DE1910477B - 2,4-disubstituted tetrahydro-1,4-oxazines and pharmaceutical preparations containing these compounds - Google Patents

Description

wherein R is a hydrogen atom or an alkyl radical having 1 to 7 carbon atoms, the allyl, cyclohexyl, Means benzyl or phenylethyl

2. A pharmaceutical preparation consisting of a tetrahydro - 1,4-oxazine derivative according to claim 1. in connection with the usual pharmaceutically acceptable carriers or auxiliaries.

The invention relates to 2,4-disubstituted tetrahydro-1,4-oxazines or morpholines as well as to pharmaceutical preparations containing these compounds as active ingredients.

In "Angewandte Chemie", 77 (1965), pp. 329 to 333, various processes for the preparation of Tetrahydro-1,4-oxazines and their substituted derivatives that serve as fungicides.

From this literature review, the most important procedures dealt with in it will be briefly discussed will. The first is that primary amines are condensed with bis (^ - halogen) diethyl ether. For example, U.S. Patent 3,155,656 describes the synthesis of Z4.6-trimethyltetrahydro-1,4-oxazine.

The second method is that bis (2-hydroxyethyl) amines with sulfuric acid (USA.Patent 3 112 311) or with p-toluenesulfonic acid (German Patent 1,137,439) or with pyrophosphoric acid (British Patent 861,463) dehydrated for cyclization.

It is also possible. Epoxies with 1-amino-2-hydroxyethanes or condense with primary amines 7u and then carry out the cyclization (See "Angewandte Chemie", op. C. p. 329. left column, and "Helv. Chim. Acta". 47 [1964], P. 2106).

It should be noted that according to Chemical Reviews. 59 (1965). P. 4. the procedure in certain cases can lead to mixtures of primary and secondary amino alcohols.

According to »Journal Prakt. Chem. «. 21 (1963). (1-2). 12-17. racemic norephedrine is condensed with glycol chlorohydrin and obtained by cyclic dehydration Tetrahydro-1,4-oxazine.

The method according to »Chem. Ber. «. 99 (1966). (8), p. 2716, in which correspondingly substituted amino alcohols are condensed with ethyl oxalate, whereby oxazinediones are obtained. The reduction of the oxazinediones is difficult, however connected. wi <! the work in »Liebigs Ann. Chem. ”, 685 (1965). Pp. 181 to 186 shows.

Finally, the French patent specification I 535 615 describes a process for the production of 2,4- and wherein R is a hydrogen atom or an alkyl radical having 1 to 7 carbon atoms, the allyl, cyclohexyl, Benzyl or Phenyläthylrest means in therapy has an effect on the central nervous system exercise.

The compounds according to the invention are used according to the following three-step process made from readily available raw materials

(1) Addition of bromine to a / i-halogenated Vinyl ether of the general formula

X - CH ₂ - CH ₂ - O - CH = CH ₂

in which X is a halogen atom, preferably chlorine, to form a derivative of the general formula

X-CH ₂ -CH ₂ -O-CH-CH ₂ -Br (II) Br

(2) Condensation of the derivative of the general formula II with an organomagnesium compound of formula III

(III)

forming a connection of general! Formula IV

(IV)

Q-A ".

■ 4 CH ₂ CH ₂

Br X

wherein X has the meaning given above

(3) Condensation of the compound of the general formula IV with a primary amine of the general formula

R-NH ₂

in which R is an alkyl radical with 1 to 7 carbon atoms, denotes the allyl, cyclohexyl, benzyl or phenylethyl radical, the desired Compound of the general formula V

(V)

in which R has the meaning given above. is obtained.

The addition reaction (1) of the bromine to the / i-halogenated Vinyl ethers I is at a temperature below normal temperature, preferably below OC. in particular between - 15 and - 10 C in a solvent or diluents, e.g. B. in chloroform carried out. The molar ratio of bromine to dem, i-halogenated vinyl ether is about 1. After When the addition is complete, the solvent can be partially recovered by distilling the reaction medium will.

The condensation reaction (2) of the brominated derivatives II with the organomagnesium compounds III can be carried out under the conditions which for the condensation according to Boord (cf. H. Krauch and H. K u η z. "Reactions of the organic Chemistry «, 3rd edition [1966]. Pp. 88 and 89) are provided. Is advantageous in an aliphatic or cyclic ether as a solvent, e.g. B. Ethyl ether. worked at the boiling point of the ether, a gentle reflux of this solvent is maintained. The molar ratio of the The brominated derivative II to the organomagnesium compound III is about 1.

The · condensation of the derivatives of the general formula IV with the primary amines is carried out with a Amount ratio of about 1 mole of the derivative IV per 3 moles of primary amine carried out. The reaction is used as a solvent aromatic hydrocarbon, e.g. B. toluene, at moderately increased Temperatures around 100 C and optionally carried out in an autoclave.

For the preparation of products of the general formula V in which R is a hydrogen atom or a methyl resl, the amine R - NH ₂ used in stage (3) can be gaseous. In practice, however, it is more advantageous to prepare these compounds by first catalytically hydrogenating 2- (3-trifluoromethyl) -phenyl-4-benzyltetrahydro-1,4-oxazine, as a result of which the benzyl substituent is removed from this compound.

The catalytic hydrogenation is carried out under normal conditions using 5% palladium-carbon carried out as a catalyst.

The compound obtained can then, if desired, in the 4-position by heating to temperatures of about 100 ° C in the presence of a mixture methylated by amcisene acid and aqueous formaldehyde (compare e.g. "Organic Reactions", Vol. V, 2nd edition [1952], pp. 307 and 308).

The new compounds have properties that make them valuable medicines, in particular soothing, analgesic and anti-inflammatory properties.

Test report ίο 1. Acute toxicity

The LD ₅₀ was calculated using the method of Behrens and Kärber (Arch. Exp. Path, Phann., 177, 1935, p. 379). The acute toxicities of the compounds according to the invention are compared in the same order as in Table A with the toxicities of the comparison compounds chlordiazepoxide *) and phenylbutazone *).

2. Soothing properties

The calming effect of the new drug was examined; and with that of a well-known sedative, namely chlordiazepoxy hydrochloride. forbid.

The calming effect of the compounds according to the invention is caused by electrical irritation Aggressive rats and mice were determined.

Experimental principle (in the rat)

The repeated electrical stimulation of two rats in the same cage caused the animals to become aggressive Behavior that is suppressed by sedatives (Siou.G.J. Physiol. Paris 50, 1958, pp. 504 and 505). The effectiveness of the sedative is based on reducing the aggressiveness determined in the treated rat.

method

Male rats from the Wistar strain, weighing between 250 and 300 g, are grouped divided into six. Half an hour after oral administration of the product or the one used Solvent (comparison animals), the animals are placed in groups of two in a cage, one Size of 24 χ 12 x 34 cm, and its bottom is made of longitudinally arranged rods made of non-

rusting steel, which are connected in pairs. 1 hour and 1.5 hours after the Administration of the product will pass the animals through every 5 seconds for a period of 1.5 minutes stimulated a current that has a voltage of 110 V, a frequency of 50 Hz and a passage time of 25 milliseconds.

In each group of animals it is determined whether the two rats are on during each stimulus place the hind paws erect opposite each other and whether such an attitude of »boxing Rats "abandoned after the irritation ceased, or longer or shorter than 2 minutes after the interruption the continuity of the current is maintained. The observer does not know the division Control animals or treated animals within the same group in the arrangement of the cages and the

*) Dial tone proposed by the WHO.

results already obtained for a given gnippe.

During each passage of the current it in turn gives the value 0 for missing and the value 1 for existing aggressive behavior during the irritation and, on the other hand, after the irritation has ceased Value 0 for maintaining the posture described above, value 1 if the same posture less than 2 minutes and a value of 2 if the aggressive posture is longer than 2 minutes is retained.

The values obtained, which are obtained for each of the three subgroups of the same group for the two irritations, are added. The percentage decrease in aggressiveness of the treated groups compared to the control groups is calculated from the sum. The dose at which the aggressiveness is reduced by 50% compared to the comparison items (ED ₅₀ ) is log from the straight line. Dose / response determined. The test results are shown in Table B.

Experimental principle (with the mouse)

The implementation is at Y e η, CY, S ta η ge r. L. and M i 11 man, N., Arch. Inteen. Pharmacodyn., Iz3, p. 179 (1959). The product is administered orally to groups of six animals each. The dose at which the aggressiveness is reduced by 50% compared to the control animals (ED ₅₀ ) is log from the straight line. Dose / response determined. The results are also compiled in Table B.

3. Anti-inflammatory properties

These properties were determined on rats by the method of G. Wi 1 he I mi and R. Domen zjo /. (Arzneimittelforschung, 1 [1951], p. 151) determined. The medicament according to the invention was compared with phenylbutazone. The anti-inflammatory effect is determined at the bottom in comparison to the acute stage of the inflammation (characterized by the strength of the vascular reactions). The inflammation is caused by injecting kaolin (0.15 ml of a 10% solution) under the tendon skin of the hind fote. The edema reaction is measured at regular intervals with the plethysmograph (modified device according to G i ο η ο and Ch ₁ ; -v i 11 ard). Comparing the volume of the paw before and after the injection makes it possible to determine the strength of the inflammation, which is calculated using the following formula:

Increase in the volume of the paw,% = volume of the inflamed paw - original volume

original volume

- · 100

The compound to be tested is taken orally for 30 minutes administered before the injection of the irritant substance. The results are expressed as the percentage of inhibition Swelling in the treated animals compared to the control animals (100%) is expressed in Table B.

4. Analgesic properties

The analgesic effect of the orally administered product is determined on the mouse using two methods:

a) thermal stimulus

Method according to N. B. Eddy and D. Leimbach (J. Pharmacol. Esn. Then, 107 [1953], pp. 385 to 393). See also J. Y. P. Chen and H. Beckmann (Science, 113 [1951]. P. 63). The pain will be at the Mouse caused by contact heat stimulus. The animals are placed on a plate which is cooked through boiling Acetone (56.5 "C) is kept at constant temperature. The time until the onset of the reaction the pain stimulus is noted. This reaction consists of licking the front paws.

The extension of the exposure time in the treated animals compared to the control animals gives the analgesic efficiency of the examined substance. The substance is 30 minutes before the attempt orally (intubation through the esophagus) in different doses in groups of 40 animals administered.

b) Chemical irritation

Method according to K o s t e r, modified by W i t k i η [R. Koster, M. Anderson and E. J. De Beer,

Fed. Proc. 18 [1959], p. 412; L.B. Wit kin, CF. Heubner, F. Galdi, E. O'Keefe, P. Spitaletta and A.J. Plummer, J. Pharmacol. Exp. Ther., 133 [1961], pp. 400 to 408).

The pain in the mouse is caused by intraperitoneal Injection of acetic acid (300 mg of a 3% solution per kilogram) is generated. This injection is calling characteristic crises of pain (twisting the trunk, stretching the hind limbs), the number of which is added over the course of 20 minutes in a group of six to eight animals. the Number of melts produced in the treated animals observed in comparison to the control animals, gives the analgesic effect, which after the is calculated using the following formula:

Number of crises in the control animals

-Number of crises in the treated animals

% Analgesia =

Number of crises in the control animals

- ■ 100

The substance to be tested is administered orally in various doses (intubation through the esophagus) minutes before the test. The ED ₅₀ in mg / kg represents the dose which reduces the number of pain crises in the treated animals by 50% compared to the comparable animals. The results obtained are shown in Table B.

Table B.

No. PO
F ₁ CI R. CH ₃
-CH
CH ₃ Acute toxicity
LD ₁₀ oral (mgAg) Calming effect Effect on the
aggressive mouse Activity index
LD ₅₀ R. -CH ₂ -CH = CH ₂ Effect on the
aggressive rat ED ₅₀ (mgAg) ED ₁₀ O ED ₅₀ (mg / kg) 7.2 51 I. 365 (90 IV) 6.5 n- (C ₄ H ₉ ) 13th 130 2 —Η # 1700 at 50 mg / kg
100% decrease 27.5 109 3 —CHj > 3000 ilOO ~ 30 57 4th C ₆ H ₁₃ 1700 - 220 5 -C ₅ H ₁ , 1730 ~ I5 4.5 133 6th -C ₃ H ₇ 600 (70 IV) 2 11th 80 7th CH ₂ CH ₂ νχ µ 1300 (110 i.v.) 15 mg / kg IO 90 8th > 900 10 90 9 > 900 at 50 mg / kg
100% decrease 10 90 10 > 900 the same ~ 20 45 Π > 900

(Continuation)

No. PO
F ₁ CI R. Chlordiazepoxide hydrochloride
(Comparison substance) acute toxicity
LD ₅₀ oral (mg, cf. Calming effect Effect on the
aggtcssivc MftiM Activity index
LD » R. / "·
-H ₂ C-CH
\
CH ₃ Phenylbutazone
(Comparative substance) Effect on As
aggressive rat ED ₅₀ (mg / kg) ED » C ₇ H ₁₅ ED ₁₀ (mg / kg) 15th 12th CH,
-CH ₂ -CH ₂ -CH 1190 ~ 7 = 30 13th CH ₃ # 3000 ~ 30 23 14th # 2000 ~ 20 80 720 30th 1100

Table B (continued).

10

No. ι R. CH ₃
-CH
CH ₃ Anti-inflammatory Decongestion
des üdöms
% effect Analgesic effect chemical stimulus
EDj ₀ mgAg -CH ₂ -CH = ^ CH ₂ dose
mg / kg 87 plani-
metric
worth Heat stimulus ED ₅₀
mgAg 150 1 O 100 460 125 -CH ₂ - ^ y 66.5 50 2 MC ₄ H ₉ ) 100 61.5 246 125 300 3 -H 100 13th 346 # 500 bad
effect 4th 50 66 42.5 ineffective 300 5 -C ₆ H ₁₃ 50 100 288 bad
effect
over 300 60 6th C ₅ H _n 100 74 542 110 280 7th -C ₃ H ₇ 100 43.5 356 280 ~ 400 8th —CH ₂ - CH ₂ - ^ ~ / 100 58.5 209 ineffective 80 9 100 82.5 301 150 80 10 100 15th 469.5 450 ~ 300 U 100 27 ineffective

(Continuation)

Nf. / \ γθν
y \ M / R. C ₇ Hu CH ₃ Phenylbutazone Anti-inflammatory Desulphurization effect Analgesic effect chemical stimulus A. _{/ CH} ,
-H ₂ C-CH / (Comparative subsidy) of the Odems EPj ₀ mg / kg CH ₃ -CH ₂ -CH ₂ -CH % plans- ~ 200 \
CH ₃ LIOSlS 39 metric Heat stimulus BD ₁ , mgAg Whom mgAg ineffective 12th 50 48 138.5 ineffective 13th 100 148.5 ineffective 200 66.5 350 14th 100 49 311 bad effect 100 270 ineffective

11 12

The new substances can be used in conjunction with the treatment of the aqueous phase with aqueous

the usual auxiliaries, such as starch, talc and Magne 50% sodium hydrochloride solution, extracted the

sium stearate, to drug preparations, such as tablet amine with ether, dries over anhydrous Na ₂ SO ₄ ,

th, capsules or dragees, are processed, whereby the ether is distilled off and the residue is rectified

for oral administration of the active ingredient also in Kap- 5 under reduced pressure, whereby one 14 g of product

his or her tablets with delayed active ingredient information,

can be incorporated boiling point 99 ° C / 3 mm Hg; µ S ¹ = 1.4751; yield

It is also possible to use the new connections as 50%.

Medicinal preparations rectally in the form of suppo- The hydrochloride is crystallized by adding the base sitorien. Rectal capsules as well as by injection, e.g. B. | _{0 taken up} in ethyl acetate and the necessary intravenous, in connection with pharmaceutically un- amount of absolute alcohol, which with dry salt-questionable auxiliary substances to be administered. acid is saturated, is added. Melting point

164 ° C.

^Beis P ^iel 'elemental _{analysis for C 14} H ₁₉ ClF ₃ NO: (molecular weight

First stage ' ⁵ 309.77):

1,2-dibromo-2- (2-chloro) ethoxyethane Calculated ... N 4.52, Cl "11.44;

640 g of bromine found N 4.49 are added dropwise with stirring. Cl "11.40.

(4 mol) to a kept at -10 ⁰ C solution of

426 g (4 mol) of 2-chloroethyl vinyl ether in 1040 mg of ChIo- 20 B e i s ρ i e 1 2

^r0f0rm · Ii ^oh "- ^rf ? ^l8tCr w ^U8 _i fo ^b rf ^W1 p ^rd Ä » ^LÖ f" Ρ '2- (3-trifluoromethyl) -phenyl-4-allyl-tetrahydro-

medium distilled, with 690 g of product obtained 1,4-oxazine hydrochloride
will.

Boiling point 102 ° C / 13 mm Hg; n'i = 1.5305: This connection is made under the same condi-

loot65%. 25 as described above for the third stage of

_ ·, C. r game 1 were described, from 18 g of allylamine and

/.weite Muie _{33 15 g (0} j _{Mo |) of the m Stufc 2 yon example, he} h _a TE!

2- {3-trifluoromethyl) -2- (2-chloro) -ethoxy-l-bromoethane 2- (3-trifluoromethyl) -2- (2-chloro) -ethoxy-l-bromo-

(3 - trifluoromethyl) - phenylmagnesium bromide is produced in ethane. After the distillation, 13.5 g

obtained from 48.6 g of magnesium in chips and 455.7 g (3-tri-30 product.

fluoromethyO-bromobenzene and 1500 ml anhydrous boiling point 103 ^& C / 2mm Hg; «!? ' - 1.4828; Made from ether. To the resulting solution of the mole 51%.

The magnesium compound is added dropwise with stirring The hydrochloride is obtained under conditions

a solution of 550 g of l, 2-dibromo-2- (2-chloro) -eth- in Example 1 for the preparation of the hydrochloride

Oxyethane is added in 300 ml of anhydrous ether in such a way that 35 are described. Melting point 140 ⁰ C.

that a slight reflux of the ether is maintained. Elemental analysis for C ₁₄ H ₁₇ ClF ₃ NO (molecular weight

will. After the addition, another 2 hours 307.75):
heated to reflux, then cooled and treated with a

Mixture of 500 g of ice and 200 ml of concentrated salt- Calculated ... N 4.55, C 1, 44;

acid is hydrolyzed. The organic 40 found N 4.50, Cl 11.50.

Phase, washing with water saturated with NaCl. · \ \

and dry over anhydrous Na ₂ SO ₄ . Man destil example 3

removes the ether and rectifies the residue un- 2- (3-trifluoromethyl) -phenyl-4-cyclohexyl-tetrahydro-

under reduced pressure, giving 361 g of product 1,4-oxazine hydrochloride

^he boiling point 98 ° C / 0.1 mm Hg; n? = 1.4970; Aus * ^{$ E} i ", ^G , ^em * ^sch _u T °" ³ - ³ : ^{15 8} <& «Mol) 2 ^ 3-Trifluor-

loot 54% methyl - 2 - (2 - chloro) - athoxy -1 - bromathane. the GE-

The product thus obtained was even after the ⁰ ^ ₁ stage of Example 1 was obtained, and was 27.7 g

Analysis by gas chromatography to obtain a purity Cyelohexyiamm JW Mol) in 100 ml of toluene

from * wa 95% and can be refluxed for 10 hours without a second rectifying effect

tion used in the subsequent reactions ^to f » ^e . ^In the manner described in bastions 1 and 2

will. worked, 19 g of product being obtained.

Boiling point 146 ° C / 1 mm Hg; »? = 1.4945; Third level loot 60%.

2- (3-Trifluoromethyl) -phenyl-4-isopropyl- "The hydrochloride is based on the in Examples 1

tetrahydro-1, 4K) xazmhydrochIorid and 2 described manner obtained. Melting point

A mixture of the following 190 ° C. is heated in the autoclave.

Composition at 100 ° C: Elemental _{analysis for C 17} H ₂₃ ClF ₃ NO (MoJ weight

2- (3-Trifluoromethyl) - _ ^M9 ^ ³⁾ \ "" _m "," ,,

2- (2-chloro> -ethox / -l-bromo- ^fa Calculated ... N 4.00, CT 0.13;

Ethane found 33.15 g (0.1 mol) .... N 4.05, CT KUO.

Isopropylamine 20 g (034 moles) Example 4

^{ToIuo1 10} ° ml 2- (3-trifluoromethyl) -phenyl-4-benzyItetrahydro-

The hydrochloride and the hydrobromide of iso- 65 1,4-oxazmhydrochloride
piopy! amine are filtered off. The solvent is driven off in the manner given in Example 3, the residue is taken up in 4N HCl, but OJMoI corresponds to 32.1 g and the aqueous phase is washed with ether. Benzyls min instead of OJMoI cyclohexylamine

be used. This gives 18 g of the abovementioned product.

Boiling point 140 ° C / 2mm Hg; «F = 1.5195; Yield 56%.

The hydrochloride is obtained in the manner described above. Melting point 152 ° C.

Elemental analysis for C ₁₆ H ₁₉ CIF ₃ NO (molecular weight 357.8):

Calculated ... N 3.91, Cl "9.90; found N 3.90, Cl "10.00.

Example 5

2- (3-trifluoromethyl) phenyl-4-n-butyltetrahydro-1,4-oxazine hydrochloride

The procedure given in Example 3 is followed, but using 18.9 g of n-butylamine. This gives 15 g of the above-mentioned product.

Boiling point 112 ° C / 2mm Hg; η? = 1.4710; Yield 52%; Melting point of the hydrochloride 153 ° C.

Elemental analysis for C ,, H ₂₁ CIF ₃ NO (molecular weight 323.79):

Calculated ... N 4.32, Cl "10.91; found .... N 4.35, Cl "11.00.

Example 6

Manufacture of 2- (3-trifluoromethyl) -phenyltetrahydro-1,4-oxazine (VI)

139 g of 2 - (3 - trifluoromethyl) - phenyl - 4 - benzyltetrahydro-1,4-oxazine in the form of the hydrochloride, which is dissolved in 250 ml of 96% ethanol and 100 ml of water, are in the presence of 14 g of 5% Palladium-carbon catalytically hydrogenated (temperature 20 ° C., initial pressure 3.5 kg / cm ² ). The theoretical amount of hydrogen has been absorbed after 6 hours. The reaction is stopped, the catalyst is filtered off, the solvent and the toluene formed are distilled off under reduced pressure and the residue is made alkaline with 40% strength NaOH. The desired amine is extracted with ether and the residue is rectified under reduced pressure. This gives 63 g of a colorless oil with an amine odor.

Boiling point 132 ° C / 10mm Hg; η? = 1.4852: yield 70%

The chromatographic analysis shows a purity of 98 to 99%.

By dissolving the amine in anhydrous ether and adding absolute ethanol, which is mixed with HCl saturated IFt, the hydrochloride is inherited, which the It is in the form of a white crystalline powder soluble in water and alcohol and insoluble in ethyl acetate. This hydrochloride has the following Properties: molecular weight 267.69; Melting point 139 ° C

Elemental Analysis for C _n H ₁₃ F ₃ ClNO: Calculated ... CT 13.24, N 5.23; found Cl "13.20, N 5.23.

Example 7

Production of 2- {3-TrifiuorniethyJ) -p1ienyI-4-methyI-tetrahvdro-l "i ^ oxazine (ViI)

23.1 g of the compound (VI) prepared according to Example 6 are added to 30 g of 98% strength with cooling Formic acid and 12 g of 30% aqueous formaldehyde are added to this solution. The mixture is heated on a water bath for 5 hours. After cooling down, give 20 ml of concentrated HCl are added and then concentrated under reduced pressure. The residue taken up in 50 ml of water is made up with 40% aqueous NaOH alkaline, extract the desired amine with ether, drive off the solvent and rectify under reduced pressure, 18 g of one being

ίο colorless oil with an amine odor.

Boiling point 124 ° C / 10mm Hg; n'S = 1.475; Yield 73%.

Chromatographic analysis shows a purity of 99%.

is In the manner given in Example 6, the Hydrochloride produced in the form of a white crystalline powder, which has the following properties: soluble in water and alcohol, insoluble in ethyl acetate. Molecular weight 281,717; Melting point 168 ° C.

Elemental analysis for C ₁₂ H ₁₅ F ₃ CINO:

Calculated ... found ....

Cl Cl

12.58, N 4.97; 12.50, N 5.02.

Example 8

Preparation of 2- (3-trifluoromethyl) -phenyl-4-n-hexyl-tetrahydro-1,4-oxazine hydrochloride

This compound is prepared under the conditions given in Example 1 with the sub decided that in the third stage 30.3 g (0.3 mol) of n-hexylamine and 33.15 g (0.1 mol) of 2- (3-trifluoromethyl) -2- (2-chloro) -ethoxy-1 - bromethane. this in Stage 2 of the synthesis given in Example 1 was obtained, are implemented. Here 17 g of the above product was obtained in a yield of 53%.

The hydrochloride is crystallized by taking up the base in ethyl acetate and adding the necessary amount of absolute alcohol, which is saturated with dry HCl. is added. Melting point 149 ^r C.

Example 9

Production of 2- (3-trifluoromethyl) -phen>; - 4-n-pentyltetrahydro-1,4-oxazine hydrochloride

This compound is prepared under the conditions given in Example 8, but with so 26.1 g (03 mol) of n-pentylamine instead of 30.3 g (03 mol) hexylamine can be used. This gives 15.6 g of the abovementioned product in a yield of 52%.

The hydrochloride is "tea" in Example 8 SS iur the production of the hydrochloride given. Conditions received. Melting point 134 ° C.

Example 10

Preparation of 2- (3-trifluoromethyl) -phenyl-4-n-propyltetrahydro-1,4-oxazine hydrochloride

This compound is prepared under the conditions mentioned in Example 8, but using 20 g (034 mol) of n-propylamine instead of 303 g of hexylamine. This gives 15 g of the abovementioned product in a yield of 54%.

15th

16

The hydrochloride is prepared under the conditions specified in Example 8 for the preparation of the hydrochloride produced melting point 183 ° C.

example

Production of 2- (3-trifluoromethyl) -phenyl-4- (2-phenylethyl) -tetrahydro-1,4-oxazine hydrochloride

This compound is under the conditions given in Example 8, but using of 363 g (0.3 mol) of 2-PhenyläthyIamhi instead of 303 g of hexylamine are produced. 17 g of the above product are produced in a yield of 51% receive.

S The hydrochloride is prepared under the conditions specified in Example 8 for the preparation of the hydrochloride receive. Melting point 246 ° C.

Table A contains a compilation of the compounds of Examples 1 to 11 as well as further ver

io bonds of the formula (V) based on the in the examples specified manner.

Table A.

CH ₃ CH

CH ₃ -CH ₂ -CH = CH ₂

n- (C ₄ H ₉ ) -H

CH ₃

C ₆ H ₁₃ -C ₅ H ₁₁ -C ₃ H ₇

C Γ12 C ΓΊ2 ~

CH ₃

-H ₂ C-CH

CH ₃

C ₇ H ₁₅

/ -CH ₂ -CH ₂ -CH

CH ₃

CH ₃ Hydrochloride 164 ° C (white crystals)

Hydrochloride 140 ⁰ C

Hydrochloride 190 ⁰ C hydrochloride 152 ° C

Hydrochloride 153 ⁰ C

Hydrochloride 139 ° C (white crystalline Powder)

Hydrochloride 168 ° C (white crystalline Powder)

Hydrochloride 149 ° C hydrochloride 134 ° C Hydrochloride 183 ° C

Hydrochloride 246 ° C

Hydrochloride 166 ° C

Hydrochloride 143 ° C

Hydrochloride 157 ° C

soluble in insoluble in Water, alcohol ether Water, alcohol Ether,
Ethyl acetate Water, alcohol ether Water. alcohol ether Water, alcohol Ethyl acetate Water, alcohol Ethyl acetate Water, alcohol Ethyl acetate water water water little in water
soluble Water, alcohol Ethyl acetate Water, alcohol Ethsr Water, alcohol ether

Claims (1)

Patent claims: I. 2,4-disubstituted tetrahydro-1,4-oxa ^ ne the general formula IO i2,4-substituted tetrahydro-l ^ -oxazines. This process consists in carrying out, in a first stage, an alkoxylation and bromination of an olefin with tert-butyl hypobromite in the presence of IC wor-2-hydroxyethane, then condensation with primary amines, the corresponding tetrahydro-1,4-oxazines being obtained . The invention now relates to 2,4-disubstituted ones Tetrahydro-1,4-oxazine of the general formula