DE2018263A1 - Process for the preparation of alkylamino alcohol derivatives - Google Patents

Description

Patent attorney

IB ie, nmmumm 3

. ; April 10, 1970

P.5O87

Sankyo Chemical Industries, I / fed * in T ky ο ο (Japan).

B = SS = B a BSSB 3 S St 3 SS 3 S = S 3 SSS S. SS = KSS = SSSSSSS = 3:

Process for the preparation of alkylamino alcohol derivatives.

The invention relates to a new and improved one Process for the preparation of alkylamino'-alcohol derivatives the formula

R ₁ - 0 - CH ₂ - CH - CH ₂ (I)

OH NHR ₂

wherein Rv represents an aryl group and R _{2 represents} a lower alkyl group or a cycloalkyl group.

The alkylamino alcohol derivatives are known compounds and they are useful as β-adrenergic blocking agents Medium (Japanese Patent Publication No. 21775/66, 14942/67, 5V69 and 2978/69).

So far it has been the preferred method of manufacture the alkylamino alcohol derivatives in Japanese Patent Publication No. 21775/66 described which Belgian patent no. 640 312 corresponds.

009841/1992

~ ' ² "20182B3

According to the said / Japanese patent, the AlJ ^ ylaminoalkoholderivate ^ manufactured by. Reaction from 1 ^ -Spoxy-J-aryloxypropane with monoalkylamine. This however, older method has some drawbacks in that the use of a large excess amount of monoalkylamine that cannot be recovered, required to prevent the formation of by-products, and it requires the operating condition of an elevated Pressure to get the desired product with high yields in a short response time. Moreover, when IL is a substituted or unsubstituted phenyl group then, in spite of using a large excess amount of monoalkylamine, tertiary amines become by-products and it is difficult to remove these by-products.

It is therefore an object of the invention to provide a new and improved process for the preparation of the alkylamino alcohol derivatives to show with high yields in which a small amount of the amine is required, and at which the reaction at a low temperature and can be done within a short period of time.

According to the present invention, the alkylamino alcohol derivatives (I) Prepared (a) by reacting fipichlorohydrin (II) with a Marine vision base of the formula

R ₅ -CH-NR ₂ (III)

around 5-chloromethyl oxazolidine derivatives of the formula Cl-OH ₂ - CH - CH ₂

⁰ V ■ / - * 2 ■ (IV)

009841/1992

and by reacting the latter compounds with a phenol of the formula

R ₁ OH (V)

to 5-aryloxymethyloxazolidine derivatives of the formula

- O - - CxIq - OM "~ - ^ vMp

ι I

0 N-Rp (VI)

\ / ■ ■

CH

to get, or

Cb) by reaction of epichlorohydrin (II) with the phenol (V) to form 1 ^ -epoxy-J-aryloxypropane of the formula

R ₁ -O- CH ₂ - CH -— CH ₂ (VII)

and by reacting the latter compound with Schiff's base (III) to form the 5-aryloxymethyloxazolidine derivatives (VI) to obtain, and by subsequent hydrolysis of the so according to (a) or - Cb) obtained compounds (VI).

In the above formulas, R _x . and R _{2 has} the meanings described above, and R ^ represents an aryl group.

Examples of R ^. and R, include a phenyl or naphthyl group which is unsubstituted or substituted with a lower alkyl group such as methyl, ethyl or propyl, a lower alkoxy group such as methoxy, ethoxy or propoxy, a halogen atom such as chlorine or bromine, a hydroxy group or a nitro group, and examples of E ₂ include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopentyl and cyclohexyl.

ORJGiNAL

20 Ί 8263

The inventive method can by The following action scheme is illustrated.

Cl - GH ₂ - CH

IL-OH (V)

- 0 - CHo -

(II)

(III)

R ₅ -CH = NE ₂

(III)

(IV)

R ₁ -O- CH ₂

CH

CHp i
N -

GH

(VI)

0 - CHo ²

II ²

OH NHR ₂

(D

0098 4 1/1992

In the above formulas, R ^, Rg and B have the above described meanings.

The 5 ~ aryloxyinethyloxazolidine derivatives (VI), which are obtained according to the invention as intermediates also useful as ß-adrenergic. blocking agents, soft so far · by reaction of the alkylamino alcohol derivatives (I) with aldehyde compounds according to the above, older methods (Japanese Patent Publication No. 11826/67).

It is therefore another object of the invention to provide a to show new and improved process for the preparation of the 5-aryloxymethyloxazolidine derivatives (VI).

When carrying out the process step for the preparation of the compound (IV) from the compound (II) the compound (II) is reacted with an equimolar amount of the compound (III) at a lower one Temperature in the presence of an inert solvent and a Lewis acid catalyst.

Carbon tetrachloride can be used very advantageously as a solvent. As the catalyst can be suitably used ^tin; - chloro id, zinc chloride and boron trifluoride, and a sufficiently large amount of the catalyst is generally from 0.05 to 0.1 mole per mole of the compound (II) (IV.). The reaction is preferably carried out by dissolving a mixture of the compound (II) and the compound (III) in the solvent and gradually adding the catalyst to the solution with cooling. The reaction temperature is usually from about 0 to 100 ^° C., preferably from 10 to 20 ^° C.

The reaction has ended satisfactorily within about 2 to 3 hours. After the reaction has finished, this will be The reaction mixture is added to a weakly alkaline ice water, and the insoluble constituents are filtered off.

009841/1992

The solvent layer is dried and. the solvent evaporates. The residue is distilled under reduced pressure, the compound (IV) being obtained in high yields, ie 80 to 90%, and high purity.

In the reaction of the compound (IV) with the compound (V) Hydrogen chloride is formed and the reaction occurs is carried out by refluxing in the presence a solvent and an acid binding agent. The compound (V) is in relation to the compound (IV) in an equimolar amount or in a slightly larger amount Amount used. As a solvent you can an alcohol such as methanol, ethanol or isopropanol, ether, dioxane, tetrahydrofuran, benzene, toluene, are used, Xylene and water. A lower alcohol is expediently used. Acid binding agents can be used metallic sodium, sodium alcoholate, sodium hydroxide and potassium hydroxide. The reaction is carried out under Heat to reflux the solvent. Since an alkali metal chloride is deposited in the course of the reaction, it will filtered off after the reaction has ended. The reaction is usually complete within 10 to 15 hours, the The salt deposited in the reaction mixture is filtered off, the solvent is evaporated and the residue is reduced under reduced pressure Distilled pressure, giving the compound (VI). In the operation described above, the connection (VI) can also be recovered as an acid salt by adding a suitable acid to the residue.

The reaction of the compound (II) with the compound (V) is carried out under the same reaction and working conditions as in the reaction of the compound (IV) with the connection (V).

The reaction of the compound (VII) with the compound (III) is also under the same reaction and working conditions as in the reaction of the compound (II) carried out with the compound (III). However, as

_ 9 ~ 009841/1992

Solvent "in this reaction is preferably dioxane or water can be used.

The hydrolytic reaction of the compound (VI) is carried out by conventional means. For example, an aqueous acidic solution such as an aqueous hydrochloric acid solution or an aqueous sulfuric acid solution is added to the compound (VI), and the resulting mixture is ^{heated at about 80 to 100 °} C. for 1 to 2 hours.

After the completion of the reaction, one becomes in the reaction mixture generated oily substance is removed by extraction with benzene, and then the aqueous layer is passed through Adding sodium hydroxide made alkaline to the to deposit oily substance. The oily substance becomes when Let stand to cool, it is filtered, washed with water and dried. The crystalline thus obtained Substance is purified by recrystallization from a small amount of cyclohexane. The crystals come with a authentic sample identified by means of the mixed melting point and the infrared spectrum. From the description above it follows that the present invention has advantages by making use of an excess amount of the Schiff do not see base and a reaction at increased pressure required while the yield is essentially the same is like the older method. Both the alkylamino alcohol derivatives (I) and the 5-aryloxymethyloxazolidine derivatives (Vl) have, as mentioned above, ^ ß-adrenergic blocking effectiveness, and they can vary depending on the treatment angina peetoris, cardiac arrhythmia and hypertension in the form of a pharmaceutical preparation, which contains the compound (I) or (VI) and a pharmaceutically acceptable carrier substance can be used. These compounds are administered orally or by intravenous injection administered, and the allocation is about 10 to 150 mg daily in divided doses.

- 8 0098.41- / 1392

The invention is illustrated by the following examples explained in more detail »

example 1
1 -Phenoxy- 3 "is opropjJ-amino ^ -propaneql

(1) Preparation of 2-phenyl ~ 3 ~ isopropyl-5-phenoxymethyloxazolidine.

Method (a)

In 400 ml of carbon tetrachloride, 159 g of N-benzylidene isopropylamine and 110 g of epichlorohydrin are dissolved. A solution of 14 g of tin (IV) chloride in 120 ml of carbon tetrachloride is added dropwise to the solution obtained over the course of about 1 hour, the internal temperature being kept below 10 ^° C. After the addition is complete, the reaction is ^{continued at 20 °} C. for 3 hours. The reaction mixture is poured into 400 ml of ice water made weakly alkaline, and the insoluble constituents are filtered off. The filtrate is separated into an aqueous layer and a solvent layer. The solvent layer is dried and the solvent is evaporated. The residue is distilled under reduced pressure to give 191 g (74% yield) of 2- "phenyl-> 3 ~ isopropyl-5 ^t " chloromethyl oxazolidine, which is obtained at 114 to 117 ° C / 2 mm Hg boils »

Are dissolved in 100 ml of methanol 24g d © s thus obtained 2-Piienyl-3-isopropyl-5 '= ⁱ Glilormethyloxasolidin and 9. »^ g phenol" To the resulting solution are added 5 * 4 g of sodium methoxide, and the mixture is 10 hours heated under reflux. After the reaction has ended, the sodium chloride which has separated out in the reaction mixture is filtered off and the precipitate is washed with 20 ml of methanol. The washes are combined with the filtrate and the methanol is evaporated under reduced pressure.

»9 009Βώ 1/1 99 /

The residue is distilled under reduced pressure, 22.3 g (75 % yield) of 2-phenyl-3-isopropyl-5-phenoxymethyloxazolidine being obtained as a viscous oil which boils at 175 to 178 ° C./1 mm Hg.

An analysis of the compound obtained by rectifying the oil showed:

For C ₁₉ H ₂₅ O ₂ N; C * 76.73%; H = 7.79%; N = 4.7Q% Found: C «76.65%; H = 7.81%; N = 4.72%

Method '(b)

19.2 g of sodium hydroxide and then 37.6 g of phenol are dissolved in 400 ml of water. To the solution obtained, 100 g of epichlorohydrin are added dropwise with cooling and stirring, the internal temperature being kept at 20 ° C. After the addition is complete, the reaction is continued for 6 hours with stirring. After allowing the reaction mixture to stand overnight, it is extracted with chloroform. The extract is washed with water, dried and the chloroform evaporated. The residue is distilled, initially below 40 mm Hg in order to evaporate the excess epichlorohydrin (70 g epichlorohydrin are obtained), and then below 1 mm Hg at 90 to 91 ⁰ C, 45.6 g (76% yield) 1 -Phenoxy-2,3-epoxypropane receives as the main fraction.

15 g of the 1-phenoxy-2,3-epoxypropane thus obtained and 17 g of N-benzylidene isopropylamine are dissolved in 40 ml of carbon tetrachloride. A solution of 2.6 g of tin (IV) chloride in 20 ml of carbon tetrachloride is added dropwise to the solution obtained, with cooling and stirring, the internal temperature being kept below 10 ^° C. After completion of the reaction for another 3 hours Hinzüfügens is continued at 20 ⁰ C. The reaction mixture is poured into 50 ml of ice water made weakly alkaline, and the insoluble constituents are filtered off

-.10-. . QGSiU 17-19-92. . .

The carbon tetrachloride layer is separated from the filtrate and the solvent evaporated. The residue is distilled under reduced pressure and a small amount of the original fractions are taken to give 23.8 g (80% yield) of 2-phenyl-3-isopropyl-5-phenoxymethyloxazolidine as a viscous oil that is 175-178 ° G / 1 mm Hg boils.
Analysis values:

Calculated for O ₁₉ H ₂₅ O ₂ N: 0 = 76.73%; H = 7.79%; 21 = 4.70% Found: C «76.71% 5 H = 7.68%; N * 4

(2) Preparation of i-phenoxy ^ -isopropylamino-S-propanol.

50 ml of 10% hydrochloric acid are added to 5 g of 2-phenyl-3-isopropyl-5-phenoxymethyloxazolidine. ^{The mixture obtained is heated to 90 to 95 °} C. on a water bath for about 1 hour, 3.4 g (96.7 % yield) of 1-phenoxy-3-isopropylamino-2-propanol being obtained at 92 to 94 ° C - ⁰ C melts. The melting point in turn corresponds to that of an authentic sample which has been produced according to an older known method.

• Example 2 (-Naphthoxy) -3-isopropylsmiino-2-propanol

(1) Preparation of 2-phenyl-3-isopropyl-5 - (^ - naphthoxymethyl) -roxazolidine.

Method (a)

In 50 ml of a 70% methanol are dissolved 10 goo-naphthol and 16.5 g of the method (a) in example 1 obtained 2-phenyl-3-isopropyl-5-chloromethyloxazolidine. 2.7 g of sodium hydroxide are added to the solution obtained and the mixture is refluxed for about 5 hours. After the reaction has finished, this will be

009841/1992

Sodium chloride precipitated in the reaction mixture is filtered off and the precipitate is washed with methanol. The washes are combined with the filtrate and the methanol is evaporated. 50 ml of water and an aqueous 10% solution of sodium hydroxide are added to the residue. The mixture is stirred and extracted with benzene. The extract is washed with water, dried and the benzene evaporated to give 16.3 % (70% yield) of 2-pheny1-3-isopropy1-5- (oC-naphthoxymethyl) oxazolidine as an oil.

Method (b)

Using the same procedure as "for method (b) in Example 1, with the difference that phenol is replaced by oC -naphthol, 1- oC-naphthoxy-2,3-epoxypropane is obtained, which at 122 Ms 123 ° C / 1 mm Hg boils. The yield is 75 %.

In 50 ml of carbon tetrachloride, 20 g of the 1 oC-naphthoxy-2,3-epoxypropane and 22 g of N-benzylidene isopropylamine are added. solved. A solution of 2.6 g of tin (IV) chloride in 20 ml of carbon tetrachloride is added dropwise to the resulting solution over a period of 30 minutes, the internal temperature being kept below 10 G. After the addition is complete, the reaction is continued at 20 ⁰ O for a further 3 hours. The reaction mixture is poured into 50 ml of ice water made weakly alkaline, and the insoluble constituents are filtered off. The solvent layer is separated from the filtrate and the solvent is evaporated. N-benzylidene isopropylamine is removed from the residue by distillation under reduced pressure, 2-phenyl-3-isopropyl ~ 5-C <^ '- naphthoxymethyl) oxazolidine being obtained as an oil »

0 0 9 8 A 1 / ι 9 9 Ί

(2). Manufacture of 1- (oc -naphthoxy) -3-isopropylamino-2-propanol.

To 7 S 2-phenyl ~ 3-isopropyl-5 ~ (C ~ naphthoxymethyl) oxazolidin 50 ml of a 10% hydrochloric acid was added, and the resulting mixture is heated for about 1 hour on a water bath at 90 to 95 ⁰ O. Oily insoluble matter is removed by extraction with benzene, and the aqueous reaction mixture is made alkaline by adding a 30% aqueous sodium hydroxide to precipitate the oily substance which is solidified by standing to cool. The aqueous reaction mixture is extracted with trichlorethylene and the extract is washed with water and dried. The solvent is evaporated and the residue is recrystallized from cyclohexane, 5 g (96.5% yield) of 1- (<? & - Naphthoxy) -3-isopropylamino-2-propanol being obtained as needles, which at 95 to 96 ^° C. melt.

This compound (free base) is reacted with concentrated hydrochloric acid in isopropanol to give the hydrochloride which is recrystallized from isopropanol yields and prisms, melting at 163-164 ⁰ C.

Example 3
1- (m-Tolyloxy) -3 "isopropylamino-2- ~ propanol

(1) Preparation of 2-phenyl-3- = isopropyl ~ 5 ~ (ia ~ tolyloxymethyl) -oxazolidine.

Method (a)

2-phenyl "3-isopropyl-5 ^m chlormethyloxazolidin, prepared by the method (a) in Example 1 is caused to react with m-cresol to give 2-Ph © nyl-3""isopropyl-5- (m ' tolylo3cyiaethyl) oxazolidine, which boils at 186 to 190 ° C / 1 mm Hg.

- 13 00 984 1/19 92

Method (b)

Epichlorohydrin is reacted with m-cresol in the same manner as in method (b) in Example 1, whereby 1- (m-tolyloxy) -2 _} 3-epoxypropane is obtained, which at 103 to 105 ° C / 1 mm Hg boils and the latter compound is reacted with N-benzylidene isopropylamine to give 2-phenyl-3-isopropyl-5- (m-tolyloxymethyl) oxazolidine.

(2) Production of 1- (m-tolyloxy) -3 ~ isopropylamino-2-propanol »

2-Phenyl-3-isopropyl-5- (m-tolyloxymethyl) oxazolidine is subjected to the hydrolytic reaction in the same manner as in Example 2- (2), using i- (m-tolyloxy) -. 3-isopropylamino-2-propanol, which ^{melts at 78 to 79 0} G, is obtained.

Example 4 1- (o-methoxyphenoxy) -3-isopropylamino-2-propanol

(1) Preparation of 2-phenyl-3-isopropyl-5- (o-methoxyphenoxymethyl) oxazolidine.

Method (a)

2-Phenyl ~ 3-isopropyl-5-chloro-methyloxazolidine, prepared according to method (a) in Example 1, is used to react brought with o-guaiacol, being 2-phenyl-3-isopropyl-5- (o-methoxyphenoxymethyl) oxazolidine obtained, which boils at 195 to 200 ° C / 1 mm Hg.

Method (b)

Epichlorohydrin is used in the same way as o-guaiacol Way implemented as in method (b) in Example 1, wherein 1- (o-methoxyphenoxy) -2,3-epoxypropane is obtained, which at.

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Ο-2ΘΊ8263

Boiling 111 to 113 ° C / 1-mm Hg, and the latter compound is reacted with N-Benzylidenisopropylamine, whereby one 2-phenyl-3-isopropyl-5- (o-metiioxyphenoxymethyl) oxazolidine receives.

(2) Preparation of 1- (o-methoxyphenoxy) -3-isopropylamino-2-propanol.

2-phenyl-3-isopropyl-5- (o-methoxyphenoxymethyl) oxazolidine is subjected to the hydrolytic reaction in the same manner as in Example 2- (2), using 1- (o-methoxyphenoxy) -3-isopropylamino- 2-propanol is obtained, which melts at 64-65 ⁰ C.

Example 5 1- (m-Tolyloxy) -3-ethyl-2-propanol

(1) Production of 2-phenyl-3-ethyl-5- (m-tolyloxymethyl) oxazolidine.

Method (a)

Epichlorohydrin is reacted with N-benzylidene ethylamine in the same way as in method (a) in Example 1, 2-phenyl-3-ethyl-5-chloromethyloxazolidine which boils at 106 to 107 ° 0 / Λ mm Hg, and the latter compound is reacted with m-cresol to give 2-phenyl-3-ethyl-5- (m-tolyloxymethyl) oxazolidine which boils at 181 to 183 ° C / 1 mm Hg.

Method (b)

1- (m-Tolyloxy) -2 _i 3-epoxypropane, prepared according to method (b) in Example 3, is reacted with N-benzylidinethylamine, 2-phenyl-3-ethyl-5- (m - tolyloxymethyl) - oxazolidine receives.

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COPY

(2) Production of 1- (m-a? Olyloxy) -3-ethyl-2-propanol.

2-Phenyl-3-ethyl-5- (m-tolyloxymethyl) oxazolidine is subjected to the hydrolytic reaction in the same manner as in Example 2- (2), 1- (in-tolyloxy) -3-ethyl-2 -propanol is obtained, which melts ^{at 60 to 64- 0 C.} ·

Example 6 1- (p-Chlorophenoxy) -3-ethyl-2-propanol

(1) Preparation of 2-phenyl-3-ethyl-5- (p-chlorophenoxymethyl) oxazolldin. " .

Method (a)

2-phenyl-3-ethyl-5-chloromethyloxazolidine according to method (a) in example 5 »is caused to react with p-chlorophenol, with 2-phenyl-3-ethyl-5- (p-chlorophenoxymethyl) oxazolidine obtained, which boils at 185 to 190 ° C / 1 mm Hg.

Method (b)

Epichlorohydrin is used in the same way as p-chlorophenol Reacted way as in method (b) in Example 1, 1- (p-chlorophenoxy) -2,3-epoxypropane being obtained, and the latter compound is made with N-benzylidene ethylamine implemented, 2-phenyl-3-ethyl-5- (p-chlorophenoxymethyl) oxazolidine receives.

(2) Preparation of 1- (p-chlorophenoxy) -3-ethyl-2-propanol.

2-phenyl-3-ethyl-5- (p-chlorophenoxymethyl) oxazolidine is subjected to the hydrolytic reaction in the same manner as in Example 2- (2), using 1- (p-chlorophenoxy) -3-ethyl-2-propanol which melts at 92 to 93 ° G.

- 16 - 00 93Λ1 / 1 932

Example 7 1- (m-Tolyloxy) ~ 5 ~ cyclohexylaiiiino - 2 - propanol

(1) Production of 2-phenyl - 3-cyclohexyl-5 - (m-tolyloxymethy1) -oxaζο1idine.

Method (a)

Epichlorohydrin is made with N ~ benzylidenecyclohexylamine implemented in the same way as in method (a) in Example 1, using 2-phenyl-3-cyclohexyl-5-chloromethyloxazolidine obtained, and the latter compound is reacted with m-cresol, whereby 2-phenyl-3-cyclohexyl-5- (m-tolyloxymethyl) - oxazolidine received as oil.

Method (b)

1- (m-Tolyloxy) -2,3-epoxypropane, prepared according to Method (b) in Example 3, is with N-benzylidenecyclohexylamine implemented, 2-phenyl-3-cyclohexyl-5- (m-tolyloxymethyl) oxazolidine receives.

(2) Preparation of 1- (m-tolyloxy) -3-cyclohexylamino-2-propanol.

2 ~ Phenyl-3-cyclohexyl-5- (m-tolyloxymethyl) -oxazolidine is subjected to the hydrolytic reaction in the same manner as in Example 2- (2), using 1- (m-tolyloxy) -3-cyclohexylamino-2 ~ Propanol obtained, which melts ^{at 98.5 to 99.5 0 C.}

Example 8 1-Phenoxy-3-isopropylamino ~ 2 "propanol

(1) Preparation of 2-m ~ tolyl- = 3-isopropyl-5-phenoxymet3ayloxazolidine.

Epichlorohydrin is combined with fi-Cm-Methylbenzylidin) -

- 17 0Q98A1 / 1992

isopropylamine implemented in the same way as for Method (a) in Example 1, using 2- (m-! Tolyl) -3-isopropyl-5-chloromethyloxazolidine which boils at 121 to 123 ° C / 1 mm Hg, and the latter compound becomes reacted with phenol, with 2- (m-! Iolyl) -3-isopropyl-5-phenoxymethyloxazolidine obtained as an oil that boils at 190 to 195 ° C / 1 mia Hg.

Method (b) .

1-phenoxy-2,3-epoxypropane, prepared according to Method (b) in Example 1, is with N- (m-methylbenzylidine) isopropylamine reacted, with 2- (m ~ tolyl) -3-isopropyl-5-phenoxyoxazolidine receives.

(2) Preparation of 1-phenoxy ~ 3-isopropylamino-2-propanol.

2-m-Tolyl-3-isopropyl-5-plienoxymethyloxazolidine is subjected to the hydrolytic reaction in the same manner as in Example 2- (2) to give 1-phenoxy-3-isopropylamino-2-propanol which is 92 to 94 ⁰ O melts.

Example 9
1- (p-Chlopphenoxy) -3-isopropylamino-2-propanol

(1) Preparation of 2-phenyl-3-isopropyl-5- (p-chlorophenoxymethyl) oxazolidine.

Method (a)

2-phenyl-isopropyl-ip-chloromethyloxazolidine, herge ^ represents according to method (a) in Example 1, is reacted with p-chlorophenol, 2-phenyl-3-isopropyl-5- (p-chlorophenoxymethyl) oxazolidine receives.

Method (b)

1- (p-Chlorophenoxy) -2,3-epoxypropane is treated with N-benzylidene isopropylamine in the same way as for

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- -18 -

Method (b) implemented in Example 1, using 2-phenyl « 3-isopropyl-5- (p-chlorophenoxymethyl) oxazolidine is obtained.

(2) Preparation of 1- (p-chlorophenoxy) -3-isopropylamino-2-propanol.

2-Phenyl-3-isopropyl-5- (p-chlorophenoxymethyl) oxazolidine is subjected to the hydrolytic reaction in the same manner as in Example 2- (2), using 1 _. (P-chlorophenoxy) -3-isopropylamino-2 propanol obtained, which melts at 99 to 100 ⁰ C.

w Example 10

1 ~ (o-Isopropoxyphenoxy) -3-isopropylamineQ-2 ~ propanol

(1) Preparation of 2-phenyl-3-isopropyl ~ 5- (o-isopropoxyphenoxymethyl) oxazolidine.

Method (a)

2-phenyl-3-isopropyl-5-chloromethyloxazolidine is reacted with o-isopropoxyphenol in the same way as in method (a) in example 1, using 2-phenyl ~ 3-isopropyl-5- (o-propoxyphenoxymethyl) oxazolidine received as oil.

Method (b)

Epichlorohydrin is reacted with o-isopropoxyphenol using the same procedure as in method (b) in Example 1, obtaining 1- (o-isopropoxyphenoxy) -2,3-epoxypropane, and the latter compound is made with N-benzylidene isopropylamine implemented, 2-phenyl-3-isopropyl-5- (o-isopropoxyphenoxymethyl) oxkzolidine receives.

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009841/1992

(2) Production of 1- (o-isopropoxyphenoxy) -3-isopropyl- • amino-2-propanol.

2 ~ phenyl-3-isoprop3rl-5- (o-isopropoxyphenoxymetnyl) -oxazolidine is subjected to the hydrolytic reaction in the same manner as in Example 2- (2), wherein 1- (o-Isopropoxyphenoxy) -3-isopropylamino-2-propanol is obtained, which melts at 60 to 61 ° 0.

Example 11 1 ~ phenoxy- »3-n-butylamino-2-propanol

(1) Production of 2-phenyl-3- * n-butyl-5 "-pb.enoxymethyl ~ oxazolidine

Method (a)

Using the same procedure as method (a) in Example 1 is epichlorohydrin with W-benzylidene-n-buty1-amine implemented, whereby 2 ~ Ph.enyl-3 ~ n-butyl-5-chloromethyl ~ oxazolidine, which boils at 135 to 137 ° Ö / 1 mm Hg, and the latter compound is reacted with phenol, where 2-phenyl-3-n-butyl ~ 5-pb-enoxymethyloxazolidine as oil receives.

Method (b)

1-phenoxy-2,3-epoxypropane is combined with N-benzylidene-n-butylamine implemented in the same way as in method (b) in Example 1, using 2-phenyl-3-n-butyl-5-phenoxymethyloxazolidine receives.

(2) Preparation of 1-phenoxy-3-n-butylamino-2-propanol.

2-phenyl-3-n-butyl-5-phenoxymethyloxazolidine is subjected to the hydrolytic reaction in the same manner as in Example 2- (2) to give 1-phenoxy-3-n-butylamino-2-propanol, which is in 77 to 79 ⁰ G melts.

Claims; \

- 20 0 0 9841/1992

Claims (6)

-20-20 Ί 8263 Claims j / LA ./Te process for the production of an alkylamino- alcohol derivatives of the formula " R. - 0 - CHp - CH - CHp OH NHR ₂ wherein R ^ is an aryl group and R ^ is a lower alkyl group or represents a cycloalkyl group, characterized in that that (a) epichlorohydrin with a Schiff base of the formula R _x - CH «N - Rp wherein R _{2 has} the meaning described above and R _{7 represents} an aryl group, reacts to form a 5-chloromethyl oxazolidine derivative of the formula Cl - CHp - CH * ί Ι Ο N N / CH to obtain, in which Rq and R have the meanings described above have, and that the latter compound with a phenol of the formula OH wherein R, - has the meaning described above, converts, to a 5-aryloxymethyloxazolidine derivative of the formula - 21 - 0098 4-1 / 1992 ~ ²¹ - yi - O ~ * CHq "~ QH O N- \ / CH to get, or that one (b) Epichlorohydrin reacts with the phenol mentioned to form a 1,2-epoxy-3-aryloxypropane of the formula H ₁ -O-CHp-CH where R * has the meaning described above, and the latter compound is reacted with the said Schiff base to obtain the said 5-aryloxymethyloxazolidine derivative and then the 5-aryloxymethyloxazolidine derivative thus obtained subject to hydrolysis. 2. The method according to claim 1, characterized in that R ,, oC-naphthyl, R ^ isopropyl and R, is phenyl, 3. Process for the preparation of a 5-aryloxymethyloxazolidine derivative the formula -IL
¹ - 0 - CHp - CH - 0 N \ / CH wherein R ^ and R, each represent an ary group and R _{2 represents} a lower alkyl group or a cycloalkyl group, characterized in that epichlorohydrin is treated with a - 22 009841/1992 Schiff's base of the formula R ₅ -GH-NE ₂ wherein Bo and R have the meanings described above, reacts to form a 5-chloro-diethyloxazolidine derivative the formula Cl - CHo - GH ■ CHp O N- CH wqrin Rp and R ^ have the meanings described above, to obtain, and that the "latter compound with a phenol of the formula R ₁ OH wherein R, - has the meaning described above. 4. The method according to claim 5, characterized in that R ^ · ÖC-naphthyl, R ₂ isopropyl and R, is phenyl. 5 · Process for the preparation of a 5-aryloxymethyloxazolidine derivative the formula R "- O - CHp - CH CHp ON - Rp "\ / ^d CH wherein R ₁ and R each represent an aryl group and R _{2 represents} a lower alkyl group or a cycloalkyl group, characterized in that epichlorohydrin is mixed with a phenol of the formula R ₁ OH - 23 -009841/1992 wherein TL · has the meaning described above, converts to a 1,2-epoxy-3-aryloxypropane of the formula R ₁ - O - CH ₂ - GH - GH ₂ ' ■. - ο where IL has the meaning described above to obtain, and that one sees the latter connection with a ship Base of the formula ■ R - GH .- N - R ₂ wherein Rp and R ^ have the meanings described above, implements. 6. The method according to claim 5, characterized in that R. eC-naphthyl, R _{2 is} isopropyl and R is phenyl. 009841/1992