KR820002230B1 - Method for producing bisphenyl alkyl amino furopanol compound - Google Patents

Abstract

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Description

Method for producing bisphenyl alkyl amino furopanol compound

The present invention relates to an improved process for the preparation of bisphenylalkylaminofuropanol compounds represented by the following structural formula (I).

(N is an integer of 1-3, and A is oxygen, nitrogen, sulfur, carbon.)

The objective compound of the present invention was developed in the early 1960's by researchers such as Volcutt Krassen and Schönbandik, the Netherlands, and has been widely known as a therapeutic agent for preventing premature birth of a fetus, which has been made possible since its synthesis. .

Conventional methods for preparing the target compound of the present invention are as follows.

1.C. A. 63. 17965h (1965) 2. BE pat 660244 (1965) 3.US pat 3410944 (1968)

first,

second,

third,

However, the first method and the second method of the conventional methods are practically inconsistent with the industry at a very high cost because the yield is only about 30%, and the third method is not suitable for mass production because the yield is about 40%.

The reason why the yield was low was that the reaction rate between the compound of formula (II) and compound (III ') was about 40-50%, and the intermediate (IV') was inevitably obtained. Therefore, only a complicated purification process can obtain the target compound (I) with good purity, and the effect on the overall yield was great.

Therefore, the present inventors are characterized in that the intermediate (IV) compound is produced in high yield by reacting the following compound of the following formula (II) with a known compound to produce the intermediate (IV) compound in high yield. The target compound (I) is prepared by hydrogenation and hydrogenation.

The method for preparing the target compound (I) from the compound of formula (IV) may be carried out by a conventional method as a known method, but according to the methods described in JP 2313625 and S. 71/4323, etc. It is very convenient. When the technical content of the present invention is displayed for each process as follows.

[Step 1]

[Step 2]

That is, the feature of the present invention is that when preparing and reacting a secondary amine of the structural formula (III), it prevents the formation of substituents of nitrogen and prevents the incorporation of impurities in comparison with the structural formula (III ') which is a primary amine. In addition, it is possible to prepare a compound of formula (IV) in high yield without a complicated purification process by substituting a benzyl group that can be removed without difficulty during the reaction and further facilitates the preparation of the compound of formula (I). The compound of formula III can be easily prepared from the corresponding 1 molar amount of amine and 2.5 molar amount of benzyl chloride as follows.

Conventional methods can be prepared only through a complex process of four or more stages, including debenzylation and hydrogenation. However, in the present invention, when phosphine and a promoter are added together with a rhodium catalyst, debenzylation and hydrogenation occur simultaneously. The reaction is possible only by the step process, which is an improvement over the conventional method.

The following examples explain in detail the preparation of the compounds used in the preparation of the compounds of the invention.

Example 1

[Method for Making En- (2- (4'-benzyloxyphenyl) ethyl) -ene-benzylamine]

In a solution of 139.5 grams (1 mol) of 2- (4-hydroxyphenyl) ethylamine in 250 milliliters of dimethyl ketone, 320 grams (2.5 mol) of benzyl chloride and 150 grams of potassium carbonate were mixed with a suspension of acetone and water. The solution is added to the solution.

Stir vigorously until the reaction is complete and then precipitate is filtered off and washed 2-3 times with ethanol and water.

The residue is taken and dried to give 297.98 grams of yield (94% yield).

Elemental Analysis C ₂₂ H ₂₃ ON MW317.34

Theoretical C 83.28 H 7.25 O 5.06 N 4.41

Found 83.15 7.27 5.09 4.34

Example 2

[Method for preparing 4'-benzyloxy-2- (2- (4-methoxyphenyl) ethylamino) propiophenone hydrochloride]

A solution of 11 grams of 2-buromo-4'-benzyloxypuropiophenone and 11 grams of 2- (4-methoxyphenyl) ethylamine in 67.5 milliliters of ethanol was refluxed for 3 hours.

Ethanol is then evaporated in vacuo and ether is added to the concentrate. The precipitate is removed and the filtrate is mixed with an excess of 2-normal hydrochloric acid. This gives a crystal, which is washed with water and ethanol and dried in vacuo to give 25.5 grams of 4'-benzyloxy-2- (2- (4-methoxyphenyl) ethylamino) propiophenone hydrochloride (yield) 43.4%).

C ₂₅ H ₂₈ O ₃ NCl MW425.5 Melting point 217-218 ° C

Example 3

[Preparation of 4'-benzyloxy-2- (2- (4-benzyloxyphenyl) ethyl-ene-benzylamino) furopiophenone hydrochloride]

212.75 grams (0.5 mole) of 2-buromo-4'-benzyloxy furopiophenone was dissolved in tert-butanol, and 112.51 grams (1.0 mole) of tertiary potassium butoxide and 108.5 grams obtained in Example 1 0.5 mole) of N- (2-4'-benzyloxyphenyl) ethyl) -ene-benzylamine is added and reacted at room temperature for 8 hours, then refluxed for 4 hours and cooled.

The resulting residue was filtered off, the filtrate was concentrated and an excess of 550 milliliters of acetonitrile and hydrochloric acid was added to the residue, followed by vigorous stirring to form a replacement. The solids are separated by filtration, washed 2-3 times with water and again with ether.

The residue was then dried by evaporation to give 272.15 grams (yield 92%) of the title compound. Melting Point 221-223 ° C

Elemental Analysis C ₃₈ H ₃₈ O ₃ NCl MW591.64

Theoretic C 77.07 H 6.42 O 8.15 N 2.36 Cl 6.00

Found 77.22 6.48 8.21 2.07 6.03

Example 4

[Method for preparing 1- (4-hydroxyphenyl) -2- (2- (4-hydroxyphenyl) ethylamino) furopanol hydrochloride]

4.19 grams (7.1 milliliters) of residue obtained in Example 3 and 5% rhodium on carbon (100 milligrams, 50% wet material: 0.49 mol of rhodium), 30 milliliters of methanol and 0.468 grams (1.8 milliliters) of triphenyl phosphine 0.06 gram (0.3 mmol) of stannous perchlorate is added to the Parr vessel, the contents of the vessel are purged with nitrogen, and then hydrogen is introduced under 50 PSI pressure.

The reaction mixture was shaken at 60 ° C. for 10 hours, the presence of the target was confirmed by thin layer chromatography, and the resulting precipitate was filtered off. The reaction mixture was cooled, 30 ml of methanol and 2 molar equivalents of hydrogen chloride gas were added overnight. Leave it.

The slurry is separated by filtration, the residue solid is collected and dried to obtain 2.09 grams (yield 96%) of the hydrochloride of the target compound.

C ₁₇ H ₂₂ O ₃ NCl MW323.87 Melting point 183-186 degrees

Claims (1)

The following compound of formula (II) is reacted with a compound of formula (III) to obtain a compound of formula (IV), followed by debenzylation and hydrogenation of the compound of formula (IV) to a bisphenylalkylaminofue of formula (I). Method for preparing a panol compound or salt thereof.

N is an integer of 1-3, A is oxygen, nitrogen, sulfur, carbon.