DE2310141A1 - PROCESS FOR THE PREPARATION OF 1PHENYL-2-AMINOAETHANOL DERIVATIVES - Google Patents

Description

Badische Anilin- & Soda-Fabrik AG 2310141

Our reference: O.Z. 29 7 ^ 4 D / Ri 6700 Ludwigshafen, February 28, 1973

Process for the preparation of l-phenyl-2-aminoethanol derivatives

The invention relates to a process for the preparation of 1-phenyl-2-aminoethanol derivatives of formula I.

HO
HO

In German Offenlegungsschrift 1,643,224, 1-phenyl-2-aminoäthanolderivate, the position J are substituted by hydroxyl and 3-position in the phenyl ring by hydroxymethyl in ¹ will be described.

According to the formula on page 15 of the OS, for example, J-Hydrojcymethyl-Jl-hydroxy - ^ - broraacetophenone diacetate with a secondary benzylamine reacted, the acetate protective groups are removed by saponification and then the reduction takes place of the carbonyl group as well as a reductive debenzylation to obtain the to obtain desired aminoethanol derivative.

It is also stated on page 18 of the OS that the phenylaminoethanol compounds can be prepared from the corresponding epoxide by reaction with an amine, the phenolic hydroxyl group can be protected e.g. by a benzyl ether group, which then has to be split off again.

However, the amine conversion of the epoxide leads to unexpected side reactions, if a hydroxymethyl group is also present in the phenyl ring in the 3-position in addition to a protected phenolic hydroxyl is, even if this is due to etherification or esterification

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is protected because nucleophilic exchange on the benzy! carbon atom easily takes place, so that in addition to the desired phenylaminoethanol compound the aminomethyl compound and the bisamine compound can be obtained.

The use of compounds with an unprotected phenolic or unprotected hydroxymethyl group as starting compounds is not possible because it is not possible to produce the epoxides from these compounds. For example, the boranate reduction leads of a p-hydroxy-w-bromoacetophenone simultaneously for salt formation and subsequent acidification to open the epoxy ring. The production of an epoxide from an aldehyde or ketocarbonyl group with dimethylsulfoxonium or dimethylsulfonium methylide, as described by E.J. Corey and M. Chaykovsky in J. Araer. Chem. Soc, Volume 87, page 1353 (1965), does not achieve the goal either in the case of free OH groups or those protected by acetate residues.

In the DT-OS 2 I65 400 are for connections from the series of Phenylaminopropanol derivatives with para hydroxyl and meta hydroxymethyl group similar complex process steps described. The starting compound is an epoxide, its phenolic hydroxyl group is protected by a benzyl group, and which has an esterified carboxyl group adjacent thereto. To After the reaction with the amine, the benzy protective group is removed by cleavage with hydrogen without the ester group being attacked is, and then this is reduced to alcohol in a further process step.

The object of the invention is to provide l-phenyl-2-aminoethano! Compounds, which are substituted in the phenyl by hydroxyl and hydroxymethyl, bypassing technically difficult process steps easily accessible.

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It has now been found that one can use l-phenyl-2-aminoethanol derivatives of the general formula I.

in which R is hydrogen, an optionally substituted, saturated, straight-chain or branched alkyl radical with 1 to 8 carbon atoms or one optionally substituted by alkyl groups Cycloalkyl radical with 3 to 6 carbon atoms in the ring means, can be prepared by a benzo-l, 3-dioxane derivative of Formula II

in which R is fluorine, chlorine, bromine, iodine, a formyl or acetyl group and R and R are identical or different and are straight-chain or branched lower alkyl with 1 to ^ C atoms

• z h

or R and R together represent a methylene group ~ ( ^CH 2 ^ _n "» where η is an integer from 3 to 5, in an epoxide of the formula III

R ³

3 k
in which R and R have the meanings given, and converts this with an amine of the formula HpN-R, in which R has the meaning given, and then hydrolyzes the reaction product to give the compound of formula I.

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The special feature of the new process is a new starting material, which compared to the known process a technically much less expensive production of phenylaminoethanol compounds allowed with a hydroxymethyl group.

Surprisingly, it has thus become possible to use a starting material for synthesis available in which the phenolic hydroxyl group and the adjacent hydroxymethyl group are provided with a protective group connecting both hydroxyl groups.

The ßenzo-l, 3-dioxane derivatives of the formula II can be obtained by adding salicylic alcohols, which are in the p-position to the phenol OH group are substituted by a substituent with the meaning given for R, with aliphatic or cycloaliphatic ketones of the formula

3 4
in which R and R have the meaning given above, is reacted in an aprotic inert solvent in the presence of a water-binding agent.

Aromatic hydrocarbons such as benzene or toluene, halogenated hydrocarbons, such as chloroform or methylene chloride, dialkyl ethers or cycloaliphatic ethers such as diethyl ether, tetrahydrofuran or dioxane, acid amides of lower fatty acids, such as dimethylformamide, or dimethyl sulfoxide or mixtures of these solvents are expedient. But it can also be the aliphatic or cycloaliphatic Ketones themselves can be used as solvents in excess amount.

Concentrated inorganic acids such as sulfuric acid or phosphoric acid, anhydrides anor-

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Chemical or organic acids, such as phosphorus pentoxide or trifluoroacetic anhydride, strong adsorbents, in particular Aluminum oxide, of activity level I, as it is used, for example, in chromatography, or organic dehydrating reagents, such as carbodiimides or ynamines. Most of the named water-binding agents act they are acids or anhydrides that can form acid with small amounts of water. The acid catalyzes the reaction. Used if plaster of paris or other hygroscopic neutral salts are used as a water-binding agent, catalytic amounts of acid can be used for example, also add in the form of ion exchangers.

The procedure for preparing the benzo-1,3-dioxane derivatives (II) is followed usually so that a solution or slurry of the water-binding agent in a solvent or in solvent mixtures a mixture of substituted salicyl alcohol with the ketone to be converted in a ratio of about 1: 1 to 1: 1.5, optionally dissolved in a little solvent, added dropwise. You can also proceed in reverse and to the two reactants, dissolved in a solvent, give the water-binding agent.

The temperature is generally in a range of -10 to +50 ⁰ C. The reaction mixture is for about 10 to 100 hours, preferably 15 - 25 hours stirring, the temperature is suitably kept within the ranges mentioned.

The reaction mixture is generally worked up in such a way that, for example, after the water-binding agent has been removed the organic phase obtained is shaken with soda solution by filtering, decanting or shaking, dries and evaporates. The residue can be obtained by recrystallization and / or distillation. The benzo-1,3-dioxane compounds are generally colorless crystals or oils.

Benzo-1,3-dioxane, made from salicyl alcohol and formaldehyde, in which R and R are hydrogen, are after work

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known from E. Ziegler et al (Chem. Ber. χ6,664, 1943). However they are stable in an acidic environment and therefore act as a protective group not suitable as it is extremely difficult to remove.

R. Adams et al in J. Amer. Chem. Soc. 45, 2417 (1923) Benzo-1,3-dioxanes from aromatic aldehydes and salicylic alcohols. These can be saponified by acids, but have the disadvantage that there is a mobile hydrogen atom on the acetal carbon leads to undesirable side reactions in the chemical reactions to be carried out. Interestingly, R. Adams describes in of the work cited above that the reaction of salicylic alcohol with simple aliphatic aldehydes does not lead to the desired results Benzo-1,3-dioxanes leads.

It is therefore surprising that substituted saligenins convert to benzo-1,3-dioxanes under the specified conditions without self-condensations or aldol condensation reactions with the ketone in the case of saligenins with carbonyl substituents enter to benzylidene ketones.

Salicylic alcohols, which are used as starting compounds for the manufacture of the benzo-1,3-dioxane compounds of the formula II are, for example:

3-hydroxymethyl-4-hydroxy-benzaldehyde,
3-Hydroxymet hy Ι-Ί-hydr oxy -acetophenon,
5-bromo-2-hydroxy-benzyl alcohol (p-bromo-saligenin), 5-chloro-2-hydroxy-benzyl alcohol

As particularly preferred carbon compounds for implementation for the benzo-1,3-dioxane compound, acetone and Cyclohexanone.

But it can also, for example, butanone, diethyl ketone, cyclopentanone be used.

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Of the benzo-1,3-dioxane compounds, formula II is accordingly called:

2,2-Dimethy1-6-bromo-benzo-1,3-dioxane, 2,2-Dimethy1-6-formyl-benzo-1,3-dioxane, 2,2-Dimethy1-6-acetyl-benzo-1,3-dioxane, 2-spirocyclohexane-6-formyl-benzo-l, 3-dioxane, 2,2-dimethy1-6-chloro-benzo-l, 3-dioxane, 2,2-dimethyl-6-fluoro-benzo-1,3-dioxane, 2,2-diethyl-6-formyl-benzo-1,3-dioxane, 2-methyl-2-ethyl-6-formyl-benzo-1,3-dioxane, 2-spirocyclopentane-6-formyl-benzo-1,3-dioxane.

The benzo-1,3-dioxanes of the formula II are converted into the epoxides of the Formula III converted.

Appropriate process conditions for the reaction are:

The halogen compound is in a known manner in a Qrignard- or lithium-organic compound transferred. This is converted to carbinol with X-haloacetaldehyde. Elimination of hydrogen halide with a strong base delivers the epoxy.

You can also halogenate 6-acetyl-benzo-1,3-dioxane in the (^ - position and then reduce with sodium borate to form the epoxide. The carbonyl derivatives of formula II can also be converted into the epoxides with dimethylsulfonium or dimethylsulfoxonium methylide.

These conditions generally correspond to the methods known in the literature for the preparation of epoxides.

For the preparation of epoxides of the formula III from compounds of the formula II with R = formyl, the method developed by E.J. Corey and M. Chaykovsky in J. Amer. Chem. Soc. 87, 1353 (1965) Method very well proven when using dimethylsulfonium methylide.

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Examples of epoxides of the general formula III include:

2,2-dimethyl-benzo-l, 3-dioxane-6-ethylidene oxide, 2-spirocyclohexane-benzo-l, 3-dioxane-6-ethylidene oxide, 2-spirocyclopentane-benzo-l, 3-dioxane-6-äthylidenoχid, 2,2-diethyl-benzo-1,3-dioxane-6-ethylidene oxide, 2-methyl-2-ethyl-benzo-1,3-dioxane-6-ethylidene oxide.

The epoxides can advantageously be processed further in the form of their raw products. A cleaning of the epoxies is not absolutely necessary.

The implementation of the epoxides with the amines of the formula

H ₂ NR ¹
is problem-free and takes place in a manner known per se.

Usually the reaction is carried out in a solvent, for example a lower alcohol, such as ethanol or isopropanol, and at the boiling temperatures of the solvents used carried out.

As stated above, when R represents an alkyl radical having 1 to C atoms, this can be substituted. As a substituent Examples include hydroxyl, alkoxy, thioalkyl, amino, cyano groups or aryl radicals, optionally through hydroxyl or alkoxy substituted, or cycloalkyl radicals with 3 to 6 carbon atoms in the ring. When R is a cycloalkyl radical with 3 to 6 carbon atoms represents in the ring, this can in particular be substituted by methyl groups.

The amine components are particularly useful for the implementation Amines:

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wetnyxamin

Ethylamine

Isopropylamine

tert-butylamine

2-methyl-butylamine-2 2-amino-butanol-1

3-amino-butanol-l

1-methoxybutylamine-2 1-methoxy-2-methyl-propylamine-2 l-methylmeΓcapto-2-methyl-propylamine-2 3-dimethylaminopropylamine-1 3-Dimethylamino-2,2-dimethyl-propylamine-1 6-dimethylamino-hexylamine-1 2-amino-2-methyl-propionitrile cyclopropylarain

1-Cyclopropylethylamine-1 1-methylcyclopropylamine-1 Cyclobutylamine

1-methylcyclobutylamine-1 Cyclopentylamine

1-methylcyclopentylamine-1 Cyclohexylamine

1-Cy clohexylethylamin-1 3, ¹ 4-Dioxymethylenebenzylamine 1-Pheny1-propylamine-2 1- (p-Hydroxypheny1) -propylamine-2 l- (p-Methoxyphenyl) -propylamine-2 1- (3 '>^' - Dioxymethylene phenyD-propylamine-2 l-phenylbutylamine-3 1- (p-hydroxyphenyl) -butylamine-3 l- (p-methoxyphenyl) -butylamine-3 1- (3'-methoxy-4 · hydroxyphenyl) -butylamine-3 1 - (3 ', b ' -Dioxymethylene-pheny1) -butylamine-3 1,1-diphenyl-butylamine-3

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This produces compounds of the formula IV

? "" \ 1 IV

OH ^R

in which R, R and R have the meanings given, the subsequently saponified to give compounds of the formula I.

Examples of compounds of the formula IV include:

2,2-Dimethy 1-benzo-1,3-dioxane-6- jöt - hydroxy-ß-amino (-tert. ButyDJ-ethyl

2,2-Dimethy 1-benzo-1,3-dioxane-6- [cc.-hydroxy-ß-amino (-isopropyl2j -

2,2-Dimethyl-benzo-1,3-dioxane-6-U'-hydroxy-β-amino (-2'-methylbuty 1-2 ·)] ethyl

2,2-dimethyl-benzo-1,3-dioxane-6-p-hydroxy-ß-amino (-l'hydroxy-

butyl-2 ·)] - ethyl

2,2-Dimethy 1-benzo-1,3-dioxane-6- | o | '-hydroxy-ß-amino (-l' -hydroxy-

butyl-3 ')] - ethyl _r

2,2-Dimethyl-benzo-1,3-dioxane-6- | C \ ^ hydroxy-β-amino (-l ^l -raethoxybutyl-3 ¹ )] ethyl

2,2-dimethyl-benzo-1,3-dioxane-6-bu-hydroxy-β-amino (-l ^l -methoxy-2'-methyl-propyl-2 ')] ethyl

2,2-Dimethyl-benzo-1,3-dioxane-6- | cu-hydroxy-ß-amino (-l'-methyl-

mercapto-2'-methyl-propyl-2 ') 1-ethyl

2,2-Dimethyl-benzo-l, 3-dioχan-6- jöo-hydroxy-ß-amino (-l ^f -dimethyl-

amino-propyl-3 ^f ) ~ | -ethyl

2,2-Dimethy1-benzo-1,3-dioxane-6- [oC-hydroxy-β-aminoC-I ¹ -dimethylamino-2 '-2 · -dimethy 1-propy 1-3 » ) j -ethyl

2,2-Dimethy 1-benzo-1,3-dioxane-6- | OIL-hydroxy-ß-amino (-1 · -dimethy 1-

amino-hexy 1-6) I-ethyl

2,2-dimethyl-benzo-l, 3-dioxan ⁱ -6- [σL ·-hydroxy-ß-amino (2 'cyanopropyl-2 ·)] - ethyl

2,2-Dimethy 1-benzo-1,3-dioxane-6-ldL-hydroxy-ß-amino (-cyc lopropyl-)] -ethyl

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2,2-dimethyl-benzo-1,3-dioxane-6- [ik-hydroxy-ß-amino (-l »-methyl-

cyclopropyl-1 ¹ ) ethyl

2,2-Dimethyl-benzo-1,3-dioxane-6- ^ oL -hydroxy-ß-amino (-l ^l -cyclo-

propylethyl-1 ^f ) I-ethyl

2,2-Dimethyl-benzo-1,3-dioxane-6 - ^ - hydroxy-ß-amino (-cyclobutyl) J-

ethyl,

2,2-Dimethyl-benzo-1,3-dioxane-6- | oC-hydroxy-ß-amino (-cyclopentyl)] -ethyl

2,2-diraethyl-benzo-1,3-dioxane-6-E, -hydroxy-ß-amino (-l-methyl-

cyclopenty1-1) I-ethyl
2,2-Dimethyl-benzo-1,3-dioxane-6-bt-hydroxy-ß-amino (-l'-phenyl-

propy1-2 ·)] - ethyl

2,2-Dimethyl-benzo-1,3-dioxane-6-jCt-hydroxy-β-amino (-3 ', V-dioxymethylene benzyl -)] ethyl

—J ι—

2 ^ -Dimethyl-benzo-l ^ -dioxane-o- KA ^ hydroxy-ß-amino (-l '-phenyl-

buty1-3 ·)] - ethyl

2,2-dimethyl-benzo-l.3-dioχan-6-hL -hydroxy-ß-amino (-1'-p-hydroxy-

phenyl-butyl-3 ')] - ethyl

2,2-dimethyl-benzo-1,3-dioxane-6- | oil-hydroxy-ß-amino (-l'-p-methoxy-

phenyl-butyl-3 ') 1-ethyl

2,2-dimethyl-benzo-l, 3-dioxane-6- lo ^ hydroxy-ß-amino (-l ', 1' -diphenyl-

butyl-3 ¹ )] - ethyl

The compounds of the formula IV do not necessarily need to be isolated. Their hydrolysis takes place under usual conditions Conditions, for example in the presence of water and traces of acid.

A particularly simple procedure consists in treating with water at room temperature or, if appropriate, at an elevated temperature up to 100 C within a period of about a few hours up to 2 days in a weakly acidic medium with the addition of excess Acid to the free base or to the salt. Sulfuric acid is preferably used.

According to the process according to the invention, known and new l-phenyl-2-aminoethanol derivatives can be prepared.

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To be emphasized are, inter alia, those compounds in which the radical R ¹ creates in
has secondary carbon atom.

the radical R ¹ in (^ position to the nitrogen atom is a tertiary or

• For example, i-propyl, 2- and 3-butyl radicals can be mentioned, which are substituted by methyl, phenyl, hydroxy, methoxy, methylmercapto, dimethylamine or cyano groups can.

Furthermore, cycloaliphatic radicals can be emphasized for R, such as cyclopropyl, cyclobutyl, cyclopentyl, optionally with lower alkyl radicals, preferably methyl _; on the carbon atom in position to the nitrogen atom, and lower alkyl radicals, preferably ethyl, with a cycloalkyl radical with 3 to 6 carbon atoms in the ring in the oil position to the nitrogen atom, such as the 1-cyclopropyl-ethyl-1-cyclobutyl-ethyl-1 , l-cyclopentyl-1-ethyl or 1-cyclohexyl-1-ethyl residue.

Further examples are n-propyl and n-hexyl radicals, which are optionally substituted by methyl and / or dimethylamino groups.

The following compounds may be mentioned as examples:

cL -tert.-Butylaminomethyl - ^ - hydroxy-m-xylyl-cC-jt-diol ^ -Isopropyl-aminomethyl- ¹ * -hydroxy-m-xy Iy lo <^ - (X? -di oil ^α - (2 ' -Methyl-butyl-2 'J-aminomethyl-M-hydroxy ^ m-xylyl - ^ - ÖC ^ -diol ⁰ ^ - (I'-Hydroxy-buty1-2' J-aminomethyl - ^ - hydroxy-m-xylyl- öir-öLr-diol ⁰ ^ - (l'-Hydroxy-butyl-3 ') ^{-aminomethyl-1} 4-hydroxy-m-xylyl-oL ¹ -c6? -diol ^α - (l ^l -Methoxy-butyl-3 ^l ) -aminomethyl-4-hydroxy-m-xylyl-cx ^ -o {? - diol ^c * - (l'-methoxy-2 '-methyl-propyl-2') -aminomethyl-4-hydroxy-mxylyl-oi3 -o <? - diol

Kf ^ - (l ^l -Methylmercapto-2 ^l -methyl-propyl-2 ^f ) -aminomethyl - ^ - hydroxym-xylyl-oC-oCT-diol

oC- (l ^l -Dimethylamino-propyl-3 ^l J-aminomethyl - ^ - hydroxy-m-xylyl-cd ¹ - ³

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ji (l «-Dimethylamine ^ ·, 2'-dimethyl-propyl-3 ') -aminomethyl-m-

xylyl-oC- <vdiol
^ - (l'-Diraethylamino-hexyl-o'J-aminomethyl - ^ - hydroxy-m-xylyl- ^ l ¹ -

₀ ^ ¹ _ (2 "-Cyano-propyl-2 ^l ) -aminomethyl-4-hydroxy-m-xylyl-oi ¹ -cx ^ -diol ^ - (CyclopropyD-aminomethyl - ^ - hydroxy-m-xylyl-a ^ o ^ -diol C ^ -U'-methyl-cyclopropyl-l ·) -aminomethy 1-4-hydroxy-m-xyIyI- ³

oC ³ -diol
_c ^ ¹ - ( ₁ i_Cyclopropyläthyl-l ') - aminomethyl-4-hydroxy-m-xylyl-iX? -oc ^ -

diol
oC ¹ - (cyclobutyl) -arainomethyl-4-hydroxy-m-xylyl-oi-cx? -diol

ö ^l i- (cyclopentyl) aminomethyl-4-hydroxy-m-xylyl (Xf-o ^ C ^ diol - (I ¹ -Methylcyclopenty 1-1 ') aminomethyl-4-hydroxy-m-xylyl ^ - ^ - diol

dC- (i «-Phenyl-propyl-2 ') -aminomethyl-4-hydroxy-m-xylyl- <X> -oe ⁾ -diol oL ^a - (3', i |« -dioxymethylene benzyl) -aminomethyl-4- hydroxy-m-xylyl-oc ^{: 1} -O ^ -diol

ot- (l ^f -Phenylbutyl-3 ') -aminomethyl-4-hydroxy-m-xylyl-c ^ - (^ - diol C ^ - (l ^l -p-methoxyphenyl-butyl-3') - aminomethyl- ^l 4 -hydroxy-m-xylyl-

C ^ - (I ', l'-Diphenyl-butyl-3') -aminomethyl-4-hydroxy-ra-xylyl-ö <3 · - ^ - diol

The l-phenyl-2-arainoethanol derivatives I, but also those of the formula IV _#, are pharmacologically active. In particular, the compounds themselves or their pharmacologically acceptable salts are used as bronchodilator agents.

The compounds can be physiologically in the usual manner compatible acid addition salts are converted from organic or inorganic acids. Suitable acids are, for example Hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, Oxalic acid, maleic acid, lactic acid or tartaric acid.

Therapeutic agents or preparations with the compounds as active ingredient can be prepared according to methods known per se to the person skilled in the art the desired type of application can be obtained.

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example 1

J-hydroxymethyl - ^ - hydroxy-benzaldehyde:

To 4,000 ml of conc. HCl, 432 ml of 40% formalin solution and 600 g of p-hydroxy-benzaldehyde are added. A vigorous stream of HCl is introduced for 3 1/2 hours with ice cooling (temp. <40 °). It is then filtered off with suction and washed thoroughly with water (cf. J. Chem. Soc. 1950, 2141). The residue is introduced into 1,800 ml of tetrahydrofuran while still moist, 1,000 ml of water and 480 g of calcium carbonate are added in portions. The mixture is stirred at room temperature for 12 hours, then the organic phase is separated off and extracted twice with diethyl ether. The combined ether phases are washed with water and dried over magnesium sulfate. 530 g of crude product are obtained. Yellow to pale pink crystals with a melting point of 130-132 ° C. are obtained from water or a tetrahydrofuran-methylene chloride mixture in a ratio of 1: 2.
Analysis: CgH ₈ O ₃ (152.1)
Calculated: C: 63.15 H: 5.3 0: 31.55 found: 62.7 5.4 31.6

Example 2

3-hydroxymethyl-4-hydroxy-acetophenone:

To a mixture of 1,000 ml of conc. HCl and 500 ml of 40 Jige Pormalin solution, 250 g of p-hydroxyacetophenone are added. It is then ^{cooled to 20 °} C. and a vigorous stream of HCl is introduced for 3 hours. The mixture is subsequently stirred for 2 hours and then left to stand for 20 hours. It is poured into 2,500 ml of water and the solid product is filtered off with suction. Wash with hot water and hot benzene. 238 g of red crystals with a melting point of 162-164 ° are obtained (lit .: R. Trave Gazz. Chira. Acta 8.1, 773 (1951) melting point: 160 °).

The crystals are dissolved in 1,000 ml of tetrahydrofuran. To this are added 350 ml of water and 250 g of calcium carbonate in portions.

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The mixture is stirred for a further 4 hours and the procedure described in Example 1 is followed on. 180 g of a brown oil are obtained which, after adding 100 ml of chloroform, slowly converts into a crystal paste. It is filtered off with suction and obtained after recrystallization

55 g of brownish crystals

Ethanol / chloroform ■ 118 in relation to 1 : 2 , 89 from Fp .: Il6 - L0 ° 3 ° C. , 9 Analysis: CH. : 65, (166.2) calculated: C; 65, 05 H: 6.07 0: 28 found: 3 6.3 28 Example 3

2,2-dimethyl-6-bromo-benzo-1,3-dioxane:

50 g of phosphorus pentoxide are added to 100 ml of anhydrous benzene. With egg cooling, 50 g of p-bromo-saligenin (5-bromo-2-hydroxy-benzyl alcohol, cf. R. Adams et al. JACS 4j>, 2417 (1923)), dissolved in 50 ml of anhydrous acetone, are slowly added dropwise . The temperature in the reaction vessel should not exceed ^{15 ° C. during this process.} The mixture is subsequently stirred at room temperature for 20 hours. The amorphous residue is poured off the benzene solution and washed with benzene. The combined benzene phases are washed with dilute soda solution and water, dried and evaporated. 53.5 g of a colorless oil are obtained, which is distilled (boiling point 100-103 ° / 0.5). 50.5 g (88 % of theory ) of pure product are obtained.
Analysis: C ₁₀ H ₁₁ BrO ₃ (243.1)
Calculated: C: 49 _V 41 H: 4.56 Br: 32.87 found: 49.9 4.7 32.6

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Example .4

2,2-Dimethyl-6-formyl-benzo-1,3-dioxane:

To 80 ml of anhydrous benzene, 57 g of phosphorus pentoxide are added and at 5 - 10 ⁰ C was added dropwise a solution of 58.0 g of 3-hydroxymethyl-4-hydroxy-benzaldehyde in 400 ml of anhydrous acetone and 60 ml of dimethylformamide was added. The mixture is stirred for a further 15 hours at room temperature, a further 48 g of phosphorus pentoxide are added and the mixture is stirred for a further 1 hour. The organic phase is poured off, washed with 3 × 100 ml of benzene, the combined organic phases are washed with dilute soda solution and dilute sodium chloride solution, dried over sodium sulfate and evaporated. 57 g of an oil are obtained which slowly crystallizes. Distillation in a Sword flask at 0.15 Torr gives 37 g (51 % of theory ) of a colorless oil which crystallizes and has a melting point of 58T. Analysis: C ₁₁ H ₁₂ O ₃ (192.2)
Calculated: C: 68.73 H: 6.29 0: 24.97 found: 68.3 6.5 25.3

Example 5

2,2-dimethyl-6-acetyl-benzo-1,3-dioxane:

160 g of 3-hydroxymethyl-4-hydroxy-acetophenone are poured into 400 ml dissolved in anhydrous acetone. This is done in portions at 0 ° C 1 ^ 2 g of phosphorus pentoxide. The mixture is stirred for 3 hours and left on Warm up to room temperature. The acetone phase is poured off and the residue is washed out with acetone. The acetone is on The rotary evaporator is drawn off and the residue is taken up in methylene chloride. The methylene chloride solution is diluted with Soda solution and water washed, dried and evaporated. 108 g of an oil are obtained, which is obtained by distillation (Bp. 121 ° / 0.2) or filtration through a column of basic aluminum oxide of activity II. With both cleaning

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methods gives a colorless oil that crystallizes and then melts at 83 - 84 ° C.

Analysis: C ₁₂ H ₁₄ O ₃ (206.2)

Calculated: C: 69.88 H: 6.84 0: 23.27 found: 69.3 6.8 23.2

Example 6

2-spirocyclohexane-6-formyl-benzo-l, 3-dioxane:

20 g of cyclohexanone and 20 g of 3-hydroxymethyl-II-hydroxybenzaldehyde in 30 ml of dimethylformamide are added dropwise to 20 g of phosphorus pentoxide in 50 ml of anhydrous benzene at a temperature of 5-10 ° C. The mixture is subsequently stirred for 15 hours at room temperature. The organic phase is poured off, the phosphorus pentoxide residue is washed out twice with 200 ml of benzene each time, the combined organic phases are washed with dilute soda solution and water, dried over sodium sulfate and evaporated. 14 g of an oil are obtained, which is distilled in a sword flask at a pressure of 0.01 mm and a bath temperature of at most 165.degree. 6.2 g of a colorless oil are obtained, n _2Q o = 1.5722. Analysis: C ₁₁₁ H ₁₄ O ₃ (237.3)
Calculated: C: 72.39 H: 6.9 ^ 0: 20.67 found: 72.1 6.8 20.3

Example 7

2,2-dimethyl-benzo-1,3-dioxane-6-ethylidene oxide:

The reaction is carried out in a dry apparatus under dry nitrogen. To 5.8 g of sodium hydride 144 ml of dry dimethyl sulfoxide are added rapidly and then slowly with stirring to 65-70 ⁰ C heated. The reaction mixture is left at this temperature for 1 hour, cooled to room temperature, 144 ml of dry tetrahydrofuran are added, cooled to 0 ° C. and 48.2 g of dry trimethylsulfonium iodide in 180 ml of dimethyl

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sulfoxide too. At the same temperature, 20.6 g of 2,2-dimethyl-6-formyl-benzo-1,3-dioxane in 50 ml of tetrahydrofuran are then added dropwise. The mixture is allowed to cool to room temperature and stirred for 1 hour. It is then poured into 1,200 ml of water and extracted several times with ether. The combined ether phases are washed with water, dried and evaporated. 21.0 g (95 % of theory ) of an oil are obtained. The absence of a carbonyl band in the IR spectrum at 6.0, u indicates the complete conversion to the epoxide. The oil is processed further without further purification. The distillation in the sword flask is carried out in the following boiling range lld, 5 - 120 ° / 0.1 n ^ - 1.5339.
Analysis: ^C ₁₂ ^H ₁ 3 4 ° (206.2).

calculated: C: 69 , 88 H: 6.84 0: 23 , 27 found: 70 , 6 7.3 23 , 6 Example 8

2,2-Dimethyl-benzo-1,3-dioxane-6- (1'-hydroxy-2'-tert.-butylamino) - ethyl:

6.85 g of 2,2-dimethyl-benzo-1,3-dioxane-6-ethylidene oxide and 3.7 g of tert-butylamine in 50 ml of isopropanol are refluxed for 8.5 hours. It is evaporated, taken up in ether, extracted with water, dried and the solvent removed on a rotary evaporator. The residue of 8.7 g of oil is in abs. Dissolved ethanol and with 2.1 g of oxalic acid in abs. Ethanol added. 5.7 g of crystals with a melting point of over 275 ° C. (decomp.) Are obtained. The analysis and the NMR spectrum are correct for the structure of a 2,2-dimethyl-benzo-1,3-dioxane-6- (l ' -hydroxy-2 ^f -tert.butylamino) ethyl oxalate.

Analysis: C ₁₇ H ₃₆ O ₅ N (324.4)

Calculated: C: 62.94 H: 8.08 0: 24.66 N: 4.32 found: 63.0 8.5 25.1 3.9

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2310U1

The free base can be released with soda solution and with methylene chloride extracted. Recrystallization from petroleum ether gives crystals with a melting point of 92-93 ° C.

Analysis: C ₁₆ H ₃₅ O ₃ N (279.4)

Calculated: C: 68.79 H: 9.02 0: 17.18 N: 5.01 found: 68.7 9.2 17.2 5.3

Example 9

o (! - tert-Butylaminomethyl-4-hydroxy-m-xylyl- (X. -c * c-diol:

4 g of 2,2-dimethyl-benzo-1,3-dioxane-6- (l'-hydroxy-2'-tert-butylamino) ethyl oxalate are dissolved in 100 ml of water while warming to the boiling point. It is cooled and removed on a rotary evaporator the resulting acetone. Then it is made alkaline with sodium bicarbonate and extracted 5 times with ether. the Ether phase is dried with sodium sulfate and evaporated. The residue is boiled with ethyl acetate and cooled. 1.8 g of precipitate are obtained, which is obtained from ethanol with the addition of Ethyl acetate is recrystallized and then has a melting point of 150 to 151 °.

Example 10

Ou -tert.-Butylaminomethyl - ^ - hydroxy-rn-xylyl-cir-iß-diol-sulfate:

3.5 g of 2,2-dimethyl-benzo-l, 3-dioxane-6-ethylidene oxide are in JO ml abs. Dissolved ethanol, mixed with 3.5 g of tert-butylamine and refluxed for 8 hours. It is then evaporated, taken up in ether and washed twice with water. After this Drying with sodium sulfate, the ether is stripped off and the oily The residue (4.0 g) was dissolved in 14.3 ml of ln sulfuric acid. One lets Stand for 2 days, shake out with ether and add about 10-15 ml of tetrahydrofuran. After a further 2 days you get 0.8 g of crystals which melt with decomposition and show the following analysis

C ₂₆ H ₁₄₂ N ₂ O ₆ . H ₂ SO ₁₄ (576.7)

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2310U1

Calcd. C: 54.15 N: 7.69 O: 27.74 S: 5.56 N: 4.86 found 54.1 7.3 28.2 5.3 4.7

Example 11

2,2-Dimethyl-benzo-1,3-dioxane-6-k-hydroxy-ß-amino- (l'-methylmercapto-2-methyl-propyl-2 ') J-ethane:

11.15 g (54.2 mmol) of 2,2-dimethyl-benzo-1,3-dioxane-6-ethylidene oxide and 6.5 s (54.2 mmol) of l-methylmercapto - ^ - methyl-propyl-amine ^ in 50 ml of isopropanol are refluxed for 12 hours. The isopropanol is removed on a rotary evaporator, taken up in 50 ml of diethyl ether, washed twice with water and dried over magnesium sulfate. After evaporation, 14.7 g of yellow oil are obtained, which is dissolved in anhydrous ethanol and treated with one molar equivalent of oxalic acid (3.4 g) dissolved in ethanol. 8.6 g (43 % of theory) of colorless crystals are obtained which, after recrystallization from aqueous isopropanol, melt at 203.degree.-2O4.degree.

Analysis: C ₁₈ H ₂₈ O ₅ SN (370.5)
Calculated: C: 58.35 H: 7.62 N: 3.78 found: 59.1 8.0 4.0

Example 12

QL - (l ^f -Methylmercapto-2'-methyl-propyl-2) -amino-methyl-4-hydroxy-m-xylyl- (X, & -diol:

10 g (27 mmol) oxalate from Example 11 in 250 ml of water are added 5 ml of 2N sulfuric acid and stirred for 2 hours at 5O ⁰ C. It is concentrated to about 200 ml on a rotary evaporator, extracted once with diethyl ether and an excess of sodium bicarbonate is added. It is shaken out several times with ether, the combined ether extracts are dried over magnesium sulphate and evaporated. 4 g (52 % of theory) of colorless crystals are obtained which, after recrystallization from ethyl acetate / cyclohexane, melt at 97.degree.

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2310U1

Analysis: ( 14 ^H 21 ° 3 NS (283.4) N: 13th 4th , 94 calculated: C: 59, 34 H: 7.47 5 ,1 found: 58 7 7.5 example

2,2-Dimethy1-benzo-1,3-dioxane-6- [d -hydroxy-ß-amino- (1'-cyclopropyl-ethyl-1 ' ) \ -ethyl:

From 10.3 g (50 mmoles) of 2,2-dimethyl-benzo-1,3-dioxane-6-ethylidene oxide and 4.3 g (50 mmoles) of l-cyclopropylethylamine-1, 6.2 g are obtained as described in Example 11 of the oxalate (37 % of theory) as colorless crystals with a melting point of 208 ° C.

Example 14

2,2-dimethyl-benzo-1,3-dioxane-6-U. -hydroxy-ß-amino- (2 ', 2 »- dimethyl-3'-dimethylamino-propyl-l) -ethyl:

Is obtained as described under Example 11 and, as oxalate, has a melting point of 215 ^° C. (Z).

Example 15

2,2-Dimethy1-benzo-1,3-dioxane-6-Li-hydroxy-ß-amino- (4 ', 4' diphenyl-butyl-2 ')] -ethyl:

Is represented as described under Example 11 and, as oxalate, has a melting point of 188 ^° C. (Z).

Example l6

2,2-Dimethyl-benzo-1,3-dioxane-6-p-hydroxy-ß-amino- (1'-pmethoxyphenyl-butyl-3 ') ~] -ethyl:

Is obtained as described under Example 11 and, as an oxalate, has a melting point of 198 to 201 ° C (Z).

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Example 17

2 _> 2-Dimethyl-benzo-l, 3-dioxane-6- k-hydroxy-ß-amino- (l'-pmethoxyphenyl-propyl-2 ') J -ethyl:

Is obtained and has as described in Example 11 as oxalate has a melting point of 212 to 21 ^ S: (Z).

Example 18 dt - (1'-Phenyl-propyl-2 '-) aminomethyl- ¹ J-hydroxy-m-xylyl

Is obtained as described in Example 10, and has a melting point of 115 to 117 ° C ^l

Example 19

(λ - (l ^l -p-methoxyphenyl-butyl-3'iaminomethyl - ^ - hydroxy-mxylyl-uf-ct? -diol:

Is obtained as described in Example 10 and melts at 98 to 105 ° C.

Example 20

Ck - (cyclopentyl) aminomethyl-4-hydroxy-m-xylyl-c \ "- $. -Diol:

Is obtained as described under Example 10 and has a melting point of 128 to 130 ^° C.

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Claims (1)

2310H1 Claims 1.] Process for the preparation of l-phenyl-2-aminoethanol derivatives of the general formula I. in which R is hydrogen, an optionally substituted, saturated, straight-chain or branched alkyl radical with 1 to 8 carbon atoms> which denotes an optionally substituted cycloalkyl radical with 3 to 6 carbon atoms in the ring, characterized in that a benzo-1, 3-dioxane derivative of the formula II II 2
in which R fluorine, chlorine, bromine, iodine a formyl vein acetyl 3 4
group and R "^ and R are identical or different and are straight-chain or branched lower alkyl with 1 to 4 carbon atoms 3 ^
or R ^ and R together are a methylene chain - (CH ₂ ) -, where η is an integer from 3 to 5, in an epoxide of the formula III in 3 j | . in which R and R have the meanings given, converts and this with an amine of the formula H _? NR, in which R has the meaning given, is reacted and the reaction product is then hydrolyzed to the compound of the formula I. 409837/1010 - 24 - - 24 - O.Z. 29 744 2310U1 Process according to Claim 1, characterized in that compounds are prepared in which R is an i-propyl, 2- or 3-butyl radical which is replaced by methyl, phenyl, hydroxy, methoxy, methyl mercapto, Dimethylamino or cyano groups can be substituted, produces. 5. The method according to claim 1, characterized in _{that M} that compounds are prepared in which R is a cycloaliphatic radical with 3 to 6 carbon atoms in the ring, which can be substituted on the nitrogen atom ^ -content carbon atom with a lower alkyl radical, manufactures. 4. The method according to claim 1, characterized in that compounds are prepared in which R is a lower alkyl radical with a cycloaliphatic radical having 3 to 6 carbon atoms in the ring on the nitrogen atom (X-carbon atom means, produces. 5. The method according to claim 1, characterized in that compounds in which R is an n-propyl or n-hexyl radical which can be substituted by methyl and / or dimethylaraino groups is prepared. 6. Compounds of formula I in which R denotes 2-methylbutyl-2-, l-hydroxybutyl-2-, l-hydroxybutyl-3-, l-methoxybutyl-3- or l, l-Diphenylbutyl-3-radical means. 7. Compounds of formula I in which R denotes the l-methoxy-2-methylpropyl-2-, l-methylmercapto-2-methyl-propyl-2-, 2-cyanopropyl-2-, l-dimethylaminopropyl-3-, l-dimethylamino-2,2-dimethylpropyl-3- or is l-dimethylaminohexyl-6-radical. 8. Compounds of formula I in which R denotes cyclopropyl, Cyclobutyl, 1-methyl-cyclopropyl-1 or 1-methyl-cyclopentyl-1 radical means. - 25 409837/1010 - 25 - O.Z. 29 744 9. Compound of the formula I in which R is the 1-cyclopropyl-ethyl radical means. Badische Anilin- & Soda-Fabrik AG J) 409837/1010