DE1643857A1 - Process for the preparation of tetrahydro-1,4-oxazines or morpholines substituted in the 2,4- and 2,2,4-positions - Google Patents

Description

Process for the production of 2,4- and 2,2,4-graduation substituted tetrahydro-1,4-oxazines or morpholines

The invention relates to the production of tetrahydro-1,4-oxazines or morpholines, especially their 2,4-disubstituted and 2,2,4-trisubstituted derivatives. These Compounds can be used as starting materials for the synthesis of pharmaceutical products.

Numerous processes for the preparation of these compounds have been proposed. In recent work (König et al., Angewandte Chemie 21 (7), page 329 (1967)) are most of the known processes for the preparation of the tetrahydro-1,4-oxazines and their substituted Derivatives lectured. This work can be considered a good literature compilation be used.

The two methods which have mainly been described and used so far are mentioned as examples. In a first process, primary amines are condensed with bis (β-halogenated) ether oxides. For example U.S. Patent 3,155,656 describes the synthesis of 2,4,6-irimethyltetrahydro-1,4-oxazine by this method. Such a method has a rather limited scope and does not allow easy manufacture

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position of all desired. Morpholine compounds.

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

There are a number of variants of this basic procedure, the main ones of which are briefly discussed below.

For example, the following sequence of stages has been proposed (King and Associates) l, e): Condensation of nitroalkanes with aldehydes, reduction of the -NOg group to NHg, condensation of the amino alcohols thus obtained with epoxides and finally cyclization by dehydration of those suitably substituted Diet Granolamine

It is also possible to condense the epoxides with primary amines by known methods and then the Make cyclization ,, This reaction leads to symmetrical tetrahydro-1,4-oxazines, which are in the 2,6-position are disubstituted (Cherbulliez et al., Helv · Chim. Aota 47 (7), p. 2 106 (1964)).

It should be noted in this connection that in certain cases and according to the work of RE Parker and NSIsaacs (Chemical Reviews £ §, (A-), August 1965) the latter process can lead to mixtures of primary and secondary amino alcohols of the following type :

R-CH-CH ₀ -N ^ + R-CH-H ^ OH CH ₂ OH

In another known method (J.ELosa, J.Prakt. Chem. 2J_ (1-2) 12-17 (1963)) one condenses racemic

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ITorephedrine with the chlorohydrin of glycol and receives Tetrahydro-1,4-oxazine by cyolizing dehydration.

In another known process (Zymalkowski and coworkers, Arch. Pharm « 294 453-468 (1961)) the amino alcohols are condensed with g-lyoxyl alcohol by catalytic hydrogenation and converted into tetrahydro-1,4-oxazine by cyclizing dehydration.

Finally, mention should be made of the known process (Drefahl and coworkers Chem. Ber. ^. ( ⁸ ) »page 2716 (1966)), in dom oxazinediones are prepared by condensation of appropriately substituted amino alcohols with ethyl oxalate. It is known, however, that the reduction of the oxazinediones presents difficulties, as in the work of Winterfeld et al. In e Ann. Ghem. 685 181-186 (1965) mentioned.

The study of various methods for the synthesis of 2,4-disubstituted and 2,2,4-trisubstituted tetrahydro-1,4-oxazineη and the value of these derivatives were Anlassezur the development of a simple method for preparing these derivatives ₀

The invention accordingly provides a process for the preparation of 2,4- and 2,2,4-substituted derivatives of tetrahydro-1,4-oxazines or morpholines, which thereby is characterized in that the following reaction steps are carried out one after the other:

1) addition of tert-butyl hypobromite at a temperature below ⁰ C, preferably at about -10 ⁰ O, to a mixture of the chlorohydrin of the glycol and an olefin of formula

R - G = GH ₂

R »

in the E a monovalent hydrocarbon residue

'; 06816/23 9 0

wise is a lower alkyl radical or an aryl radical which may contain halogen substituents, and R ^{1 represents} a hydrogen atom or a lower alkyl radical, with formation of an intermediate compound of the formula

R «
RC-CH ₂ -Br

O - CH ₂ - CH ₂ - Cl

2) Condensation of about 1 mole of this intermediate compound with 3 moles of a primary amine of the formula Rj-NH ₂ , in which RJ is any monovalent organic radical in P, linear or branched chain, which can contain rings or heterocycles, to form the desired cyclized Derivatives of the formula

R '

RA-CH ₂ - KR ₁ 0 - CH ₂ - CH ₂

in which R, R ¹ and R ^ have the meaning mentioned.

This two step process leads to 2,4-disubstituted or 2,2,4-trisubstituted tetrahydro-1,4-oxazines leads, has the following fc advantages over the methods described:

a) Only two reaction stages are required while the other processes already have several stages for the preparation of the suitably substituted Bis- (2-hydroxyethyl) amines are required.

b) in the first stage will be simple, marketable and cheap starting materials are used, e.g. olefins, chlorohydrin of glycols and those for the formation of tert-butyl hypobromite required reagents, in the known processes are much more complex and for this stage more expensive raw materials are used.

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1843857

c) The second stage allows the introduction of the various groups R ₁ in the 4-position, which is not always possible when cyclization by dehydration with strong acids hei! temperatures of 80 "performs to 14O ⁰ C. Further, the excess of primary amine used can be recovered.

d) In contrast to other processes, the process also enables the production of tetrahydro-1,4-oxazines, which contain a benzyl radical in the 2-position "

The method according to the invention can be represented by the following scheme:

First stage:

CH ₃

R - C = CH ₉ + CH ₉ - CHQH + CH ^ -C- OBr ι 2 ι 2 3 ^ s.

R ¹ Cl CH,

Al

RO-CH ₉ -Br + CH, -C -OH

I ^{2 3}

O - CH ₂ - CH ₂ - Cl

Second step:

RC- CH ₂ Br

R - C - CH ₂ - Ii - R ₁ + R ₁ - ΝΗ ₂ · Η01 + R ₁ - NHg.HBr O - CH

2 ^w "2

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1843857

The first stage thus consists of an alkoxybromination

to the
of an olefin with / chlorohydrin of glycol with the help of

tert-Butyl hypobromite The reaction is preferably carried out at a temperature of about -10 ⁰ O by slowly adding the tert-butyl hypobromite to the mixture of the olefin and the chlorohydrin of the glycols in a solvent or diluent such as carbon tetrachloride.

In the second stage, the intermediate product obtained in the first stage is _{condensed with the primary amine of the formula RJ-NH 2} by refluxing the reaction mixture in a solvent such as benzene, toluene or xylene. If the amine R ^ -NH _{2 is} volatile, work is carried out in a closed vessel.

The invention is further described by the following examples, which are not intended to be limiting, since the method described above is applicable to a very large number of starting compounds, which are under the the above definitions fall

Examples 1 and 2 and Table I illustrate the first stage reaction, while the remaining examples and tables relate to the actual preparation of the desired substituted tetrahydro-1,4-oxazines

Example 1 2-Phenyl-2- (2-chloro) ethoxyethyl bromide

ψ > -CH - CH ₂ - Br

0 - OH ₂ - OH ₂ - 01

The tert * butyl hypobromite is instant of use according to the method of A. Kergomaaid (Bull.Soc. Chim.Prance 1961, p. 2360). For this purpose, for example, 187 g of crystallized sodium bromide are dissolved in 625 ml of sodium hypo-

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chlorine solution (corresponding to 1.3 mol NaQCl). This solution is poured into a decanter, the elongated part of which is provided with a jacket, through which caustic solution of about -10 ⁰ O is circulated. After adding 80 ml of glacial acetic acid and 100 g of tert-butyl alcohol, the mixture is stirred and the reagent is allowed to settle down.

To a mixture of 104 g of styrene, 160 g of chlorohydrin of glycol and 150 ml of carbon tetrachloride CCII is added dropwise with stirring, the tert-butyl hypobromite prepared in the manner described above, while keeping the temperature "at about -10 ⁰ C. The mixture is allowed to Warm up to room temperature, wash the reaction mixture with water, dry over anhydrous Na ₂ SO, drive off the solvent and rectify under reduced pressure to give 115 g of the desired product.

Boiling point 116 to 118 ° C / 1.5 mm Hg; nj ⁹ » ⁸ = 1.5; 510 purity, determined by gas chromatography: $ 96 to $ 98.

Example 2 2.2-Dimethyl-2- (2-chloro) ethoxyethyl bromo id

CH

O - CH ₂ - Br ₅ O - CH ₂ - CH ₂ - Cl

One operates as in Example 1, adding the same amount Terto-Butylhypobrömit at -10 ⁰ C to 160 g of chlorohydrin glycol and 150 ml of CCl, and initiate isobutylene in the reaction mixture. This gives 93 g of the desired

Product.

Boiling point 63.5 ° C / 4 mm Hg $ n ^ ² = 1.4-i 765

Purity determined by gas chromatography ϊ 95-98? Ί ·

Example 3

2-Phenyl-4-benzyltetrahydro-1,4-oxazine is subjected to catalytic hydrogenation In the presence of Seiger palladium

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1843857

money. This reaction leads to 2-phenyltetrahydro-1,4-oxazine. For this product, which is made with a mixture of formaldehyde and formic acid according to that of Eschweiler-Clark described method (Organic Reactions, Volume V, p.3O7) is treated, 2-phenyl-4-methyltetrahydro-1,4-oxazine is obtained

The following Table I lists the compounds which are obtained after the first stage of the reaction, if is operated in the manner described in Example 1.

R ' Table I. ⁿ D / ° c H R '
RC- CH ₂ Br 1, 5510 / 19.8 H O - CH ₂ - CH ₂ Cl 1, 5640/18 R. boiling point
° c / mm Hg 0 116-118 / 1.5. ci- / 7 \ 125-126 / 0.5

H -

79/11

OH - 63.5 / 4

1.475 / 19 1.4765 / 22

H -

140/2

1.5280 / 19.6

Example 4 2-phenyl-4-oyolohexyl tetrahydro-1,4-oxazine

39.52 g of the 2-phenyl-2- (chlorine) prepared according to Example 1 ethoxy-ethyl bromide with 44 g of Oyclohexylamin in 150 ml of toluene heated under reflux for 12 hours. Filter

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the precipitated cyelohexylamine hydrobromide and hydrochloride are extracted, the amine is extracted from the toluene phase with about 4N HCl, the aqueous phase is _{rendered alkaline, extracted with ether, dried over anhydrous Na 2} SCh and the solvent is driven off. After rectification under reduced pressure, 26 g of a colorless liquid are obtained · boiling point 197 ° 0/13 mm Hg; n ^ ¹ - 1.5 | 370

Quantitative determination (HClO ₄ ): 98.8Ji

The hydrochloride is prepared by dissolving the product in ethyl acetate and adding a slight excess of HCl gas dissolved in anhydrous ethanol. Melting point 162 ⁰ O

= 281.83

N: calculated 4 | 97, found 4.97 01 "calculated 12.58, found 12.60

Example 5

2- (4-chloro) ~ phenyl ~ 4-n-butyltetrahydro ~ 1,4-oxazine

from In the manner described in Example 4 / 29.8 g of 2- (4-chloro) phenyl-2- (2-chloro) ethoxy-ethyl bromide and 21.9 g of n-butylamine in 100 ml of toluene 20 g of a colorless liquid with a boiling point of 123 ° 0/1 mm Hg.
n _D ⁹ » ⁸ » 1.5; 268

Quantitative determination (HOlO ₄ ) t 98.5 # The hydrochloride is prepared in the manner described in Example 4. Melting point 155 ⁰ O.

₁₄₂₁₂ = 290.24 N: calculated 4 »82, found 4» 90 Cl: calculated 12.21, found 12.10

Example 6 2- (4-fluoro) -benzyl-4-iaopropyl-tatrahydro-1. 4-oxamine

W _e ia · to the described in Example 4 is obtained from 109816/2300

29.55 g of 3- (4-fluoro) phenyl-2- (2-chloro) ethoxy-propyl bromide, and 17 "7 g of isopropylamine in 100 ml of benzene is heated to 110 ⁰ C, and after 12 hours of heating in Autokl _a ven 21 g of a colorless liquid with a boiling point of 110 ° 0/2 mm

» ² _{m 1 # 5} . ₀₄₈

Quantitative determination (HClO,): 99 # purity hydrochloride: melting point 141 ⁰ O

₁₄₂₁ = 273.78

N: calculated 5 »11» found 5 »12 01t calculated 12.99, found 12.90

Example 7 2 o 2-dimethyl-4- (2-phenyl) propyltetrahydro-1,4-oxazine

21.55 g of 2,2-dimethyl-2- (2-chloro) ethoxyethyl bromide and 40 g of DL-amphetamine in 120 ml of xylene are refluxed for 12 hours and 13 g of a colorless liquid are obtained. Boiling point 126 ° C / 3 mm Hg? n * ¹ »*» 1.5; 098 Quantitative determination (HClO ₄ ) 1 98.5 # purity.

Hydrochloride: Melting point 165 ⁰ CC ₁₅ H ₂₄ NOCl * 269.83 N: calculated 5.19, found 5.21 01: calculated 13.14, found 13.16

Example 8

2- »methyl-4 (2-phenyl) tetrahydro-1,4-oxazine

and 20.15 g of 2-methyl-2- (2-chloro) ethoxyethyl bromide, 32.7 pounds of 2-phenylethylamine in 120 ml of toluene are refluxed for 12 hours and 21 g of a colorless liquid are obtained boiling point 14t ° C / 11 mm Hg; aj ⁹ » ⁶ » 1.5? 183 Quantitative determination (SCLO _4): 99.2 ^ Hydroohlorid: mp 166 ⁰ C.

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»24-1.76

N: calculated 5.79, found 5 # 90 Cl: calculated 14 »66, found Η» 50

From 2-phenyl-4-benzyltetrahydro-1,4-oxazine you can go through Hydrolysis of 2-phenyltetrahydro-1,4-oxazine to the following Example described way received

Example 9

2-phenyltetrahydro-1,4-oxazine

102 g of 2-phenyl-4-benayltetrahydro-1,4-oxazine hydrochloride are dissolved in 600 ml of ethanol and hydrogenated at room temperature under an initial pressure of 3.2 atmospheres of hydrogen in the presence of 11 g of 5% palladium-on-carbon "After 12 hours is the theoretical Amount of hydrogen absorbed. The catalyst is filtered off, the solvent is driven off under reduced pressure and the residue is taken up in 200 ml of water and made alkaline with 50% aqueous NaOH. It is extracted with ether, dried over anhydrous Na ₂ SO, the solvent is driven off and rectified reduced pressure, giving 5115 g of product with a boiling point of 97 ° C./2 mm Hg. n | ¹ » ⁶ = 1.5} 482 Quantitative determination (HGlO ^) t
Hydrochloride: melting point 148 ° C.

_10n = 199.68

N: calculated 7.01, found 6.04 Cl: calculated 17.55, found 17.65

In the literature (GDR patent specification 20 678) a boiling point of 130 ° C / 12 mm Hg is given. Hydrochloride melting point 151 ⁰ C ₀

Example 10 2-Phenyl-4-methyl-teti? Ahydro-1 , 4-oxazine

24 g of 2-phenyltetrahydro-1,4-oxazine and 35 g of formic acid are heated and 19 g formaldehyde in 30 # aqueous solution

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6 hours on the steam bath. It is taken up in 20 ml of concentrated HCl, evaporated under reduced pressure and taken up in 50 ml of H “O, which is again evaporated under reduced pressure. The residue is taken up in 50 ml of H ₂ O and made alkaline with 50 # strength aqueous NaOH. The mixture is extracted with ether, dried over anhydrous sodium hydroxide, the solvent is driven off and rectified under reduced pressure, 20.2 g of a colorless liquid being obtained.

Boiling point 95 ° C / 5 mm Hg; n ^ ³ = 1.5; 260 Quantitative determination (Holo.): 98.8 $ Hydrochloridi melting point 145 ⁰ C C ₁₁ H ₁₆ ITOCl = 213,71

N: calcd 6.55, found 6.47 CIi calcd 16.59, found 16.45

In the following tables II and III are the key figures a number of compounds are given which have been prepared by the method according to the invention "

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Table II

C R- ^ I

CEo

R R *

Boiling point ° C / ima Hg

Melting gross formula of the analysis

ρ point Hydrochloride "S, f> Cl"

des Hydro »" ber. ber ·

Chloride, found gef ·

⁰ Vr

CH

CD OC -A

- σ>

! Ali · »- Wü ·» -

κ> CO

CD

GH, - Cn -.-

CH,

CE

CH-

CH,

65/14

CH-CE ₉ -CH ₉ - 89.5 / 13

CE

3 «A-cs.

-CH ₂ -CH-CE,

106/2

1.4415 / 22

1.4478 / 21.4 1.5092 / 21.2

126/3 1.5098 / 21.4 C ₉ H ₂₀ NOCl * 193.72

_4th
= 221.77

255.79

₂₄ IiOCl 269.83

C ₁₅ H ₂₄ IiOCl

7.23 18.30 7.12 18.18 6.31 15.98 6.31 15.80 5.47 13.86 5.44 13.70 5.19 13.14 5.21 13.16

Table III

4th Λ ■ at boiling point R-CE 9H ₉ v °° E CE ₂
^ N
I. Gross formula analysis Cl, '
"ber
found 1 ⁰ C / mm Hg c: Enamel of the Hydro
chloride "about *
gef, 16, R. -CH ₂ -CH ₂ - 95.5 1.526 / 23 Point
of the hy
dro chlo-
rids, ⁰ C C ₁₁ H ₁₆ NOCl 6.55 16, 145 = 213/71 6.47 14, / TV ^CH 3 105/1 1.5174 / 20, C ₁₃ H ₂₀ NOCl 5.79 14, Vl / y 2 158 «241.76 5.90 14, * - * CE · »·
c ''"> ^ ~~ "* 2 ~ 98.1 1.5519 / 19, C ₁₃ H ₂₀ NOCl 5.79 14, 4 156 = 241.76 5.80 14, ^ CH, - (CE ₂ ) ₂ -CH ₂ - 92.1 1.5300 / 20 C ₁₃ H ₁₈ NOCl 5.84 14, If ■ + **
• ^ CH ' 149 »239.75 5.90 13, O ⁰ ^ ₂ > E-CE ₂ - 160/13 1.5120 / 23 C _n H ₂₂ NOCl 5.47 13, 165 β 255.79 5.42 13,
14, H ng 97.1 1.5100 / 19 C ₁₄ H ₂₂ NOC1
= 255.79 5.47
5.45 155 *
•
• 59 45 66 70 66 70 78 9 86 85 , 86
00

CE,

O)
H
H

approx

• ίΗ «Η

Ht) ID O ₁ Q QD

*, (U <D

a)

ο ο h ω

Cj- | ιχ $ ϊ ^ 5

O}> 3 · Η

+ "'O
Ö CQ H

H »Λ

co do

H4ö
0) 4 »

co

τ)
I -H
O MO
H OO

O
O

• ο QO

4 »W

Ρ «

(U "

• rtO
(DO • Η OQ

KN O KN O TTT-CVl

KN KN KN KN

cn in cn in

τ- τ- τ- CVJ

• k ·> O ·>

m in in in

H CM VO H CM O ω CM O 00 O • «4-cn O cn CM Il VO CM CM ιη W. τ— ιη Il τ-

in

CM

C- VO

CM

CM

in

O KN CM CM -v σν ω OO O O in in

KN O

cn ο

^ J- vo

KN VO

cn cn

ο co ο in

00 ο ο in
in vo cn co

vo ο in o

KN «φ τ- CVi

CO KN O VO VO CM T-

CM CMCMt-T-t-t-t-y-t-t-CMCM

C-C-O 00

cn cn C- vo

cnoocM T-OKNKN • «Φ in -« 4- ** ■ vovo oocn

ti rl * - *

ο ο kn ο

O - «J- O 00 O C—

[25 00 Ϊ2Ϊ * J2? CO

VO> xj- CO

CM KN CM τ- CM C—

M co W ω W cn

VO CM VO CM C-CM

H H

O O

O O VO

I ^ cn ^ co

KNt- CM C-

W τ- fcd T-

00 KN CJNKN

HO

CM *

CM KN

M O

00 KN

O 11 Ό Il O Il O II

KN

CM

CM τ-

CM C- cn C- T— m KN ON ω -φ C- VO

'CM O ιη

CM

κ \

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O KN O T-

i25 00 Iz? 00 O

O Il OH

O CM O ιη C- ο VO -φ VO KN νο VO VO

KN cn CM co τ— CM CM Τ CM CM O in Ο ω O τ- C- CM τ- C- Ο KN O Ο VD VO c— in in U.N. in in in

Table HI (Ports «)

R. Tt ! "Π I. CH ₃ Boiling point, 1.5469 / 18 , 2 Enamel Gross formula analysis 01.0 I. OO CH ₃ ° C / mm Hg point of of N, Ί <> about he" CT? ^ CH-OH ₂ -CH ₂ - 1.5042 / 20 , 2 Hydro HydroChlorids ber. found I. ^. Cl- <ιρ> -CHo-CHo- chloride,
⁰ C found 10.48 CO \ »/ 2 2 160 \ jf λ Q, Π ft ■ · Jak \ J W -Lfi 4.14 O 10.30 ν, _ / CH ₂ -CH ₂ - 1.5100 / 20 , 4 = 338.28 4.14 14.54 η I.
OH 124 C ₁₂ H ₁₈ NO ₂ Cl 5.75 14.55 CH-
CH-O- (CH ₂ ) ₃ - Pestilence 1.5040 / 20 , 2 * 243.74 5.70 11.82 CH ₃ ^ Melting point 59 ° C 148 C ₁₆ H ₂₆ NO ₂ Cl 4.67 11.89 M. 1.5482 / 21 , 6 = 299.84 4.75 > C ₂ H ₅ -O-CCH ₂ ) ₃ - 128/1 1.5218 / 19 , 6 12.40 W. γ \ {L U ^ * * \ 150/3 143 C ₁₅ H ₂₄ NO ₂ Cl 4.90 12.50 = 285.82 4.90 11.29 n H 1.5219 / 19, ,8th 145 C ₁₇ H ₂₈ NO ₂ Cl 4.46 11.20 = 313.86 4.50 17.75 « 146/3 148 C ₁₀ H ₁₄ NOCl 7.01 17.65 = 199.68 7.04 12.83 173/3 165 C ₁₃ H ₂₉ NOCl ₂ 12.75 = 276.21 97/2 11.65 170 C ₁₅ H ₂₃ NOCl ₂ 11.60 122/1 = 304.27 ' 141/1

! gabeile III (ports.)

Boiling point, ° C / nm Hg melting point of
Hydrochloride, ^

Frying formula

of
HydroChlorids

analysis

ber.
found

ber .

^oil ~ \ Ψ

CH, -

CE

H ₉ -O- (CE ₂ )

-CH ₂ -

CH ₂ -CH-

-CE ₀ -CH ₀ -

123/1 166/1 175.1

165/2 183.2 167.1 148.5 / 11

141/11

1.5268 / 19.8 1.5475 / 21.6 1.5143 / 20.2

1.5211 / 21
1.5135 / 21
1.5755 / 21.8 1.5180 / 19.6

1.5182 / 19.6

159
178
172

168
168
162
164

166

= 290.24

C ₁₆ H ₂₃ NO
= 316.28

C ₁₆ H ₂₅ UO
= 334.29

C ₁₅ H ₂₃ SO ₂ Cl ₂
β 320.27

»348.32
C ₁₇ H ₁₉ NOCl ₂
= 324.26

_4th
= 255.79

C ₁₃ H ₂₀ NOCl
= 241.76

4.82
4.90

4.42
4.36

4.37
4.40
4.06
4.02
4.32
4.25
5.47
5.50

5.79
5.90

12.21 12.10

11.21 11.15

10.66 10.60

11.07 11.20 10.18 10.30

10.93 11.00 13.86 13.75

H, 66 14.50

Table III (Ports.
RR ₁

Boiling point, ²¹ T) Z ⁰ C ° C / mm Hg

Melting point gross formula

des des

E ^ droehlorids, Hydrochlorids

analysis

ber.

found

fief

CH ₃ - Cl

- (V \ -CH ₂ -

CH, - CH, 0- j

P- φ (Hr CH,

CH

• _o CH ₃ -CE ₂ -CS ₂ -.

CD CO

• .— CE,

Ϊ ^ CH-CHjj-CEj, -

k> CE, ^{& c}

to ?

• ο CE,

- ^ ^x OE-O- (CE ₂ ).

151/11 1.5335 / 19.4

115/2 1.5210 / 22

132/2 1.5332 / 21.4

110/2 1.5048 / 20.2

111/2 1.5022 / 19.4

141/15 1.4950 / 21.9

157/1

1.4905 / 21.8 163

Dihydrochloride

165

172

141

140
149

135

= 260.17
= 265.19
= 237.79

= 275.78

Q ₁₄ H ₂₁ NOClP
= 273.78

- 301.84

C ₁₇ E ₂₇ NO ₂ ClP
= 331.86

5.38 5.40

10.56 10.59

4.86 4.97

5.11 5.12

5.11 5.14 4.64 4.70

4.22 4.25

13.62 13.40

26.74 26.50

12.32 12.30

12.99 12.90

12.99

12.90

11.74 11.85

10.69 10.80

table III (Ports.)

Boiling point, ° C / mm Hg

V ° ^C

Melting gross formula Analysis point of the _w ^ of the hydrochloride J »J Hydro- ^feer ·

Chloride,

found

"ber.

yj \ -CH _{2 -CH 3} -CH ₂ -CH ₂ -CH ₂ - 127/2

1.4988 / 19.4

152 C ₁₅ H ₂₃ NOOIF 4.86 12.31 - 287.81 4.89 12.20

σ co co

CD

NJ to

CH ₃ -

151/2

164/2

1.4972 / 22

145 O ₁₇ H ₂₇ NOOIF 4.43 11.22 = 315.86 4.40 11.00

175 C ₁₇ H ₂₅ NOClF 4.46 11.29 = 313.85 4.30 10.95

Claims (1)

Claims 1) Process for the preparation of 2,4- and 2,2,4-positions substituted tetrahydro-1,4-oxazines or morpholines daduroh characterized that one becomes a mixture of Olykolchlorhydrin and an olefin of the general formula RC = CH ₂ , R ¹ in which R is a monovalent hydrocarbon ^{radical and R 1 is} a hydrogen atom or a lower alkyl radical, at temperatures below 0 ^° C. tert-butyl hypobromite to form a compound of the general formula R ¹ RC-CH ₂ -Br O - CH ₂ - CH ₂ - Cl in which R and R ^{1 have} the meaning given above, and add about 1 mol of this intermediate compound with j5 mol of a primary amine of the general formula R, -NHp, in which R, any monovalent, linear or branched, ¹ optionally containing cyclic or heterocyclic compound organic residue is condensed. 2) Process according to claim 1, characterized in that one olefins of the formula given, in which R is an optionally is halogen-substituted lower alkyl radical or aryl radical, alkoxybrominated. Process according to Claim 1 or 2, characterized in that the alkoxybromination of the olefin is carried out at about -10 ⁰ C in a solvent or diluent. 109816/2300 4) Method according to claim 1 to 3 # characterized in that the intermediate compound with the amine by heating the reaction mixture in a solvent on Reflux condensed. 5) 2-phenyl-2- (2-ehlor) ethoxy-ethyl bromide of the formula CH - GH ₂ - Br O - CH ₂ - CH ₂ - Cl 6) 2,2-Dimethyl-2- (2-chloro) ethoxy-ethyl bromide of the formula CH : C - CH ₂ - Br O - GH ₂ - CH ₂ - Cl γ) 2- (4-chloro) -phenyl-2- (2-chloro) ethoxy-ethyl bromide der formula IH - CH ₂ - Br 0 - CH ₂ - CH ₂ - Cl 8) 2-methyl-2- (2-chloro) ethoxyethyl bromide of the formula CH, - GE - CH ₂ - Br - CH ₂ - CH ₂ - Cl 9) 2- (4-fluoro} fesnzy formula i2-olor) ethoxy-ethyl bromide der - CH - CH ₂ - Br O - CH ₂ - CH ₂ - Cl 1038 IS / 2300 10) Substituted ^T etrahydro-1,4-oxazines of the general formula ^R l in which R is a monovalent hydrocarbon radical, preferably an optionally halogen-substituted lower alkyl radical or aryl radical, R ^{1 is} a lower alkyl radical and R- is any monovalent, linear or branched organic radical, optionally containing cycles or heterocycles, and salts thereof, preferably with mineral acids, for example hydrochloride. 11) compound according to claim 10 with R = ₃
CH,
() - CH - R ¹ = CH,) 12) compound according to claim 10 with R - R ¹ = R = CH, ¹ j - CH - CHp - CHp 13) compound according to claim 10 with R =
R '= 14) compound according to claim 10 with R - CH, - R ¹ 109816/2300 15) Substituted tetrahydro-1,4-oxazines of the general formula in which the radicals R and R have the meaning given in claim 10 and their salts, preferably with mineral acids, for example hydrochloride. 16) compound according to claim 15 with R = phenyl R ₁ = 17) compound according to claim 15 with R = phenyl - R ₁ = CH ₅ - CH ₂ --CH ₂ - 18) compound according to claim 15 with R = phenyl - ) ₂ -CH- 19) compound according to claim 15 with R - phenyl - R = CH ₂ = CH - CH ₂ - 20) compound according to claim 15 with R = phenyl - R ₁ = CH ₅ - (CHg) ₂ -CH ₂ - 21) compound according to claim 15 with R = phenyl - R ₁ = (CH ₃ ) ₂ -CH-CH ₂ -109816/2300 22) compound according to claim 15 with R = phenyl - R ₁ = CH ^ - (CH ₂ ) ^ - CH ₂ - 23) compound according to claim 15 with R = phenyl - R-] - (ΟΗ · ζ) ρ - CH - CHp - CHp 24) compound according to claim 15 with R «phenyl - R ₁ «CH ^ - (CHg) ₄ -CH ₂ - 25) compound according to claim 15 with R = phenyl R ₁ = 26) compound according to claim 15 with R = phenyl - R ₁ = CH ^ - (CH ₂ ) c - CHg - 27) compound according to claim 15 with R = phenyl - R ₁ = CH ₃ - (CH ₂ ) ₆ - CH ₂ - 28) compound according to claim 15 with R = phenyl 29) Compound according to claim 15 with R = phenyl - ^CH 2 " ^CH 2" A compound according to claim 15 with R = phenyl - 10 9 8 16/230 G CHp - 31) compound according to claim 15 with R = phenyl - CH ₂ - CH ₂ - 32) compound according to claim 15 with R s phenyl - 3H ₂ -OH ₂ - Ci 33) compound according to claim 15 with λ R »phenyl - R ₁ = (CH ^) ₂ - CH - 0 - (CH ^ - CH ₂ - 34) compound according to claim 15 with R = phenyl R ₁ = C ₂ H ₅ - 0 - 35) compound according to claim 15 with R = phenyl - R ₁ = nCjjHg - 0 - (CH ₂ ) ₂ - 36) compound according to claim 15 with R = Cl- 37) compound according to claim 15 with - CH - CH ₂ - CH ₂ - 109816/2300 58) compound according to claim 15 with R = Cl -CH ₂ -39) compound according to claim 15 with R - Cl ^R l ^β 4θ) compound according to claim 15 with R = Cl- / \ - CH - O - 4l) compound according to claim 15 with -CH ₂ - -CH ₂ - 42) compound according to claim 15 with R ₁ = C ₄ H ₉ - O - (CHg) ₂ - CH ₂ 43) Compound according to claim 15 with R = Cl- / 109816/2300 R = CH ₃ - 44) compound according to claim 15 with 5 ■ " ^ CH ₂ -CH- CH, A compound according to claim 15 with VV-CH ₂ -CH ₂ -46) compound according to claim 15 with R = CH, - R » = Cl 47) compound according to claim 15 with 5 "
V— CH ₂ - R = CH, - 48) compound according to claim 15 with R = R ₁ = CH, ( CH ₂ - 49) compound according to claim 15 with R = F— / R ₁ = -CH- 50) Compound according to claim 15 with R = F- / \ --CH ₂ R ₁ = CH ₅ - CH ₂ - CH ₂ - 10 9 8 16/2300 51) compound according to claim 15 with R = F - / \ - CH ₂ - R ₁ - (CH,) ₂ - CH - CH ₂ - CH ₂ 52) compound according to claim 15 with 55) compound according to claim 15 with R ₁ = CH, - (CJH ^ -CH ₂ -54) compound according to claim 15 with R - - (CH ₂ ) ₄ -CH ₂ - 55) compound according to claim 15 with R = P- / CH ₂ - - C 1 0981 6/2300 COPY