DE1445973C - Process for the preparation of N Carbal koxy tetrahydro 1,3 oxazines - Google Patents

Description

The invention relates to a process for the preparation of N-carbalkoxy-tetrahydro-l ^ -oxazines of the general formula I.

R ₄

H-CH-C-CH ₂ -NH ₂
OH

(I.

R ₁ - C - R

■ 2 - '

IH

in which R ₁ and R _{2 have} the meaning given above, reacted under dehydrating conditions in a manner known per se and then the intermediate product of the general formula IV obtained

IV

^ o

with a chloroformic acid ester of the general formula V

Cl - C - OR

natural ² ) and cracks _; in the. Compared to untreated fiery the T); iiier, Hes SeKhifes; ■ '■ ■ ·'"■' ¹ V ^r <^; - * ϊ ■

in which R ₁ , R ₂ , R ₃ and R ₄ denote alkyl groups or the benzyl radical and R ₁ and R ₂ together also denote the pentamethylene radical and R denotes an alkyl radical.

The process is characterized in that a 1,3-aminopropanol of the general formula II ■ ·· ■ · ■> ^{: /:?}

UU ₅₁ ,
mg / kg sc ' Sleep extension relative to
Comparative substance percentage substance 3900 5 example 1 3380 143 ■ Xy.i Example 3 1850 96 6th . Example 4 ■. 1230 - 153 . '■ "1 Meprobamate 27

in which R ₃ and R _{4 have} the meaning given above, with a ketone of the general formula III

¹ '"■ ν ■ · ■ · ') Meprobamat = international abbreviation for 2,2-Di-

(carbamoyloxymethyl> -pentane.
') llcxobarbital = international abbreviation for 5- (Cy-

clohexen-l-yl) -l, 5-dimethylbarbituric acid c.

B cis ρ ie I ^1;

I ^ -Pentamethylcn-ß-carbethoxy-S-propyl-5-ethyl-tetrahydro-1,3-oxazine

HA _n / ^ 4 ... ■ ·

NC-OC ₂ H ₅

/ CH ₂ -Clk; v

H ₂ C C-:; , CH ₂ V;

^ O ^ ^ CH ₂ - CH ₂ ⁷ ^

30 g I-amino - 2 - ät'hyj - 2 - propyl - propanol - 3 are dissolved in 250 ml of toluene and mixed with 40 g of cyclohexanone and 300 mg of p-toluene sulfonic acid.

The reaction mixture is boiled with stirring and reflux until the separation of water in a water separator has ended. Thereafter, 24 g of triethylafnine are added to the solution and 22 g of chloroformic acid are added dropwise while cooling with ice and stirring ^; ethyl ester, dissolved in Ί 00 nil anhydrous; toluene, to it. The mixture is then stirred for 1 hour at room temperature, the precipitated salt is filtered off with suction, the toluene solution is shaken out with water, dried with sodium sulfate and finally the solvent is distilled off. Fractionation in a high vacuum of 0.15 torr gives the substance with a boiling point of 122 to 124 ° C. and a refractive index η Ii ¹ = 1.4771 in a "yield of 30%

35

40 theory, based on the starting amine.

in which R has the meaning given above, in the presence of a basic hydrogen chloride acceptor reacts in a manner known per se;

The new process products have a strong effect on the nervous system, with a strong dampening effect on the central nervous system in the foreground. When using equitoxic doses, they are, for example, ^{considerably superior to the carbamic acid ester meprobamate 1} ) selected as a comparison substance in the barbiturate potentiation test (compare, for example, Holten and Larsen, Acta pharmacol. Et toxicol., 12 [1956], p. 346 ff.), Such as the the following results show:

2 hours after application of the test substance sc to white mice in an amount of 5% of the DL ₉₀ found, 100 mg of hexobarbital- ί ' ^: ■ ·' ■ - ■ · ■:. '■ .- · ■■' ^: B ' ei £ ρ i el 2 '&;■'

2-Ethyl-i-methyl-1-carbethoxy-, M 5,5-diethyl-tetrahydro-1,3-oxazine

- 26.2 g of 2,2 - diethyl - ^: 3 * hydroxypropylamine, 17.2 g of ethyl methyl ketone ün'd 0; 3 g of p-toluenesulfonic acid are refluxed in 100 ml of absolute toluene for 3 hours. Thereafter, heating is carried out using a water separator until all of the water has separated out. The toluene is distilled off and the residual product is subjected to fractional distillation. Yield: 23 g = 62% of theory 2-ethyl-2-methyl-5,5-diethyl-tetrahydro-1,3-oxazine, boiling point "107 to 112" C, n'J = 1.5481.

18.5 g of 1-ethyl-Z-methyl- ^ S-diethyl-tetrahydrofo-1,3-oxazine are dissolved in 50 ml of absolute toluene and 12 g of triethylamine are added. While stirring and cooling with ice, 11 g of ethyl chloroformate, dissolved in 50 ml of absolute toluene, are added dropwise. The mixture is stirred for 1 hour, 100 ml of water are then added, the toluene phase is separated off, the toluene is distilled off and the residue is fractionated. You get. 14g = 54.7% of theory l-ethyl ^ -methyl-S-carbäthoxy-Sj
tetrahydro-1 ^ oxazine. Bp. _{0> 2} 80 to 82 ° C.

Example 3

i ₀

5,5-dipropyl-tetrahydro-1,3-oxazine

31.9 g of 2,2-dipropyl-3-hydroxypropylamine, 38.8 g of benzyl propyl ketone and 0.3 g of toluenesulfonic acid are refluxed in 100 ml of absolute toluene for 3 hours and worked up as in Example 2. Yield: 28 g = 46% of theory 2-benzyl-2-propyl-5,5-dipropyl-tetrahydro- _{1,3-oxazine, boiling point ox} 145 ° C., n ² S = 1.5060.

25 g of 2-benzyl-2-propyl-5,5-dipropyl-tetrahydro-1,3-oxazine, dissolved in 50 ml of absolute ethanol, are mixed with 10 g of triethylamine. While stirring and cooling with ice, 10 g of isopropyl chloroformate in 50 ml of absolute ether are slowly added dropwise. Working up is carried out as in Example 2. Yield: 19 g = 59% of theory of 2-benzyl-2-propyl-S-carbisopropoxy-S ^ -dipropyl-tetrahydro-l ^ -oxazine, b.p. _0> 3160 ° C., ni ⁵ = 1.4970.

35 Example 4

2-Ethyl-2-propyl-5-benzyl-5-propyl-3-carbethoxy-tetrahydro-1,3-oxazine

2-Ethyl - 2 - propyl - 5 - benzyl - 5 - propyl - tetrahydro-1,3-oxazine is obtained by heating 41.4 g of 2-benzyl-2-propyl-3-hydroxypropylamine, 24 g of ethyl propyl ketone and 0 , 3 g of p-toluenesulfonic acid prepared analogously to the precursor of Example 2. Yield: 40 g = 69.4% of theory, _{boiling point 015} 145 to 148 ° C, nf = 1.5128.

28.9 g of 2-ethyl-2-propyl-5-benzyl-5-propyl-tetrahydro-1,3-oxazine are dissolved in 50 ml of toluene and 12 g of triethylamine are added. While stirring and cooling with ice, 11 g of ethyl chloroformate, dissolved in 50 ml of absolute toluene, are added dropwise. Working up is carried out as in Example 2. The product obtained is extracted by shaking with dilute hydrochloric acid, neutralized and washed with water. Yield: 14 g = 38.8% of theory, _{boiling point ol5} 155 ° C., η I ⁵ = 1.5086.

Claims (1)

Claim: Process for the preparation of N-carbalkoxytetrahydro-1,3-oxazines of the general formula I. in which R ₁ , R ₂ , R ₃ and R ₄ denote alkyl groups or the benzyl radical and R ₁ and R ₂ together also denote the pentamethylene radical and R denotes an alkyl radical, characterized in that a 1,3-aminopropanol of the general formula II OH in which R ₃ and R _{4 have} the meaning given above, with a ketone of the general formula III III in which R ₁ and R _{2 have} the meaning given above, reacted under water-splitting conditions in a manner known per se and then the intermediate product of the general formula IV obtained R ₄ IV with a chloroformic acid ester of the general formula V Cl - C - O --R Il ■ ν in which R has the meaning given above, in the presence of basic hydrogen chloride acceptors brings to reaction in a manner known per se.