JPS60152478A - Piperazine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (X is H, F or methoxyl) or a methoxyl) or a salt thereof. EXAMPLE:3-(4-Phenethyl-1-piperazinyl)propanol. USE:Useful as a synthetic intermediate for 2,4-(1H,3H)-quinazolinedione derivatives useful as a vasodilator, etc. PREPARATION:3-(1-Piperazinyl)propanol expressed by formula II is reacted with a compound expressed by formula III (Y is halogen) in a solvent, e.g. methanol, if necessary in the presence of a catalyst, acid acceptor or reaction accelerator at 0-160 deg.C reaction temperature under ordinary pressure-10atom reaction pressure for 0.5-60hr to afford the aimed compound expressed by formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel piperazine derivative represented by the formula (wherein X means a hydrogen atom, a fluorine atom, and a methoxyl group) or a salt thereof.

The compounds of formula (I) provided by the present invention are compounds useful as vasodilators, blood flow improvers, antihypertensive agents or antiarteriosclerotic agents. (3-(4-phenethyl-1-zperazinyl)propyl:]-3-(α,α,α-trifluoro0
-) -2,4(IH,3H)-quinazolinedione and 6-ethoxycarponyl-1-[:3-[4-(
p-fluorophenethyl]-1-biradinyl]propyl]-5,7-nomethyl-3-(α,α,α-trifluoro-tolyl)-2,4(LH,3H)-quinazolinedione, etc. When the compound of formula (1) provided by the present invention is reacted with a halodanating reagent, 2 represents a halodane atom), while compounds of formula (II) are obtained with 2.4 (I) as described in the cited patent.
It serves as an intermediate raw material for producing H,3H)-quinazolinedione derivatives.

Examples of the compound of formula (1) include (1) a method of reacting 3-(1-piperazinyl)zolopanol with phenethyl chloride or bromide or its p-fluoro or methoxy substituted product, and (2) a method of reacting 3-chloro (or bromo). ) phenethylpiperazine or its p in propatool
- It can be produced by a method of reacting a fluoro or methoxy substituted product.

All of the above reactions are preferably carried out in a suitable solvent. Examples of solvents used in this case include water, alcohols (e.g., methanol, ethanol, impropatol, n-butanol, etc.), ethers (e.g., dioxane, tetrahydrofuran, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), Hydrocarbons (benzene, toluene, xylene, etc.), dimethylformamide, dimethyl sulfoxide, and other various solvents are used, and these solvents may be used alone or as a mixed solvent, or may be a heterogeneous solvent.

Catalysts, acid acceptors, reaction accelerators, etc. are always necessary, and examples include organic amines such as pyridine, dimethylaniline, and triethylamine, sodium, potassium, or calcium carbonate, sodium or potassium bicarbonate, sodium hydroxide, and potassium. Alternatively, the reaction may be carried out in the presence of an alkali metal or alkaline earth metal salt such as calcium, an inorganic base such as a hydroxide, or a quaternary amine salt such as tetrabutylammonium bromide.

The reaction conditions are not necessarily limited, but it is generally appropriate to carry out the reaction within the following range.

Molar ratio of piperazine derivative, halide, acid acceptor, etc. used as necessary: 1:0.5 to 5:0 to 5, preferably 1:1 to 2:0 to 2; Reaction temperature: 0 to 160 ℃
, preferably room temperature to boiling point of reaction solution: reaction time = 0.5 to
60 hours, preferably 2 to 30 hours; reaction pressure - normal pressure
10 atoms, preferably at normal pressure: with or without stirring.

There are no special requirements for the post-treatment after the reaction and the purification of the target product, and the reaction can be carried out as appropriate by commonly used methods.

As mentioned above, the compound of the present invention is 6-ethoxycarbonyl-5,7-dimethyl-1-[3-(4-phenethyl-1
-14radinyl9propyl]-3-(α,α,α-triful,10-0-tolyl)-2,4(1■,aa)-
This compound is useful as an intermediate for the synthesis of quinazolinedione, etc., and below, methods for synthesizing the compound of the present invention from known compounds, and methods for synthesizing known intermediates from the compound of the present invention leading to the known compound, respectively. A representative example will be shown and more specifically explained. However, these are merely examples for purposes of explanation, and it goes without saying that the present invention is not limited to these in any way.

Example-1 3-(1-piperazinyl)pronognol 27.9# ethanol 207mA! Triethylamine 19.5Ii and phenethyl bromide 46.6.9
'i and heated under reflux for 26 hours. Diethyl ether was added to the residue from which ethanol was distilled off from the reaction mixture, and 40
After washing the diethyl ether layer with an aqueous sodium hydroxide solution, the diethyl ether is distilled off. Distillation of the residue under reduced pressure gives a boiling point of 183-190°C/0.4' mTlH
3-(4-phenethyl-1) as a fraction of g (uncorrected)
-piperazinyl) propatool 35.0g (yield 73
section).

Nuclear magnetic resonance spectrum: δ (measured in ppm r CDCt3) 1.70 (2H, triplet), 25-2.9 (
14H, multiplet), 3.74 (2H, triplet), 5.1
2 (II (mono-H), 7.t~7.3(s@, 9t
, a) Infrared absorption spectrum Niji (Crn-1) 310
0-3400.2900,2800゜1 4 5 0
, 1 1 4. 0, 1 0 6 0, 1
0 0 0 mass spectrum: rrV/e 248(M), 217,203,157,127°10
5.98.70 Example-2 In place of phenethyl bromide in Example-1, p
- By performing the same operation using fluorophenethyl chloride, the boiling point is 180-185°C/0.1-In
mHg (uncorrected) fraction, 3-1:47(p-fluorophenethyl)-1-pylanonyl]propatur is obtained in a yield of 47%.

Nuclear magnetic resonance spectrum: δ (ppm, measured in CDCl5) 1.70 (2H, triplet), 25-2.9 (
14H, multiplet), 3.80 (2H, triplet), 68~
72(4I], multiplet) Actual Example 16-3 To a solution of 11.5 g of 3-(1-py<radinyl)furonoyanor in ethanol (30 ml) was added 81!9 triethylamine and 192 g of phenethyl bromide to 30
Heat to reflux for an hour. After the reaction mixture was allowed to cool and the precipitate was removed, Solution E was concentrated under reduced pressure to dryness. 5Qm on the residue
1 of ethanol was added to dissolve it, and then a 15% (by weight) hydrogen chloride ethanol solution 5C17 was added and the precipitated crystals were counted. When this is recrystallized from methanol, the melting point is 20
3-(4-phenethyl-1-piperazinyl)propanol dihydrochloride at 8-214°C 20.8. ! 7 (Yield 81%
) is obtained.

Nuclear magnetic resonance coverage: δ (ppm, measured in CDCl5) 1.97 (2H, triplet), 2.8-3.3
(14H, multiplet), 3.74 (2I (, triplet), 5
．． 40 (IH.

Single line), 71-7.3 (5H, multiplet line)) Mass square: rn/e 248 (M-72), 217, 203, 157° 127
, 98 , 84. , 70 Example-4 p instead of phenethyl bromide in Example-3
- By performing the same operation using fluorophenethyl chloride, 3-[l4-(
p-fluorophenethyl)-1-piperazinyl] pro-
Qnol dihydrochloride is obtained in a yield of 63 el).

Red evening (line absorption vector: ν((J)3400,
2900-3000, 24 00-2700.15
10,1220.830 mass range: m/e 266 (M″-72), 248,235,221°2
03.172, 157, 127, 98.70 Example-5 3- (1-t<lanonyl)furonoyanor5.8.9
8.1 g of phenethyl bromide was added to a solution in 12 m, l of ethanol, and the mixture was heated under reflux for 34 hours.

The reaction mixture was allowed to cool, and the precipitate was collected and washed with about 3 ml of ethanol to obtain 8.8 g of 3-(4-phenethyl-1-piperazinyl)propatur hydrobromide with a melting point of 114-116°C (yield: 67°C). ) can be obtained.

Example-6 In Example 5, after the reaction was completed and before the solid precipitated, 12 ml of ethanol containing 1.5.9 ml of dry hydrochloric acid gas was added, allowed to cool, the precipitate was collected, and reconsolidated with methanol, resulting in a melting point of 206
14.6.9 (yield: 76) of 3-(4-phenethyl-1-piperazinyl)propanol-hydrobromide hydrochloride at ~210 DEG C. is obtained.

Example-7 3-(1-4'-4:radinyl)furopanol 2.88
466 g of anhydrous sodium carbonate and 444 g of p-methoxyphenethyl chloride were added to a solution of No. 9 in 25 ml of n-butanol, and the mixture was heated under reflux for 48 hours. N-butanol is distilled off from the reaction mixture, acetone is added to the residue, insoluble matter is removed in an oven, and then acetone is distilled off. Reconsolidation of the residue with n-hexanenoethyl ether gives a melting point of 70
3-(4-(p-methoxy/phenedyl)-1 at ~72°C
-Piperazinyl]pro-gunol was obtained in an amount of 2.229% (yield: 4°).

Nuclear magnetic resonance spectrum: δ (ppm, measured in CDCl3) 1.74 (2I (, triplet), 25-2.8 (1
4H, multiplet), 3.79 (5H, single line'' - triplet)
, 697 (4H1 quartet) Infrared absorption spectrum: ν (my) 3150-3350.2920, 2800°1600.
1500, 1450, 1300°124, 0, 115
0, 1130, 1030.

20 Mass spectrum: m/e 278 (M), 233,157,135,127°98
, 84 , 70 Example-8 Phenethylpiperazine 19.9 ethanol 10 rnl
Triethylamine], 3.9 was added to the solution, and then 18 g of 3-bromoprogol was added and the mixture was heated under reflux for 8 hours. After the reaction mixture was allowed to cool and the precipitate was removed, the p solution was concentrated to dryness under reduced pressure. Ethanol of IQi+f7 was added to the residual stream, and then 6 g of a 15% (weight) hydrogen chloride ethanol solution was added to collect the precipitated crystals 20Ti. When this was recrystallized from methanol, 3-(11-feothyl-1-piperanonyl)pro-yanol dihydrochloride 16
g (yield 50%).

Reference Example-1 3-(4-Phenethyl-1-piperazinyl)proi8nol dihydrochloride 7.4j9 was added little by little to 25m6 of thionyl chloride, stirred at room temperature for 3 hours, and then heated to 60°C to give 2.
The mixture was further heated to 90° C. for 16 hours and allowed to react under stirring. Next, after distilling off thionyl chloride, 20 ml of ethanol was added to the residue and heated to 70 to 80°C for 30 minutes while stirring. Ethanol is distilled off under reduced pressure and the residue is recrystallized from ethanol to give 1-(3-
55 g (yield: 70%) of chloropropyl-4-phenethylpiperazine dihydrochloride are obtained.

Nuclear magnetic resonance spectrum (free salt 28): δ (ppm.

Measured in CDC, g3) 1. 95 (2H, triple line), 24-30 (141
1, multiplet), 3.58 (2H, triplet), 71-73
(5H1 multiplet) Infrared absorption spectrum rainbow (CRN) 2950.2350-2600.14・10°1, 0
90, 950, 760, 700 mass spectrum: m/e 266 (M-72), 231, 203, 175° 139
, 132, 70 Reference Example-2 3-C4- instead of 3-(4-phenethyl-1-piperazinyl)propanol dihydrochloride in Reference Example-1
By performing the same operation using (p-fluorophenethyl)-1-piperazinyl]pro-gunol dihydrochloride, 1-(3-chloropropyl) with a melting point of 180-190C was obtained.
-4-(p-fluorophenethyl)pyranone dihydrochloride is obtained in a yield of 73%.

Nuclear magnetic resonance spectrum: δ (ppm, measured in D20) 227 (2H, triplet), 3.13 (2H, triplet), 34-3.8 (14H, multiplet), 71-74 (4
H1 multiplex, gland) Infrared absorbing lens: v (C1rL')34
00, 2980, 2400-2650.

1600.1510,1450,1220゜960.8
30 Mass coverage: m/e 284 (M'-72), 249.221. 189
.

175.139, 132, 123, 98.70 Reference example-
3 3-[4-
By performing the same operation using (p-methoxyphenethyl)-1-piveranonyl] propatool, the melting point was 19.
1-(3-chloropropyl)-4-(p
-Methoxyphenethyl) piperazini hydrochloride yield 43%
It can be obtained with

Nuclear magnetic resonance spectrum: δ (ppm, measured in D20) 2.29 (2H, triplet), 3.1.0 (2H1
triple line), 34-3. s (1,4H, multiplet), 3
．． 82 (3H.

single line), 7.17 (4H, quartet) Infrared absorption cover: ν (cm”) 3400. 2950. 2300-2650.

1610.1510,1450,1250゜1030
．． 960. 830 Mass spectrum: m/e 29'6 (M+-72), 261,233,175°1
39.135,132,98.70 Reference Example-4 Monobromic acid monohydrochloride was added to the dihydrochloride of 3-(4-phenethyl-1-pyradinyl)pro-p-nol in Reference Example-1. By performing the same operation using
1-(3-chloropropyl)-4-phenethylhyherazine-bromate-hydrochloride at a temperature of 5 to 197°C is obtained with a yield of 73%.

Continued from page 1 0 Inventor Kura 1) Yohei Tamagawa Chemical Research Institute, Ota-ku, Tokyo 0 Inventor Norio Kanuma Tamagawa Chemical Research Institute, Ota-ku, Tokyo

Claims (1)

[Scope of Claims] A piperazine derivative represented by a one-stage formula (wherein X means a hydrogen atom, a fluorine atom, and a methoxyl group).