JPH03188030A - Method for removing benzyl group - Google Patents

Abstract

PURPOSE:To safely perform the reaction in a conventional open system without employing any specific reaction device by using hydrazine or the hydrate thereof as a hydrogen source when an amine having a benzyl group to a benzyl group- removing reaction in the presence of a palladium catalyst. CONSTITUTION:An amine having a benzyl group such as 1'-benzyl-4'- carbamoyl-1,4-bipipelidine is profitably subjected to a benzyl group-removing reaction with hydrazine or the hydrate thereof as a hydrogen source in the presence of a palladium catalyst. The method has excellent safety compared with the ordinary pressure hydrogenation debenzylation reaction, permits to perform the reaction in the conventional open container without a specific closed reactor and provides the objective compound in a good yield in a short time because of capability of being heated.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an industrially advantageous dehensylation method for amines having a benzyl group.

[Prior art/problems to be solved by the invention] Conventionally, the debenzylation reaction of benzylamine compounds has been carried out using a platinum catalyst or a palladium catalyst in the presence of hydrogen at a temperature of several hundred degrees above room temperature under normal pressure or increased pressure. It is well known that this can be accomplished reductively over several tens of hours rather than several hours. However, since the hydrogen used is a gas and is easily flammable and explosive, special consideration must be given to the operating method and reaction equipment.

Therefore, there is a need for a method that does not require the use of a special sealed reaction container and can be carried out safely in a container used for ordinary chemical reactions. One possible solution to this problem is to use hydrazine instead of hydrogen. However, reactions using hydrazine as a hydrogen source in catalytic reduction reactions include reactions that convert nitro groups to amino groups, hydrogenation of double bonds, reduction of ketones at benzylic positions, and debenzylation of benzyl esters or benzylphenyl ethers. The debenzylation reaction of benzylamine is not known.

[Means to solve the problem]

In particular, the catalytic reductive debenzylation reaction requires much stronger reaction conditions and catalyst activity than the nitro group reduction reaction, but since hydrazine itself has a catalyst poisoning effect,
It appears that no reductive debenzylation reaction using hydrazine has been attempted until now. However, when the present inventor used hydrazine as a hydrogen source instead of gaseous hydrogen and performed the debenzylation reaction in the presence of a palladium catalyst, it was found that the debenzylation proceeded easily and quickly with a good yield. did.

That is, the present invention provides a method of subjecting an amine having a benzyl group to a debenzylation reaction in the presence of a palladium catalyst, which is characterized by using hydrazine as a hydrogen source.

According to the method of the present invention, the debenzylation reaction can be safely carried out in an ordinary open system without using any special reaction equipment.

The reaction is carried out by dissolving or suspending the raw material benzylamine compound in a reaction-inert solvent (methanol, ethanol, propatool, isopropyl alcohol, water, ethyl ether, tetrahydrofuran, dioxane, etc.), adding palladium on carbon to this solution, The reaction temperature, which then proceeds by dropwise addition of hydrazine (preferably the hydrate), ranges from room temperature to the reflux temperature of the solvent used.

If the raw material benzylamine compound has a group reactive with hydrazine, hydrazine is added dropwise as the hydrazine is consumed. The progress of the reaction is confirmed by foaming and the generation of ammonia, but the completion of the reaction can be determined by confirming the disappearance of raw materials by thin layer chromatography, etc., and the reaction is usually completed in about 1 hour. The amount of hydrazine used is usually sufficient at equimolar amounts, but the amount may be increased if necessary. Excess hydrazine is decomposed into ammonia by boiling under reflux, and residual hydrazine can be removed by distillation under reduced pressure, so there is no problem even if it is used in excess.

Examples of compounds that can be synthesized by debenzylation according to the method of the present invention are listed below, but the scope of the present invention is not limited thereto.

◎ 4°-carbamoyl-1,4°-bipiperidine ◎ 4-carbamoyl-4-dimethylaminopiperidine ◎ 2-(N-methylaminomethyl)morpholine ◎ 2
-(N-acetylaminomethyl)morpholine ◎ 4-hydroxy-4-phenylpiperidine ◎ 4-
hydroxy-4-(3-)lifluoromethylphenyl)
Piperidine◎ 4-Carbamoyl-4-(l-pyrrolidinyl)piperidine◎ 4-Carbamoyl-4-morpholinopiperidine◎ 4-hydroxy-4-(4-methylphenyl)piperidine◎ 4-(3-methyl-2,4-di Oxohexahydropyrimidin-1-yl)piperidine◎ 4- (2,4
-Dioxohexahydropyrimidin-1-yl)piperidine ◎ 4- (3,5-dimethylhydantoin-1-yl)piperidine ◎ 4- (3,5,5-)dimethylhydantoin 1-
yl)piperidine◎ 4-dimethylaminopiperidine◎ 4-aminopiperidine◎ 4-monomethylaminopiperidine◎ 4-pyrrolidinopiperidine◎ 4-piperidinopiperidine◎ 4-hexamethyleneiminopiperidine◎ 4-(4
-Methylpiperazino)piperidine◎ 4-phenylpiperidine◎ 4-(4-methylphenyl)piperidine◎ 4-(
4-methoxyphenyl)piperidine◎ 4-phenyl-
1,2,3,6-titrahydrobiridine ◎ 4-anilinopiperidine ◎ 4-(N-propionylanilino)piperidine ◎ 4-carbamoyl-4-hexamethyleneiminobiberidine ◎ 4-carbamoyl-4-( 4-Methyl-1piperazinyl)piperidine◎ 4-Hydroxy-4-benzylpiperidine◎ 4-
Hydroxy-4-(2-phenylethyl)piperidine◎ 4-methoxy-4-phenylpiperidine◎ 4-hydroxymethyl-4-phenylpiperidine◎ 4-dimethylamino-4-phenylpiperidine◎ 4-cyano-4-phenylpiperidine◎ 4-Carbamoyl-4-phenylpiperidine ◎ 4-(1-pyrrolidinylcarbonylamide) 4-phenylpiperidine ◎ 4-(2-oxo-1-benzimidazolyl)piperidine ◎ 4-(2-oxo-1-benzimidazolyl) )1,
2. 3. 6-titrahydropyridine ◎ 4-ethoxycarbonyl-4-phenyl-piperidine ◎ 1.3.8-) rearade 2.4-dioxospiro(
4,5) Decane◎ 2.8-Diaza-1,3-dioxo-spiro(4,
5) Decane◎ 1,3.8-1-diaza-4-oxo-1-phenyl-spiro(4,5)decane◎ 3-hydroxy-3-phenylpyrrolidine◎ 4-
Phenylpiperazine◎ 4-(4-methylphenyl)piperazine◎ 4-(
2-methylphenyl)piperazine◎ 4-(3-trifluoromethylphenyl)piperazine◎ 4-ethoxycarbonylpiperazine◎ 4-(3-
cyanopropyl)piperazine ◎ 4-(2-phenylethyl)piperazine ◎ 2-anilinomethylmorpholine ◎ 2-phenoxymethylmorpholine [Function and effects of the invention] Since the method of the present invention uses hydrazine instead of hydrogen,
Superior safety compared to atmospheric hydrogenation debenzylation reaction,
The reaction can be carried out in an ordinary open vessel without the need for special closed reaction equipment. In addition, since heating is possible, the desired product can be obtained in a short reaction time and in high yield.
This is an industrially advantageous method.

The compounds obtained by the method of the present invention are useful as intermediates for pharmaceuticals.

〔Example〕

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 20 g of 1°-benzyl-4'-rubamoyl-1,4°bipiperidine and 4 g of palladium on carbon were dissolved in 200 g of ethanol, and 80% hydrazine hydratrog was added at room temperature while stirring. Gradually raise the temperature and boil under reflux. Reflux for 15 minutes to 1 hour and continue for an additional 30 minutes after the starting materials have disappeared. Filter palladium on carbon,
When ethanol is distilled off, 4°-carbamoyl-1,4°-biviperidine having a melting point of 125° C. is obtained (yield 90%).

Example 2 In the same manner as in Example 1, 1-benzyl-4-carbamoyl-4-dimethylaminopiperidine was prepared with a melting point of 118 to 1.
4-Carbamoyl-4-dimethylaminopiperidine at 21° C. is obtained (yield 93%).

Example 3 In the same manner as in Example 1, 2-(N-benzyl-Nmethylaminomethyl)-4-benzylmorpholine was prepared with a melting point of 122.
2-(N-methylaminomethyl)morpholine dihydrochloride hydrate at ~124°C is obtained (yield 95%).

Example 4 2-(N-acetylaminomethyl)morpholine is obtained from 2-(N-acetylaminomethyl)-4-benzylmorpholine in the same manner as in Example 1 (yield 88%).

IR73500~3250.30B0.2950.28
50.16601565, 1550.1110cm-'
NMR: 1.92 (IH, s), 2.00 (3H
, s), 2.40-3.20 (5H, m), 3.3
5-3.65 (3H, m), 3.80 (IH, t, J
= 12Hz) Example 5 1-benzyl-4-hydroxy-
4 with a melting point of 159-160°C from 4-phenylpiperidine
-Hydroxy-4-phenylpiperidine is obtained (yield 94%).

Example 6 1-benzyl-4-hydroxy-
4-Hydroxy-4-(3-)lifluoromethylphenyl)piperidine having a melting point of 87 to 89°C is obtained from 4-(3-trifluoromethylphenyl)piperidine (yield 91%).

Example 7 In the same manner as in Example 1, 1-benzyl-4-carbamoyl-4-(1-pyrrolidinyl)piperidine, melting point 14
4-carbamoyl 4-(1-pyrrolidinyl)piperidine at 1-142° C. is obtained (yield 94%).

Example 8 In the same manner as in Example 1, ■-benzy-4-carbamoyl-4-morpholinopiperidine was prepared with a melting point of 182 to 186.
C. 4-carbamoyl-4-morpholinopiperidine is obtained (yield 91%).

Example 9 In the same manner as in Example 1, 1-benzyl-4-hydroxy-4-(4-methylphenyl)piperidine with a melting point of 13
4-Hydroxy-4-(4-methylphenyl)piperidine at 6-137° C. is obtained (yield 94%).

Example 10 50 g of 1-benzyl-4-(3-methyl-2,4-dioxohexahydropyrimidin-1-yl)piperidine and 10 g of palladium on carbon were dissolved in isopropyl alcohol 2
00-, 10 g of 80% hydrazine hydrogen chloride was added over 30 to 60 minutes at room temperature while stirring, and the temperature was gradually raised while stirring to reflux. After the ingredients have disappeared, continue for another 10 minutes. When palladium on carbon is filtered and isopropyl alcohol is distilled off, 4-(3-methyl-2,4
-dioxohexahydropyrimidin-1yl)piperidine is obtained (yield 90%).

Example 11 1-benzyl-4-(2,4-
4-(2,4-Dioxohexahydropyrimidin-1-yl)piperidine having a melting point of 217 to 219°C is obtained from dioxohexahydropyrimidin-1yl)piperidine (yield: 86%).

Example 12 l-benzyl-4-(3,5-
4-(3,5-dimethylhydantoin-1-yl)piperidine with a melting point of 267-270°C is obtained from dimethylhydantoin-1-yl)piperidine (yield 92%).
.

Example 13 1-benzyl-4-(3,5,
4-(35,5-trimethylhydantoin-1-yl)piperidine hydrochloride having a melting point of 300°C or higher is obtained from 5-)dimethylhydantoin-1-yl)piperidine (
yield 90%).

Claims (1)

[Claims] (1) A method of subjecting an amine having a benzyl group to a debenzylation reaction in the presence of a palladium catalyst, the method comprising using hydrazine or a hydrate thereof as a hydrogen source.