JPH0455426B2 - - Google Patents

Description

[Detailed description of the invention]

<Industrial Application Field> The present invention relates to a method for producing 1,4-dihydropyridine-monoester-monocarboxylic acid. More specifically, 1,4-
The present invention relates to a method for producing dihydropyridine monoester-monocarboxylic acid. <Prior art> 1,4-dihydropyridine-3,5-dicarboxylic acid diesters have blood flow increasing effects and blood pressure lowering effects, and are widely used as pharmaceuticals. Monoester monocarboxylic acid derivatives of 1,4-dihydropyridine-3,5-dicarboxylic acid are important intermediates for such useful diesters, and methods for producing the monoester monocarboxylic acids are known. That is, a production method using a symmetrical diester as a raw material and a hydrolysis reaction under alkaline conditions [References J. Heterocycl. Chem., Vo112,
363 (1975)] or a production method using a symmetric diester with the nitrogen atom at the first position protected [Chem.Pharm.Bull., vo127, 2809 (1980)], etc. are known. <Problems to be Solved by the Invention> However, according to the former method, the yield of the target product is reported to be only 2%. The latter method is also not necessarily satisfactory. There is no known method for producing such monoester-monocarboxylic acid derivatives of 1,4-dihydropyridine-3,5-dicarboxylic acid selectively and in high yields under mild reaction conditions. <Means for solving the invention> The present inventors have discovered that 1,4-dihydropyridine-
Monoester of 3,5-dicarboxylic acid As a result of intensive research aimed at finding a method to selectively produce monocarboxylic acid in high yield under mild reaction conditions, we found that a specific 1,4-dihydropyridine derivative and tricarboxylic acid The present invention was achieved by discovering that the above object can be achieved by reacting with an alkyl iodosilane. The present invention is based on the following formula [] In the formula, R ¹ and R ² are hydrogen atoms, halogen atoms,
Or it represents a nitro group, and R ¹ and R ² are not hydrogen atoms at the same time. R ³ and R ⁶ represent a C ₁ to C ₅ straight chain or optionally branched alkyl group, R ⁴ represents a C ₃ to _{C 6} branched alkyl or benzyl group, and R ⁵
teeth

[Formula] (In the formula, R ¹⁰ and R ¹¹ represent a C ₁ to _{C 3} alkyl group or a benzyl group.)
Represents a _C1 to _C6 alkyl group. 1,4-dihydropyridine-diester derivative represented by and the following formula [] In the formula, R ⁷ , R ⁸ and R ⁹ represent a C ₁ to C ₄ alkyl group which may be linear or branched. The following formula [] is characterized by reacting with a trialkyliodosilane represented by and then hydrolyzing it. In the formula, R ¹ , R ² , R ³ , R ⁵ and R ⁶ are as defined above. This is a method for producing 1,4-dihydropyridine monoester monocarboxylic acid represented by: In the above formula [], R ¹ and R ² are hydrogen atoms,
R ¹ represents a halogen atom, such as a fluorine atom, a chlorine atom, a bromine atom, and further represents a nitro group.
and R ² are not hydrogen atoms at the same time. R ³ and R ⁶ may be the same or different and represent a C ₁ to _{C 5} straight-chain or branched lower alkyl group, such as methyl, ethyl, n
-propyl, iso-propyl, n-butyl, iso-
Represents butyl, sec-butyl, tert-butyl, n-bentyl, etc. R ⁴ represents a C ₃ to C ₆ branched lower alkyl group, such as iso-propyl, iso-butyl,
sec-butyl, tert-butyl, iso-pentyl,
Examples include neo-pentyl, t-pentyl, 1,1-dimethylbutyl, among others, tert-pentyl, t-pentyl, 1,1-dimethylbutyl, etc.
-Butyl is preferred. Moreover, R ⁴ represents a benzyl group. ^R5 is

[Formula] (wherein R ⁹ and R ¹⁰ represent a C ₁ to C ₆ alkyl group which may be substituted with (representing a C ₁ to _{C 3} alkyl group or a benzyl group). R ⁵ is In particular, a group different from R ⁴ is preferred. The compound can be produced by a conventionally known method (Reference, Chem Pharm Bull vol. 27,
1426 (1979)). In the above formula [], R ⁷ , R ⁸ and R ⁹ may be the same or different and represent a C ₁ to _{C 4} linear or branched lower alkyl group (e.g. methyl,
(ethyl, propyl, butyl, pentyl, etc.). According to the present invention, 1 represented by the above formula [],
By reacting the 4-dihydropyridine-diester derivative with trialkyliodosilane represented by the above formula [], one of the ester residues is selectively cleaved to form 1,4 represented by the above formula [].
-dihydropyridine monoester monocarboxylic acid can be produced. That is, 1,4- expressed by the above formula []
One equivalent of the dihydropyridine diester derivative and 1 to 10 equivalents, preferably 1.5 to 3 equivalents, of the trialkyliodosilane represented by the above formula [] are mixed without a solvent or with a dry aprotic solvent, such as a halogenated hydrocarbon, specifically the above-mentioned Dichloromethane, chloroform, carbon tetrachloride; for example, nitriles, specifically acetonitrile; for example, amides, specifically dimethylformamide, etc.; carried out at -10 to 120°C, preferably in the range of 0° to 100°C. Can be done. The reaction time varies depending on the reaction conditions, but may be carried out for 30 minutes to 48 hours. The reaction mixture is treated with water containing a reducing agent such as sodium thiosulfate, sodium sulfite, etc., and then the target product is separated by normal operations, and if necessary, normal purification operations such as recrystallization chromatography etc. If you do this, you can collect the target object. <Effects of the Invention> According to the production method of the present invention, the desired 1,4-dihydropyridine monoester monocarboxylic acid can be selectively provided in a good yield under mild reaction conditions by a simple method. can. <Examples> The present invention will be explained in more detail below using examples. Reference example 1 2,6-dimethyl-4-(3-nitrophenyl)
Synthesis of -1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-tert-butyl ester Dissolve m-nitrobenzaldehyde (4.53 g) and methyl acetoacetate (3.48 g) in toluene (20 ml). Then, HCl gas was passed through the solution for about 15 minutes under ice cooling, and the solution was left overnight. The reaction mixture was washed with water, dehydrated and dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in isopronol (40ml) and 3-aminocrotonic acid tert-butyl ester was added followed by triethylamine (3.0g). After heating the mixture under reflux for 2 hours, the solvent was distilled off, and the residue was dissolved in dichloromethane, washed with dilute hydrochloric acid, and then with water. After the organic phase was dehydrated and dried using sodium sulfate, the solvent was distilled off. The residue was crystallized from n-hexane and ether to obtain 10.2 g of the desired product. The physical property values are as follows. MS M ⁺ /e 388 NMR δppm (CDCl ₃ ) 8.1-7.2 (4H, m), 5.86 (1H, Bs), 5.00 (1H, s), {3.60 (3H, s)}, 2.30 (6H, s) , 1,38 (9H, s) Reference Example 2 Synthesis of tert-butylethyl 3-aminocrotonate Tert-butyl acetoacetate (20.0 g) was dissolved in methanol (40 ml), and ammonia gas was passed through it for 10 minutes under ice cooling. . Attach cold fingers of dry ice and leave overnight. The solvent was distilled off and the residue contained n-
When hexane was added and the mixture was cooled to -30°C, it crystallized.
The desired product 15.1G was obtained by recrystallization from n-hexane. mp 35−37℃ NMR δppm (CDCl ₃ ) 4.34 (1H, s), 1.86 (3H, s), 1.42 (9H,
s) Elemental analysis C ₈ H ₁₅ N ₁ O ₂ Experimental value C: 60.8%, H: 9.6%, N: 8.8% Theoretical value C: 61.1%, H: 9.6%. N; 8.9% Example 1 2,6-dimethyl-4-(3-nitrophenyl)
Synthesis of -1,4-dihydropyridine-3-methoxycarbonyl-5-carboxylic acid 2,6-dimethyl-4-(3-nitrophenyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-tert-butyl ester (1.158 g) was dried in chloroform (20
ml), and trimethyliodosilane (0.6 ml) was added dropwise in an argon atmosphere at room temperature. After stirring overnight at room temperature, ice-cooled aqueous sodium sulfite solution was added to the reaction mixture, causing discoloration. Add 2N hydrochloric acid
When the pH was adjusted to 1.0 and the mixture was left to cool on ice, crystals were precipitated, which were collected and recrystallized from methanol to obtain 0.8 g of the desired product. The physical property values are as follows. mp 222−223° (decomp) NMR δppm (CD ₃ OD−CD ₃ SOCD ₃ ) 7.9–7.2 (4H, m), 5.03 (1H, s), 3.56 (3H, s), 2.31 (6H, s) Implementation Example 2 2,6-dimethyl-4-(2-fluoro-5-
Synthesis of 2,6-dimethyl-4-(2-fluoro-5-nitrophenyl)-1,4-dihydropyridine-3-methoxycarbonyl-5-carboxylic acid
Nitrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid-3-methyl ester-5
-tert-butyl ester (4.06 g) was dissolved in dry chloroform (40 ml), and trimethyliodosilane (2.17 ml) was added dropwise at room temperature in an argon stream and stirred overnight. An aqueous sodium thiosulfate solution was added to the reddish-brown colored reaction mixture and the mixture was stirred, causing the color to fade. The pH was adjusted to 2.0 with dilute hydrochloric acid under ice cooling, and crystals were precipitated when left to stand. Recrystallization from methanol-ethyl acetate yielded 2.1 g of the desired product. mp 239−241° (decomp) Elemental analysis value C ₁₆ H ₁₅ FN ₂ O ₆ Experimental value C 58.7% H 4.3% N 8.0% Theoretical value C 54.4% H 4.2% N 7.9% Example 3 2,6-dimethyl- 4-(2-fluoro-5-
Nitrophenyl)1,4-dihydropyridine-
Synthesis of 3-methoxycarbonyl-5-carboxylic acid 2,6-dimethyl-4-(2-fluoro-5-
Nitrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid-3-methyl ester-5
-Benzyl ester (440 mg) was dissolved in dry chloroform, trimethyliodosilane (0.2 ml) was added at room temperature in an argon stream, and the mixture was stirred overnight.
The product was treated in a conventional manner to obtain 200 mg of the desired product. The physical properties were the same as those of Example 2. Example 4 2,6-dimethyl-4-(2-fluoro-5-
Nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid [5-[3-(N-benzyl-
Synthesis of N-methylamino)-2,2-dimethylpropoxycarbonyl]-3-carboxylic acid 2,6-dimethyl-4-(2-fluoro-5-
Nitrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid-3-tert-butyl ester-5-[3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl] ester (405 mg) was dissolved in dry chloroform (2 ml). Trimethyliodosilane (0.14 ml) was added dropwise at room temperature in an argon stream, and the mixture was stirred overnight. When sodium thiosulfate was added to the reddish-brown colored reaction solution, the color faded. After adjusting the pH to 2.0 with dilute hydrochloric acid, the mixture was extracted with chloroform, the organic phase was separated, washed with water, dehydrated and dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and chloroform-
Fractions eluted with an ethyl acetate-methanol mixture (7:3:0.7) were collected to yield 195 mg of the desired product. The physical property values are as follows. mp 148−152° (decomp) NMR δppm (CDCl ₃ − CD ₃ OD) 8.2−6.7 (8H, m), 5.2 (1H, s), 3.75 (2H, q, J = 15Hz), 3.57 (2H, s ), 2.40 (2H, s), 2.20 (9H, s), 0.82 (6H, s) IR cm ^-1 (KBr) 3400−2800, 1675, 1600, 1530, 1490,
1350,132 0,1250,1220 Example 5 2,6-dimethyl-4-(3-nitrophenyl)
Synthesis of -1,4-dihydropyridine-3-isopropoxycarbonyl-5-carboxylic acid 2,6-dimethyl-4-(3-nitrophenyl)
The desired product (190
mg) was obtained. The physical property values are as follows. mp 182−184° (decomp) MS M ⁺ /e360

Claims (1)

[Claims] 1. The following formula [] In the formula, R ¹ and R ² are hydrogen atoms, halogen atoms,
or represents a nitro group, and R ¹ and R ² are not hydrogen atoms at the same time. R ³ and R ⁶ represent a C ₁ to C ₅ straight chain or optionally branched alkyl group, R ⁴ represents a C ₃ to _{C 6} branched alkyl group or a benzyl group, and R ⁵
represents a C 1 -C ₆ alkyl group which may be substituted with [Formula] (wherein R ¹⁰ and R ¹¹ represent a C _{1 -C 3} alkyl group or a benzyl group). 1,4-dihydropyridine derivative represented by and the following formula [] In the formula, R ⁷ , R ⁸ and R ⁹ represent a C ₁ to C ₄ alkyl group which may be linear or branched. The following formula [] is characterized by reacting a trialkyliodosilane represented by and then hydrolyzing it. In the formula, R ¹ , R ² , R ³ , R ⁵ and R ⁶ are as defined above. A method for producing 1,4-dihydropyridine-monoester-monocarboxylic acid represented by