Method for the preparation of 3-substituted 1-amino-propanolol-

 

(57) Abstract:

Method for obtaining 3-substituted 1-amino-propanolol-2, the General formula

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where R = H, alkyl, CH2CH2OH, (CH2)3OH, PhCH2CH2;R' = OH, alkoxy, substituted or unsubstituted, phenoxy-, amino-, alkylamino, dialkylamino, hydroxyethylamino, morpholino-, piperidino, piperazine derivatives -, substituted or unsubstituted, phenylamino, phenylalkylamine-, COOH, azido-SH, namely, that 1-halogen-2-hydroxypropanesulfonic, the General formula II,

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where R has the above meanings, M is a cation of an alkali metal, X = Cl, Br subjected to interaction with the appropriate nucleophilic reagent at a temperature of 0 - 120oC in the medium of water or its mixture with an aprotic solvent, followed by treatment of the resulting 3-substituted 2-hydroxypropylamino, the General formula III,

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where R, R', and M have the above meanings, with aqueous solutions of mineral acids at temperatures of 80 - 160oC. Method allows to obtain 3-substituted 1-amino-propanolol-2 outputs 60 - 90% of which are of interest as monomers, plasticizers and hardeners for plastics, paints, modifiers Moto is I organic chemistry, namely, the method of production of 3-substituted 1-amino-propanolol-2 General formula I.

< / BR>
where

R = H, alkyl, CH2CH2OH, CH2CH2CH2OH, PhCH2CH2; R' = OH, alkoxy, substituted or unsubstituted, phenoxy, alkylamino, dialkylamino, hydroxyethylamino, morpholino-, piperidino, piperazine derivatives -, substituted or unsubstituted, phenylamino, phenylalkylamine-, -COOH, azido-, SH.

The proposed compounds I are of interest as monomers, plasticizers and hardeners for plastics, paints, modifiers motor fuels, biologically active substances and in organic synthesis (patent DE 2421618, JP 74. 027 398, Vishnyakov, Etc., Stabilizers, modifiers, M. Chemistry, 1990, patents JP 72.39.398, US 5 232 472.

The literature discusses various methods for the synthesis of 3-substituted 1-amino-propanolol-2, most of which are based on the reaction of amines with prior functional oxirane.

A method of obtaining 1,3-diaminopropanol by condensation of epichlorohydrin with amines (patent US 2715631)

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To obtain the target product II required a large excess of amine component (5 to 20 fold). There are difficulties with widecombe distillation, or extraction of a large amount of solvent (ether). The yields of the target compounds comprise from 20 to 70%, depending on the excess amine components. Moreover, the regeneration of a large excess of amine components.

The known method for the preparation of 3-substituted 1-amino-propanolol-2, the interaction of amines with prior functional oxirane (Rev. Chim., 22, 645, (1971)).

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R = H, alkyl, hetaryl; R' = OH, alkoxy, phenoxy

To get the target I needed an excess of amine component (5 to 15 fold). The reaction was carried out at room temperature in aqueous solution within 24 - 48 hours in Addition to the target product I obtained a number of side products, which reduces the yield of the target product to 50% and there are difficulties with the selection. Moreover, the regeneration of an excess of an amine component and an independent synthesis of the original oxirane, which is often difficult to access.

The closest analogue adopted us for the prototype, is a method for the preparation of 3-substituted 1-amino-propanol-2, which consists in the interaction of salts of sulfamic acid with functionally substituted by oxirane in the environment, water, aprotic organic R is BR>
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The known method requires to obtain the compound I of the synthesis of the corresponding oxirane IV, and unsuitable for the synthesis of substances I, where R' is an amino group.

The present invention is to provide a novel method for the preparation of 3-substituted 1-amino-propanolol-2, increase the yield of target products, the expansion of raw materials and the range of the obtained compounds.

This object is achieved by the proposed method for the preparation of 3-substituted 1-amino-propanolol-2 General formula I,

< / BR>
where

R = H, alkyl, CH2CH2OH, CH2CH2CH2OH, PhCH2CH2; R' = OH, alkoxy, substituted or unsubstituted, phenoxy, alkylamino, dialkylamino, hydroxyethylamino, morpholino-, piperidino, piperazine derivatives -, substituted or unsubstituted, phenylamino, phenylalkylamine-, -COOH, azido-SH, using sulpham in the environment of water or its mixture with a Protic solvent and subsequent treatment with an aqueous solution of mineral acid at a temperature of 80 - 160oC, characterized in that as sulpham use the 3-halogen-2-hydroxypropanesulfonic General formula II,

< / BR>
where

R have the above values (formula I); M - cation - 120oC with 3-substituted-2-hydroxypropanesulfonic General formula III:

< / BR>
where

R and M have the above meaning, R" = OH, alkoxy, substituted or unsubstituted, phenoxy, alkylamino, dialkylamino, hydroxyethylamino, morpholino-, piperidino, piperazine derivatives -, substituted or unsubstituted, phenylamino, phenylalkylamine-, -CN, azido-, SNa.

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The process of condensation of II with the nucleophilic reagent is carried out in the presence of an alkaline component, for example, NaOH, KOH, LiOH, NaHCO3, K2CO3and so on for such nucleophiles such as water, alcohols, phenols, amines and anilines, or without it if the nucleophile - NaN3, KCN, Na2S.

As the nucleophilic reagent is used, for example, water, alcohols, phenols, amines, NaN3, KCN, Na2S.

The intermediate product of the formula III,

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you can select or processing of the reaction mixture containing III, are the solution of mineral acid at a temperature of 80 - 160oC without highlighting.

As the aprotic solvent used, for example: alcohol, acetone, ethyl acetate.

The proposed method provides the 3-substituted 1-amino-propanolol-2, formula I, with the outputs from 60 to 90%, does not require

The method is quite versatile and allows to obtain a wide range of products, the synthesis of which in other ways is difficult, for example, asymmetric 1,3-dialkylphenols-2; many of synthesized products obtained for the first time.

Conclusion about the structure of the connections made on the basis of elemental analysis, IR, PMR-spectra, and by comparison of the physico-chemical properties of known substances.

Example 1. Obtaining 3-methylamino-propane diol-1,2 (Conn. 6)

To a solution of 5.4 g (0,02 mol) of sodium salt of 3-methylsulfonate-1-bromo-propanol-2 in 20 ml of water is added 0.05 g of NaOH and incubated at 100oC 30 min, added 7.0 g of 95% H2SO4and incubated for 7 hours the Reaction mass is neutralized with NaOH to a pH of 12.0, evaporated on a rotary evaporator at 70oC. To the residue is added 30 ml of a mixture of ethanol-acetone (5:1), filtered off the precipitated crystals, the filtrate is evaporated. Output 3-methylamino-propane diol-2 - 1,94 g (92%), so Kip. 238 - 242oC/745 mm RT.article Lit. the data of the 239 - 241/748 mm RT.article Ber. 32, (754).

Similarly obtained Conn. 7, 8.

Example 2. Getting 1-methylamino-3-morpholinopropan-2 (Conn. 14)

To a solution 7,26 g (0.03 mol) of 3-chloro-2-hydroxypropyl-N-methylsulfonate potassium in 5 ml of H2O the>C the reaction mixture is evaporated, the residue is treated 2 x 20 ml ether. The residue is dissolved in 25 ml of H2O add of 12.6 g of 96% H2SO4and incubated for 6 h at 100oC. After cooling, the reaction mixture is alkalinized to pH = 12,5, evaporated, the residue is extracted with 2 x 20 ml of alcohol. The extracts are evaporated, the residue extracted with ether. UPrev ether extracts are derived 4,28 g 1-methylamino-3-morpholino-2-propanol.

Similarly obtained Conn. 12 - 27.

Example 3. Obtain 1-amino-3-methoxypropanol-2 (Conn. 5)

To a solution of 0.66 g of 85% KOH (10 mmol) in 5 ml of absolute methanol is added 2.28 g (10 mmol) 3-chloro-2-hydroxypropanesulfonic potassium. After holding the reaction mixture at 100oC for 14 h its neutralized to pH = 7.0 and evaporated on a rotary evaporator. The residue is extracted with hot ethanol, the extract evaporated. The residue is 3-methoxy-2-hydroxypropanesulfonic potassium dissolved in 20 ml of H2O add 5,07 g of 35% HCl and incubated for 15 h at 120oC. the Reaction mass is alkalinized to pH = 12.5 and evaporated on a rotary evaporator. The residue is extracted with 30 ml of a mixture of the alcohol - ether 1:2, the extract evaporated, obtaining 0.9 g of 1-amino-3-ethoxy-2-propanol.

Similarly obtained Conn. 1-4,9-11.

Example 4. Pathemata sodium (0.01 mol) in 3 ml of H2O add 0,98 g (0.015 mol) of KCN. The reaction mixture was kept at 20oC for 4 h, then the reaction mixture is added 10 ml of H2O and 5.1 g of 96% H2SO4and incubated for 6 h at 100oC. After cooling, the reaction mixture is neutralized with a solution of Ba(OH)2before the end of the precipitated, filtered, the filtrate evaporated. The residue is recrystallized from H2O/EtOH, getting 0.84 g of 4-methylamino-3-hydroxybutanoic acid.

Similarly obtained Conn. 28.

Example 5. Getting 1 azido-3-metilaminopropanola-2. (Conn. 30)

To a solution 2,42 g of 3-chloro-2-hydroxypropyl-N-methylsulfonate sodium (0.01 mol) in 5 ml of H2O add 1.3 g (0.02 mol) NaN3. The reaction mixture was kept at 80oC for 4 h, then the reaction mixture is added 10 ml of H2O and 5.1 g of 96% H2SO4and incubated for 6 h at 100oC. After cooling, the reaction mixture is alkalinized to pH = 12,4, evaporated, the residue is extracted with 20 ml of alcohol, the extract evaporated, the residue is extracted with 2 x 15 ml ether. The ether extracts evaporated, getting to 1.14 g of 1-azido-3-metilaminopropanola-2.

Example 6. Obtain 1-amino-3-mercaptopropanol-2. (Conn. 31)

To a solution of 2.28 g of 3-chloro-2-hydroxypropanesulfonic sodium (0.01 m the temperature at night next, to the reaction mixture are added 10 ml of H2O and 6,13 g of 96% H2SO4and incubated for 6 h at 100oC. After cooling, the reaction mixture is alkalinized to pH = 10, evaporated, the residue is extracted with 20 ml of alcohol, the extract evaporated, the residue is extracted with 2 x 20 ml of a mixture of ethanol/ether (5: 1). The extracts are evaporated, receiving of 0.83 g of 1-amino-3-mercaptopropanol-2.

Below, in tables I and II shows the main parameters of the production method, the yields and spectral data of the products.

Method for the preparation of 3-substituted 1-amino-propanolol-2 General formula

< / BR>
where R is hydrogen, alkyl, CH2CH2OH, (CH2)3OH, PhCH2OH;

R1- OH, alkoxy, substituted or unsubstituted, phenoxy-, amino-, alkylamino, dialkylamino, hydroxyethylamino, morpholino-, piperidino, piperazine derivatives -, substituted or unsubstituted, phenylamino, phenylalkylamine-, -COOH, azido-SH,

using sulpham in the environment of water or its mixture with a Protic solvent and subsequent treatment with an aqueous solution of mineral acid at 80 - 160oC, characterized in that as sulpham use the 3-halogen-2-hydroxypropanesulfonic General formula

< / BR>
where R is ecotecture nucleophilic reagent at 0 - 120oC to obtain the corresponding 3-substituted 2-hydroxypropanesulfonic General formula

< / BR>
where R and M have the above meanings;

R" is OH, alkoxy, substituted or unsubstituted, phenoxy-, amino-, alkylamino, dialkylamino, hydroxyethylamino, morpholino-, piperidino, piperazine derivatives -, substituted or unsubstituted, phenylamino, phenylalkylamine-, CN, azido-, SNa.

 

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