LU83751A1 - NEW METHOD FOR PRODUCING CYCLOALIPHATIC KETO AND HYDROXYAMINES - Google Patents

Description

- 4 - 80 256 PH

11/12/1980 1 Degussa Aktiengesellschaft

Weißfrauenstraße 9, 6000 Frankfurt / Main 5 New process for the production of cycloaliphatic,

Keto and Hydroxyamines 10 Description:

DE-OS 29 19 495 describes various processes for the preparation of compounds of the general formula 15 R3 e1-x-ch-ch2-nh-ch (ch3) -ch (oh) - (/ «2 \ = / where X is the Group CO or CH (OH), R2 is hydrogen or a C ^ -Cg-alkyl group and R3 is hydrogen or a hydroxy group and means the adamantyl radical or a saturated or monounsaturated C3 ~ c-jg "cycloalkyl radical, this C ^ -C ^ g-Cyclo-2 ^ alkyl radical can also be substituted by a C ^ -C ^ alkyl group or a s halogen atom and their salts are known.The most important of these processes is that an amine of the general formula 30 / T ~ i

H ^ N-CH (CH3) -CH (OH) U

wherein R3 has the meanings given with a 35 - 5 - j compound of the general formula

R ^ -X-C = E

«2 '5.

implemented, where X and R2 have the meanings given and E is a methylene group or a hydrogen atom and the group -CH2-NRaRb and R & and R ^ are low molecular weight alkyl radicals which can also be closed to form a ring or wherein E also means two hydrogen atoms can, if X is the CO group and is carried out in the presence of formaldehyde or a formaldehyde-supplying substance and, if necessary, reduces an isolated double bond and / or a CO group in the compounds obtained.

The other processes specified in DE-OS 29 19 495 are more complicated and are practically out of the question for industrial production.

20th

The process according to the invention represents a new route for the preparation of compounds of the formula I; for example, it provides better yields and is easier to carry out.

25th

In formula I, R2 is preferably a C 1-4 alkyl group, in particular methyl or ethyl. The saturated or unsaturated C 1-6 cycloalkyl radical preferably consists of 3 to 12 carbon atoms, in particular 3 to 3Q 8 carbon atoms If this cycloalkyl radical is substituted, then it is preferably one or two identical or different substituents such as methyl, ethyl, chlorine, bromine and / or fluorine.

The process according to the invention is carried out, for example, by reacting 1 mole of a compound of the formula II with 2-3 moles, in particular 2.3-2.5 moles, of a 6-1 ketone of the formula R ^ -CO-CR2H2 Acid in a solvent at temperatures between 20 to 150 ° C.

5 The process is generally carried out in an inert solvent or suspension medium at temperatures between 5 and 250 ° C., preferably 20 and 150 ° C., in particular between 40 ° C. and 90 ° C. Examples of suitable solvents are ^ 0 lower aliphatic alcohols (ethanol, methanol, isopropanol, propanol), saturated alicyclic and cyclic ethers (dioxane, tetrahydrofuran, diethyl ether), lower aliphatic ketones (acetone), lower aliphatic hydrocarbons or halocarbons Hydrogen (chloroform, 1,2-dichloroethane), aromatic hydrocarbons (benzene, xylene, toluene), glacial acetic acid,

Water or mixtures of these agents).

The reaction solution must be made acidic in any case, preferably by mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid. However, organic acids and acidic ion exchangers can also be used for this. Examples of suitable organic acids are: Saturated and monounsaturated C.-C.-aliphatic 25 14

Mono- and dicarboxylic acids such as formic acid, acetic acid,

Propionic acid, oxalic acid, maleic acid, fumaric acid? aromatic carboxylic acids such as benzoic acid, C ^ -C ^ alkylbenzoic acids or aliphatic or aromatic sulfonic acids such as methanesulfonic acid, ethane-30 sulfonic acid, benzenesulfonic acid, toluenesulfonic acid (for example p-toluenesulfonic acid). Mixtures of these acids can also be used. Examples of suitable acidic ion exchangers are those which are described in the book by K. Dorfner, Ion Exchanger, Verlag De. Gruyter, 3rd edition, 1970, in volume 1 of the work 1 · · - 7 - 1 ion exchanger by E. Helfferich, Verlag Chemie, 1959 or in Römpps Chemie Lexikon Volume 3, pages 1616 - 1618 (1976). Specifically, these are, for example, organic ion exchangers 5 whose active, that is, ion-forming group, the «

Carboxyl group or an organic acidic group such as the sulfonic acid group (S03H) or phosphoric acid group, while the high molecular structure (matrix) made of a synthetic resin (acrylic resin, polystyrene resin, 10 styrene-divinylbenzene copolymer, styrene-acrylic acid)

Copolymer, divinylbenzene polymer, vinylbenzene polymer, condensation products of phenol and formaldehyde). Also considered are: acidic cellulose, starch and dextran ion exchangers, 15 carbon ion exchangers (from sulfonated high molecular weight t

Humus coal) and acidic inorganic ion exchangers such as zeolites and aluminum silicates.

The pH of the reaction solution or the reaction mixture should be between 1-6, preferably 20 2-3.

The starting materials of formula II can be obtained, for example, by using a phenylethylamine of the general formula R, OH CH, 25 1 1

^ \\ - CH - CH - NH2 IV

with formaldehyde, which can also be used in the form of a conventional formaldehyde-producing substance. This reaction takes place in a solvent or suspending agent at temperatures between 20 and 180 ° C., in particular between 30 ° C. and 150 ° C. The possible solvents or suspending agents are: water, lower saturated 35 aliphatic C 1 -C 6 -alcohols, lower aliphatic saturated ethers with alkyl residues from 1 - 5'C atoms, • · · y - 8 - Ί aromatic hydrocarbons such as benzene, methylbenzenes (toluene), dimethylbenzenes (xylene). In general, one works at the boiling point of the solvent used. The water 5 formed in the reaction can be added, for example, by adding drying agents, such as sodium sulfate, potassium carbonate, potassium chloride,

Molecular sieves (for example Type 4A) or by azeotropic distillation (for example when using aromatic hydrocarbons as solvents) can be removed.

The process must be carried out with the exclusion of acids, since the process products are acid-labile.

In general, 1.5 - 5 moles of formaldehyde are used per 1 mole of phenylethylamine '^ of formula IV. It is preferred to use 3 moles of formaldehyde or the equivalent of a formaldehyde-supplying substance per 2 moles of phenylethylamine of the formula IV

Polyformaldehyde, paraformaldehyde. When using formaldehyde-supplying substances in which the

Formaldeyhd is released in the acidic medium, the formaldehyde release should precede the actual reaction and excess acid should be carefully neutralized so that the desired dimeric oxazolidines are not exposed to the acidic environment.

For example, the N, N'-methylene-bis- (4-methyl-5-phenyl-oxazolidine) can be obtained as follows: 30 400 g (2.6 mol) · £ -norephedrine base are dissolved in 800 ml of water in the Dissolved heat and 330 g of 35% aqueous formalin solution added dropwise. The reaction mixture is heated in a boiling water bath for 4 hours.

Then it is repeatedly hydrogenated with methylene chloride extra-35 · · · - 9 - 1, dried with 1 ^ CO ^ and the solvent removed in vacuo. The solid residue is recrystallized from diisopropyl ether.

Yield: 423 g (94.5%) 5 f .: 98-99 ° C.

f

This compound can also be prepared in the following modified manner: 10 g (0.066 mol) of 16-norephedrine base, 4 g (0.132 mol) of IQ paraformaldehyde, 6.6 g of sodium sulfate anhydrous, are suspended in 100 ml of dried xylene and with stirring Heated under reflux for 5 hours.

The inorganic constituents are filtered off, the solvent is concentrated in vacuo and the solid crude product is recrystallized from diisopropyl ether.

Yield; 6.1, g - 55% F .: 98 - 99 ° C.

, 10 g (0.066 mol) ^ - norephedrine base, 4 g (0.132 mol) 20 paraformaldehyde, are suspended in 150 ml xylene and heated in a water separator for 5 hours under reflux. The solvent is concentrated in vacuo and the solid residue is recrystallized from diisopropyl ether.

25 Yield: 7.6 g = 68% F .: 100 ° C.

• · · 3 ° 35 -ιοί starting materials of formula II, wherein R3 represents a hydroxy group, may contain a conventional protective group which is split off after the reaction. These are, in particular, residues which can easily be split off by hydrolysis in a non-acidic medium and which may already be split off during the reaction. If such protective groups are not split off in the process reaction, they are split off after the reaction. The starting compounds frequently already contain protective groups of this type due to their preparation.

These protecting groups are, for example, easily solvolytically cleavable acyl groups. The solvolytically cleaving protecting groups are formed, for example, by saponification using basic substances (potash, soda, aqueous alkali solutions, alcoholic alkali solutions, aqueous NH3) at temperatures between 10 and 150 ° C., in particular 20 ° C. '100 ° C, split off. Examples of solvents or suspending agents for this are in

Consider: water, lower aliphatic alcohols, cyclic ethers such as dioxane or tetrahydrofuran, aliphatic ethers, dimethylformamide and so on, and mixtures of these agents.

25 Examples of hydrolytically removable radicals are: ‘trifluoroacetyl radical, phthalyl radical, trityl radical, p-toluenesulfonyl radical and similar and lower alkanoyl radicals such as acetyl radical, formyl radical, tert.-butyloxicarbonyl radical and the like. The carbalkoxy group (for example of low molecular weight) can also be used. 1 35 · · - 11 - 1 The subsequent reaction, if any

Reduction of the keto group of compounds in which X is the group ^ CO to compounds in which X is the group ^ CHOH, and the reduction of a double bond 5 of the radical R, j is generally carried out by catalytic

Performed hydrogenation. Examples of suitable catalysts are the customary finely divided metal catalysts, such as noble metal catalysts, for example Raney nickel, platinum or, in particular, palladium. The process can be carried out at normal temperatures or elevated temperatures. It is expedient to work in a temperature range from about 40 to 200 ° C., if appropriate under increased pressure (1-100, in particular 1-50 bar). If the 15 phenolic hydroxyl group contains the benzyl protecting group, this is split off simultaneously in the catalytic hydrogenation if, for example, a palladium catalyst is used.

20 Reduction of the keto group is, however, to others

Also possible, for example using complex metal hydrides (e.g. lithium aluminum hydride, sodium borohydride, cyanoborohydride, lithium tri-tert-butoxy aluminum hydride) or using 25 aluminum alcoholates according to Meerwein and Ponndorf (for

Example using aluminum isopropylate) at temperatures between 0-150 ° C., in particular 20-100 ° C. As a solvent or suspending agent for these

Reaction can be considered, for example: lower 30 aliphatic alcohols, dioxane, tetrahydrofuran, water or aromatic hydrocarbons such as benzene, toluene and mixtures of these agents.

A selective reduction of a double bond of the R ^ radical is possible, for example, under mild conditions by hydrogenation in the presence of noble metal catalysts (Pd, Pt) or Raney nickel.

The starting amine of formula IV used can belong to the diastereomeric series of ephedrine (erythro series) 5 or pseudoephedrine. Both the pure enantiomers and the corresponding racemates can be used. Accordingly, bis-oxazolidines of the formula II are obtained, which belong to either the Erythro series or the Threo series.

10 The bis-oxazolidines of the two series differ in the position of the CH ^ group and the phenyl ring. The position of the two substituents is shown in the two stereotypes below: ’” Ô Ô I »\ £“ 1 '.

i> '! erythro thre0 (pseudo) -j 25

Depending on whether one starts from corresponding pure enantiomers or racemates of the starting materials IV, the bis-oxazolidines of the formula II are also obtained in the form of the pure enantiomers or the racemates. When the bis-oxazolidines are cleaved under acidic conditions, the centers of asymmetry are not touched, so that this takes place while maintaining the respective configuration.

Those process products of formula I and also 35 the starting bis-oxazolidines of formula II, which as

Racemates obtained can be split into the optically active isomers in a manner known per se, for example by means of an optically active acid under mild conditions at low temperatures.

It is of course also possible to use optically active or diastereomeric starting materials from the outset, in which case a corresponding purely optically active form or diastereomeric configuration is obtained as end product I. For example, these are compounds of the norephedrine 10 configuration (erythro series) and the pseudonorephedrine configuration (threo series). Diastereomeric racemates can also occur because two or more asymmetric carbon atoms are present in the compounds produced. Separation is possible in the usual way,> 15 for example by recrystallization.

Depending on the process conditions and starting materials, the end products of the formula I are obtained in free form or in the form of their salts. The salts of the end products 20 can be converted back into the bases in a manner known per se, for example with alkali or ion exchangers. From the latter, salts can be obtained by reaction with organic or inorganic acids, in particular those which are suitable for the formation of salts which can be used therapeutically. Examples of such acids are: hydrohalic acids, sulfuric acid,

Phosphoric acids, nitric acid, perchloric acid, organic mono-, di- or tricarboxylic acids of the aliphatic, alicyclic, aromatic or heterocyclic series as well as sulfonic acids. Examples include: ant, vinegar, propion, amber, glycol, milk, apple, wine, lemon, ascorbic, maleic,

Fumaric, hydroxymaleic or benztraubic acid; Phenyl-35 acetic, benzoic, p-amino-benzoic, anthranil, p-hydroxy-benzoic, salicyl or p-amino-salicylic acid, 1 · · - 14 - 1 embonic acid, methanesulfonic, ethanesulfonic, Hydroxy ethanesulfonic, ethylenesulfonic acid? Halogenobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acid or sulfanilic acid or 8-chloro-theophylline.

5 10 15 20 25 • 30 35 * - 15 - 1 Example 1

The reaction mixture of 16.92 g (0.05 mol) £ -N, N'-5 methylene-bis- (4-methyl-5-phenyl-oxazolidine) (made from -f-norephedrine), 15.14 g (0.12 mol) acetyl-cyclohexane, 35 ml of isopropanol and 19 ml of 5.1N iso-propanolic hydrochloric acid is heated with stirring and reflux for 6 hours. The reaction mixture is left overnight at room temperature. The product crystallized out is filtered off with suction and washed with 5 ml of isopropanol and 20 ml of acetone. For example, 32.58 g (67% of theory) - £ - / 3-hydroxy-3-phenyl-propyl- (2 | 7- / 3-cyclohexyl-3-oxo-propyl7-amine-hydro- * T5 chloride) are obtained .

F .: 219 - 221 ° C.

\ 20 25 * .30 35

Claims (4)

1. Process for the preparation of compounds of the «general formula / PX'H R. -X-CH-CH 0-NH-CH (CH-,) -CH (OH) - // ✓Λ) I 20 I \ = / R2 where X is the group> CO or> CH (OH), R2 is hydrogen or a C ^ -Cg alkyl group and R ^ is hydrogen or a hydroxy group and R ^ is the adamantyl radical or one means saturated or monounsaturated C ^ -C ^ g cycloalkyl radical, where this C ^ -C ^ g cycloalkyl radical can also be substituted by a C ^ -C4 alkyl group or a halogenator and their acid addition salts, characterized in that a Ν , Ν'-methylene-bis-oxazolidine of the formula II 35 • · · «'à? · R> ß CH-CH CH-CH ^ 15 41 14 51 5 O 1 3 N - CH0 - N 3 1 Ο II \ 2/2 \ 2 / CH2 CH2 'where Rg has the meanings given with a ketone of the formula III Ä' R. - CO - CH0 III = 1 I 2 * 2 15 wherein R ^ and R2 have the meanings given above in the presence of an acid or acidic ion 2q from the exchanger and, if appropriate, in the compounds of the formula I, wherein R ^ contains a double bond and / or X denotes the CO group , optionally this double bond and / or this> CO group is reduced. H 25 "* t 2. The method according to claim 1, characterized in that compounds of formula I are prepared, 2Q wherein R2 and Rg are hydrogen and is a saturated or monounsaturated Cg-Cg-cycloalkyl radical. 35 ... - 3 - 3. The method according to one or more of the preceding claims, characterized in that one leads the process products in the salts over-5. 4. The method according to one or more of the preceding claims, 10 characterized in that the starting compounds contain protective groups and these protective groups are split off during or after = the process reaction. 15 v b • · · 20 # 25 ► 30 35