JPH0348180B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides 2-carbamoyloxyalkyl-
The present invention relates to a novel method for producing 1,4-dihydropyridine derivatives. 2-Carbamoyloxyalkyl-1,4-dihydropyridine derivatives are
The substituents at position and 6 have an asymmetric structure, which is described in the patent application filed by the present inventors, JP-A-57-118565. However, according to the method described in the publication, in order to produce a dihydropyridine derivative having a carbamoyloxyalkyl group at the 2-position, a 2-hydroxydihydropyridine derivative must be used as a starting material; The conventional manufacturing method cannot be said to be an industrially preferable method since it requires multiple manufacturing steps, and a better manufacturing method is desired. In synthesizing asymmetric 1,4-dihydropyridine derivatives, conventional methods have used 4-substituted acetoacetate, 4-substituted-2-ylideneacetoacetate, or 4-substituted-3-aminocrotonic acid ester as raw materials. (Japanese Patent Application Laid-open No. 52-5777, Japanese Patent Application Laid-open No. 53-79873). However, 4-carbamoyloxy-3 of the enamine compound, which is considered as a raw material when synthesizing 1,4-dihydropyridine derivatives with an asymmetric structure,
-Aminocrotonic acid ester or 4-carbamoyloxytetrolic acid ester of an acetylene compound has not been described in literature so far. As a result of intensive research, the present inventors found that 4-carbamoyloxy is a raw material for synthesizing 2-carbamoyloxyalkyl-1,4-dihydropyridine derivatives in which the substituents at the 2- and 6-positions of the dihydropyridine ring are asymmetric. -2-Carbamoyloxyalkyl-1, 2-carbamoyloxyalkyl-1,
The present invention was completed by discovering that 4-dihydropyridine derivatives can be synthesized. The present invention is based on the general formula () [In the formula, R ¹ means a halogen atom, a cyano group, a nitro group, or a lower alkoxy group, and R ² and
R ³ are the same or different, lower alkyl, group,
Haloalkyl group, lower alkenyl group, lower alkynyl group, aralkyl group, aryl group, hydroxyalkyl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group, or

[Formula] (B represents a linear or branched alkylene group, R ⁶ and R ⁷ are the same or different and each represents a lower alkyl group, an aralkyl group, or an aryl group. However, R ⁶ and R ⁷ may form a heterocyclic group together with a nitrogen atom)
, R ⁴ represents a hydrogen atom or a lower alkyl group, A represents an alkylene group, and R ⁵ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkenyl group, an aralkyl group, or an aryl group, respectively. In producing a 2-carbamoyloxyalkyl-1,4-dihydropyridine derivative represented by (a) the general formula [] An enamine compound represented by the general formula (wherein R ³ , A and R ⁵ have the same meanings as above) [In the formula, R ¹ , R ² and R ⁴ have the same meanings as above] or (b) the enamine compound of the above general formula () is reacted with the enamine compound of the general formula () Aldehyde compounds represented by the general formula () R ⁴ −CO−CH 2 −COOR ² () [wherein R 2 and R ⁴ have the same meanings ^as above] and the general formula () R 4 −CO−CH ₂ −COOR ² () do〕
(c) General formula () R ³ OOC-C≡C-A-OCONH-R ⁵
() [In the formula, R ³ , A and R ⁵ have the same meanings as above] is reacted with the benzylidene compound of the above general formula () and ammonia or a salt thereof, or (d) the above 2-carbamoyloxyalkyl of general formula () characterized by reacting an acetylene compound of general formula () with an aldehyde compound of the above general formula (), a β-ketoester compound of the above general formula (), and ammonia or a salt thereof. The present invention relates to a method for producing -1,4-dihydropyridine derivatives. Compound (2) obtained by the method of the present invention
Specific examples of preferred substituents of the -carbamoyloxyalkyl-1,4-dihydropyridine derivatives will be described below. Examples of R ¹ include halogen atoms such as fluorine, chlorine, bromine and iodine, cyano groups, nitro groups, hydroxyl groups, disubstituted amino groups such as dimethylamino, diethylamino and dipropylamino, or methoxy, ethoxy, propoxy and butoxy. and lower alkoxy groups. The lower alkyl group for R ² and R ³ is methyl,
Examples of haloalkyl groups include ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl, and examples of haloalkyl groups include β-chloroethyl, β-bromoethyl, β-chloropropyl, γ
-chloropropyl, ω-chlorobutyl, β, β-
dichloroethyl, trifluoromethyl and β,
Examples of lower alkenyl groups include vinyl, allyl, 3-butenyl, and isopropenyl; lower alkynyl groups include propargyl and 2-butynyl; and aralkyl groups include benzyl and α-methylbenzyl. Aryl groups include phenyl and naphthyl groups, and hydroxyalkyl groups include β-hydroxyethyl, β-
Hydroxypropyl, β-hydroxybutyl, γ
-Hydroxypropyl, ω-hydroxybutyl, β, γ-dihydroxypropyl, etc.; lower alkoxyalkyl groups include β-methoxyethyl, β-ethoxyethyl, β-propoxyethyl, β-isopropoxyethyl, β-butoxyethyl, β-isobutoxyethyl, β-tert-butoxyethyl, β-methoxypropyl, β-ethoxypropyl, β-propoxypropyl, β-isopropoxypropyl, β-butoxypropyl, γ-methoxypropyl, γ-ethoxypropyl, γ- Propoxypropyl, γ-butoxypropyl, ω-propoxybutyl, etc., and lower alkenyloxyalkyl groups include β-vinyloxyethyl, β-allyloxyethyl, β-(3-butenyloxy)ethyl, β-isopropenyloxyethyl, and β-allyloxypropyl, etc.
Aralkyloxyalkyl groups include β-benzyloxyethyl, β-phenethyloxyethyl and β-(αmethylbenzyloxy)ethyl, and aryloxyalkyl groups include β-phenoxyethyl, β-phenoxypropyl and β-phenoxypropyl.
phenoxybutyl etc., or

[References: K. Bowden etal., “Researches on acetylenic compounds. ．． (A)The addition of amines to ethynyl ketones. J.Chem.Soc., 1946, 45-52, (1946)]

The raw materials () used in methods (c) and (d) are:
As shown in the following reaction formula, any of the following can be produced by reacting a known 3-hydroxyalkylpropiolic acid ester () with an isocyanate (). [References: SRSandler and W. Karo,
“Organic Functional Group Preparations”
Vol.2, chapters.10, 11, Academic Press
(1971)] R ³ OOCC≡C-A-OH+R ⁵ NCO→R ³ OOCC
≡C-A-OCONH-R ⁵ () ()
() The manufacturing method of the present invention will be explained in detail below. Methods (a) and (b) relate to a method for producing compound () by reacting an enamine compound () with a benzylidene compound () or an aldehyde compound () and a β-ketoester compound (). The reaction conditions for producing compound () in methods (a) and (b) are appropriately selected depending on the type of raw material used, but generally the benzylidene compound () is )
Alternatively, the aldehyde compound ( ) and the β-ketoester compound ( ) are each preferably used in approximately equimolar amounts. The molar ratio can be varied over a wide range without adversely affecting the results. The reaction temperature is usually carried out under cooling, room temperature, or heating. As the reaction solvent, water, an inert organic solvent, or a mixed solvent of water and an inert organic solvent can be used. Examples of the inert organic solvent include alcohols such as methanol, ethanol, propanol, isopropanol, and butanol, diethyl ether,
Dioxane, tetrahydrofuran, acetonitrile, acetone, N,N-dimethylformamide,
Ethyl acetate, benzene and chloroform are used. The reaction can be promoted using a catalyst such as an acid such as acetic acid, a base such as piperidine, or a salt of an acid and a base. Methods (c) and (d) involve the use of an acetylene compound (), a benzylidene compound (), and ammonia or its salt, or an aldehyde compound (), β-
The present invention relates to a method for producing a ketoester compound () and a compound () by reaction with ammonia or a salt thereof. The reaction conditions for producing compound () in methods (c) and (d) are appropriately selected depending on the type of raw materials used, but generally the acetylene compound () and benzylidene compound () involved in the reaction are ), aldehyde compound () and β-ketoester compound () are each used in approximately equimolar amounts, and ammonia or its salt is used in excess. The molar ratio can be varied over a wide range without adversely affecting the results. Ammonia salts include acetic acid, formic acid, tartaric acid,
Ammonium salts of organic acids such as benzoic acid and phenylacetic acid, ammonium salts of inorganic acids such as carbonic acid and boric acid, etc. are used. The reaction temperature is usually carried out under cooling, room temperature, or heating. As the reaction solvent, water, an inert organic solvent, or a mixed solvent of water and an inert organic solvent can be used. Examples of inert organic solvents used include alcohols such as methanol, ethanol, propanol, isopropanol and butanol, diethyl ether, dioxane, tetrahydrofuran, acetonitrile, acetone, N,N-dimethylformamide, ethyl acetate, benzene and chloroform. The reaction can be promoted using a catalyst such as an acid, a base, or a salt of an acid and a base. The compound () synthesized by the method of the present invention is purified, isolated, and collected by conventional operations such as extraction using an organic solvent, separation and purification by chromatography using a carrier such as silica gel or alumina, and crystallization. be able to. Further, in the case of a compound having salt-forming ability, it can be an addition salt of an inorganic acid such as hydrochloric acid or an organic acid such as citric acid. The compound () obtained by the method of the present invention has vasodilatory and blood pressure lowering effects, and has particularly strong coronary vasodilatory action and extremely low toxicity, resulting in hypertension, cardiac dysfunction, angina pectoris, myocardial infarction, and cerebral infarction. It is a drug that is expected to treat circulatory system diseases such as vascular disorders. Pharmacology A drug efficacy test and a toxicity test were conducted on the 2-carbamoyloxy-1,4-dihydropyridine derivative obtained by the method of the present invention. (1) Test method (a) Coronary artery dilator effect Coronary artery dilator effect was examined by the Langendorff method using isolated rabbit hearts. The strength of the coronary dilator effect was evaluated by the sample dose that increased the coronary blood flow by 50%, ie, ICD ₅₀ (g/ml). Literature: O. Langendorff; Pflu¨gers arch.ges.
phisiol., 61, 291-332 (1895). (b) Acute toxicity test DM male mice (18-22g) were administered intravenously according to the up-and-down method.
The _LD50 value was determined. (c) Coronary artery dilation effect in dogs Under anesthesia with pentobarbital sodium salt, a beagle dog (13-16 kg, male) was chest-opened, a probe was attached to the origin of the left anterior descending coronary artery of the heart, and an electromagnetic blood flow meter was measured. Coronary blood flow (CF) was measured. In addition, a probe was attached to the exposed right femoral artery and the femoral artery blood flow (FAF) was measured.
was measured using an electromagnetic blood flow meter. A cannula was inserted into the left femoral artery, and systemic blood pressure (BP) was measured invasively via a transducer. Heart rate (HR) was derived by electrocardiogram.
The sample solution was administered by injection into the right femoral artery. Coronary blood flow (CF), femoral artery blood flow (FAF),
In addition, heart rate (HR) was expressed as a % increase when each sample was injected relative to the respective control value when physiological saline was injected. Systemic blood pressure (BP) was expressed as % reduction relative to control. (2) Results The coronary artery dilation effect in isolated rabbit heart specimens and the acute toxicity in mice are shown in Tables 1(a) and 1(b) using the Langendorff method.

【table】

【table】

[Table] The compound obtained by the method of the present invention acts on coronary blood vessels and exhibits a strong coronary artery dilating effect.
Also, acute toxicity is 1/6 to 1/1 compared to nifedipine.
It has been reduced to 7 (intravenous injection). The coronary artery dilation effect in beagle dogs is shown in Table 2.

【table】

[Table] Five representative compounds obtained by the method of the present invention increase coronary blood flow (CF) in a dose-dependent manner, and the effect is as strong as or more potent than nifedipine. Furthermore, it exhibited a coronary artery dilating effect with almost no decrease in systemic blood pressure (BP), and a coronary artery dilating effect with almost no change in heart rate (HR). Therefore, it can be said that it is a coronary artery dilator that is easy to use and has reduced toxicity because it does not place a burden on the heart. Further, as a result of another pharmacological test, the compounds of Examples 3, 26, and 38 were observed to increase cerebral blood flow and peripheral blood flow by 40 to 50% when administered intravenously at a dose of 1 to 10 μg/Kg. From these facts, it can be said that the compound obtained by the method of the present invention is a cerebral vasodilator as well as a peripheral vasodilator. The compound () obtained by the method of the present invention is expected to be useful as a vasodilator and an antihypertensive agent, and the administration form for this purpose is generally intravenous, subcutaneous or intramuscular injection, or rectal administration. Examples include parenteral administration, and oral administration using tablets, powders, granules, capsules, sublingual tablets, syrups, and the like. The dosage varies depending on the patient's symptoms, age, weight, and dosage form, but the usual daily dose for adults is 0.1
The amount is from 1 to 1000 mg, preferably from 1 to 100 mg.
Each of the above formulations can be manufactured by a well-known method. Next, the manufacturing method of the present invention will be explained in detail with reference to Examples, but the present invention is not particularly limited thereto. Reference Example of Synthesis of Raw Materials 1 Methyl 4-hydroxytetrolate 11.5g
(0.1 mol) in dichloromethane (150 ml),
9.6 ml (0.11 mol) of chlorosulfonyl isocyanate is removed at -10 to -20°C. After stirring the reaction solution at -10°C for 30 minutes to react, 50 ml of water is added while cooling and maintaining the temperature at 0 to 5°C. The reaction mixture was separated into an aqueous layer and a dichloromethane layer, and the aqueous layer was extracted twice with ethyl acetate (100 ml). The ethyl acetate extract is washed with water, dehydrated with sodium sulfate, and then concentrated. When the concentrated solution is mixed with the above dichloromethane layer and concentrated under reduced pressure, crystals are generated. The crystals were collected and dried to give 14.3 g of methyl 4-carbamoyloxytetrolate (yield: 91
%) is obtained. mp; 113-114℃ UV; λ ^MeOH _nax. 207nm (ε2800) IR (KBr); 3410; 3350, 3300, 3220, 2250,
1750, 1700, 1620, 1440, 1320, 1295, 1090,
1050, 930, 750cm ^-1 . NMR (90Hz, DMSO- _d6 ); δ3.77 (s, 3H),
4.82 (s, 2H), 6.8 (broad s, 2H) Reference example 2 Methyl 4-carbamoyloxytetrolate
Dissolve 14.3g in methanol (200ml), add 35g of ammonium acetate, and stir at 50-60°C for 3 hours to react. The reaction mixture was concentrated under reduced pressure, and the oily residue was extracted with ethyl acetate (200 ml). The ethyl acetate extract is washed with water, dehydrated with anhydrous magnesium sulfate, and concentrated. The residue was crystallized from ethyl acetate to obtain 13 g of crystalline methyl 4-carbamoyloxy-3-aminocrotonate (yield: 82%). mp; 90-92℃ UV; λ ^MeOH _nax. 274nm (ε14000) IR (KBr); 3500, 3370, 3220, 1730, 1650,
1620, 1570, 1440, 1400, 1335, 1280, 1170,
1070, 950, 920, ^{800, 785cm -1} . NMR (90MHz, CDCl ₃ ); δ3.64 (s, 3H), 4.58
(s, 2H), 4.63 (s, 1H), 5.9 (broad s,
2H) 6.4-7.2 (broad, 2H). Example 1 of the process of the invention 9.4 g (50 mmol) of ethyl 4-carbamoyloxy-3-aminocrotonate and 13.2 g (50 mmol) of ethyl 2-(0-nitrobenzylidene)acetoacetate
mmol) in ethanol (200 ml), 60
Stir and react for 16 hours at ~70°C. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-hexane to give crystalline 4-(1-nitrophenyl)-2-carbamoyloxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarphonic acid. 12.6 g (yield 58%) of diethyl ester are obtained. mp; 128-132℃ UV; λ ^MeOH _nax. 235, 350nm IR (KBr); 3540, 3400, 3000, 1710, 1690,
1535, 1495, 1340, 1205, 1120, 1100, 1095,
780, 755, 715 cm ^-1 . NMR (90MHz, CDCl ₃ ); δ1.18 (t, J=7Hz,
6H), 2.35 (s, 3H), 4.15 (m, 4H), 5.38
(broad s, 4H), 5.96 (s, 1H), 7.1~8.0
(m, 5H). Examples 2 to 6 Compounds listed in Table 3 are obtained according to the method described in Example 1.

【table】

[Table] Example 7 10.1 g (50 mmol) of ethyl 4-N-methylcarbamoyloxy-3-aminocrotonate and 13.2 g (50 mmol) of ethyl 2-(0-nitrobenzylidene)acetoacetate were added to ethanol (200 ml).
and react by stirring at 60-70°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether-hexane to give crystalline 4-(0-nitrophenyl)-2-N-methylcarbamoyloxymethyl-6-methyl-1,4.
12.4 g (yield 55.5%) of -dihydropyridine-3,5-dicarboxylic acid diethyl ester are obtained. mp; 165-169℃ UV; λ ^MeOH _nax. 235, 350nm IR (KBr); 3380, 3000, 1690, 1680, 1535,
1495, 1355, 1280, 1205, 1100, 785, 760,
715 cm ^-1 . NMR (90MHz, CDCl ₃ ); δ1.2 (t, J=7Hz,
6H), 2.38 (s, 3H), 2.91 (d, J=6Hz,
3H), 4.18 (m, 4H), 5.15 (m, 1H), 5.38 (s,
2H), 5.98 (s, 1H), 7.2-8.0 (m, 5H). Examples 8 to 17 According to the method described in Example 7, the compounds listed in Table 4 are obtained.

【table】

【table】

【table】

[Table] Example 18 9.4 g (50 mmol) of ethyl 4-carbamoyloxy-3-aminocrotonate and 15.4 g (50 mmol) of 2-(m-nitrobenzylidene)acetoacetic acid β-ethoxyethyl ester were mixed with isopropyl alcohol (200 ml). ) and react by stirring at 60-70°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether-hexane to give crystalline 4-(m-nitrophenyl)-2-carbamoyloxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid. 12.9 g (yield 54%) of 3-ethyl ester 5-β-ethoxyethyl ester are obtained. mp; 135-138℃ UV; λ ^MeOH _nax. 236, 355nm IR (KBr); 3520, 3360, 2990, 1705, 1690,
1645, 1610, 1525, 1485, 1350, 1205, 1120,
1105, 1055, 905, 830, 780, 755, ^{720cm -1} . NMR (90MHz, DMSO-d ₆ ); δ1.07 (t, J=8
Hz, 3H), 1.15 (t, J=3Hz, 3H), 2.37 (s,
3H) 3.45, (q, J = 8Hz, 2H), 3.62 (t, J
=4Hz, 2H), 4.08 (q, J = 8Hz, 2H), 4.12
(t, J=4Hz, 2H), 4.97(d, J=12Hz,
1H), 5.1 (s, 1H), 5.13 (d, J=12Hz,
1H), 6.7 (br.s, 2H), 7.6-8.2 (m, 4H), 9.11
(s, 1H) Examples 19-32 According to the method described in Example 18, the compounds listed in Table 5 are obtained.

【table】

【table】

【table】

【table】

[Table] Example 33 10.1 g (50 mmol) of ethyl 4-N-methylcarbamoyloxy-3-aminocrotonate and β-2-(m-nitrobenzylidene)acetoacetate
Dissolve 15.4 g (50 mmol) of ethoxyethyl ester in n-propanol (200 ml) at 65-75℃.
Stir and react for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether-hexane to give crystalline 4-(m-nitrophenyl)-2-N-methylcarbamoyloxymethyl-6-methyl-1,4-dihydropyridine-3,5. -dicarboxylic acid 3-ethyl ester 5
-β-ethoxyethyl ester 11.1g (yield 45
%) is obtained. mp; 148-149℃ UV; λ ^MeOH _nax. 236, 355nm IR (KBr); 3390, 3280, 2980, 1680, 1640,
1610, 1535, 1480, 1355, 1280, 1205, 1120,
1095, 905, 830, 780, 760, 715 cm ^-1 . NMR (90MHz, DMSO- _d6 ); δ1.11 (t, J=8
Hz, 3H), 1.19 (t, J=7Hz, 3H), 2.39 (s,
3H), 2.67 (d, J = 4.5Hz, 3H), 3.48 (q, J
=8Hz, 2H), 3.65 (t, J = 5Hz, 2H), 4.12
(q, J=7Hz, 2H), 4.15(t, J=5Hz,
2H), 5.06 (d, J=12Hz, 1H), 5.14 (s,
1H), 5.18 (d, J=12Hz, 1H), 7.22 (m,
1H), 7.6-8.25 (m, 4H), 9.18 (s, 1H). Examples 34 to 42 According to the method described in Example 33, the compounds shown in Table 6 are obtained.

【table】

【table】

[Table] Example 43 8.7 g (50 mmol) of methyl 4-carbamoyloxy-3-aminocrotonate and 19.1 g (50 mmol) of 2-(m-nitrobenzylidene)acetoacetic acid β-(N-methylbenzylamino)ethyl ester ) in ethanol (300ml), 60-70
The reaction is stirred at ℃ for 20 hours. The reaction mixture is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography. Using ethyl acetate as a developing solvent, the effective fractions were collected and concentrated under reduced pressure, the residue was dissolved in acetate, a hydrochloric acid-ethanol solution was added thereto, the resulting precipitate was collected, and the resulting precipitate was dissolved in acetone-ethanol.
Crystallization from ethyl acetate produces crystalline 4-(m-
Nitrophenyl)-2-carbamoyloxymethyl-6-methyl-1,4-dihydropyridine-
3,5-dicarboxylic acid 3-methyl ester 5-β
9.2 g (yield 32%) of -(N-methylbenzylamino)ethyl ester hydrochloride is obtained. mp; 117.5-121℃ UV; λ ^MeOH _nax. 236, 355nm IR (KBr); 3400, 2950, 1720, 1690, 1640,
1610, 1525, 1475, 1350, 1320, 1210, 1010,
900, 825, 780 ^{, 740, 700cm -1} . NMR (90MHz, DMSO-d ₆ ); δ2.37 (s, 3H),
2.57 (s, 3H), 3.36 (m, 2H), 3.68 (s, 3H),
4.25 (s, 2H), 4.43 (m, 2H), 4.88 (d, J=
14Hz, 1H), 5.03 (d, J = 14Hz, 1H), 503
(s, 1H), 6.73 (br.s, 2H), 7.42 (s, 5H),
7.5-8.2 (m, 4H), 9.2 (s, 1H). Examples 44-50 According to the method described in Example 43, the compounds shown in Table 7 are obtained.

【table】

【table】

[Table] Example 51 Ethyl 4-N-methylcarbamoyloxy-3-aminocrotonate 10.1 g (50 mmol), m-
7.6 g (50 mmol) of nitrobenzaldehyde and 6.5 g (50 mmol) of ethyl acetoacetate are dissolved in ethanol (200 ml) and reacted by stirring at 60-70°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether to give crystalline 4-(m-nitrophenyl-2-N-methylcarbamoyloxymethyl-6-methyl-1,
7.6 g (yield 34%) of 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained. mp; 192-193°C The UV, IR and NMR instrumental analysis data of this product showed good agreement with that of the product of Example 8. Example 52 9.2 g (50 mmol) of ethyl 4-N-methylcarbamoyloxytetrolate, 13.2 g (50 mmol) of ethyl 2-(m-nitrobenzylidene)acetoacetate and 10 g (125 mmol) of ammonium acetate were added to ethanol (200 ml). ) dissolved at 60-70℃,
Stir and react for 16 hours. The reaction mixture was concentrated under reduced pressure and the oily residue was extracted with ethyl acetate (200 ml). The ethyl acetate extract is dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. Preparative liquid chromatography device for residue (Worss, System 500A)
Using Prep PAK-500/SILICA column, ethyl acetate-hexane (2:1) is developed and separated and purified. The effective fractions were collected and concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether to give crystalline 4-(m-nitrophenyl)-2-N-methylcarbamoyloxymethyl-6-methyl-1,
4.8 g (yield 21.5%) of 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained. mp; 192-193°C The UV, IR and NMR instrumental analysis data of this product showed good agreement with that of the product of Example 8. Example 53 9.2 g (50 mmol) of ethyl 4-N-methylcarbamoyloxytetrolate, 7.5 g (50 mmol) of m-nitrobenzaldehyde, 6.4 g (50 mmol) of ethyl acetoacetate and ammonium acetate.
Dissolve 10 g (125 mmol) in ethanol (200 ml) and stir at 60-70°C for 16 hours to react. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200ml).
Extract and process. The extract is dehydrated with anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is separated and purified using a preparative liquid chromatograph (Waters Corporation, System 500A) on a Prep PAK-500/SILICA column by developing ethyl acetate-hexane (2:1). The effective fractions were collected and concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether to give crystalline 4-(m-nitrophenyl)-2-N.
-Methylcarbamoyloxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester 5.0 g (yield 22.3%) is obtained. mp: 192-193°C The UV, IR and NMR instrumental analysis data of this product showed good agreement with that of the product of Example 8.

Claims (1)

[Claims] 1. General formula [] [In the formula, R ¹ means a halogen atom, cyano group, nitro group or lower alkoxy group, R ² and
R ³ is the same or different, and is a lower alkyl group,
haloalkyl group, lower alkenyl group, lower alkynyl group, aralkyl group, aryl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group or [Formula] (B is a linear or branched The alkylene group, R ⁶ and R ⁷ are the same or different and each means a lower alkyl group, an aralkyl group or an aryl group. However, R ⁶ and R ⁷ may form a heterocyclic group together with a nitrogen atom. ), R ⁴ means a hydrogen atom or a lower alkyl group, A means an alkylene group, R ⁵ means a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkenyl group, an aralkyl group or an aryl group. In producing carbamoyloxyalkyl-1,4-dihydropyridine derivatives represented by the general formula [] An enamine compound represented by the general formula [wherein R ³ , A and R ⁵ have the same meanings as above] A 2-carbamoyloxyalkyl-1,4-dihydropyridine derivative of the general formula [], which is reacted with a benzylidene compound represented by [wherein R ¹ , R ² and R ⁴ have the same meanings as above] manufacturing method. 2 General formula [] [In the formula, R ¹ means a halogen atom, cyano group, nitro group or lower alkoxy group, R ² and
R ³ is the same or different, and is a lower alkyl group,
haloalkyl group, lower alkenyl group, lower alkynyl group, aralkyl group, aryl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group or [Formula] (B is a linear or branched The alkylene group, R ⁶ and R ⁷ are the same or different and each means a lower alkyl group, an aralkyl group or an aryl group. However, R ⁶ and R ⁷ may form a heterocyclic group together with a nitrogen atom. ), ^R4 means a hydrogen atom or a lower alkyl group, A means an alkylene group, ^R5 means a hydrogen atom, a lower alkyl group, a silcoalkyl group, a lower alkenyl group, an aralkyl group or an aryl group. In producing carbamoyloxyalkyl-1,4-dihydropyridine derivatives represented by the general formula [] An enamine compound represented by the general formula [wherein R ³ , A and R ⁵ have the same meanings as above] Aldehyde compounds represented by the formula [wherein R ¹ means the same as above] and the general formula [] R ⁴ -CO-CH ₂ -COOR ² [wherein R ² and R ⁴ have the same meanings as above] ]
A method for producing a 2-carbamoyloxyalkyl-1,4-dihydropyridine derivative of the general formula [], which comprises reacting with a β-ketoester compound represented by the formula []. 3 General formula [] [In the formula, R ¹ means a halogen atom, cyano group, nitro group or lower alkoxy group, R ² and
R ³ is the same or different, and is a lower alkyl group,
haloalkyl group, lower alkenyl group, lower alkynyl group, aralkyl group, aryl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group or [Formula] (B is a linear or branched The alkylene group, R ⁶ and R ⁷ are the same or different and each means a lower alkyl group, an aralkyl group or an aryl group. However, R ⁶ and R ⁷ may form a heterocyclic group together with a nitrogen atom. ), R ⁴ means a hydrogen atom or a lower alkyl group, A means an alkylene group, R ⁵ means a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkenyl group, an aralkyl group or an aryl group. In producing a carbamoyloxyalkyl-1,4-dihydropyridine derivative represented by the general formula [ ] R ³ OOC-C≡C-A-OCONH-R ⁵ [wherein R ³ , A and R ⁵ means the same as above] is an acetylene compound represented by the general formula [] 2-Carbamoyloxyalkyl-1 of the general formula [], which is reacted with a benzylidene compound represented by [wherein R ¹ , R ² and R ⁴ have the same meanings as above] and ammonia or a salt thereof. , 4-dihydropyridine derivative manufacturing method. 4 General formula [] [In the formula, R ¹ means a halogen atom, cyano group, nitro group or lower alkoxy group, R ² and
R ³ is the same or different, and is a lower alkyl group,
haloalkyl group, lower alkenyl group, lower alkynyl group, aralkyl group, aryl group, lower alkoxyalkyl group, lower alkenyloxyalkyl group, aralkyloxyalkyl group, aryloxyalkyl group or [Formula] (B is a linear or branched The alkylene group, R ⁶ and R ⁷ are the same or different and each means a lower alkyl group, an aralkyl group or an aryl group. However, R ⁶ and R ⁷ may form a heterocyclic group together with a nitrogen atom. ), R ⁴ means a hydrogen atom or a lower alkyl group, A means an alkylene group, R ⁵ means a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkenyl group, an aralkyl group or an aryl group. In producing a carbamoyloxyalkyl-1,4-dihydropyridine derivative represented by the general formula [ ] R ³ OOC-C≡C-A-OCONH-R ⁵ [wherein R ³ , A and R ⁵ means the same as above] is an acetylene compound represented by the general formula [] An aldehyde compound represented by the general formula [wherein R ¹ has the same meaning as above] R ⁴ -CO-CH ₂ -COOR ² [wherein R ² and R ⁴ have the same meaning as above] ]
1. A method for producing a 2-carbamoyloxyalkyl-1,4-dihydropyridine derivative of the general formula [], which comprises reacting a β-ketoester compound represented by the formula and ammonia or a salt thereof.