DE2318024A1 - PROCESS FOR THE PREPARATION OF 2-PHENYLALCOXYCARBONYL-TETRAHYDRO-1,4-OXAZINES - Google Patents

Description

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A 12 628

CENTER EUROPEEN DE RECHERCHES MAUVERNAY ¹¹ CERM "Route de Marsat, 63200 RIOM, France

Process for the preparation of 2-phenyl-alkoxycarbonyl-tetrahydro-1,4-oxazines

The invention relates to a new process for the preparation of morpholine derivatives, namely 2-phenyl-alkoxycarbonyl-tetrahydro-1,4-oxazines, the general formula:

^G 6 ^H 5 R.

in the mean

R _{1 is} a carboxylic acid, alcohol or ester radical and R "is a hydrogen atom or an alkyl or aralkyl radical,

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The compounds given above are new and constitute valuable ones Synthesis intermediates, especially those intended for synthesis? Heterocycles.

It is already known that compounds of the formula

in which R is -CO - NH - CH ₂ - CH ₂ OH, after processes described in US Pat. No. 2,918,466 can be prepared which comprise the following steps:

a) Treatment of p-methoxycinnamaldehyde with hydrogen peroxide in an alkaline medium with the formation of the alkali metal salt of the acid

CH-CH-COOH

b) treating the latter with ethanolamine and then

c) Cyclization of the compound obtained in this way by dehydration.

However, this process results in two isomers, namely the compounds

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and CH ₃ O

In addition, this known method has the disadvantage that, due to its complexity and due to the fact that the two isomers B and C have to be separated from one another, cannot be carried out on an industrial scale can.

In contrast, it is according to the method according to the invention possible to prepare in a simple manner the compounds of the general form A given above, which are not through to the Compound C analogous isomers are contaminated. The method according to the invention comprises two stages:

First_Sttif es alkoxybromination of a cinnamic acid ester with tert-butyl-hypobromite in the presence of excess glycol chlorohydrin and

Second stage: conversion of the intermediate product obtained in this way with a primary amine.

The process of the invention can be carried out by the following reaction scheme being represented:

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CH = CH-COOR +

CH ₂ OH -

Cl + (CH ₃ ) C-OBr

COOR

Cl + (CH _{3) 3} C - OH

ROOC

A ¹

This gives compound A ¹ , which is compound A, in which R ₁ - COOR and R ₃ φ Η.

To prepare the compound A, where R "= H, one of a catalyst, subjecting the compound A ¹ in the presence (5% Pd / C) to hydrogenolysis. To prepare the compounds A, in

COOH, reduced or saponified

which R,

CH ₂ OH and R,

Compound A ¹ .

The invention is illustrated in more detail by the following examples, without being restricted thereto. In the following examples the implementation of the method according to the invention is based on the preparation of eight special compounds, which are given in the table below, explained in more detail.

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Connection no. ^R l R ₂ ■ · 9 H ^C 6 ^H 5 Melting boiling point
point ⁰ C
(HCl)
⁰ C 1 -COOC ₂ H ₅ -CH ₂ mm H ^C 6 ^H 5 218 2 -COOCH ₃ -CH ₂ H 82 3 -COOCH ₃ -G ₄ H mm - * 137 (0.5 4th -COOC ₂ H ₅ H 191 5 -COOCH., 214 6th -COOH ^C 6 ^H 5 278 (decomp.) 7th -CH ₂ OH -CH ₂ 219 8th -CH ₂ OH 191

example 1

^ Connection no,

First stage production of 2-bromo-3- (2-chloro) ethoxy-3-phenylethyl propionate.

To a mixture of 176 g (1 M) ethyl cinnamate in 400 ml glycol chlorohydrin, the temperature of which was kept at 0 C, tert-butyl hypobromite was added dropwise with thorough stirring, which was immediately before its use according to the method of A. Kergomard in " Bull.Soc.Chim.de France ", 1961, page 2360. The reaction mixture was then poured into 1000 ml of cold water and extracted with ether. After drying over anhydrous Na ₉ SO ₁ . the ether was

driven and the residue was rectified under vacuum.

This gave 170 to 180 g of the product, E ₁ - 125 ° C,

20th
n "« 1.5290, purity «98-99% (gas chromatography).

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Analysis: C (%) HOO M = 335.64 Calculated: 46.52 4.80
found: 46.28 4.72

Second stage: 435 g of the product obtained in the first stage and 420 g of benzylamine in 800 ml of toluene were refluxed for 12 hours. After evaporation of the toluene was the residue taken up in 500 ml of absolute ethanol and acidified with dry gaseous hydrogen chloride. It was cooled and the crystals formed were filtered off. After recrystallization from ethanol, 211 g of the product were obtained.

Hydrochloride : F - 218 ° C M = M - 361.87 N (%) 325.41 N (%) Analysis: C (X) H (%) H (%) 3.87 4.30 ber .: 66.38 6.68 7.12 3.90 4.32 found: 66.27 7.03 7.02 Base: F - 51 ° C Analysis: C (X) ber .: 73.82 found: 73.20 Example 2

YS £ l ££ & ££ .. ϊίϊι - l · 1

First stage: Production of 2-bromo-3- (2-chloro) ethoxy-3-phenylmethylpropionate.

The procedure of step 1 of example 1 was repeated, where-

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this time, however, 162 g methyl cinnamate were used. Man received 157 to 165 g of product.

Vs- 127 ° C n ^ = 1.5325 H (X) M - 321.61 analysis : C (X) 4, 39 ber .: 44.81 4, 17th found: 45.09 second Level of ex Second Step: The procedure of

was repeated, this time 150 g of the product of the first stage V '
(Base).

Stage were used. 5.71 g of product were obtained, mp 82 ° G

Analysis: C (%) H (%) N (X)

ber.ι 73.25 6.79 4.49

Found: 73.51 7, -10 4.45

Example 3

2-Pheny_l-3-methoxy _> carbony ^ -42n-buty_l tetrahydro-Ij, 4-oxazine

The first stage was identical to that of Example 2. In the second stage, 32.15 g of the product of the first stage and 30 g of n-butylamine in 120 ml of toluene were refluxed for 12 hours. After the solvent had been stripped off, the residue was taken up in ether and the product was extracted with 2N HCl. The aqueous solution was _{treated with Na2C0 3} and the base was extracted with ether. After evaporation of the solvent, the residue was rectified in vacuo. 12 g of product were obtained in this way.

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E _{n ς} - 137 ° C n ^ ⁰ - 1.5130

U, ο υ

Hydrochloride: M.p. 182 ° G M = 313.83

Analysis: 61.23 ber .: 61.05 found: Example 4

7.71 4.46

7.83 4.50

2-pheny _> l-3-ethoxy _> carbony _> tetrahydro-l ^ -oxazine £ Compound No. 4 ^

144 g of compound no. 1 (product of Example 1) in the form of the hydrochloride were in a mixture of 300 ml of ethanol dissolved by 90 ° and 100 ml of water. 14 g of 5% palladium on activated carbon were added as a hydrogenation catalyst. the Hydrogenation was carried out at ambient temperature and under a pressure of 3 atmospheres of hydrogen. After the In the reaction, the catalyst was filtered off, the solvent was stripped off and the product was anhydrous in 300 ml Isopropanol added. 92 g of product were obtained in this way in the form of the hydrochloride.

Hydrochloride: C. F. 191 ° C 235 , 28 M = H <%) 271, 75 N (% ) Analysis: 66 C. (%) H (%) 6.67 5.15 found: 66 57 , 45 7, 28 6.87 5.20 ber .: 57 , 60 7, 42 Base: mp 88 ° C M - Analysis: <%> N (7o found: , 36 5.95 ber .: , 67 6.04

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Example 5

2-PhenYl-3-methoxYcarbon ^ l-tetrah ^ dro-l _i 4-oxazine £ Compound No.

Under the same conditions as in Example 4, but this time however, starting from Compound No. 2 (Example 2), by hydrogenating this compound, Compound No.

H ^ drochloridi Mp 214 ° C M = 257.72 N (X) Analysis: C (%) H (X) 5.42 found: 55.92 6.25 5.20 about ,: 55.56 6.14 Base: M.p. 120 ° C M - 221.26 N (%) Analysis: C (X) H (X) 6.32 found: 65.14 6.83 6.31 ber .: 64.90 6.82 Example 6 ^ Compound 6 2-Pheny ^ -3-hjrdrox £ carbonYl-tetrahydro- l ₂ 4-oxazine

This compound was obtained by saponifying the corresponding ester (Compound No. 4). For this purpose 10 g of compound no. 4 were dissolved in 90 ml of 2N NaOH. It was an hour heated to boiling for a long time, filtered and the pH was brought to 6.2 by adding acetic acid. After a night in The precipitate formed was filtered off with suction in a refrigerator. After drying, the product was boiled with three 100 ml portions washed with absolute ethanol, with 6.5 g of product remaining (mp 278 ° C., decomposition).

Analysis: C (%) H (X) N (%)

calc .: 63.75 6.32 6.76

Found: 64.00 6.50 6.78

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-ίο. 231802η

The N-acetyl derivative of this compound had a melting point

from 171 C. C. tt) H ν '° / N , 62 Analysis: 62 , 64 6, 06 5 , 60 ber .: 62 , 55 6, 25th 5 found: Iroxymi example 7th 2-phenyl -3-hy_c

This compound was prepared by reducing the corresponding ester (Compound No. x 2). For this purpose, 59 g of compound no. 2 were added with stirring to a suspension of 10.2 g of lithium aluminum hydride in 450 ml of anhydrous ether, the temperature being kept below 10 ° C. This addition was followed by refluxing for two hours, then allowed to cool to ambient temperature. Then 15 ml of ethyl acetate were slowly added, the flask was placed in an ice bath and it was hydrolyzed with 60 ml of a saturated NH, C1 solution. After Eindampfendes ether, the residue was recrystallized twice from Gyclohexan to give 35 g of product (m.p. 102 ⁰ C).

H (X). N (%) 7.46 4.94 7.00 5.02

Analysis: G (%) ber .: 76.29 found: 76.00 Hydrochloride: Mp 213 ° C.

Example 8

This compound was obtained by filtering Compound No. 7. For this purpose, 28.3 g of Compound No. 7 Dissolved in 180 ml of ethanol at 96 ° and 2.8 g of 5% strength were obtained

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Palladium on activated carbon was added as a catalyst. The hydrogenation was carried out at ambient temperature and under a pressure of 3 kg / cm hydrogen. After completion of the implementation the catalyst was filtered off, the solvent and the toluene formed were stripped off under vacuum. The solid residue was recrystallized from absolute ethanol, 18.5 g of product remaining (mp 191 ° G, hydrochloride).

Analysis: C (%) H (%) N (%)

calc .: 57.52 7.01 6.09

found: 57.36 7.01 6.10

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Claims (5)

- 12 - Claims Process for the preparation of 2-phenyl-alkoxycarbonyl-tetrahydro -1,4-oxazines of the general formula CHC ₆ H X) ^R 2 in which: R, a carboxylic acid, alcohol or ester radical and R «is a hydrogen atom or an alkyl or aralkyl radical, characterized in that, for the preparation of compounds of the general formula given above, in which R, an ester radical and R "denotes a radical different from H, in one first stage alkoxybrominated a cinnamic acid ester with tert-butyl hypobromite in the presence of excess glycol chlorohydrin and in a second stage the compound obtained is reacted with a primary amine. 2. The method according to claim 1, characterized in that one for Preparation of compounds of the general formula given in claim 1, itjÖer R, means a carboxylic acid residue, compounds, in which R, denotes an ester radical, saponified. 3. The method according to claim 1, characterized in that for the preparation of compounds of the general formula given in claim 1, in which R _{1 is} an alcohol radical, compounds in which R 1 is an ester radical, reduced. 309844/1132 4. The method according to claim 1, characterized in that one for the preparation of compounds of the general stated in claim 1 Formula in which R ~ denotes a hydrogen atom, which in products obtained by the process according to claim 1 catalytically hydrogenated 5. Compounds as used in the method according to any one of the claims 1 to 4 can be obtained. 309844/1132