JPS5835499B2 - 1↓-(3↓-trifluoromethylphenyl)↓-2↓-(2↓-benzoyloxyethylamino)↓-propane production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 1-(3-)lifluoromethylphenyl)-2 having the formula (I): (wherein Ar is a 3-4!J fluoromethylphenyl residue) The present invention relates to a novel method for producing -(2-pentyloxyethylamino)-propane.

The compound (I) represented by the formula (I) has an interesting curing activity for hyperlipidemia (hypo 1 i pae mi z
ing ☆☆activity).

According to a known document (Class Patent No. 1517587), the substance is 1-(3-)lifluoromethylphenyl)-2-(2-hydroquinethyl-amino)-propane as shown in the following formula. It is produced by the benzoylation reaction of

(wherein Ar is as defined above) Such reactions are characterized by low yields due to competitive benzoylation at the nitrogen atom.

Further, the starting material, compound (II), as shown in the following formula, can be produced only by reacting the corresponding primary amine ([[) with ethylene oxide.

(wherein Ar is the same as above) Such a reaction is a highly unsatisfactory process because large amounts of bishydroxyethyl derivatives are produced even in the presence of substoichiometric amounts of ethylene oxide. It shows.

This by-product has to be separated from compound (It) by distillation under reduced pressure, which has some drawbacks.

Amine (III) itself is produced from (3-trifluoromethylphenyl)acetone by catalytic reduction, for example with an oxime.

This product can only be obtained in very low yields.

The low conversion yield in the final stage of synthesis is due to compound (I)
This greatly affects the economic efficiency of the synthesis process.

This is particularly true since the aforementioned side reactions destroy the trifluoromethyl substituent in the molecule, which is a very expensive component.

It has been found that the above-mentioned drawbacks can be overcome in the synthesis of compound (I) by using the new production method described below.

That is, the present invention provides 1-('3
−)! , J fluoromethylphenyl)-2-[N-
1-(3-
1-(3-trifluoromethylphenyl)-2, characterized in that it produces trifluoromethylphenyl)-2-(2-benzoyloxyethylamino)-furopane.
The present invention relates to a novel method for producing -(2-benzoyloxyethylamino)-propane.

The debenzylation reaction is carried out in the presence of a palladium catalyst.

Mata Sai 1 (3-trifluoromethylphenyl)-
2-(N-(2-benzoyloxyethyl)-N-benzylaminoco-propane (■) has the formula: (wherein Ar is the same as above) (3-trinorolomethylphenyl ) Acetone is reacted with benzylamine to form a Schiff base having the formula (■): (where Ar is the same as above), and then the Schiff base (IV) is reduced with sodium borohydride. 1-(3-
) IJ fluoromethylphenyl)-2-(2-N-benzylamino)-propane, which is then reacted with ethylene oxide to produce a compound having the formula (wherein Ar is the same as above) and further reacting this compound (VI) with benzoyl chloride.

The thus obtained compound (■) can be converted into 1-(3-trifluoromethylphenyl)-2-(2-benzoyloxyethylamino)-propane (I) by hydrogenation reaction in the presence of a palladium catalyst. It will be done.

Schiff base (IV) can be easily produced and the desired product is obtained in almost quantitative yield.

The same holds true for the next reduction to the N-benzyl derivative (V).

In practice, the reduction with borohydride is carried out using the Schiff base (I
V) without isolating the crude reaction product of (3-trifluoromethylphenyl)acetone and benzylamine (
IV) is preferably carried out directly.

1-(3-)lifluoromethylphenyl)-2-(2-
The hydroxyethylation reaction of N-benzylamino)-propane (V) is carried out smoothly, and compound (VI) is obtained in high yield with virtually no by-products.

Since no hydrogen atom is bonded to the nitrogen atom in this amine, the subsequent benzoylation reaction is also carried out in a single reaction, and the reaction is carried out directly with benzoyl chloride without adding an acid acceptor. It is done.

Finally, catalytic debenzylation reaction of compound (■) gives the expected product (I) in high yield and purity.

As is clear from the above description, the method of the present invention provides a novel manufacturing method that is significantly improved over conventional methods.

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

Note that the present invention is not limited only to these examples.

Example (a) 1-(3-)IJ fluoromethylphenyl)
-2-(2-N-benzylamino)-propane(3-)
(lifluoromethylphenyl)acetone 101f (0,5
mol) and benzylamine 53S' (0.5 mol) in 500 ml of benzene, a solution obtained by continuously removing the generated water (a device that can be suitably used is, for example, a Marcussen device).
The mixture was refluxed in a 5000 ml (n'5device).

When no more water was released, the benzene was finally distilled off under reduced pressure using a rotary evaporator.

147 g of a residue consisting mainly of Schiff base (IV) was dissolved in 500 ml of ethanol, and 7.0 g of sodium borohydride was then added to 200 ml of ethanol.
A suspension obtained by adding 5f (0.2 mol) was slowly added under stirring.

During such addition, the outside of the container is cooled to a temperature of 15-20°C.
It was kept at ℃.

Once the addition was complete, the mixture was stirred at room temperature for 10 hours, then most of the ethanol was distilled off (finally under reduced pressure).

After diluting with 400 ml of water, the reaction mixture was dissolved in 2N-HC.
Acidified with I.

A small amount of unreacted ketone was extracted with CH2Cl□, and the aqueous layer was
The organic base was made alkaline with 5% NaOH and CH2C1
Extracted with □.

After drying the organic layer over 2CO3, the solvent was removed and the residue was distilled under reduced pressure.

The product was obtained in a yield of 1291.

bpo, 5130-133°C. The yield was 88% based on the starting material ketone.

IR and NMR analyzes were consistent with the expected structure.

(b) 1- (3-)! J Fluoromethylphenyl)-2-CN-(2-hydroxyethyl)-N-benzylaminoco-furopane 1 ml of water was added to the product 58.6P (0.2 mol) obtained in the previous step a). Place the mixture in an autoclave for 1 hour.
Cooled to 0°C.

Then, 16f of liquefied ethylene oxide (-10°C) (
0.36 mol) was added.

The reaction mixture was heated at 100-115° C. for 8 hours, cooled and mixed with 300 ml of toluene.

This material was washed with water (200ml x 2), and then Na
Dry with 2SO4.

Solvent was removed under reduced pressure.

60.6 P of product (90% of theory) was obtained as a colorless liquid.

Results of IR and NMR analysis, The result was consistent with the expected structure.

This is pre(e) 1-(3-trifluoromethylphenyl)-
2-(N-(2-benzoyloxyethyl)-N-benzylamino]-7'ropane 1-(3-)lifluoromethylphenyl)-2-(N-(2-"it) in 200ml of anhydrous toluene (oxyethyl)-N-benzylaminoco-propane 50.5f
? (0,15 mol) and benzoyl chloride 22,1' (0,
16 mol) was heated at 70-80° C. for 6 hours with stirring.

After cooling, the hydrochloride salt of the benzoylation reaction product was separated.

This material was filtered with suction, thoroughly washed with toluene, and dried.

mp140℃. Yield 58.6F (82% of theory).

Results of IR and NMR analysis, The result was consistent with the expected structure.

This product was prepared by adding 47.7 f (0.1 mol) of the hydrochloride obtained in Prewar C) to 400 ml of ethanol and heating it at room temperature in the presence of 5% palladium 2.51 on a carbon carrier. A hydrogenation reaction was carried out under pressure.

During 1.5 hours, 0.1 mole of hydrogen was consumed.

The catalyst was separated from the P and the solvent was removed under reduced pressure.

The residue was mixed with 150 d of ethyl acetate and, after one suction, the crystalline product obtained was washed with a small amount of ethyl acetate.

The obtained 1-(3-)lifluoromethylphenyl)-2
The hydrochloride of -(2-pentyloxyethylamino)-propane had a melting point of 160-161°C.

No melting point depression was observed in the mixture with the product prepared according to FR 1,517,587.

The yield in the debenzylation step was over 95%.

Claims (1)

Claims: 1-(3-trifluoromethylphenyl)-2=(N-(2-benzoyloxyethyl)- N-benzylaminoco-propane was subjected to a catalytic debenzylation reaction in the presence of a palladium catalyst to obtain 1-(3-
)! 1-(3-)lifluoromethylphenyl)- which is characterized by producing Jfluoro7notylphenyl)-2-(2benzyloxyethylamino)-fluorane
A method for producing 2-(2-benzoyloxyethyl'amino)-propane. (3-trifluoromethylphenyl) having (wherein Ar is a 3-trifluoromethylphenyl residue)
Acetone is reacted with benzylamine to form a Schiff base with (where Ar is the same as above) and then the Schiff base (IV) is reduced with sodium borohydride (where Ar is 1 (3-) with (same as above)
! J fluoromethylphenyl)-2-(2-N-benzylamino)-propane is produced, which is then reacted with ethylene oxide to produce a compound having the formula (wherein Ar is the same as above). , further produced by reacting this compound (VI) with benzoyl chloride (wherein Ar is the same as above) 1-(3-)! J fluoromethylphenyl) -2-(N-('2-benzoyloxyethyl)-N-benzyl★amino]-propane was subjected to a catalytic debenzylation reaction in the presence of a palladium catalyst, (wherein Ar is the 1 (3-) with
1-(3-trifluoromethylphenyl)-, which is characterized by producing IJ fluoromethylphenyl)-2-(2-benzyloxyethylamino)-furopane.
A method for producing 2-(2-benzoyloxyethylamino)-propane. 3 Reduction with sodium borohydride forms a Schiff base (
3. Process according to claim 2, characterized in that it is carried out directly on the crude reaction product of (3-trifluoromethylphenyl)acetone and benzylamine without isolating IV).