JPH01104046A - 1,4-dihydropyridine derivative, production thereof and drug containing said derivative as active ingredient - Google Patents

Abstract

PURPOSE:To obtain the titled compound, having sustained hypotensive action and effective in use for treating hypertension, etc., by reacting 1,4- dihydropyridinecarboxylic acid with an azetidinium salt. CONSTITUTION:A 1,4-dihydropyridinecarboxylic acid expressed by formula I (R1 is alkyl; X, Y and Z are H, halogen, trifluoromethyl, nitro, etc.) is reacted with an azetidinium salt expressed by formula II [R2, R3 and R4 are H, alkyl or (substituted) alkyl; L(-) is anion residue] to provide a 1,4-dihydropyridine derivative expressed by formula III or an acid addition salt thereof. The com pound expressed by formula I has powerful calcium antagonistic action and hypotensive action, on the other hand, excellent action selectivity without antiblood platelet agglutination action and is chemically stable and readily prepared a pharmaceutical.

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to a method for producing 1,4-dihydropyridine derivatives,
The present invention relates to a 1,4-dihydropyridine derivative having a single absolute configuration at position 04, and a drug containing the same as an active ingredient.

More specifically, the present invention relates to the production of 1,4-dihydropyridine derivatives which have pharmacological effects such as strong hypotensive action and vasodilatory action, and which are characterized by long-lasting effects. The present invention relates to an active 1,4-dihydropyridine derivative and a drug containing the same as an active ingredient.

<Prior Art> A large number of 1,4-dihydropyridine derivatives have been known as compounds having pharmacological effects such as blood pressure lowering effect and vasodilator effect. For example, 4-(2-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3
, 5-dicarboxylic acid dimethyl ester (hereinafter abbreviated as nifedipine) is known to have strong pharmacological activities such as coronary vasodilatory action (see US Pat. phenyl)-2,
Medyl-2-(N-benzyl-N-methylamine)ethyl 6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (hereinafter abbreviated as nicardipine) is widely known (US Patent No. 3985758 @Specifications). (see book).

According to the research of the present inventors, 1.4-
Dihydropyridine derivatives do not have sufficiently strong pharmacological activities such as hypotensive action, nor do they have a sufficiently long duration of action.

On the other hand, it has high pharmacological activity and a sufficiently long duration of action.
, 4-dihydropyridine derivative, the following formula LIV]
is known (see Japanese Unexamined Patent Publication No. 61-57556)
.

As a method for producing the above-mentioned 1,4-dihydropyridine derivative, so-called Hodified tlantz
sch reaction is disclosed.

In addition, as another production method, a method is known in which 1,4-dihydropyridinecarboxylic acid or a reactive derivative thereof is reacted with an alcohol to produce a 1,4-dihydropyridinecarboxylic acid ester derivative (for example, T
, ShibanUma et al.: Chem.

Pharm, Bull, vol, 28.2809-
2812 (1980)).

The present inventors have discovered a novel method previously unknown for 1,4-dihydropyridine derivatives in which the ester residue in the side chain is a 3-aminopropyl group,
We have arrived at the present invention.

On the other hand, as mentioned above, many conventionally known 1.4
It is known that the pharmacological activity of some -dihydropyridine derivatives differs both qualitatively and quantitatively between optical isomers [K, Tamazawa et al: J.

) led, Chem,, vol, 29.2504-
2511 (1986); Rune Fosshei
m, Acta Chemica 5candi
navica, vol.

841, 581-588 (1987), etc.].

In producing such optically active 1,4-dihydropyridine derivatives, optically active 1,4-
Dihydropyridine carboxylic acid is used. As a method for producing it, for example, racemic 1-ethoxymethyl-2
,6-dimethyl-1,4-dihydropyridine-3,5-
1-ethoxymethyl-2,6-dimethyl-3-methoxycarbonyl-1,4-dihydropyridine-5-carboxylic acid obtained by hydrolyzing dimethyl dicarboxylate under harsh alkaline conditions using optically active amines. A method of optical resolution is known [T, Shibanum
a et al: Chem, Pharm, Bull,
, vol, 28.2809-2812 (1980)
reference]. Similarly, a pair of diastereomers obtained by condensing racemic 1,4-dihydropyridinecarboxylic acid with optically active 2-methoxy-2-phenylethanol was separated by chromatography or the like to obtain 04 Diastereomers having different absolute configurations are transesterified with alcohols corresponding to the desired ester residues to obtain the desired optically active 1. produces a-dihydropyridine (J, E, ArrOWSm
ith et al.

J.) Ied, Chem, vol. 29.1696-1
702 (1986), JP-A-58-180483, JP-A-59-5183, JP-A-56-36
(See Publication No. 455, etc.). However, in these methods, the transesterification reaction is important, and the reaction selectivity largely depends on the type of alcohol introduced and the type of ester group at the 3-position, and there is a significant limit to the killing effect.

Among the methods for producing 1,4-dihydropyridine derivatives, the present inventors focused on the method for producing 1,4-dihydropyridine derivatives, which are roughly optically active, and as a result of intensive research, they arrived at the present invention. .

(3) Object of the invention The object of the present invention is to provide a process for producing racemic or optically active 1.4-dihydropyridine derivatives, 1,4-dihydropyridine derivatives in which the C4 position has a single absolute configuration. .

Another object of the present invention is to provide an optically active 1,4-dihydropyridine derivative which has pharmacological activities such as strong hypotensive action and vasodilatory action, and whose action lasts for a long time.

Another object of the present invention is to provide a therapeutic agent for circulatory system diseases using an active 1,4-dihydropyridine derivative.

Objects and advantages of the invention will become apparent from the following description.

<Structure and effects of the invention> That is, the first invention of the present invention provides a 1,4-dihydropyridinecarboxylic acid represented by the following formula [I], and a 1,4-dihydropyridinecarboxylic acid represented by the following formula [I].
A method for producing a 1,4-dihydropyridine derivative represented by the following formula [I11] or an acid addition salt thereof, which comprises reacting the 1,4-dihydropyridine derivative represented by the following formula [I11], or an azetidinium salt represented by e.

The 1,4-dihydropyridine derivative provided by the production method of the present invention has a structural feature of being a carboxylic acid ester having a substituted phenyl group at the 4-position and an N-substituted aminopropyl group at the 5-position.

According to the present invention, in the 1°4-dihydro[1pyridinecarboxylic acid represented by the above formula [I], X.

Y and Z are the same or different and represent a hydrogen atom; for example, a halogen atom such as a fluorine atom or a chlorine atom; a 1 to fluoromedyl group or a nitro group, and the present production method is not affected by the type and type of substitution of these substituents.

R1 represents an alkyl group, and examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-
Butyl, 5ec-butyl, tert-butyl.

Examples include C1 to C6 linear or branched alkyl groups such as n-pentyl and n-hexyl.

Among them, C1 to C4 straight alkyl groups such as methyl, ethyl, n-propyl, and n-butyl are preferred, and methyl and ethyl are particularly preferred.

The 1,4-dihydropyridinecarboxylic acid represented by the above formula [I] can be produced as a racemate or an optically active form by a known method. For example, T, Shiba
numa et at: Chen, Pharm
, Bull, vol.

28.2809-2812 (1980) and JP-A-61-161263 disclose the manufacturing method thereof.

In the azededinium salt represented by the above formula [n],
R2, R3 and R4 are the same or different and represent a hydrogen atom or an alkyl group. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-
-C1 to C4 argyl groups such as -butyl. Among them, methyl and ethyl are preferred.

R5 represents an alkyl group or a substituted or unsubstituted aralkyl group. As the alkyl group, for example, C1 to C4
an alkyl group, such as methyl.

Ethyl is preferred. Examples of substituted or unsubstituted aralkyl groups include benzyl group, α-phenethyl group, and β-phenethyl group.
Examples include phenethyl group. Examples of substituents on the aralkyl group include fluorine and chlorine.

Halogen atoms such as bromine: C1 to C6 alkyl groups such as methyl, ethyl, n-propyl, n-pentyl, n-hexyl; methoxy, ethoxy, n-p[1boxy, n-butoxy, n-pentoxy, etc. C1-C6 alkoxy groups; halogenated methyl groups such as chloromethyl, dichloromethyl, and trifluoromethyl; niamino groups: 21-ro groups; lower alkyloxycarbonyl groups, and the like. Lθ is
Represents an anion residue, such as a halogen ion such as a chloride ion, bromide ion, or iodide ion; a sulfonate ion such as methanesulfonate (CH3SO:+-), l''lifluoromethanesulfonate (ChSO:+-), h-luenesulfonate; Perchlorate ion (GO+ −
): Fluoroborate ion (BF4-) and the like.

The azededinium salt represented by the above formula [n] can be produced by a known method [for example, tleterocy
clic compounds: vol, 42. p
art 2. pl.

Ed, by 8, 1lassner, Jo
hn Wiley and 5ons (1983
)reference].

According to the present invention, the 1°4-dihydropyridinecarboxylic acid represented by the above formula [I] and the azededinium salt represented by the above formula [n] are reacted, and 1 represented by the above formula [I11], 4-dihydropyridine derivatives or acid addition salts thereof can be produced.

The acids for such acid addition salts include mineral acids, organic carboxylic acids,
Examples include organic sulfonic acids, among which mineral acids are preferred.

Examples of mineral acids include hydrochloric acid, hydrobromic acid, and sulfuric acid.

Examples of organic carboxylic acids such as phosphoric acid include acetic acid.

Propionic acid, succinic acid, citric acid, mandelic acid.

Examples of the sulfonic acid include maleic acid, fumaric acid, glutamic acid, lactic acid, etc., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.

Azededinium salts are known to react with strong nucleophiles to give ring-opening reaction products [V.

R, Gaertner: Tetrahedron L
343-347 (1967)] are not known to react with carboxylic acids to form esters.

Surprisingly, according to the present invention, when 1,4-dihydropyridinecarboxylic acid (formula [■] above) and azededinium salt (formula [■] above) are reacted, the four-membered ring is cleaved and 1 , 4-dihydropyridinecarboxylic acid (formula [■] above) was obtained in high yield under mild conditions. The ring opening position of the azededinium salt is between the bond between the nitrogen atom and the adjacent carbon atom.

Specific embodiments of the present invention are as follows.

1,4-dihydropyridinecarboxylic acid (1 equivalent) represented by the above formula [I] and an azededinium salt (1,0 to 2.0 equivalents) represented by the above formula [n] are mixed in a solvent in the presence of a base. , at the usual reaction temperature, i.e., in the range of -20'C to 200'C, preferably in the range of -10°C to 150'C, and the usual reaction time, i.e., within 48 hours, often 24
This can be carried out by reacting for about a period of time. Examples of the base include toluethylamine and diethylisopropylamine.

Amines such as pyridine; caustic soda, caustic potash.

Inorganic alkali salts such as potassium carbonate; NaH, KH.

Hydrogenation metals such as caH2; alkyl dielectrics such as n-BuLi, etc. can be used within the range of 1 to 2 equivalents to the azededinium salt.

Solvents used here include water, alcohols such as methanol and ethanol, and chloroform.

Halogenated hydrocarbons such as methylene chloride; benzene,
Hydrocarbons such as toluene; ethers such as ether and tetrahydrofuran; aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide, and the like can be preferably used.

After carrying out such a reaction, isolation and purification of the target product can be achieved by conventional operations such as extraction, recrystallization, chromatography, etc.

In the method for producing a 1,4-dihydropyridine derivative of the present invention, when an optically active form is used as the 1,4-dihydropyridinecarboxylic acid represented by the above formula [I],
It is possible to provide an optically active 1,4-dihydropyridine derivative or an acid addition salt thereof, in which the 04-position represented by the following formula [III-al or the following formula [III-b] has a single absolute configuration. can. Such optically active 1,4
-Dihydropyridine derivatives, especially the above formula [I[-
Those represented by al have excellent pharmacological effects as described below and are useful as agents for the circulatory system.

That is, the second invention of the present invention is a 1,4-dihydropyridine derivative represented by the following formula % or an acid addition salt thereof.

Such combinations of X, Y, and Z include, for example, when X is a nitro group, either Y or Z is a fluorine atom and the other is a hydrogen atom, or both Y and Z are hydrogen atoms, or It is preferable that Y be a chlorine atom or a fluorine atom, and Z be a hydrogen atom, since they have excellent pharmacological effects as described below.

Such an optically active compound of the above formula [111-al or [ll1
-b] When the production method of the present invention is used, racemization of the target product does not occur, which is particularly preferable.

On the other hand, the optically active 1°4-dihydropyridinecarboxylic acid represented by the above formula [I] can be obtained by a known method as described above, but the present inventors have found a method that is particularly simple and efficient, and has high optical purity. proposed a method for producing 1,4-dihydropyridinecarboxylic acid [Patent application 1983-183]
No. 628].

An example is provided below to illustrate this method.

(Step 1) Synthesis of optically active acetoacetic ester ＼ h C[13 (Step 2 > Synthesis of 1,4-dihydropyridine C by the lantzsch method) 43 ノ (Mixture of a pair of diastereomers) (Step 3) Diastereomer (Step 4) Synthesis of 1,4-dihydropyridinecarboxylic acid by selective cleavage of ester group by fractional recrystallization of 1,4-dihydropyridinecarboxylic acid with high optical purity. One child of dihydropyridinecarboxylic acid is produced.

By esterifying the optically active 1,4-dihydropyridinecarboxylic acid represented by the following formula [I-a] or the following formula [I-b] thus obtained, the corresponding following formula [In -a] or the following formula [I
-b] An optically active 1°4-dihydropyridine derivative or a salt thereof is produced.

↓ Esterification 1 ↓ Esterification Furthermore, using the 1,4-dihydropyridinecarboxylic acid represented by the above formula [I-a] or [I-b], the corresponding corresponding An optically active 1,4-dihydropyridine derivative represented by the above formula [111-a] or [III-b] can be produced.

That is, 1,4-dihydropyridinecarboxylic acid represented by the above formula [I-a] or the above formula [I-b] is used, or a reactive derivative of the carboxylic acid, such as an acid halide or an acid anhydride, is used. 1,4-dihydropyridine represented by the above formula [111-al or [III-b]] by reacting with the aminopropanol represented by the following formula [V] 1 in the presence of a suitable condensing agent or base. A derivative is produced.

According to the present invention, the formula [l11-al or [1-b
] The optically active 1,4-dihydropyridine derivative or its acid addition salt has excellent pharmacological effects such as vasodilatory effect, blood flow increasing effect, and blood pressure lowering effect.

It is known that in 1,4-dihydropyridines, there are differences in pharmacological action between optical isomers derived from the asymmetric carbon at the C4 position. For example, for nicardipine hydrochloride (+)
The vasodilatory effect of the -isomer is reported to be three times stronger than that of the (-)-isomer [Ding.

Shibanuma et al: Chem, Ph
arm, Bull, vol, vine, 2809-2
812 (1980)].

When an asymmetric carbon exists in the ester residue of the carbon-aromatic ester moiety at the 5-position, four types of diastereomers exist together with the asymmetric carbon at the 4-position, and differences in pharmacological activity among these isomers have also been reported. There is. For example, 2,6-cymethyl-4-(3
-nitrophenyl)-1,4-dihydropyridine-3,
In benzyl-3-pyrrolidyl 5-dicarboxylate methyl ester, the ED of the coronary vasodilatory effect of the (43,S), (43,f?), (4R,S), and (4R,R) bodies. (μg, ia) were considered, respectively 0.57.1.6. ``9.1.3.1, and the activity ratio is 1: 1/2.8: 1/16:
Estimated to be 115.4 [in, Tamazawa;
J, Hed, Chem, vol., 29°2504-2511 (1986)].

As a result of extensive investigation into the pharmacological effects of optically active 1,4-dihydropyridine derivatives, the present inventors found that the formula [l1l-
Among the 1,4-dihydropyridine derivatives represented by al or [111-b], the optical isomer with (-) optical rotation has a vasodilatory effect, blood flow increasing effect, Approximately 8 desirable pharmacological effects such as blood pressure lowering effect
It was found to be about 1,800 times stronger. (+)−
The absolute configuration of an optical isomer having optical rotation is determined by heavy atom X-ray crystal structure analysis to be S configuration, that is, the above formula [I[I-
It was found that al.

That is, according to the present invention, it has (+)-optical rotation and C
The 1,4-dihydropyridine derivative represented by the above formula [111-al, in which the absolute configuration of the 4th position is the S configuration, has strong vasodilatory effects, blood flow increasing effects, and blood pressure lowering effects, and the duration of these effects is also long. It has extremely excellent pharmacological effects and is useful as a medicine.

The third aspect of the present invention is a circulatory system agent containing a 1,4-dihydropyridine derivative represented by the following formula [1[1-al] or an acid addition salt thereof as an active ingredient.

The 1,4-dihydropyridine derivatives of the present invention are particularly effective in treating or preventing hypertension, cerebral blood flow disorder, angina pectoris, and the like. The 1,4-dihydropyridine derivative of the present invention has a strong calcium antagonistic effect. In addition, 1 of the present invention,
4-''' dihydropyridine derivatives have strong hypotensive and vasodilatory effects, but on the other hand, they have no antiplatelet aggregation effect, which is a specific pharmacological action, and they are excellent in action selectivity.Also, the present invention The 1,4-dihydropyridine derivative is a chemically stable compound and therefore has the advantage of being easy to formulate into various dosage forms.

The 1,4-dihydropyridine derivative of the present invention can be administered orally,
Alternatively, it can be administered parenterally, such as intravenously, subcutaneously, intramuscularly, transdermally, or rectally.

Examples of dosage forms for oral administration include tablets and pills.

Examples include granules, powders, suspensions, capsules, and the like.

For tablet form, for example, lactose, starch.

It can be molded by a conventional method using an excipient such as crystalline cellulose; a binder such as carboxymethyl cellulose, methyl cellulose, or polyvinylpyrrolidone; and a disintegrant such as sodium nyalginate, sodium bicarbonate, or sodium lauryl sulfate.

Pills, powders, and granules can also be formed using the above-mentioned excipients and the like in a conventional manner.

Solutions and suspensions are formed by conventional methods using glycerin esters such as tricaprylin and triacetin, alcohols such as ethanol, and the like. Capsules are formed by filling granules, powders, liquids, etc. into capsules made of gelatin or the like.

Dosage forms for subcutaneous, intramuscular, and intravenous administration include injections in the form of aqueous or non-aqueous solutions. As the aqueous solution, physiological saline or the like is used.

The 1,4-dihydropyridine derivative of the present invention is relatively easily soluble in water, so it can be easily used as an injection.

Examples of non-aqueous solutions include propylene glycol.

Polyethylene glycol, olive oil, ethyl oleate, etc. are used, and preservatives, stabilizers, etc. are added to these as necessary. Injectables are sterilized by appropriate treatments such as filtration (through a bacteria-retaining filter) and addition of sterilizing agents.

Examples of dosage forms for transdermal administration include ointments and creams; ointments use fatty oils such as castor oil and olive oil; vaseline and the like; creams use fatty oils; diethylene glycol and sorbitan monofatty acid esters. It is molded by a conventional method using an emulsifier such as.

For rectal administration, conventional suppositories such as gelatin soft capsules are used.

The administration m of the 1,4-dihydropyridine derivative of the present invention is
Type of disease, route of administration, age and gender of the patient.

Although it varies depending on the severity of the disease, it is usually 15 to 75 mg/day, preferably 1 to 20 mg/day for an adult.

The present invention will be explained in more detail below with reference to Examples.

Reference example 1 <(S)-(-)-acetoacetic acid M1-phenylethyl>
(S)-(-)-1-phenylethanol (Tokyo Kasei) (4,88o) and triethylamine (1d) were added to benzene (10rIdl), heated to 75°C, and diketene (3,767) was added with stirring. The solution was added dropwise and further heated for 1 hour.The solvent was distilled off under reduced pressure, the residue was dissolved in dichloromethane, washed with water and dried with sodium sulfate, the solvent was distilled off, and the residue was distilled under reduced pressure. Collecting the .5° fraction yielded 7.05 g of the desired product.

'H-NMR (CDCff1.+) δppm: 1.
57 (d, 3H, J=6.6Hz), 2.22 (s,
3H).

3.44 (s, 2H), 5.93 (q, ill, J=
6.611z).

7, 33 (m, 5 old.

H3 Ct(:+C0C)lzcOo-C...-H\h Reference Example 2 <(S)-(-)-3-aminocrotonate 1-phenylethyl> rsi-(-)-acetoacetate 1-phenylethyl ( 14
, Oo) was dissolved in methanol (50%), ammonia gas was passed through the solution for about 10 minutes under water cooling, and the mixture was stirred for 1 night with a dry ice-acetone cold finger attached. After evaporating the solvent, the residue was subjected to silica gel column chromatography, and both fractions eluted with n-hexane-ethyl acetate (9:1) were collected to obtain the desired (S)-(-).
-1-phenylethyl-3-aminocrotonate ([α]B
'-1s9.9° (C=0.55.EtOH),
NMR (CDCR3) δppm: 1.53 (d,
3H), 1.86 (S, 3H), 4.62 (s, III
), 5.92 (Q, 1N).

7,36(S, 511)) was obtained.

H3 Reference Example 3 <(R)-(+)-1-phenylethyl acetoacetate> In the same manner as in Reference Example 1, (R)-(+)-1-phenylethanol (Chisso) was converted into (R)-(+ )-acetoacetic acid 1-
Synthesized phenylethyl.

The physical property values are as follows.

h CI-hcoCH2CO2-C...old\CH3 Reference example 4 <1-benzyl-1,3,3-1-limethylazetidinium trifluoromethanesulfonate> 3-(N-benzyl-N7 methylamino)-2゜2-Dimethylpropanol (376111 (+)) and pyridine (190 μi) were dissolved in anhydrous CH2α2, cooled to 0°C, and trifluoromethanesulfonic anhydride (
370 μl) was added dropwise while stirring.

The reaction mixture was stirred at 0°C for 10 minutes. This reaction mixture was poured into an ice-water solution of sodium bicarbonate, and stirred until the generation of charcoal gas had ceased.

The organic layer was separated, the aqueous layer was extracted with CH2α2, the aqueous layers were combined, washed with water, dried over Glauber's salt, and the solvent was distilled off under reduced pressure. When the remaining solid was crystallized from a mixture of ethyl acetate and n-hexane, the desired product was obtained in a yield of 60% (378 mq).

The physical property values are as follows.

m, p, 92.2-93.0°C NMR (CDC2: + > δppm: 0.96 (s,
3N), 1.40(s, 3N), 3.30(s, 3
tl).

3.95 (d, 2N), 4.41 (d, 2 old, 4.
55 (s, 2tl).

7, 4-7.6 (brs, 511).

Reference Example 5 1-Benzyl-1,3,3-trimethylazetidinium iodide> 1-benzyl-3,3-dimethylazetidine (References; A, G, Anderson: J, Org,
Chem, vol.

33, 2123 (1968)) was dissolved in 10 d of acetonitrile, iodomethyl (308 mg) was added under water cooling, and the mixture was stirred for 6 hours. It was crystallized to obtain 560 mg (m, p, 161-163°C) of the target product.

Example 1 <(4R)-2,6-dimethyl-4-(2-fluoro-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl (IS)-1-phenylethyl> 2 -Fluoro-5-21-benzaldehyde (10,
14 (1) and methyl acetoacetate (6,96 (1) were dissolved in toluene (8), stirred with water cooling, and hydrogen chloride was added to 10
It was left for a minute and overnight.

After adding ether, washing with water and drying with Glauber's salt, the solvent was distilled off to obtain a yellow oil. A portion of the residue (7,2a) was dissolved in isopropyl alcohol (30d), and 1-phenylethyl (S)-(-)-3-aminocrotonate (4,95 g) obtained in Reference Example 2 was added. Next, triethylamine (2.5d) was added and the mixture was heated under reflux for 4 hours.

The solvent was distilled off, the residue was subjected to silica gel column chromatography, and both fractions eluted with n-hexane-ethyl acetate (7:3) were collected to give 2,6-dimethyl-4-(2-
Fluoro-5-nitrophenyl)-1,4-dihy, I-
'Ropyridine-3,5-dicarboxylic acid methyl(S)-1
- mixture of diastereomers of phenylethyl (8,1
(II) was obtained.

2, 6, which is a mixture of a pair of diastereomers obtained
-Methyl (S)-1-phenylethyl-dimethyl-4-(2-fluoro-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate is a silica gel TI
-C (Herck, F, 0.25mm) (JEI
By developing the mixture several times using an opening solvent n-hexane-ethyl acetate/3), each diastereomer could be separated.

The diastereomer mixture was fractionally recrystallized using ether-hexane to yield 3.28 g of (4R)-2゜6-
Cymethyl-4-(2-fluoro-5-nitrophenyl)
Methyl -1,4-dihydropyridine-3,5-dicarboxylate (IS)-1-phenylethyl was obtained.

(Physical property values) nl, p, 147-149°C [α]i+166° (C=1.00. EtOH)N
MR (CDC23>δppm 1.54 (d, J=6.6Hz, 3tl), 2.31
(s, 3N).

2.34(s, 311), 3.62(s, 3)i),
5.32 (s, E).

5.85 (Q, J = 6.6Hz, 1ff), 5.9 (
s, ■).

6.9-7.3 (m, 6H), 7.9-8.2 (m
, 211) cm-1.

IR(llr)ν,.

3350, 1695. '1680.1490.134
5 Example 2 <(4S)-2,6-dimethyl-4-(2-fluoro-
5-nitrophenyl)-1,4-dihydropyridine-3
, methyl (Is)-1-phenylethyl 5-dicarboxylate> When fractional recrystallization is performed with n-hexane-ether using the mother liquor of fractional recrystallization obtained in Example 1, (43)-2,
Methyl 6-dimethyl-4-(2-fluoro-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (IS)-1-phenylethyl (1,3(])
was gotten.

(Physical property values) m, p, 170-172℃ "αko3'+237° (C=1.OO, Etoll)
NMR (CDCffl: + > δppm: 1.3
4(d, J=6.6tlz, 3N), 2.31(s,
8tl).

3.63 (s, 3N), 5.37 (s, IH).

5.8(Q, J=6.6Hz, 1N), 5.9(s
, 1 old.

7.0-7.3 (m, 6l-1), 8.2-8.3
(m, 2tl) IR (, KBr) cllll-1゜-@＾x0 3380, 1710. 1690. 1490. 1
350 Example 3 <(43)-2,6-dimethyl-4-(2-fluoro-
5-nitrophenyl)-3-methoxycarbonyl-1,
Synthesis of 4-dihydropyridine-5-carboxylic acid> (4R)-2,6-dimethyl-4- obtained in Example 1
Methyl (2-fluoro-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (IS)-
1-Phenylethyl (1,054(+)) was dissolved in dichloromethane (5 ml), and 1-iodo-lymethylsilane (400 μl) was added dropwise under an argon atmosphere while cooling with water. The mixture was returned to air temperature and stirred overnight.

The reaction mixture was ice-cooled and an aqueous Na2SO3 solution was added.

When the mixture was stirred vigorously under water cooling, pale yellow crystals were precipitated in about 15 minutes. crystal). ) The two liquids were separated, the aqueous layer was extracted with dichloromethane-ethanol, the aqueous layer was combined, dried with Glauber's salt, the solvent was distilled off, and the residue was crystallized from methanol. ) The crystals were combined and recrystallized from methanol to obtain the desired product (480 mg, yield: 59%).

(Physical property value) ..., 0. 183℃ [α][)+31° (C=1.OO, EtO old NMR
(d6-DMSO) δppm: 2.28 (s, 611
), 3.51(s, 3tl), 5.10(s, I
H).

7.34 (dd, old l to J=101), 8.1 (m
, 2N).

8.99 (br s, 1M), 11.75 (br
s, IH) cm-1.

IR (KBr) ν, Ie.

3350, 1670. 1660. 122OOz Example 4 <(4R)-2,8-dimethyl-4-(2-fluoro-
5-nitrophenyl)-3-methoxycarbonyl-1,
Synthesis of 4-dihydropyridine-5-carboxylic acid> Synthesis of 4-dihydropyridine-5-carboxylic acid> Synthesis of 4-dihydropyridine-5-carboxylic acid
S)-2,6-dimedyru-4-(2-fluoro-5-nitrophenyl)-1,4-dihydropyridine-3,5-
Methyl dicarboxylate (1S)-1-phenylethyl (1
,30 (]) and iodotrimethylsilane (0,497)
The desired product (0.59 g, yield 59%) was obtained.

(Physical property values) m, p, : 182°C Oz Example 5 < (4R)-(-)-2,6-dimedyroux 4-(2-
fluoro-5-nitrophenyl)-1,4-cyhydrohyridine-3,5-dicarboxylic acid methyl 3-(N-benzyl-N-methylamine)-2,2-dimethylpropyl> Obtained in Example 3 (4S)-2,6-cymethyl-4-
(2-Fluoro-5-nitrophenyl)-3-methoxycarbonyl-5-carbonyl (2.49 g) and 3-(N-benzyl-
N-methylamine)-2,2-dimethylpropanol (
1.87 (1) and dicyclohexylcarbodiimide (2
．． 39(]) and ]4-N,N-dimethylaminopyridine (123 mg) were dissolved in dichloromethane and stirred at room temperature for 4 days. Separate one precipitated body, concentrate the liquid from two houses,
The target product (free base> (3.05a) was obtained by subjecting it to silica gel column chromatography and collecting both fractions eluted from a mixture of hexane and ethyl acetate, which was treated with hydrogen chloride to form the hydrochloride. .

(hydrochloride) m. p. Approximately 180' (crystallized from acetone) [α
] -114° (C-1.00, EtO old elemental analysis C29H34FN3 06 ・To1: Theoretical value (%) C: 60.47 H: 6.12N
: 7.29 measured value (%) C: 59.99 H
: 6.1ON : 7.26IR (KB)cm
-1' 3400, 1698. 1B76, 1526, 1
486, 1344.

1212, 1116 Example 6 < (43)-(+) -2. 6-cymethyl-4-(
Methyl 3-(N-benzyl-N-methylamino-2,2-dimethylpropyl)-1,4-dihydropyridine-3,5-dicarboxylate (2-fluoro-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate obtained in Example 4 (4R)-2,6-dimethyl]4-
(2-fluoro-5-nitrophenyl)-3-methoxycarbonyl-1,4-dihydropyridine-5-carboxylic acid (2,93 g) and 3-(N-benzyl-N-methylamino)-2,2-dimethyl Proper tool (2,33g)
and dicyclohexylcarbodiimide (2.69g) and 4
-N,N-dimethylaminopyridine (151 mg) was added to dichloromethane (30d) and reacted at room temperature for 4 days. The precipitated solid was separated from each household, the liquid was concentrated to dryness, subjected to silica gel column chromatography, and hexane-
Both fractions eluted from the ethyl acetate mixture were collected to yield the desired product (free base) (3,580), which was treated with hydrogen chloride to yield 1q of the hydrochloride.

(hydrochloride) m, p, 180' (crystallized from acetone) [α]
D+115° (Cm1.OO, Etoll) Elemental analysis value C29t-134FN: + 06 ・To1α: Theoretical value (%) C: 60.47 H: 6.12N:
7.29 Measured value (%) C: 60.301-1:
6.14N: 7.20IR(KBr)νCm"' 3400, 1698. 1676, 1526. 1
48B, 1344°1212, 1116 Example 7 < (4f?) -2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl(IS)-1-phenyl Ethyl〉m-
Nitrobenzaldehyde (4,53(1)), methyl 3-aminocrotonate (3,45(]), and (S)-(-)-acetoacetate 1-phenylethyl obtained in Reference Example 1 (
6,18111) to isopropyl alcohol (4(7!
) and heated with centrifugal flow for 5 hours.

The solvent was distilled off from the reaction solution, the residue was subjected to silica gel chromatography, and both fractions eluted with a dichloromethane-n-hequiline-ethyl acetate mixture were collected. A diastereomer mixture (4.2 g) containing the target product was obtained. ) was reduced by 1q.

This mixture of diastereomers is crystallized from a mixture of ether-n-hekirin and fractionated recrystallization yields the desired (4R)-2,6-dimethyl-4-(3-nitrophenyl)-1, Methyl 4-dihydropyridine-3,5-dicarboxylate (IS)-'l-phenylethyl is 1.39
0 was obtained.

The physical properties of this product are as follows.

m, p, 15B-157°C (recrystallized from ethanol) 1H-NMR (CDCJh > δppm: 1.54
(d, 311.J=6.5Hz), 2.33(s, 3
tl).

2.37 (S, 3H), 3.65 (s, 3H), 5
．． 12 (s, IH).

5.71 (bS, il+), 5.80 (Q, IH, J
=6.5H7).

6.9-7.3 (m, 6N), 7.53 (d, IN,
J=7Hz).

7.8-8.1 (m, 2H).

IR(KBr) )'Cm-' H3340
, 1675, 1530, 1495, 1350, 1220
゜Example 8 <(43)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl (IR)-1-phenylethyl> Obtained according to Reference Example 3 (R)-(1-phenylethyl acetoacetate (2,06+11), m-nitrobenzaldehyde (1,51(1) and methyl 3-aminocrotonate (1,
15(]) was dissolved in isopropyl alcohol (20d>) and heated under reflux for 4 hours. After depositing the solvent, the residue was subjected to silica gel column chromatography and eluted with a mixture of dichloromethane-ethyl acetate-n-hexane. By collecting both parts, a diasdoleomer mixture (1,18(]) containing the target product was obtained.

Crystallization from ether-n-hexane and fractional recrystallization yield the desired product (4S)-2,6-dimethyl-4-(3
-nitrophenyl)-1,4-dihydropyridine-3,
Methyl (IR)-1-phenylethyl 5-dicarboxylate (515 mg) was obtained.

The physical property values are as follows.

m, p, 155.5-155.6 °C (recrystallized from ethanol) 1H-NMR (CDC (2:l) δppm
:1.54 (d, 311.J=6.5H2), 2.
33(S,3)1).

2.37 (s, 3H), 3.65 (s, 3 old, 5.
12 (S, l11).

5.71 (bs, 11), 5.80 (q, IH, J=
6.5 tlz).

6, 9-7.3 (m, 611), 7.53 (d,
IH, J = 7H2).

7.85-8.10 (m, 2H).

I R(K B l')')' Cm-I +3340
, 1675.1530.1495.1350.1220
゜Example 9 <(43)-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonyl-1,4-dihydropyridine-5-carboxylic acid> (4R)- obtained in Example 7 2,8-dimethyl-4-
Methyl (1S)-phenylethyl (3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (1,045 g) was dissolved in a mixture of dichloromethane (5rd!) and carbon tetrachloride (5mi), Iodotrimersilane (0,417) was added dropwise under argon atmosphere with water cooling and stirring.The water bath was removed, the temperature of the reaction solution was gradually returned to room temperature, and the mixture was stirred for 3 hours.After the reaction was completed, a sodium sulfite aqueous solution was added dropwise. Then, the reaction solution faded to pale yellow.The precipitated solid was collected, washed with water, and dissolved in methanol.
Separate the insoluble matter, concentrate and dry the liquid, and obtain the target substance (6
4.7 mg) was obtained.

The physical property values are as follows.

m, p, 181-182°C:, (decomp,
) (recrystallized from methanol) 11-1-NMR (d6-DMSO>δppm: 2.
29 (s, 6ft), 3.56 (s, 3N), 5.
00 (S, 1ff).

7, 8 (m, 2 old, 7.9 (m, 211), 8.
90 (S, 1N).

11.75 (bS, 1 old.

IR(KBr))-/'p; : 3350, 1660.1530.1480.1350.
1225゜Milli 83: M/Z 332.0
989 (C1BH18N205) Example 10 <(4R)-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonyl-1,4-dihydropyridine-5-carboxylic acid> Obtained in Example 8 ( 43)-2,6-cymethyl-4-
(3-nitrophenyl)-1,4-dihydropyridine-
Methyl (1R)-phenylethyl 3,5-dicarboxylate (200 mg) was dissolved in a mixture of dichloromethane (2III1) and carbon tetrachloride (2d), and the solution was cooled on ice under an argon gas atmosphere. This was added to iodotrimethylsilane (0,078
mff) was added dropwise. The water bath was removed, and the mixture was allowed to return to room temperature and stirred for 3 hours. The target material (66 m
g) was obtained.

The physical property values are as follows.

m, l), 180-181°C (decamp) [α]
D-38.7° (C=0.500.)feel)
IH-NMR (da-DMSO> δppm
:2.28 (s, 6N), 3.55 (S, 311
), 5.00 (S, 11I).

7.6 (m, 2N), 7.9 (m, 211), 8.
90 (s, 1N).

11.75 (BS, IH).

IR(KBr)νCm” 3350, 1660.1530.t480.1350
．． 1225° Hi If i HS: M/2
332.0957 (C16th 16N20s
) 1 Example 11 < (4R)-(-)-2,6-cymethyl-4-(3-
Nitrophenyl)-1,4-dihydropyridine-3,5
-Methyl dicarboxylate 3- <N-benzyl-N-methylamino)-2,2-dimethylpropyl> (43)-2,6-dimethyl-4-(3-nitrophenyl)-3 obtained in Example 9 -Methoxycarbonyl-1,4-dihydropyridine-5-carboxylic acid (7ang) and 3-(N-
benzyl-N-methylamine)-2,2-dimethylpropatur (72.9 mg) and dicyclohexylcarbodiimide-N. N-dimethylaminopyridine (4.3111(I)
t) was added to dicyclomethane (2d), and the mixture was stirred in air for 6 days. Separate the precipitate, remove the solvent from the solution, apply the remaining residue to silica gel column chromatography,
The desired product (free base) (87 mg) was obtained by collecting both fractions eluted from -hexane-ethyl acetate.

Ether-hydrogen chloride gave the hydrochloride salt.

The physical property values are as follows.

[α]. -54° (C = 1.00, EtOf
l) (@Rise salt arrival [α] D-75 (C=1
．． 00, Et (hydrochloride) free base 1H NMR (CDCJh) δp
pm: 0, 83 (S, 3 old, 0.87 (S, 3)
Old, 2.08 (S, 3N).

2, 24 (s, 2H), 2.31 (s, 3H), 2
．． 39 (s, 311).

3, 44(s, 2tf), 3.68<s, 311),
3.92 (s, 211).

5, 16 (s, IH), 6.14 (bs, IN),
7.2-8.3 (m, 911).

Milli 83: )l/Z 521.238B
Theoretical value 521.25237 (029H35N:l
06>O2 Example 12 < (43)-(+)-2.6-dimethyl-4-(3-
Nitrophenyl)-1,4-dihydropyridine-3,5
-Methyl dicarboxylate 3-(N-benzyl-N-methylamino)-2.2-dimethylpropyl> (4R)-2.6-dimethyl-4-(3-nitrophenyl)-3 obtained in Example 10 -Methoxycarbonyl-1,4-dihydropyridine-5-carboxylic acid (114ml!l) and 3-
(N-Benzyl-N-methylamino)-2,2-dimethylpropanol (1071117), dicyclohexylcarbodiimide (106mg) and 4-N,N-dimethylaminopyridine (6mc+) were added to dichloromethane and stirred at room temperature. .

The desired product (free base) was obtained in the same manner as in Example 11, and converted into a hydrochloride using hydrogen chloride-ether.

The physical property values are as follows.

[α] D +52 (C=1.00
, EtO)1n (free base) [α]2D1+
γ7° (C=1.00, EtOH) (hydrochloride)
Free base ito1-NMR (CDCR:+) δ p
pm: 0, 82 (s, 3N), 0.86 (s,
3 old, 2.08 (s, 3N).

2, 24 (S, 2 old, 2.33 (s, 3H), 2.
40 (s, 3 old.

3,44(S,2H), 3.68(S,3+1),
3.91 (S, 211).

5, 16 (s, 1N), 5.73 (bs, IN),
7.2-8.3 (m, 91).

) (illi HS: M/Z 521.2530J
Theory (direct 521.25237 (C2gH35N3
06) Example 13
-Fluoro-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl> Argon in anhydrous tetrahydrofuran (2d) Under air flow O'
Add NaH (35111(1)) with water and stir.
Optically active (4R)-2,6-dimethyl-4-(2-fluoro-5-nitrophenyl)-1 obtained in Example 4
,4-dihydropyridine-3-methoxycarbonyl-5
A solution of anhydrous tetrahydrofuran (2d>) of -Carboni (230m(]) was added dropwise and stirred for 30 minutes, and then 1-benzyl-1,3,3-trimethylazededinium trifluorosulfonate (290ff1g) was added thereto. The reaction mixture was heated and stirred at 45°C overnight.

Water was added to the reaction mixture, extracted with acetic acid and ethyl, the organic layer was washed with water, dried with sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography. When both fractions eluted from 4:1) were collected, 251 mg (yield 73%) of the target product was obtained. This gave the hydrochloride salt with hydrochloric acid.

The physical property values completely matched those of Example 6.

Example 14 < (4R)-(-)-2,6-cymethyl-4-(2
-Fluoro-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl> Performed in the same manner as in Example 13. The optically active (
43)-2,6-dimedyru-4-(2-fluoro-5-
21-[1phenyl)-1,4-dihydropyridine-3
-Me-1-xycarbonyl-5-carboxylic acid (230 mg
) and 1-benzyl-1,3,3-trimethylavidedinium trifluoromethanesulfonate to give the desired product.

The physical property values completely matched those of Example 5.

Example 15 <2,6-dimedyru-4-(2-chloro-3-trifluoromethylphenyl)-1,4-dihydropyridine-3
, methyl 5-dicarboxylate 3- (N-benzyl-N-
methylamino)-2,2-dimethylpropyl> Similarly to Example 13, 2,6-dimethyl-4-(2-chloro-3-trifluoromethylphenyl)-1,4-dihydropyridine-3-methoxycarbonyl-trimethyl The reaction was quenched using dilyazetidinium].rifluoromethanesulfonate to obtain the desired product.

[Physical property values] NMR (CDCQ+ > δppm: 0, 83 (s, 6N), 1.98 (s, 3N), 2
．． 22 (s, 2H).

2, 25 (s, 6N), 3.35 (s, 2 old, 3.
47 (S, 3tl).

3, 79 (S, 2N), 5.42 (S, Ill),
8.23 (S, 1N).

6, 95-7.65 (m, 8N).

Example 16 <2.6-dimethyl-4-(3-chloro-2-fluorophenyl)-1.4-dihydropyridine-3,5-dicarponylate methyl 3-(N,N-dimethylamino)-2.
2-dimethylpropyl> 2,6-dimethyl-4-(3-chloro-2-fluorophenyl)-1,4-dihydropyridine-3-methoxycarbonyl-5-carboxylic acid and Na in the same manner as in Example 13
) (and then reacted with 1-benzyl-1.3.3-tetramethylapitidinium iodide obtained in Reference Example 5 to obtain the desired product.

[Physical property values] NMR (CDCff13) δppm: 0.81 (s,
3 old, 0.85 (s, 3tl), 2.06 (s, 2
11).

2.14 (s, 6 old, 2.23 (s, 311), 2
．． 29 (s, 3N).

3.62 (s, 3H), 3.83 (s, 211),
5.30 (s, 111).

6.36 (s, 1N), 6.77-7.41 (m,
311).

Cm”.

IR (Neat) v-,,.

3000, 1720.1453.1362゜Example 17 N-benzyl-N-methylamine)-2,2-dimethylpropyl> anhydrous tetrahydrofuran <2d> without cooling in an argon stream under water bath.
a1-1 (38m(1)) was added and stirred. On stirring, 2,6-dimethyl-4-(2-fluoro-5-nitrophenyl)-1, dissolved in anhydrous tetrahydrofuran (2m),
4-dihydropyridine-3-meth1hexycarbonyl-5
-Carboxylic acid (260 mg) was added dropwise and stirred for 30 minutes. Next, 1-benzyl-1,3, obtained in Reference Example 4
3-Trimethylazededinium trifluoromethanesulfonate (280mc+) was added. The reaction mixture was
Warmed to °C and stirred overnight.

Water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was washed with water, dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography 1 and both fractions eluted with ethyl acetate-n-hexane (1:4) were collected to obtain 313,111 g (81% yield) of the desired product.

[Physical property values] NMR (CDG!3) δppm: 0.86 (S, 3H), 0.89 (S, 3 old, 2.
10 (s, 3H).

2.28 (s, 2tl), 2.30 (s, 3H),
2.36 (s, 3 old.

3.47 (s, 2H), 3.64 (s, 3 old, 3.
92 (S, 3N).

5.35 (s, 111), 5.9 (brs, l1l
).

7.06 (d, d, J=9H2, IH), 7.26 (
S, 5N).

7, 9-8.3 (m, 2H).

Example 18 Inhibitory effect on hyperpotassium contraction of isolated rat aorta> The thoracic aorta of a male Wistar rat (350-400a) was excised, a spiral specimen was prepared, and the contraction was measured isometrically according to the Magnus method.

High-potassium contraction was performed, and the test compounds listed in Table 1 were applied to the point where the contraction reached its maximum and stabilized and observed for 2 hours.

The results are shown in Table 1.

Table 1 The compounds of the present invention have a stronger vasorelaxant effect than nicardipine hydrochloride, and have a molecular weight of about 800 to 180% between the optical isomers.
It showed an efficacy ratio of 0.00 times.

Example 19 <Hypertensive effect upon oral administration in SHR> The test compound listed in Table 2 was orally administered to a male SHR who had withdrawn from membership for about 14 years, via a cannula previously inserted into the left femoral artery. Blood pressure was measured using a pressure transducer, and the results are shown in Table 2.

Table 2 (hypertensive activity ED20% (mo/Kg)
Example 20 Blood pressure lowering effect upon intravenous administration in rats> Male Wistar rats of about 7 years old were treated with urethane (500 m(]/K())
) and α-chloralose (100 mg/K(1)) were intraperitoneally administered as a mixed anesthetic for anesthesia.

A catheter was inserted into the right femoral artery, and blood pressure was measured with a pressure amplifier (AP-621G, Nihon Kohden) via a pressure trandulie (P231D, Statham) and recorded using a polygraph.

The test compounds listed in Table 3 were used and rapidly injected through a catheter inserted into the left femoral vein. The injection volume was 1/9 in 1 ml.

Table 3 Example 21 Manufacture of tablets (4S)-(+)-2,6-dimedyru-4-(2-fluoro-5-nitrophenyl)-1,4 obtained in Example 6
-dihydropyridine-3,5-dicarboxylic acid methyl 3-
Tablets containing 3 mo of (N-benzyl-N-methylamino)-2,2-dimethylpropyl hydrochloride were manufactured according to the following formulation.

(43)-(+)-2,6-dimethyl-4-(2-fluoro-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl 3-゛(N-benzyl-N-methyl amino) -2,2-dimethylpropyl salt [[3111(1 lactose
87mg starch 30m
g Magnesium stearate 2mg Example 3
2 (4S)-('')-2,6- obtained in Example 6 during production 1d of injection
Cymethyl-4-(2-fluoro-5-nitrophenyl)
= 1,4-dihydropyridine-3,5-dicarboxylic acid methyl 3- (N-benzyl-N-methylamino)-2,
An injection solution containing 0.05 mg of 2-dimethylpropyl hydrochloride was prepared according to the following formulation.

(4S)-(-)-2,6-cymethyl-4-(°2-fluoro-5-nitrophenyl)-1,4-cyhitcJ
Methyl 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl pyridine-3,5-dicarboxylate hydrochloride 5mg common salt
900mq distilled water for injection
Example 33 Production of powder A powder was produced according to the following recipe.

(43)-(+)-2,6-dimethyl-4-(2-fluoro-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate methyl 3-(N-benzyl-
N-methylamino)-2,2-dimethylpropyl hydrochloride 5mg lactose
100mg starch 100
m (1 hydroxypropyl cellulose i omg
Reference Example 6 <(4S)-2,6-dimethyl-4-(2-fluoro-
5-nitrophenyl)-1,4-dihydropyridine-3
, 5-dicarboxylic acid methyl 4-bromophenacyl> (4R)-2,6-dimedyru 4- obtained in Example 4
(2-Fluoro-5-nitrophenyl)-1,4-dihyde "copyridine-3-methoxycarbonyl-5-carbonyl M (349 mq), p-bromophenacylbromide (349 mrJ) and potassium fluoride (107 mCI)" Add DMF (4m!) and heat for 1 hour at 90'C, then perform column chromatography on ether Jo 1 inlet b L/silica gel. Both fractions eluted from n-hexane-ethyl acetate were collected and crystallized from methanol to yield 342 mg of the desired product.
It's 17.

The +1 value is as follows.

Box-NMR (CDCR, + > δppm: 2.37 (
s, all), 3.60 (s, 3H), 5.23 (
s, 2! I).

5.39 (S, IH), 6.4 (BS, 1ll)
.

7.02 (dd, ill,, J-911Z), 7.
52-7.78(m, 4tlL7.96-8.26(m
, 2H).

Reference Example 7 Determination of absolute structure by X-ray crystal structure analysis> (43)-2,8-dimethyl-4-(2-fluoro-5-nitrophenyl)-1, which was 1q in Reference Example 6, Methyl 4-bromophenacyl 4-dihydropyridine-3,5-dicarboxylate is a transparent pale yellow columnar crystal and is necessarily monoclinic space group P2+.
Met.

a = 20.713 people b = 7.401 eight
〇 = 15.7228 β = 103°44° V = 23
44.3 people Z = 4dcal = 1.549g/cm3 Using an automatic 4-axis diffractometer (Rigaku Denki RASA-5RP model), 4437 independent reflections were obtained with MOKα rays and the structure was analyzed by the direct method. .

The absolute structure was analyzed from the anomalous scattering based on the bromine atom, and the absolute structure at position 4 was determined to be the S configuration using the Bifoot method.

Claims (1)

[Claims] 1. The following formula [I], ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [I] [In the formula, R_1 represents an alkyl group, and X, Y and Z
are the same or different and represent a hydrogen atom, a halogen atom, a trifluoromethyl group or a nitro group. However, X, Y, and Z are not hydrogen atoms at the same time. ] 1,4-dihydropyridinecarboxylic acid represented by the following formula [II], ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[II] [In the formula, R_2, R_3 and R_4 are the same or different and hydrogen It represents an atom or an alkyl group, R_5 represents an alkyl group or a substituted or unsubstituted aralkyl group, and L^■ represents an anionic residue. ] The 1,4-dihydropyridine derivative or its acid addition represented by the following formula [III], ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[III], which is characterized by reacting with the azetidinium salt represented by Method of manufacturing salt. 2. The method for producing a 1,4-dihydropyridine derivative or an acid addition salt thereof according to claim 1, wherein R_5 is a substituted or unsubstituted benzyl group or a substituted or unsubstituted phenethyl group. 3. The method for producing a 1,4-dihydropyridine derivative or an acid addition salt thereof according to claim 1, wherein X is a nitro group, Y is a hydrogen atom, and Z is a fluorine atom. 4. The method for producing a 1,4-dihydropyridine derivative or an acid addition salt thereof according to claim 1, wherein X is a nitro group and Y and Z are both hydrogen atoms. 5. The method for producing a 1,4-dihydropyridine derivative or an acid addition salt thereof according to claim 1, wherein R_1, R_2, R_3 and R_4 are methyl groups. 6. The method for producing a 1,4-dihydropyridine derivative or an acid addition salt thereof according to claim 1, wherein the 1,4-dihydropyridinecarboxylic acid represented by the formula [I] is an optically active 1,4-dihydropyridinecarboxylic acid. 7. The 1,4-dihydropyridinecarboxylic acid according to claim 1, wherein the 1,4-dihydropyridinecarboxylic acid represented by the formula [I] is a 1,4-dihydropyridinecarboxylic acid having (-)-optical rotation.
A method for producing a dihydropyridine derivative or an acid addition salt thereof. 8. 1,4-dihydropyridine derivative or its acid addition salt represented by the following formula [III-a] ▲Mathematical formulas, chemical formulas, tables, etc.▼... [III-a]. 9. A (+)-optically active 1,4-dihydropyridine derivative represented by the above formula [III-a] or an acid addition salt thereof. The above formula [III-a
] A 1,4-dihydropyridine derivative or an acid addition salt thereof. 11. The 1,4-dihydropyridine derivative or acid addition salt thereof according to claim 8, wherein R_1, R_2, R_3 and R_4 are methyl groups. 12. The 1,4-dihydropyridine derivative or its acid addition salt according to claim 8, wherein X is a nitro group, Y is a hydrogen atom, and Z is a fluorine atom or a hydrogen atom. 13. The 1,4-dihydropyridine derivative or its acid addition salt according to claim 8, wherein X is a nitro group, and Y and Z are both hydrogen atoms. 14. A circulatory system agent containing a 1,4-dihydropyridine derivative represented by the above formula [III-a] or an acid addition salt thereof as an active ingredient.