JPS6399042A - Benzene based compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [Z is OH or R<3>-CO-CH2- COO- (R<3> is alkyl, cycloalkyl or alkoxyalkyl); A is alkylene; B is -N(R<6>)2, formula II (R<6> and R<7> are H, alkyl, cycloalkyl, aralkyl, aryl or pyridyl; Ar is aryl or pyridyl; n is 0-2). EXAMPLE:2-(p-Dimethylaminophenyl) ethylacetoacetate. USE:A synthestic intermediate of dihydropyridine derivative useful as a medicine, etc. PREPARATION:A compound expressed by formula III is reacted with a compound expressed by formula R<6>-E (E is halogen) in a solvent such as N,N- dimethylformamide, etc., preferably in the presence of alkali salt at 10-120 deg.C for 1-5hr to provide a compound expressed by formula I [Z is OH, when B is N(R<6>)2].

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel compound useful as an intermediate for synthesizing dihydropyridine derivatives useful as pharmaceuticals and the like.

[Prior Art/Problems to be Solved by the Invention] As dihydropyridine derivatives, for example, nifedipine, nicardipine, etc. are known. These compounds are known to be useful as antihypertensive agents, peripheral and cerebral vasodilators, and agents for treating coronary artery disease (angina pectoris).

The present inventors have proposed novel dihydropyridine derivatives, especially for organs,
In order to create a compound that has excellent weave selectivity and is highly safe, we have continued our intensive research to create a compound with -g formula: (where Rt, R''
and R3 are the same or different and are alkyl, cycloalkyl, or alkoxyalkyl; R4 and R8 are the same or different and are hydrogen atom, halogen, nitro, halogenated alkyl, alkylsulfonyl, halogenated alkoxy, alkylsulfinyl, alkyl, cycloalkyl, Alkoxy, cyano, alkoxycarbonyl or alkylthio (however, R4 and R5 are not hydrogen atoms at the same time), x is a group represented by vinylene or azomethine, A is alkylene, B is -N (R')!
or 1 (R' and R7 each represent a hydrogen atom, alkyl, cycloalkyl, aralkyl, aryl or pyridyl,
Ar represents a group represented by aryl or pyridyl, and n represents an integer from 0 to 2, respectively. They discovered that dihydropyridine derivatives (A) can be produced efficiently and in high yields by using the new compound (1) described below as a raw material compound, and conducted further research. The present invention was completed.

An object of the present invention is to provide a novel compound useful for efficiently producing dihydropyridine derivatives (A).

[Means for solving problems]

That is, the present invention is based on the general formula (1) % formula % () [wherein Z is a hydroxyl group or the general formula R'-CO-CHt-COO- (wherein R' represents alkyl, cycloalkyl or alkoxyalkyl] ), A is alkylene, B is -N(R')z or (R' and R? are each hydrogen atom, alkyl, cycloalkyl, aralkyl, aryl or pyridyl, Ar is aryl or pyridyl) and n represents an integer of 0 to 2, respectively).

In the above formula, the alkyl represented by R3 may be linear or branched, and lower alkyl (Ct-*) is particularly preferable, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ee-butyl, t -butyl,
Examples include pentyl, isopentyl, neopentyl, hexyl, etc., with C1-4 being particularly preferred. Lower cycloalkyl (C3-
4) (for example, cyclopropylmethyl,
cyclobutylethyl, cyclopentylmethyl), cycloalkyl, and lower (C2-4) cycloalkyl are preferred, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Furthermore, as alkoxyalkyl, the total number of carbon atoms is 3 to 7.
are preferred, such as methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-
Methyl ethyl, 2-ethoxy-! -Methyl ethyl and the like.

R6 and R? Examples of the alkyl and cycloalkyl represented by include those exemplified for R3 above. Aralkyls include phenyl-benzyl, α-phenylethyl, β-phenylethyl, T-phenylpropyl, etc.
Examples of substituents on these aromatic rings include C1- and alkyl; examples of aryl include phenyl and naphthyl; these aromatic rings may have the same or different substituents at any position; Examples include halogen atom, nitro, halogenated alkyl, alkylsulfonyl, halogenated alkoxy, alkylsulfinyl, alkyl, cycloalkyl, alkoxy, cyano, alkoxycarbonyl, alkylthio, and the like. Examples of pyridyl include 2-pyridyl, 3-pyridyl, and 4-pyridyl, which may have the above-mentioned substituents.

The alkylene represented by A is preferably after C2-1, and may be either linear or branched, and examples thereof include ethylene, trimethylene, tetramethylene, 1°2-dimethylethylene, and the like.

Aryl and pyridyl represented by Ar include those exemplified above for R'' and R7, and may have similar substituents.

The compound (1) of the present invention is generally produced as follows.

+1) Compound (III) (1-1) in which Z is a hydroxyl group and B is -N (R')t (in the formula,
A and R- have the same meanings as above, E represents a halogen atom) The reaction in which the compound (1-1) of the present invention can be obtained by reacting the compound (I [[) with the compound (fV)) is as follows: The reaction is carried out in an inert solvent (eg, N,N-dimethylformamide, dimethyl sulfoxide, diglyme, ethylene glycol monomethyl ether, etc.) at 10 to 120°C for about 1 to 5 hours. Moreover, it is preferable to carry out in the presence of an alkali salt (for example, potassium carbonate, etc.).

1i*-(C1l), 1-Ar (wherein A%Ar%R? and n have the same meanings as above, El
and E! each represents a halogen atom) First, compound (III) and compound (V) are reacted to form compound (
Vr) can be carried out using an inert solvent (e.g. n-
butanol, 5ec-butanol, propatool, etc.)
The process is carried out under heating under reflux for about 20 to 30 hours.

Next, the compound (Vl) and the compound (■) can be reacted to obtain the compound (1-2) of the present invention.

The conditions for this reaction are the same as in Production Method (11).

(3) Z is R” Co CHg Coo (D
Compound (1-1 or l-2)
(%1N) [In the formula, R'' is a lower alkyl group (usually
C+-*), and all other symbols have the same meanings as above.] That is, it is produced by reacting the compound (1-1 or !-2) with diketene or the compound (■). Compound (■-
The reaction between 1 or Natsu-2) and diketene is carried out by heating the mixture without a solvent or in a solvent inert to the reaction, usually at about 40 to about 130°C, or in a solvent inert to the reaction. in a solvent (e.g., ethyl ether, tetrahydrofuran, dimethoxyethane, etc.) in the presence of a catalyst such as, for example, varadimethylaminopyridine, from about -20°C to about 40°C.
Can be done at ℃. In addition, the compound of the present invention (1-3)
can be produced by reacting the compound (Ll or l-2) with the compound (■). For example, sodium methoxide, sodium ethoxide, potassium [-butoxide, sodium hydride, sodium amide, metal The reaction is carried out at about 0°C to about 100°C in the presence of a base such as sodium, in an inert solvent or without a solvent.

The novel compound (1) thus produced can be collected in any purity by appropriately using known separation and purification means, such as trall, extraction, chromatography, reprecipitation, recrystallization, etc.

[Action/Effect]

The compound (1) of the present invention is particularly useful as a raw material for producing the dihydropyridine derivative (A).

Dihydropyridine 1m form (A) using compound (1)
An example of the manufacturing method is as follows.

The dihydropyridine derivative can be produced by reacting the compound of the present invention with the remaining components by a method known per se, particularly by subjecting it to a dehydration ring closure reaction. For example,
It is manufactured as follows.

(X) R3COCHICOO-A-■-I3 (13)-→
Dihydropyridine derivative (A) (wherein R', R", R, R', R', X,
A and B have the same meanings as defined above) Compound (L3), Compound (IX) and Compound (X)
The reaction is usually carried out at about 20°C to 160°C, preferably about 30°C.
The reaction is carried out at ~130°C, and any solvent can be used as long as it is inert to the reaction, including methanol,
Ethanol, propatool, isoproptool, butanol% 5ec-Alkanols such as butanol, ethers such as ethyl ether, dioxane, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, acetic acid, pyridine, such as N,N-dimethylformamide , dimethyl sulfoxide, acetonitrile and the like are suitable. The usage amounts of Compound (1-3), Compound (IX) and Compound (X) are as follows: 1 mole of one of the three compounds to 1 mole of each of the other two compounds; 1-1.
This is done by using 5 mol.

It usually takes 1 to 30 hours until the reaction is completed.

〔Example〕

Hereinafter, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to these Examples.

Example 1 2-(p-dimethylaminophenyl)ethanol (3,131 g, 18.9 mwo
1), an air-cooled tube in the center, a thermometer on one side, and a septum rubber on the other. Tetrahydrofuran (T)IF) (59m) was added to the flask, and after melting the contents, -
Cool to 13 to -12°C (ice-salt) and diketene (1,
912g, 22.7m++5ol) and 4-dimethylaminopyridine (DMAP) (10mg, 0.082
The reaction mixture was stirred at the same temperature for 30 minutes and then at room temperature for 18 hours. The reaction solution was cooled with water, 0.1% aqueous sodium hydroxide solution (75@j) was added, and extracted with ethyl acetate (90
The ethyl acetate layer was washed with a 0.1% aqueous sodium hydroxide solution (75d), washed with water (twice at 50s7), dried, and then evaporated under reduced pressure. The residue (5,069 g) was purified by column chromatography [silica gel, ethyl acetate-n
-hexane (1:2)) to separate and purify 2-(
3.592 g of p-dimethylaminophenyl)ethyl acetoacetate was obtained (yield near 6%).

I Rv2! ';r cm-': 1740 (C=
OL 1710 (C=O)'11-. NMRδ: ? , 02.6.63 (4H,^z B * Q +
J −91(z) +4.27 (2+1.t,
J=7Hz), 3.38 (21+, s).

2.89 (611,s), 2.84 (211,t
, J-782).

2.20 (3H, s) Example 2 +112-(-dibenzylaminophenyl)etham 2-(p-aminophenyl)ethanol (1,041 g, 7.59 m + 5 ol) was placed in a 50-mm three-neck flask, and the center A Zimroth cooler was installed and septum rubber was installed on the left and right sides. Add N,N-dimethylformamide (DMF) (8.6 mj) into the flask, dissolve the contents, and then add potassium carbonate (4,195 g, 30.4 mmol) and benzyl bromide (2,985 g, 17.5 meal).
was added and stirred at room temperature for 2.5 hours, and then water (40
-) and extracted with diethyl ether (40atZ
The ether layer was washed with water (once at 25 d), dried and evaporated under reduced pressure, and the residue (3,042 g) was subjected to column chromatography [silica gel, chloroform-methanol (
981) 3 to obtain 275 g of 2-(p-dibenzylaminophenyl)ethanol (yield:
94%).

IRν:::Lcm-': 3350(OH)'I
I-NMRδ near, 18 (IQII, s).

6.92.6.62 (411, AIBvQ, J=8.
5112).

4.56 (41(,s), 3.71 (2H,t,
J-6tlz).

2.69 (211,t, J=6Hz), 1.48
(18,5) 2-(p-dibenzylaminophenyl)ethanol (7,020 g,
22.1 mmo 1 ) was placed in the tube, and an air-cooled tube was placed in the center, a thermometer was attached to one end, and a septum rubber was attached to the other end. Add diethyl ether (68a7) to the flask, dissolve the contents, and cool to -13 to -12°C (ice-salt) to dissolve diketene (2,113 g, 25.1 wmol) and DMA.
P (9w, 0.074 + mmol) was added, and the mixture was stirred at the same temperature for 40 minutes and at room temperature for 16.5 hours. The reaction solution,
Ice-cold 0.1% aqueous sodium hydroxide solution (90d) (
After washing, the diethyl ether layer was separated. Extract the aqueous layer with ether (11
The ether layers were combined, washed with 0.1% aqueous sodium hydroxide solution (twice at 90°C), and washed with water (
After drying, the mixture was distilled off under reduced pressure. Residue (7,
972g) was subjected to column chromatography [silica gel,
Separation and purification using ethyl acetate-〇-hexane (1:3) gave 7.266 g of 2-(p-dibenzylaminophenyl)ethyl acetoacetate (yield: 82%).
).

I Rj'::Pcl1-': 1740 (C-0
), 1720(C-0)'H-NMRδ Near, 19 (1011,s), 7.1-6.8
(211).

6.75-6.5 (211), 4.57 (
411, s).

4', 25 (211,t, J・611z),
3.36 (211, s).

2.81 (211,t, J=611z),
2.15 (311, s) Example 3 (1) ``2'' ≧ (Shiotsumumu Gosanka and λnonol 20
2-(p-aminophenyl) in a 0 ml eggplant flask
Ethanol (10,153g, 74.0m5ol) and bis(2-chloroethyl)amine hydrochloride (6,60ml)
5g, 37.0+m5ol), added n-butanol (66aZ), equipped with a Dimroth cooler,
．． After cooling the 0 reaction solution heated under reflux for 5 hours to around room temperature,
It was added to water (218117) in a 500 m/m beaker. Under water cooling, 15% aqueous sodium hydroxide solution was added to adjust the pH to ~11, followed by extraction with chloroform (30%
The chloroform layer was washed with water (150+a
/ twice), dried, and then evaporated under reduced pressure to obtain a residue (13,48
5 g) was separated and purified by column chromatography (silica gel, chloroform-methanol (1:1)) to obtain 5.996 g of the title piperazine compound (yield near 9%).

I RuHHCm-' = 3300 (OH) heavy H-N
MRδ near, 15-6.95 (2H), 6.95-6.7
(2H).

3.77 (2)1. t, J=6Hz), 3.2
-2.8 (8H).

2.75 (211,t, J=6Hz), 2.10
(2H,5) The product of (1) (piperazine compound) (5,996 g, 29.1 mmo
1), a Dimroth cooler was installed in the center, and septum rubbers were installed on the left and right sides. Add DMF (33m) to the flask and dissolve the contents, then add potassium carbonate (8,034g,
5B, 1 soso o1) and promodiphenyl remethane (
7,543g, 30.5wmol) was added and stirred at room temperature for 2 hours.The reaction solution was added to water (80-) placed in a 200- Erlenmeyer flask, and extracted with diethyl ether (1
The ether layer was washed with water (twice at 40°C), dried and evaporated under reduced pressure, and the residue (10,616g) was purified by column chromatography [silica gel, ethyl acetate].
Separated and purified using n-hexane (1:1)), 2-
(p-(4-benzhydrylpiperazino)phenyl)
6.188 g of ethanol was obtained (fresh yield 57%).

I Ry:::”cm-’: 3600(
OR)'H-N M Rδ near, 55-6.9 (1211), 6.9-6.55
(2H).

4.23 (IH, s), 3.72 (2H, t,
J=611z).

3.3-2.95 (4+1), 2.95-2.35
(611).

1.71 (IH, 5) Product of (2) (benzhydrylpiperazine) (5
, 970 g - 16.0 mmol) was placed in a 200-meter three-hole flask, and an air-cooled tube was placed in the center, a thermometer was attached to one end, and a septum rubber was attached to the other end. Add diethyl ether (50d) to the flask, dissolve the contents, and then heat to -13 to -12°C.
(ice-salt) and diketene (1,531g-18
, 2 mmol) and DMAP (7at, 0.05
7 nnol) and incubated at the same temperature for 30 minutes at room temperature.
．． The reaction solution stirred for 5 hours was ice-cooled, 0.1% aqueous sodium hydroxide (65@l) was added, and after washing, the diethyl ether layer was separated. Extract the aqueous layer with ether (12
The ether layers were combined and washed with 0.1% sodium hydroxide aqueous solution (twice at 65-cm), and then washed with water (
2 times at 50 s7), and after drying, distilled off under reduced pressure to obtain 2- (p
-(4-benzhydrylpiperazino)phenyl]ethyl acetoacetate 7.364 g was quantitatively obtained.

I RvQ:j'cm-': 1740 (C=O)
, 1720 (C=0) II-NMR δ near, 6-6.9 (12H), 6.9-6.65 (
211).

4.29 (21,t, J=6.5H2), 4.2
4 (Ill, s) + 3.39 (211, s),
3.35-3.0 (411).

2.85 (28,t, J=6.5)1z), 2.
7-2.4 (4)1).

2.18 (3H,s) Example 4 3-instead of 2-(p-aminophenyl)ethanol
The procedure of Example 3 (1821) was followed except that (p-aminophenyl)propanol was used to obtain the target compound.

Properties of target compound Colorless oil I Rv:a:"cm-': 3600(OH)'
H-NMR δ near, 5-7.05 (Loll), 7.05-6.8
5 (211).

6.85-6.6 (211), 4.19 (IH,
s).

3.55 (21,t, J=611z), 3.25
~2. '15 (411).

2.75-2.35 (6H), 2.05-1.45
Example 3 (except using the product of (2+1)11)
The desired compound was obtained according to 3).

IRν, knee'''cm-': 1740 (C-0)
, 1720(C=O)'H-N M Rδ near, 6-7.1 (1011), 7.1-6.9 (
2+1).

6.9-6.65 (2H), 4.27 (IH,s
).

4.12 (2H, t, J-6Hz), 3.42
(2H, s).

3.35~3.0 (411), 2.8~2.4 (
611).

2.26 (3H,s), 2. INl, 6 (2
H) Procedures (Ichi Masakichi (voluntary) July 13, 1986

Claims (1)

[Claims] General formula ▲ Numerical formulas, chemical formulas, tables, etc. or alkoxyalkyl), A is alkylene, B is -N(R^6)_2 or ▲Numerical formula, chemical formula, table, etc.▼ (R^6 and R^7 are each a hydrogen atom , alkyl,
a group represented by cycloalkyl, aralkyl, aryl or pyridyl, Ar represents aryl or pyridyl, and n represents an integer of 0 to 2, respectively.