JPS6197264A - Production of dihydropyridine derivative - Google Patents

Abstract

PURPOSE:To obtain nicardipine hydrochloride in high yield easily, by replacing phenylsulfonyloxy group of 1,4-dihydropyridine derivative corresponding to the aimed compound with N-methylbenzylamine, wherein the phenylsulfonyloxy group may contain a substituent group such as halogen, etc. CONSTITUTION:A compound shown by the formula I (X is H, halogen, lower alkyl, lower alkoxy, etc.) is reacted with N-methylbenzylamine in a solvent such as toluene, xylene, etc., or in the absence of a solvent, to give the aimed compound shown by the formula II having improved pharmaceutical action such as vasodilating action, antihypertensive action, etc., industrially advantageously. The compound shown by the formula I is obtained in high yield by reacting a compound shown by the formula III (R' is Me) with a compound shown by the formula IV, it has extremely high reactivity and its easily reacted with N-methylbenzylamine.

Description

Detailed Description of the Invention A. 1,4-dihydropyridine derivatives and acid addition salts thereof [hydrochloride: nicardipine hydrochloride (1), A.
rzneis, -Forsch, 26.2172 (1
976), et al.]. Nicardipine hydrochloride has excellent pharmacological effects such as vasodilation and antihypertensive effects, and is widely used clinically.

B. Prior art and problems Nicardipine hydrochloride is known to be produced by the following production method [JP-A-50-84576.50-845]
77.55-85563: Chem, Phara+, B
See Ull, 27.1426 (1979), etc.]
.

Manufacturing method 1 [JP-A-5G-84577, 55-85563; C
heIIl, Pharm.

See, e.g., Bull, 27.1426 (1979).

] Production method 1 is considered to be the most advantageous production method industrially, but the yield is extremely low at 19%.

Manufacturing method 2 [JP 50-101365; Chei+, Pha
The yield of rm, Bull, 27°l is reported to be 61%. but.

The synthesis of the 1,4-dihydropyridine compound as a raw material is carried out as follows [JP-A-49-+27979; Ches+,
Phara+, Bull, 27.1426 (1979
), etc., but the yield is as low as 20%, and the total yield in these two steps is 12%, which is extremely low.

Manufacturing method 3 [JP-A-5G-84576; Chem, Phar+
g, Bull, 27.1426, (1979)
See Co-Production Method 4 [Ches, Phara, Bull, 27.
1426 (1979) etc., Co-Production Method 5 [Chem, Phara, Bull, 27.
1426 (1979), etc.] 2,) (cJL Manufacturing Method 6 [Chea+, Pharv, Bull, 27
．． 1426 (1979) etc. Manufacturing method 7 [Chem, Ph
ar,m,Bull,,27,1426. (1979)
etc.] Production method 3-7 has a drawback in the production method of the raw material compound. Alternatively, it may be considered impractical due to the low yield of the target compound.

As clarified above, conventional nicardipine hydrochloride (1
), the yield is low, and the synthesis of the raw material compound is low yield. Or it is difficult to purify industrially.
Many problems remain, such as the fact that u must be used in the next reaction.

Problems to be Solved by the C0 Invention As mentioned above, the process for producing nicardipine hydrochloride has problems such as low yield, low yield of the raw material compound, and difficulty in production.

Means for Solving the D0 Problem The present inventors have conducted research on l,4-dihydropyridine derivatives, discovered a compound with excellent pharmacological action, filed a patent application, and reported it [JP-A No. 58-676]
68.121288.146565.201764; Patent 59-4115; 5th Sy+*posiun+
on Medicinal Chelstry.

Kyoto, Dec, 1983. ! i performance abstract collection + p, 6
0; J, Pharm, Dyn, ? , 5-94 (19
84) etc. ], Furthermore, to the compound represented by these (in the formula, R means a lower alkyl group) (JP 58-201764), a compound represented by the general formula (in the formula, When reacting, compounds represented by the general formula (wherein R1 and They discovered that these compounds (wherein X has the same meaning as above) are reacted with N-methylbenzylamine, and filed a patent application (Japanese Patent No. 111159-) with good yields. It was discovered that compound (1) can be produced.

The present invention has now been completed.

E0 action: Compound (II) is reacted with N-methylbenzylamine by heating in a reaction-inert solvent such as toluene or xylene or without a solvent.

(2) can be produced with good yield. (2) has extremely high reactivity and easily reacts with N-methylbenzylamine.

By this production method, nicardipine hydrochloride can be produced industrially advantageously.

F, Example 1.2-(p-)luenesulfonyloxy)ethyl methyl 1.4-dihydro-2,6-cymethyl-4-(3
-Nitrophenyl)pyridine- After the reaction at 3°C, N-methylbenzylamine was distilled off under reduced pressure, the residue was dissolved in dichloromethane, washed with 5% aqueous sodium hydroxide solution, then washed with water, dried over magnesium sulfate, and the solvent was distilled off. The resulting oil was purified by column chromatography (silica gel, ether) to obtain a pale yellow oil, which was crystallized from isopropyl ether to give methyl 2-(N-methylbenzylamino)ethyl 1,4-dihydro -2゜Pale yellow crystals of 6-cymethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate and calcibin), mp7B-
78” (4.8 g, 76%) was obtained.

NMR (CDC13) a: 2.19 (3H, s)
, 2゜35 (6H, s) , 2.63 (2H, t
, J = 6.1Hz).

3.49 (2H, s), 3.63 (3H, s), 4.1
6(2H,t, J=6.1)1z), 5.12
(I H, s), 5.97 (I H, b r s)
, 7.24 (5H, s) , 7.30 (IH, t
, J = 7.5Hz), 7.63(I H,d
t, J=7.5.1.7Hz), 7.87-8
．． 13 (2H, m) - Hydrochloride (nicardipine hydrochloride): mp168-170' (acetone).

G, Reference example 2-hydroxyethyl methyl 1,4-dihydro-2
, 6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate (5,0g), ) ethylamine (5 ml), tetrahydrofuran (50 ml)
), p-toluenesulfonyl chloride (5,0g) was gradually added to the mixture while stirring and cooling in an ice-salt bath, and
x'? t% stirring.

Then, water (5 ml) was added dropwise, stirred for 10 minutes, poured into dilute hydrochloric acid water containing ice, extracted with dichloromethane, the organic layer was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
(p-)LuenesulfoninoFoxy)ethyl methyl
A pale yellow oil (7.0 g, 100%) of 1,4-dihydro-2°6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-pcarboxylate was obtained.

NMR (CD CI,) σ: 1.65 (3H,S), 2
゜25 (3H, s), 2.29 (3H, s), 2.36
(3H.

s), 3.57 (3H, s), 4.11 (4H, s)
, 4°98 (IH, s), 5.80 (IH, brs),
7.12-7.40 (3H, m), 7.45-
7.76 (3H, m), 7゜82-8.07
(2H, m).

Effects of the Invention H1 As is clear from the Examples and Reference Examples, the production method according to the present invention allows nicardipine hydrochloride to be easily produced in good yield, and is extremely useful industrially.

Dec. 6, 1980 1, Display of case 1982 Patent Application No. 217993 3, Detailed description of the invention in the specification of the person making the amendment Column 5, Contents of the amendment (1) Specification "(Patent 59-)" written on page 7, line 11 of the bookcase
” shall be amended as “(Patent No. 59-215532).

(2) rNMR (CDC1) described on page 9, line 11 of the same book.
3) Correct σ:'' to rNMR(CDCt3')δ:''.

(3) rNMR (CDC) described on page 10, line 16 of the same book.
13) Correct σ:'' to rNMR(CDC13')δ:''.

Claims (1)

[Claims] A compound represented by the formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ (wherein, X means a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, etc.) A method for producing a 1,4-dihydropyridine derivative and its acid addition salt represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ characterized by reacting benzylamine.