NZ216242A - Oxazole derivatives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £16242 2lfc24a Under the provrsions cf Regulation 23 (I) the Coyy\f i Specification has been ante-date<ij to - I9J3-I j initials N.Z.No.

NEW ZEALAND Patents Act, 1953 COMPLETE SPECIFICATION "Compounds" We, HOECHST AKTIENGESELLSCHAFT, a corporation organized under the laws of the Federal Republic of Germany, of D-6230 Frankfurt/ Main 80. Federal Republic of Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: - Priority Date(s): 9_*9L Complete Specification Filed: 77.

Class: ..., k.o.iD.z&y^ Publication Date: ?. P. P.9T.!???.

P.O. Journal, No: . -J3o.).

This invention relates to compounds which are intermediates in a process for inverting the configuration of compounds of the formula I OH I A - 0 - CH2 - CH - CH2 - NHR (I) * in which A represents 2-cyclopentyl-phenyl and R represents t-butyl. ■ " New Zea 1 ? n n" The process is described and claimed in I Patent specification No. 205115, the contents of which are incorporated by reference. Broadly, the present invention provides a compound of the formula III H I /c\ ® °\ /N R © A-0-CH2~CH-CH2 x (III) * in which A and R have the meanings defined above and in which represents the anion of a strong acid or of a ha logen atomk 216242 New Zealand inter alia (patent Specification No. 205115 relates Ito a process for inverting the configuration at the optically active carbon (*) in compounds of the formula I OH I A - O - CH7 - CH - CH~ - NHR (I) *■ * ^ in which A represents 2-cylopentyl-phenyl and R represents t-butyl which comprises converting these compounds by formylation into optically active compounds of the formula II A - O - CH~ - OH I CH O = C - H CK2 -*• N - R (II) in which A and R have the neanings defined above, while maintaining the configuration at the carbon atom (*), converting these compounds, by treatment with a strong acid 15 or an acid halide, into optically active cyclic compounds of the formula III iO\l H I .C; X \ 0 A-O-CH 2 ~ CH-C H £ „© (III) in which A and R have the meanings defined above and in 216242 which represents the anion of a strong acid or of a halogen atom, and converting these oxazolinium derivatives (III), by acid or alkaline hydrolysis, into optically active compounds of the formula IV OH I A-0-CH2-CH-CH2-NH-R (IV) * in which A and R have the meanings defined above, possessing the same structure as the starting material I, but having an opposite configuration at the carbon atom (*) , and, if desired, converting a free compound of the formula I into a salt or converting a resulting salt into the free compound.

The inversion of configuration according to the invention relates to the secondary alcohol group which is present in the group OH I -O - CH2 - CH - CH2 - NH - R * and which contains a chirality center and can therefore exist either in the S-configuration or in the R-configura-t i o n.

Accordingly, a (2S)-3-amino-2-propanol of the formula I is converted by the process according to the invention into the corresponding (2R)-3-amino-2-propanol, or a (2R)-3-amino-2-propano I of the formula I is converted into the corresponding (2S)-3-amino-2-propanol. If no further chirality center is present in a compound of the 216242 formula X/ this inversion of configuration effects an Inversion in the direction of optical rotation.

The above radicals A is 2-cyclopentyl-phenyl 216242 R is the tert.-butyl radical, A process for inverting the configuration of optically active compounds is known > In this process an optically active ccnpound is converted into the corresponding N-acyl derivative of the formula V.

OH 0=C-R' A-O-CH2-CH-CH2- NR (V) In this process R' is a monocyclic or pcrylcyclic, carbocyclic or heterocyclic radical or an optically substituted aliphatic, cycloali-phatic or araliphatic hydrocarbon radical.

IVie N-acyl derivative (V) is cyclized to give the corresponding oocazolinium salt of the formula VI ■\ ^ pounds of the formula 11, which can then be cyclized to 216242 - 7 -R' I °\ /N © (vl> A-0-CH2-CH-CH2 Xw * which is then hydrolyzed to give an optically active compound having the same structure, but the opposite configuration to that of the starting material.

In attempts to apply this process to the convei— sion of 1-aryloxy-3-tert.-butylamino-2-propano Is, it has now been found that, using known acylating agents, such as, for example, acetic acid, acetic anhydride, ethyl acetate or acetyl chloride, 1-aryloxy-3-tert.-butylamino-2-10 proponols of this type (R = tert.-butyl) can only be converted into compounds of the formula (V) (R1 = CHj) in yields of less than 5%, even if reacted for several days. Hence it was no longer possible either to prepare the cyclic intermediate products (VI) (R' = CH3) which are 15 required for inverting the configuration, in satisfactory yields; a useful inversion of configuration could not be achieved in this way. the/ It has now been found, surprisingly, t hat\l-ary l-oxy-3-tert.-buty lamino-2-propanoI of this type, of the 20 formula I, can be converted in good yields in accordance with methods which are in themselves known by means of 'formylating agents into the corresponding N-formyl com- of a strong acid or by means of an acid halio'e, at tempera- 216242 tures from -20°C to ♦ 150°C, preferably at 0 to 50°C.

These salts are hydrolyzed in an acid or basic medium/ if appropriate via the stage of the inverted N-formyl compound, to give an optically active 1-aryloxy-3-tert.-butylamino-2-propanol of the formula (IV) having the .same structure but the opposite configuration to that of the starting material of the formula I.

A further advantage of the new process is the use of formic acid or derivatives thereof as the reagent for the prepsration of the intermediate products, since formic acid and its derivatives are readily available and (on a 20 quantity basis) are generally cheaper than the homologous carboxylic acids and corresponding derivatives thereof.

Examples of suitable formylating agents are formic acid or derivatives thereof (for example the mixed anhydride formed from formic acid and acetic anhydride, phenyl formate //% ^\\ V 251u methyl formate, ethyl formate and butyl formate). Instead 2.7AUGV874 jj of the pure formic acid esters, it is also possible to prepare the latter in situ by azeotropic es t e r i f i c a t i on 216242 - 9 ~ and to employ them without further purification for for** mylating the amino-2-propanols of the formula I.

Suitable cyclizlng reagents arc strong, oxygen-containing inorganic or organic acids, such as, for example, concentrated sulfuric acid or phosphoric acid or a strong organic sulfonic acid, for instance an aliphatic sulfonic acid, for example methanesuIfonic acid, or en aromatic sulfonic acid, such as an optionally substituted phenyIsulfonic acid or halides thereof, primarily the chlorides or bromides, such as thionyl chloride, thionyl bromide, sulfuryl chloride, chlorosulfonic acid, phosphorus trichloride, phosphorus pentachloride, phosphorus oxy-chloride or methanesulfonyI chloride. Furthermore, it is also possible to use mixed esters corresponding to the 15 said halides, such as, for instance, a lower alkoxysul- fonyl halide or phosphorus acid lower alkyl ester-haIides. The cyclization is carried out either in the melt or in a suitable inert solvent (for example methylene chloride or toluene).

If acids are used, a temperature range from 50° to 150°C is preferred, while if an acid chloride is used it is preferable to carry out the reaction at -20° to 80°C.

The hydrolysis is carried out in an acid or basic medium. Acid agents suitable for the hydrolysis are aqueous acids, for instance aqueous mineral acids, for example aqueous hydrochloric acid, sulfuric acid or phosphoric acid. The acid hydrolysis is carried out within a temperature range from 0° to +120°C, advantageously at -10. 216242 410 to 450°C. Examples of suitable basic media are aqueous alkaline solutions, for Instance those of the alkali or alkaline earth metals, such as sodium hydroxide or potassium hydroxide or the hydroxides of calcium or magnesium, and it is advantageous to employ the said reagents at an elevated temperature, for instance within a range from 50 to 150°C. The hydrolysis can be carried out in a homogeneous phase as well as in a multi-phase system.

The process according to the invention can also be carried out without isolating the intermediate product of the formula II, which is then processed further in the same reaction mixture to give the compound of the formula III, and the resulting compound of the formula III is subjected to hydrolysis without further purification.

The invention relates to optically active compounds of the formula III in which A, R and have the above meanings or to such compounds in the form of free bases.

Preferred compounds of the formula III are those in whi ch ^represents an anion of sulfuric acid, phosphoric acid or a strong organic sulfonic acid, such as p-to luenesu Ifonic acid or benzenesu Ifonic acid, or a chloride or bromide.

CXsing to their pharmacological properties the ccnpounds of formula IV can be used as medicaments.

The examples vfaich follow serve to illustrate the invention without limiting it to the compounds mentioned as representatives: 216242 - ii - Example 1: The inversion of (4)-1-(2-cyclopentylphenoxy)-3-tert.-butylami no-2-propanol a) (♦)-1-(2-Cyclopentylphenoxy)-3-N-tert.~butyl-N-for»nyl-ami no-2-propanol A solution in 60 g of methyl formate of 29.1 g of 1-(2-cyclopentylphenoxy)-3-tert.-butylamino-2-propanol (81% (+)-configuration and 19% (-)-configuration, [**-1)20 + D .0° (5% strength in isopropanol)> is heated under reflux for 48 hours. The crude (+)-1-C2-cyclopentyIphen- oxy)-3-N-tert,-butyl-N-formyI amino-2-propanoI is obtained after evaporating the solution in vacuo. This compound can be rec rysta I li zed from n-hexane (C^^O + 11.0°).

D b) 1-t er t .-But y 1-4- (2-cyclopcnt>'lphenoxyrr,cthyl)-oxszclin-ium chloride.

The crude (+)-1-(2-cyclopentylphenoxy)-3-N-tert.-butyl-N-forir.ylamino-2-propanol is dissolved in 50 ml of toluene. 7.5 ml of thionyl chloride are added dropwise to this solution, while cooling with ice, at such a rate that the temperature does not exceed 20°C. Stirring is continued for 15 minutes, and the crude 1-tert.-buty1-3-(2-cycIo-pentylphenoxymethyl)-oxazo li ni urn chloride is Obtained after evaporating the solution in vacuo.

The crude oxazolinium salt can be recrysta 11 ized from toluene ([cO20 ♦ 8.2°). c) (-)-1-(2-Cyclopentylphenoxy)-3-tert.-butylamino-2-propanoI The crude 1-tert.-butyl-4-(2-cyclopentylphenoxy-methyI)-oxazolinium chloride is dissolved in 60 ml of iso- "2116242 propenol, 400 nl of 4N sodium hydroxide solution are added and the mixture 1s boiled under reflux for 3 hrs. while stirring vigorously. After cooling to room temperature, the organic phase is separated off.

It contains 27.0 g of 1-(2-cyclopentylphenoxy)-3- tert.-butylamino-2-propanol (67% (-)-configuration and 33% (+)-configuration, = -5.5° (measured in a 5% strength solution of isopropanol; content of base determined titri-metrically using hydrochloric acid)). This corresponds to 10 an optical yield of 55%. The isopropanol solution is filtered and 12.2 g of D-(-)-mandelie acid are added to the filtrate, whereupon (-)-1-(2-cyclopentylphenoxy)-3-tert.-butylamino-2-propanol D-(-)-mandelate is precipitated, which is purified by recrystallization from 50 ml of iso-15 propanol.

Yield: 22.0 g (D^D*0 = -52.4° (1% strength solution in isopropanol)), = 61.3% of the (+)-base present in the starting material and 74.1% of the (-)-base present in the saponification solution.

Example 2: The inversion of (4)-1-(2-cyclopentylphenoxy)-3-tert butylamino-2-propanol. a) (4)-1-(2-Cyclopentylphenoxy)-3-N-tert.-butyl-N-formyl-amino-2-propanol. 291 .0 g of 1 - (2-cy.c lopenty Iphenoxy)-3-t e rt ,-buty l- amino-2-propanol (81% (+)-configuration and 19% (-^con-figuration, 0*320 - + 10.0° (5% strength in isopropanol)) " 4jUNI987£l) and 306 g of butyl formate are heated at reflux temperature Vor ^ ^ours• he crude ( + )-1 - (2-cyclopentyIphenoxy)-3-N- '216242 tert.-butylamino-N-formylamino-2-propanol 1s obtained after evaporating the reaction mixture in vacuo. b> 1-tert.-Butyl-4-(2-cyclopentyIphenoxymet hyt)-oxazoli niubi chlori de.

The crude ( + )-1-(2-cyc lopentylphenoxy)-3-N-tert butyl-N-formylamino-2-propanol is dissolved in 240 ml of toluene. 95 ml of thionyl chloride are added, while cooling, to this solution at such a rate that the temperature does not exceed 40°C. Stirring is continued for 2 hours 10 at this temperature. c) (-)-1-(2-Cyclopentylphenoxy)-3-tert.-butylamino-2-propanoI The solution in toluene of the crude 1-1ert.-butyl- 4-(2-cycI opentyIphenoxymethyI)-oxazoIinium chloride is sub- jected to acid hydrolysis by adding this solution dropwise to 100 ml of water at such a rate that the temperature does not exceed 60°C. Stirring is continued for 2 hours at 60°C and 800 ml of 18% strength sodium hydroxide solution are then added. The toluene phase is separated off, washed with 100 ml of water end filtered; it contains 280.2 g of (-)-1-(2-cyclopentyIphenoxy)-3-tert.-butyl- ami no-2-propanoI (titrated with hydrochloric acid). [e*}20 . _ 8.2° (5% strength in isopropanol; 76% (-)-D configuration and 24% (+)-configuration) Optical yield: 82%.

^ Further purification is effected via the diastereo- ,V% :r>A meric salt with D- (-)-mande lie acid, as described in Example 'o'j 1 c) . 216242 Example 3 The Inversion of (•»?-1-(2»cyclopentylpbenoxy)»3-tert.-butylami no-2-propanol. a) (+)-1-(2-CyclopentyIphenoxy)-3-N-tert,-butyl-N-formyl-ami no-2-propanol A mixture of 110 g of 85% strength formic acid, 148 g of n-butanol and 35 g of toluene is heated under a water separator. After 2 hrs. 50 ml of water (containing 11% of formic acid) have been separated off and a clear distillate runs off. 291 g of 1-(2-cyclopentyIphenoxy)-3-tert.-butylamino-2-propanol (81% (+)-configuration and 19% (-)-configuration, + 10.0° (5% strength in isopropanol)) are added to the solution, and the mixture is heated under reflux for 16 hours. The solven t s (butyl, formate, butanol and toluene) are removed, first under normal pressure and then in vacuo; crude ( + )-1-(2-cyc lopenty Iphenoxy)-3-N-tert.-butyl-N-f ormyIamino-2-propanoI is obtained.

The mixture of solvents which has been removed can be re-used for further similar reactions after replenishing the formic acid.

Further working up is carried out as described in Example 2 b) and 2 c). The toluene solution contains 271.2 g of (-)-1 -(2-cyclopentyIphenoxy)-3-tert.-butylamino-2-propanoI (titrated with hydrochloric acid).

C*020 . -7.2° (5% strength in isopropanol; 73% (-)-configuration and 27% (+)-configuration). Opt icalyield:72% 216242 Example A: The Inversion of (+>-1-(2-cyclopentylphcnoxy)-3-tert.-butylami no-2-propanol a) (+)-1 -(2-Cyclopentylphenoxy)-3-N-tert.-butyl-N-formyl-5 amino-2-propanol 145.5 g of 1-(2-cyc lopentylphenoxy)-3-tert,-butyl-amino-2-propanoI (81% (+)-configuration and 19% (-)-con-figuration, = 10.0° (5% strength in isopropanol)) are dissolved in 172 ml of toluene, and 54.1 g of 85% 10 strength formic acid are added dropwise at room temperature. The mixture is heated for approx. 7 hours under a water separator, in which time 31 g of water (containing approx. 60% of formic acid) are separated off. After removing the solvent end excess formic acid by vacuum dis-15 filiation, the crude (+)-1-(2-cyclopentyIphenoxy)-3-N- tert.-butyl-N-formylanino-2-propanoI is left as the residue. b) 1-tert.-Butyl-4-(2-cyclopentylphenoxymethyl)-oxazolinium chloride 37.5 ml of thionyl chloride are added dropwise, while cooling, to a solution of the crude (+)-1-(2-cyclopentylphenoxy)-3-N-tert.-butyl-N-formylami no-2-propanol in 150 ml of toluene at such a rate that the temperature does not exceed A0°C. Stirring is then continued for 2 hours at this temperature. c) (-)-1-(2-Cyclopentylphenoxy)-3-tert.-butylamino-2-propanoI The solution in toluene of the crude 1-tert.-butyl-3-(2-cyclopentyIphenoxymethyl)-oxazolinium chloride is added dropwise, while stirring, to 50 ml of water at such a rate AT* ri W987?li H' 'f I p 2T6242 - xe - that the tenperature does not exceed 60°C. The solution is stirred tor a further 2 hours at 60°C, and 375 ml of 18* strength sodium hydroxide solution are then added. The organic phase is separated off, washed with 50 inL of water 5 and filtered; it contains 130.9 g of (-)-1-(2-cyclopentyl-phenoxy)-3-tert.-butylamino-2-propanol (titrated with hydrochloric acid). : -5.7° (5% strength in isopropanol; 68% (-)- D configuration and 32% (+)-configuration) 10 Optical yield: 57%.

Further purification is effected via the diastereo-meric salt with D-(-)-mande lic acid, as described in Example 1 c) .

Example 5 The inversion of (-*) 3-{4-/3- (3.4-dimethoxyphenylethyl- amino)-2-hydroxy-propoxy_/phenyl^crotonic acid nitrile a) ( + ) 3-{4-jf3-(3.4-dimethoxyphenylethyl-N-formylamino)-2-hydroxy-propoxjr/phenyljcrotonic acid nitrile 300 g of (+)-^4-/3-(3.4-dimethoxyphenylethylamino)-2-20 hydroxypropoxy/phenylj crotonic acid nitrile(/<7^ - 4 9/2* /5 % strength in methanol?, 98 % (+)-configuration and 2 % (-)-configuration) are dissolved in 2 1 of toluene and 84.2 g of 100 % strength formic acid are added dropwise at 60°C. The mixture is heated for 3 hours under a water 25 separator in which time.4 0 g of water (containing about 70 % of formic acid) are separated off. After removing the solvent and excess of formic acid by distillation the crude 218242 4JUNM7 i v (♦) 3-^4-/3- (3.4-dimethoxyphenylethyl-N-formylamino) -2-hydroxy-propox^/phenyl^crotonic acid nitrile is left as the residue. b) 5-/*/4- (2-cyano-1-methylethylenyl)phenox^ methyl7-3-(3.4-dimethoxypheny1)ethyl-2-oxazolinium chloride The crude (+) 3-{4-/3-(3.4-dimethoxyphenylethyl-N-formylamino)-2-hydroxy-propoxy7phenyl}crotonic acid ni-t-r-il-e is dissolved in 700 ml of chloroform and 72,6 ml of thionylchloride are added dropwise at such a rate that the temperature does not exceed 40°C. Stirring is then continued for 2 hours at 40°C. c) (-)3-/4-/3-(3,4-dimethoxyphenylethylamino)-2-hydroxy-propoxy7~pheny^crotonic acid nitrile The solution of the crude (2-cyano-1-methy1- ethylenyl)phenoxyjmethyl7-3- (3.4-dimethoxypheny1)ethyl-2-oxazolinium chloride in chloroform is subjected to acid hydrolysis by adding to this solution 75 ml of water at such a rate that the temperature does not exceed 60°C. Stirring is continued for 2 hours at 60°C and 300 ml of 5 N sodium hydroxide solution are then added. The chloroform phase is separated off and washed once more with 200 ml of water, dried and the solvent is distilled off in vacuo. The residue is dissolved in 1.4 1 of isopropanol by heating under reflux. Thereafter the solution is cooled to 0.°C for 6 hours. The precipitated (-)3—^4-/3-(3.4-dimethoxyphenylethylamino)-2-hydroxy-propoxy/phenyljcrotonic acid nitrile is filtered off with suction and dried in vacuo. , • 218242 - 18 ~ Yield: 261 g (chemical yield: 87 %> fit-8,7*/5 * . strength in methanol/; 95 % (-)-configuration and 5 % (♦)-configuration). Optical yield: 94 %.

The solid substance is dissolved in 1,7 1 of acetone, 260 g of (-)-dibenzoyl-tartaric acid are added and the vhole is heated under reflux for 0.5 hours. After cooling for 12 hours at 0°C 10.4 g of (+) 3-/4/3-(3.4-dimethoxyphenylethylamino) -2hydroxypropoxy/phenyl2crotonic acid nitrile-dibenzcyltartrate precipitates. The precipitate is filtered off. Dry HCl-gas is introduced into the acetonic solution while cooling at 0°C until a pH-value of 1 is reached. Stirring is continued for 0.5 hours, the precipitate is filtered off with suction and washed with 300 ml of cold acetone. The precipitated (-) 3-f4-/3-(3.4-dimethoxyphenylethylamino)-2-hydroxypropoxy7phenyl^-crotonic acid nitrile-hydrochloride is purified by re-crystallization from 1 1 of ethanol.

Yield: 200.8 g = -14.1° [b % strength in methar.olj corresponding to 98 % (-)-configuration and 2 % (+)-con- figuration =61 % of the (+)-base present in the starting «/* material and = 70.5 % of the (-)-base present in the saponification solution.

Example 6: The inversion of ( + ) 3-^4-/3-(3.4-dimethoxyphenyl-ethvlamino) -2-hydroxypropoxy7phenylJ crotonic acid nitrile a) (+) 3-^4/3-(3.4-dimethoxyphenylethyl-N-formylamino)-2-hydroxypropoxy/phenyljcrotonic acid nitrile 216242 -I960 .0 g of (+) 3-f4-/3-(3.4-dimethoxyphenylethyl-amino)-2-hydroxypropoxy7phenyljcrotonic acid nitrile (96 % (+)-configuration and 4 % (-)-configuration, [dCJ22 e+8.8c(5 % strength in methanol)) and 110 g of butylformate are heated at reflux temperature for 1.5 hours. The crude (+) 3-/4-/3-(3.4-dimethoxypheynlethyl-N-formylamino)-2-hydroxypropoxy7phenylJcrotonic acid nitrile is obtained after evaporating the reaction mixture . b) 5-/if4-(2-cyano-1-methylethylenyl)phenoxy]methy17-3-(3,4-dimethoxyphenyl)ethyl-2-oxazolinium chloride The crude ( + ) 3-/4-/3- (3.4-dimethoxyphenylethyl-N-formylamino)-2-hydroxypropoxy7phenylJcrotonic acid nitrile is dissolved in 120 ml of chloroform and 14.4 ml of thionyl chloride are added dropwise. Stirring is continued for 2 hours at 40°C. c) (-) 3-/4-/3-(3.4-dimethoxyphenylethylamino)-2-hydroxy-propoxy/phenyljcrotonic acid nitrile The chloroformic solution of the crude 5- f{4-( 2-cyano-1-methylethylenyl)phenoxy3*methyl7-3-(3.4-dimethoxy-phenyl) ethyl-oxazolinium chloride is subjected to acid hydrolysis by adding to this solution dropwise 15 ml of water at such a rate that the temperature does not exceed 60°C. Stirring is continued for 2 hours at 60°C and 200 ml of 2 N sodium hydroxide solution are then added. The chloroform phase is separated off, washed with 100 ml of water and dried. The solvent is removed in vacuo. The crystalline residue is stirred with 200 ml of isopropanol 216242 for 2 hours at room temperature^ then filtered off, washed with 50 ml of cold isopropanol and dried.

Yield: 48.1 g « -7.20 (5% strength in methanol) = 80.2 % chemical yield and 82 % optical yield.

Further purification is effected via the diastereo-meric salt with (-)-dibenzoyl-tartaric acid as described in Example 5c). 216242 - 21 "

Claims (3)

WHAT WE CLAIM IS:

1. An optically active cyclic compound of the formula III CH O -R ^ £> A-O-CH^-CH-CHp X (III) in which A represents 2-cyclopentyl-phenyl and R represents t -butyl and in which X represents the anion of a. strong acid or of a halogen atom.

2. A compound of the formula III as claimed in claim 1, wherein ^ denotes an anion of sulfuric acid, phosphoric acid or a strong organic sulfonic acid or a chloride or bromide.

3. A compound according to claim 1 substantially as herein described. HOECHST AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES LIMITED By: