SU937453A1 - Process for producing 2,4-disubstituted morpholines or their salts - Google Patents

Description

The invention relates to a new method for producing 2,4-disubstituted mor-j folins of the formula for denunciation with the corresponding amine [13.

The interaction is primary in terms of

It where ^R 1

lower alkyl or benzyl;

- hydrogen, chlorine or bromine or methoxy group, salts that can be found or their use as intermediates, as well as components of fuel compositions.

A known method for producing 2,4-di- substituted morpholines of the formula (I), where R ^ has the indicated meanings and R <^ is halogen, consists in the fact that | b -halogenated vinyl ether is reacted with bromine, resulting in 1,2 -dibromo-2- (2-haloethoxy) -ethane is reacted with halogen-substituted phenylmagnesium bromide and the resulting 2-halogen-substituted phenyl-2- (2-haloethoxy) -1-bromoethane is subjected to

preferably

I -, - ΝΗ ^

G & lOvN in chlorine; indicated values; halogen.

The attacks of the known method are its multi-stage processes; the non-bromination of bromine is a poisonous and burn-causing substance.

The purpose of the invention is to simplify the process, as well as expanding the range of target products.

This goal is achieved by the method of obtaining 2,4-disubstituted morpholines of the formula (I), or they consist in the ether of the formula, the ability to use an organomagnesium reagent, which leads to fire and explosion hazard of the process. In addition, the ilyl ether used as the starting material is not a commercial product and, in turn, it is necessary, in turn, to obtain it in several stages, proceeding from available raw materials.

The closest in technical essence and the achieved effect is a method for producing 2,4-disubstituted morpholines encompassed by the formula (D), where R ^ has all the indicated values, and R ^ is hydrogen or chlorine or methoxy group, salts, consisting in nolaminoacetophenone of the formula or what their R-, p and ^R 1 "g

(ϊα) о ^н 2

COCH _e Bt * - * -— values for R ^ are greater

it has the indicated compounds, except for the bromine atom, in the form of a free base or its salt, it is cyclized by heating in the presence of formic acid or a compound decomposing when heated under reaction conditions to form formic acid, such as formamide or dimethylformamide, and the target product is isolated in free or in salt form.

The process can be carried out in a solvent medium or without it, using ^: excess formic acid [2].

A disadvantage of the known method is that the starting ethanolaminoacetophenones of the formula (Ta) used are not widely available products, and they can be obtained by two-stage synthesis by brmsmirovaniya corresponding acetophenone and then the interaction of the resulting • oL-bromoacetophenone with the corresponding aminoethanol according to scheme ⁴⁵ in addition to the intermediate formed d-bromoacetophenones are lacrimatants, and used for salts, which is what acyloin o

II

R _g

where Rιχ has the indicated values, is subjected to interaction with a C ^ N-mono-substituted aminoethanol of the formula HC —NH-CH q-CH q-OH (III) where R ^ has the above meanings when heated in formic acid medium and the desired product is isolated in the free state or in the form of salt. The starting acyloin esters of formula (II) can be prepared in one step from the corresponding acetophenones with lead tetracetate in 80% yield. Thus, the proposed method allows to simplify the process, to use more affordable products obtained in fewer stages as initial products, and is universal for producing 2,4-disubstituted morpholines that were previously synthesized by various methods and not obtained in a single way. Starting materials, the acyloin ester of the formula (ΙΓ) and ethanolamine of the formula (III), as well as formic acid are used in a molar ratio of 0.5: 1: 1, respectively.

The yield of the target products is 41-81%, based on the starting compound of the formula (II).

The compounds of formula (I) can be obtained in the form of bases or salts. All 2,4-disubstituted morpholines of the base are colorless, liquid with the so-called. 100-150 ° C / 215 mm Hg, which are difficult to mix with water and easily with various organic solvents, form stable salts with mineral and organic acids, which are crystalline substances that are soluble in water.

-; The structure of the obtained ⁵⁵ and their salts is confirmed by analysis and IR data and are given in the table.

“Compounds are elemental * NMR spectra,

I

Π g 1 b 1 1 X 4 " 1 a • t 1 1

in

*.

fs w

1P

I "

0S <4 r *> Ui

t

e

L>

CO σ \ in

1.1

m m · r- I <I ♦ * · * tf>. tn w

x · ”and y- ^I <X *

Ϊ Y υ · δ ·.

Jt

Wl I χ- * <Γ

ξ, χ

Example 1. Obtaining 2- (4-bromophenyl) -4-methylmorpholine.

To 13.5 g (0.18 mol) of 2-methylaminoethanol previously neutralized with 8.30 g (0.18 mol) of 98% formic acid, 23.1 g of 5 (0.09 mol) 4-bromo si-acetoxyacetophenone. The mixture is heated until the carbon dioxide evolution is completely stopped (180-190 ° C, 20 h), then cooled. Under similar conditions, the remaining 2,4-disubstituted morpholines of general formula (I) are shown in the table.

give to room temperature and poured 10 into water (300-400 mp) containing 27 ml of 25% hydrochloric acid. The acidic solution is extracted with benzene to remove minor products, and the residue is alkalinized with sodium hydroxide solution to a pH of 11-12. The precipitated base is extracted with ether, the ether extract is dried with sodium sulfate, the solvent is distilled off, and the residue is distilled in vacuum.

11.3 g (49%) of 2- (4-bromophenyl) -4-methylmorpholine are obtained, boiling point 136137 ° C / 5 mmHg.

2- (4-Bromophenyl) -4-methylmorpholine hydrochloride, mp 215.5-217 ° C (ethanol).

• 2- (4-Bromophenyl) -4-methylmorpholine oxalate, mp. 154-155 ° C (ethanol).

Found,.%: C 44.66; H 4.78;

N 3.80, Vg 23.45.

С ₁₃ Н ₁ ВгМО ₅ "Calculated,%: С 45,10; H 4.66; N, 4.05; Vg, 23.08.

IR spectrum of the base (in liquid paraffin), -U, cm ¹ : 825 (1,4-di-substituted benzene ring), 1115 (С-О-С),

NMR-H ¹ dart TMS, 7.25 (4H) 4.38 (1H)

Claims (2)

The requirement is to use an organomagnesilicane reagent, which leads to a thermal and explosive process. In addition, the inyl ether used as the starting material is not a marketable product and, in turn, must be obtained in several stages if we proceed from the available raw materials. The closest in technical essence and diminutive effect is a method of obtaining 2,4-disubstituted morpholines covered by the formula (G), where R has all the indicated values, and Rn is hydrogen or chlorine or a methokeigroup, or their salts, consisting in this nolaminoacetophenone of the formula HO-CHf-Ct -N-CHf-CO R. Where it has the indicated values and Rjj has the values indicated for R, in addition to the brol atom, as a free base or its salt, is subjected to cyclization while nagging lots or compounds decomposing when heated in the reaction conditions with the formation of formic acid, such as formamide or dimethylformamide, and the desired product is isolated in free form or in the form of a salt. The process can be conducted in a solvent medium or without it, using an excess of formic acid 2. A disadvantage of the known method is that the starting ethanolamine acetophenones of the formula (Go) are not widely available products, and they can be obtained by two-step synthesis The brsmirin of the corresponding acetophenone and then the interaction of the forming eL-bromoacetophenone with the corresponding aminoethanol according to the scheme KiNHCHiCHfO — SchCH-N-CHj-CQ In addition, the intermediate A-bromoacetophenones are the olzuemy bromine for bromination is as poison, and the substance causing burns. The purpose of the invention is to simplify the process, as well as expand the range of target products. This objective is achieved by a method for the preparation of 2,4-disubstituted morpholines of formula (1) or their salts, which consists in the fact that the acyloin ester of the formula V CH is -O-LH,; where RI has the indicated values, is reacted with an N-monosubstituted aminoethanode of the formula R -NH-CHi -CHij-OH (1GG) where R has the above values, when heated in formic acid, and isolate the target product in free form or as a salt . The starting acyloin esters of Formula 1 (II) can be obtained in one stage from the corresponding acetophenones with lead tetracetate in 80% yield. Thus, the proposed method allows to simplify the process, use more available products as starting materials, obtained in fewer stages / and is universal for obtaining 2,4-disubstituted morpholines, which were previously synthesized by various methods and not obtained in a single way. The products of the acyloic ester of the formula (1G) and ethanolamine of the formula (Itl), as well as formic acid, are used in a molar ratio of 0.5: 1: 1, respectively. The yield of the desired products is 41-81%, calculated on the starting compound of formula (II). The compounds of formula (D) may be prepared as bases or salts. All 2,4-disubstituted morpholins of the base are colorless colors with a bp. 100-150 ° C / 215 mm Hg, which are difficult to mix with water and easily with various organic solvents, form stable salts with mineral and organic acids, which are crystalline substances soluble in water. ; The structure of the obtained compounds and their salts was confirmed by elemental analysis and the data of IR and NMR spectra shown in the table. Example 1. Preparation of 2- (4-bromophenyl) -4-methylmorpholine. To 13.5 g (0.18 mol) of 2-methylamine ethanol, previously neutralized with 8.30 g (0.18 mol) of 98% formic acid, was added 23.1 (0.09 mol) of 4-bromo- oo-acetoxyacetophenone. The mixture is heated to completely stop the evolution of carbon dioxide (180-19 ° C, 20 hours), then it is cooled to room temperature and poured into water (300-400 ml) containing 27 ml of 25% hydrochloric acid. The acidic solution is extracted with benzene to remove minor products, and the residue is alkalinized with sodium hydroxide solution to a pH of 11-12. The base that was isolated was extracted with ether. The ether extract was dried with sodium sulfate, the solvent was distilled off, and the residue was distilled in vacuo. 11.3 g (49%) of 2- (4-brs 1phenyl) -4-methylmorpholine are obtained, bp 1336137 C / B mm Hg. 2- (4-Bromophenyl) -4-methylmorpholine hydrochloride, m.p. 215.5-217C (this NOL). Oxalate 2- (4-bromophenyl) -4-methylmorpholine, so pl. 154-155 ° C (ethanol) Found,%: C 44.66; H 4.78; N 3.80, Br 23.45. (, VGY05. Calculated,%: C 45.10; H 4.66; N 4.05, Br 23.08. IR spectrum of the base (in vaseline oil), l), cm-: 825 (1.4- diabased benzene ring), 1115 (C-O-C), 1495 and 1600 (). NMR-H spectrum, CC24., External standard TMS, 80 Hz, 21 "C, s /, ppm : 7.25 (4H) (aromatic protons); 4.38 (1H) (-0-CH-); 3.70 (2H) m. (-0-CH (i-); 2.65 (2H) t. (-N-CHrj-), 2.22 (3N) s. (-N-CHj); 1 , 88 (2H) M. (-N-CHC-). NMR-13 C spectrum, cf, ppm: C, C (, 64.77; Cz 58.02, € 5 53.31. Spectrum with incomplete suppression of sp of the new interaction: i. C, -D; C, Cj and. Under similar conditions, the remaining 2,4-disubstituted morpholines of the general formula (I) are given in the table. dis) essential morpholines of the formula I: where R is lower alkyl or bNsyl; Rft is hydrogen, chlorine or bromine, or methoxy,; or their salts, using formic acid as the reaction medium and isolating the desired product in free form or in salt form, characterized in that, in order to simplify the process and expand the range of target products, in the medium of formic acid, the acyloin ester of the formula 11 c-chg-c-cn, where Ri has the indicated values, is reacted with N- monosubstituted aminoethanol of the formula in R - "H-CH, 1-CH where R has the indicated values when heated. Sources of information taken into account in the examination 1. US patent No. 3637680, cl. 260-247, publ. 1972. 2. The patent of Great Britain 862198, cl. 2 (3) B4D, publ. 1961 (prototype).