Patent GB-860300-A (GB)
Title: Improvements in the production of water-soluble derivatives of compounds
IPC: C07J75/00
Filed: 1958-03-21
Abstract: The invention comprises polyoxyalkylene carboxylic esters of the general formul\m 9 <FORM:0860300/IV (a)/1> wherein Z represents a radical derived by the elimination of one or more hydroxyl groups from a steroid, a vitamin, a stilboestrol or a hexestrol containing one or more hydroxyl groups, A represents -CH2CH2-, -CH2CH2 CH2- or -CH2CH(CH3)- A1 represents a direct link or -CH2-, -CH2CH2-, -CH2 COOCH2-, -CH2CH2COOCH2-, -CH2 COOCH2CH2-, or -CH2CH2COOCH2CH2-, R represents hydrogen or the methyl or ethyl group, n represents an integer from 3 to 100, and x represents an integer equal to the number of eliminated hydroxyl groups, and the preparation thereof by normal esterification methods used for esterifying carboxylic acids with alcohols, e.g. by reacting the required free polyoxyalkylene mono- or di-carboxylic acids or esters or acid chlorides derived therefrom with the required hydroxy substituted steroid or vitamin or the stilboestrol or hexestrol, or an alkali metal derivative thereof. An alternative method for the preparation of the above polyoxyalkylene carboxylic esters when A1 represents -CH2COOCH2-, -CH2CH2 COOCH2-, -CH2COOCH2CH2- or -CH2 CH2COOCH2CH2- comprises reacting compounds of the general formula (X-A111-COO)x-Z wherein X represents a halogen, A111 represents -CH2- or -CH2CH2-, and Z and x have the above significance, with a polyoxyalkylene derivative of the formula <FORM:0860300/IV (a)/2> wherein Y1 represents an alkali metal, A11 represents -CH2- or -CH2CH2-, and A, R and n have the above significance.  The group Z may be derived from Vitamin A alcohol, Vitamin E (a -tocophenol), prednisolone, hydrocortisone, testosterone, oestradiol, diethylstilboestrol and hexestrol.  The Specification refers to a number of polyoxyalkylene mono- and dicarboxylic acids and acid chlorides and methyl and ethyl esters derived therefrom having 18 polyoxyethylene and polyoxypropylene units.  In the examples: an o -methoxypolyoxyethylene acetic acid (average molecular weight 866) is converted to its acid chloride and methyl ester which are then each reacted with Vitamin A alcohol (in the former case the potassium derivative of Vitamin A alcohol is also used) to form the corresponding Vitamin A esters; Vitamin E is reacted with o -methoxypolyoxyethylene acetyl chloride (average molecular weight 952) and with o -methoxypolyoxyethylene acetic acid (average molecular weight 829) to form the corresponding Vitamin E esters; hydrocortisone is reacted with o -methoxypolyoxyethylene acetyl chloride (average molecular weight 1050) and with o -methoxypolyoxyethylene propionyl chloride (average molecular weight 847) to form the corresponding hydrocortisone 21-ester; o -methoxypolyoxyethylene propionyl chloride (average molecular weight 848) is reacted with prednisolone to form the corresponding prednisolone 21-ester and with diethylstilboestrol to form the corresponding di-ester of diethylstilboestrol; Vitamin E is reacted with monochloracetyl chloride and the resulting chloracetate is reacted with the sodium salt of o -methoxypolyoxyethylene acetic acid (average molecular weight 680) to form an o -methoxypolyoxyethylene acetoxy acetate of Vitamin E; oestradiol is reacted with monochloracetyl chloride to form the 3,17-di-(chloracetate) of oestradiol which is then reacted with the sodium salt of o  - methoxypolyoxyethylene propionic acid (average molecular weight 790) to form the 3,17 p  - di - o  - methoxypolyoxyethylene propionyloxyacetate of oestradiol; testosterone is reacted with chloracetyl chloride to form the chloracetate of testosterone which is then reacted with the sodium salt of o -methoxypolyoxyethylene propionic acid (average molecular weight 790) to form the o -methoxypolyoxyethylene propionyloxyacetate of testosterone; dimethyl polyoxyethylene diacetate (average molecular weight 1580) is reacted with Vitamin A alcohol to form the polyoxyethylene diacetic acid diester of Vitamin A alcohol.ALSO:The invention comprises esters of the general formulae <FORM:0860300/IV (b)/1> and <FORM:0860300/IV (b)/2> wherein Z represents a radical derived by the elimination of one or more hydroxyl groups from a steroid, a vitamin, a stilboestrol or hexestrol containing one or more hydroxyl groups, A represents -CH2CH2-, -CH2CH2CH2-, or -CH2CH(CH2)-, A1 represents a direct link or -CH2-, -CH2CH2-, -CH2COOCH2-, -CH2CH2COOCH2-, -CH2COOCH2CH2-, or -CH2CH2COOCH2CH2-, R represents hydrogen or the methyl or ethyl group, n is an integer from 3 to 100, and x represents an integer equal to the number of eliminated hydroxyl groups, and the preparation thereof by normal esterification methods used for esterifying carboxylic acids with alcohols, e.g. by reacting the required free polyoxyalkylene mono- or dicarboxylic acids or esters or acid chlorides derived therefrom with the hydroxy-substituted steroid or vitamin or the stilboestrol or hexestrol, or an alkali metal derivative thereof in which an alkali metal replaces the hydrogen atom of the hydroxy group.  The group Z may be derived from Vitamin A alcohol, Vitamin E (a -tocopherol), prednisolone, hydrocortisone, testosterone, oestradiol, diethylstilboestrol and hexestrol.  An alternative method for the preparation of the esters of the above general formula wherein A1 represents-CH2COOCH2-, -CH2CH2COOCH2-, -CH2COOCH2CH2- or -CH2CH2COOCH2CH2-, comprises reacting compounds of the general formula (X-A111-COO)x-Z, wherein X represents a halogen, A111 represents -CH2- or -CH2CH2-, and Z and x have the above significance, with a polyoxyalkylene chain derivative of the formula <FORM:0860300/IV (b)/3> or <FORM:0860300/IV (b)/4> wherein Y1 represents an alkali metal, A11 represents -CH2- or -CH2CH2-, and A, R and n have the above significance.  The Specification refers to a number of polyoxyalkylene chain free acid, acid chloride, and methyl and ethyl ester reactants having 18 polyoxyethylene or polyoxypropylene units.  In the examples: on o -methoxypolyoxyethylene acetic acid (average molecular weight 866) is converted to its acid chloride and methyl ester which are then reacted with Vitamin A alcohol, and in the former case the vitamin alcohol may be used in the form of its potassium derivative to form Vitamin A esters; Vitamin E is reacted with o  - methoxypolyoxyethylene acetyl chloride (average molecular weight 952) and with o -methoxypolyoxyethylene acetic acid (average molecular weight 829) to form Vitamin E esters; hydrocortisone is reacted with o -methoxypolyoxyethylene acetyl chloride (average molecular weight 1050) and with o -methoxypolyoxyethylene propionyl chloride (average molecular weight 847) to form a hydrocortisone 21-ester; o -methoxy-polyoxyethylene propionyl chloride (average molecular weight 848) is reacted with prednisolone to form a prednisolone 21-ester and with diethylstilboestrol to form a di-ester of diethylstilboestrol; Vitamin E is reacted with monochloroacetyl chloride and the product with the sodium salt of o -methoxypolyoxyethylene acetic acid (average molecular weight 680) to form an o -methoxypolyoxyethylene acetoxy acetate of Vitamin E; oestradiol is reacted with monochloroacetyl chloride to form the 3,17-di-(chloroacetate) of oestradiol which is then reacted with the sodium salt of o -methoxypolyoxyethylene propionic acid (average molecular weight 790) to form the 3,17 - di - o  - methoxypolyoxyethylene propionyloxyacetate of oestradiol; testosterone is reacted with chloroacetyl chloride to form the chloroacetate of testosterone which is then reacted with the sodium salt of o -methoxypolyoxyethylene propionic acid (average molecular weight 790) to form the o -methoxypolyoxyethylene propionoyloxyacetate of testosterone; dimethyl polyoxyethylene diacetate (average molecular weight 1580) is reacted with Vitamin A alcohol to form the polyoxyethylene diacetic acid diester of Vitamin A alcohol.