piperidine derivatives can be easily obtained by the methods described in, for example, JP-B-61-25029, JP-B-62-34035, and JP-A-2-212473.

[0018] The 4-methyl-2-piperidinecarboxylic acid lower alkyl ester N ² - in engaged nitro -L- arginine and condensation - (3- (a hydrogen atom or a lower alkyl) -8-quinolinesulfonyl) -N ^G Any method may be employed as long as it can be used as a method for dehydrating and condensing an amino group and a carboxyl group, such as an acid halide method, a mixed acid anhydride method, an active ester method, or a method using a condensing agent. As a preferred embodiment of the present invention, a method for performing condensation using phosphorus oxychloride is described in detail in Examples. This reaction can be carried out usually in an organic solvent such as tetrahydrofuran at 10 ° C or lower, preferably at 5 ° C or lower, particularly preferably at 0 ° C or lower. After dropping phosphorus oxychloride, 4-
The reaction is carried out by sequentially adding methyl-2-piperidinecarboxylic acid lower alkyl ester and a suitable base such as triethylamine to the reaction system.

When the reaction is carried out using a condensing agent, the condensing agent is not particularly limited. For example, N ', N'-dicycloalkylcarbodiimides such as N', N'-dicyclohexylcarbodiimide (DCC); Carbodiimide derivatives such as -ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAPC) and benzotriazole derivatives such as 1-hydroxybenzotriazole (HOBT), N-hydroxy derivatives,
Disulfide compounds, succinic acid compounds, phosphinic chloride compounds, oxalate derivatives; triarylphosphines, N-lower alkyl-5-arylisoxazolium-3'-sulfonates, diheteroaryl diselenides , Arylsulfonyltriazolides,
2-Halo-1-lower alkylpyridinium halides, diarylphosphoryl azides, imidazole derivatives, dicarboximide derivatives, and the like can be used.

When the active ester method is used, examples of the active esterifying agent include N-hydroxysuccinimide and 1-hydroxysuccinimide.
Examples include N-hydroxy compounds such as hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide or disulfide compounds such as dipyridyl disulfide. When a carboxyl group is converted into an acid halide according to the acid halide method, for example, phosphorus pentachloride, thionyl chloride, oxalyl chloride, or the like can be used as a halogenating agent. However, a method and a reagent for condensing the above compound can be appropriately selected by those skilled in the art, and are not limited to the above.

1- [N ^G -nitro] produced as described above
-N ² - (3- (a hydrogen atom or a lower alkyl) -8-quinolinesulfonyl) -L- arginyl] -4-methyl-2-piperidine carboxylic acid lower alkyl ester, hydrolysis and catalytic method known per se By subjecting it to reduction, 4-methyl-
1- [N ^2- (3- (hydrogen atom or lower alkyl) -1,2,3,4-tetrahydro-8-quinolinsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid, preferably 4-methyl- 1- [N ^2- (3-methyl-1,2,3,4-tetrahydro-8-quinolinsulfonyl) -L-
Arginyl] -2-piperidinecarboxylic acid, more preferably
(2R, 4R) -4-methyl-1- [N ^2- (3-methyl-1,2,3,4-tetrahydro-8-quinolinsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid, particularly preferred Is (2R, 4R) -4-methyl-1-
[N ^2- (3-Methyl-1,2,3,4-tetrahydro-8-quinolinsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid monohydrate can be produced. For example, Tokiwa 1-3500
The methods of steps (D) and (E) described on page 8 to 9 of No. 0, or the steps (D) and (E) described on page 7 to 8 of JP-B-61-48829. It is preferable to carry out the reaction according to a method or the like.

[0022]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to these examples. (1) 20 g of ^NG -nitro-L-arginine was dissolved in a 25% aqueous sodium hydroxide solution, and 9.7 g of sodium carbonate was added to the aqueous solution. The reaction mixture was cooled,
-A solution of 27.4 g of quinoline sulfonyl chloride in tetrahydrofuran (360 ml) was added dropwise, and after completion of the addition, the reaction solution was returned to room temperature and stirred for 2 hours. The reaction solution was adjusted to pH 2.7 with dilute hydrochloric acid under water cooling, and the solvent was distilled off under reduced pressure. 270 ml of methanol was added, and the mixture was further evaporated under reduced pressure. The slurry obtained by cooling was filtered, washed with water, and N ^2- (3-
Methyl-8-quinoline-sulfonyl) -N ^G - was obtained nitro -L- arginine (35 g). Melting point 196-198 ° C Optical rotation [α] _D ²⁴ + 116 ° C (c = 1, 2N HCl) IR (kBr, cm ^-1 ) 1700, 1650, 1330, 1170

[0023] ⁽²⁾ N 2 - (3- methyl-8-quinoline-sulfonyl) -N ^G - cooled nitro -L- arginine (35 g) for dissolution to -10 ° C. in tetrahydrofuran (360 ml). 19.5 g of phosphorus oxychloride in tetrahydrofuran (9
0 ml) solution was added dropwise at -10 ° C. Next, (2R, 4R) -4-methylpiperidine-2-carboxylic acid ethyl ester (20 g)
Of tetrahydrofuran (90 ml) to the above reaction mixture
At 0 ° C, add 24 g of triethylamine at -10 ° C.
Was dropped. After completion of the dropwise addition, the reaction solution was stirred at -5 ° C for 1 hour. After completion of the reaction, by the addition of 330 ml saturated brine, and the mixture is separated, (2R, 4R) -1- [ N G - nitro -N ² - (3- methyl-8-quinoline-sulfonyl) -L- arginyl] -4 A solution of ethyl-methyl-2-piperidinecarboxylate in tetrahydrofuran was obtained. The total yield of the above steps (1) and (2) is 78%
Met.

(3) (2R, 4R) -1- [N ^G obtained in the above (2)
- Nitro -N ² - (3- methyl-8-quinoline-sulfonyl) -L- arginyl] -4-methyl-2-piperidinecarboxylic acid ethyl ester, example of KOKOKU 2-31055 Patent Publication No. 7 pp (D )
And according to the method shown in (E), (2R, 4R) -4-methyl-1-
[N ^2- (3-Methyl-1,2,3,4-tetrahydro-8-quinolinsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid monohydrate crystals were obtained. The IR spectrum of this monohydrate crystal was identical to that of the compound manufactured and sold under the generic name “argatroban”.

[0025]

According to the method of the present invention, on an industrial scale,
It is possible to efficiently produce N ² -arylsulfonyl-L-argininamides. Further, N ² provided by the present invention - (3- (a hydrogen atom or a lower alkyl) -8-quinolinesulfonyl) -N ^G - nitro -L- arginine, useful as active ingredients of medicaments N ² - arylsulfonyl -L- It is useful as a production intermediate for efficiently producing argininamides.

Claims (9)

[Claims] 1. A method comprising condensing ^NG -nitro-L-arginine with 3- (hydrogen atom or lower alkyl) -8-quinoline sulfonyl chloride, comprising the step of condensing N ^2- (3- (hydrogen atom or lower alkyl) -8-Quinolinesulfonyl) -N ^G -nitro-L-
Method for producing arginine. 2. N ^2- (3- (hydrogen atom or lower alkyl) -8-
Quinoline sulfonyl) -N ^G - nitro -L- arginine. (3) (2R, 4R) -4-methyl-1- [N ^2- (3-methyl-1,
The compound according to claim 2, which is used as an intermediate for producing 2,3,4-tetrahydro-8-quinolinsulfonyl) -L-arginyl] -2-piperidinecarboxylic acid. 4. N ^2- (3- (hydrogen atom or lower alkyl) -8-
Quinoline sulfonyl) -N ^G - and nitro -L- arginine 4-
Comprising the step of condensation of methyl piperidine-2-carboxylic acid lower alkyl ester, 1- [N ^G - nitro -N ² - (3- (a hydrogen atom or a lower alkyl) -8-quinolinesulfonyl) -L- arginyl] A method for producing a lower alkyl ester of -4-methyl-2-piperidinecarboxylic acid. 5. The method according to claim 4, wherein the condensation step is performed in the presence of phosphorus oxychloride. 6. The method according to claim 4, wherein the ester compound is (2R, 4R) -4-methylpiperidine-2-carboxylic acid ethyl ester. 7. 1- [N ^G -nitro-N ^2- (3- (hydrogen atom or lower alkyl) -8-quinolinsulfonyl) -L-arginyl] -4-
A method for producing a lower alkyl ester of methyl-2-piperidinecarboxylic acid, comprising the steps of (a) reacting ^NG -nitro-L-arginine with 3- (hydrogen atom or lower alkyl) -8-quinoline sulfonyl chloride. by reacting N ² - (3- (a hydrogen atom or a lower alkyl) -8-quinolinesulfonyl) -N ^G - producing nitro -L- arginine; and (b) N ² obtained in the above step - ( 3- (a hydrogen atom or a lower alkyl) -8-quinolinesulfonyl) -N ^G - nitro -L
-A process comprising the step of condensing arginine with a lower alkyl ester of 4-methylpiperidine-2-carboxylic acid. 8. A method according to claim 7, wherein the 1-
[N ^G - nitro -N ² - (3- (a hydrogen atom or a lower alkyl) -8-quinolinesulfonyl) -L- arginyl] -4 After hydrolysis of methyl 2-piperidine carboxylic acid lower alkyl ester, contact Reduction to give (2R, 4R) -4-methyl-1- [N ^2- (3-methyl-
1,2,3,4-tetrahydro-8-quinolinesulfonyl) -L-arginyl] -2-piperidinecarboxylic acid. 9. Use of 3-methyl-8-quinoline sulfonyl chloride as 3- (hydrogen atom or lower alkyl) -8-quinoline sulfonyl chloride, 4-methylpiperidine-2-
The method according to claim 7 or 8, wherein (2R, 4R) -4-methylpiperidine-2-carboxylic acid ethyl ester is used as the carboxylic acid lower alkyl ester.