Patent GB-856816-A (GB)
Title: Antibiotic substances related to novobiocin
IPC: C07H17/075
Filed: 1957-04-16
Abstract: The invention comprises substituted coumarins of the general formula: <FORM:0856816/IV(b)/1> wherein R represents an acyl group, 8-desmethylnovobiocin of the formula:  <FORM:0856816/IV(b)/2> 8-desmethyldihydronovobiocin of the formula:  <FORM:0856816/IV(b)/3> 8-desmethylcyclonovobiocin of the formula:  <FORM:0856816/IV(b)/4> and 7 - (3 - carbomyl - 4 - methylnovobioxyloxy) - acetomido - 4 - hydroxycoumarin of the formula:  <FORM:0856816/IV(b)/5> and a process for the preparation of compounds of the general formula: <FORM:0856816/IV(b)/6> wherein R represents an acyl radical, by reacting a 3 - acylamino - 4, 7 - dihydroxy - coumarin with 2 - acyl - 3 - carbamyl - 4 - methyl - novobiosyl chloride in the presence of silver oxide and hydrolysing with a base the resulting product of the general formula:  <FORM:0856816/IV(b)/7> to remove the R radical from the novobiosyl radical.  Thus the specific compounds referred to above may be prepared by reacting in the presence of silver oxide 2-acyl-3-carbamyl-4-methylnovobiosyl chloride with 3-(3-[g , g -dimethylallyl] - 4 - acyloxybenzamido) - 4, 7 - dihydroxycoumarin, with 3 - (3 - [3 - methylbutyl] - 4 - acyloxybenzamido) -4, 7 - dihydroxycoumarin, with 3 - (2, 2 - dimethylchroman - 6 - carboxamido)-4, 7-dihydroxycoumarin, and with 3 - acetamido - 4, 7 - dihydroxycoumarin respectively, and subjecting the resulting reaction products to alkaline hydrolysis. The above processes may be modified in that (1) the 3-acylamino-4, 7-dihydroxycoumarin is prepared by treating 4, 7-dihydroxycoumarin with nitrous acid to form 2, 4-dioxo-7-hydroxy-3-oximinochroman, reducing this compound in the form of its hydrochloride with hydrogen in the presence of a noble metal catalyst to 3-amino-4, 7-dihydroxycoumarin and acylating this compound; (2) the 3-(3-[g , g -dimethylallyl] - 4 - acyloxybenzamido) - 4, 7 - dihydroxycoumarin is prepared by acylating 3-(g , g -dimethylallyl)-4-hydroxy-benzoic acid, treating the sodium salt of the acylated compound with oxalyl chloride in a solvent medium to form 3-(g , g -dimethylallyl)-4-acyloxybenzoyl chloride and acylating 3-amino-4, 7-dihydroxycoumarin with this compound; (3) the 3-(3-[3-methylbutyl]-4-acyloxybenzamido)-4, 7-dihydroxycoumarin is prepared by acylating 3-(3-methylbutyl)-4-hydroxybenzoic acid, treating the sodium salt of the acylated compound with oxalyl chloride in a solvent medium to form 3-(3-methylbutyl)-4-acyloxybenzoyl chloride, and acylating 3-amino-4, 7-dihydroxycoumarin with this compound; (4) the 3-(2, 2-dimethylchroman-6-carboxamido)-4, 7-dihydroxycoumarin is prepared by reacting 2, 2-dimethylchroman-6-carboxylate with thionyl chloride at room temperature to produce 2, 2-dimethylchroman-6-carbonylchloride and acylating 3-amino-4, 7- dihydroxycoumarin with this compound; and (5) the 3-acetamido-4, 7-dihydroxycoumarin is prepared by reacting 3-amino-4, 7-dihydroxycoumarin with acetic anhydride in the presence of pyridine to produce 4-acetoxy - 3 - acetamido - 7 - hydroxycoumarin and selectively hydrolysing this compond. Processes (2) to (5) may be modified in that 3-amino-4, 7-dihydroxycoumarin is prepared by treating 4, 7-dihydroxycoumarin with nitrous acid to form 2, 4-dioxo-7-hydroxy-3-oximinochroman and reducing this compound in the form of its hydrochloride with hydrogen in the presence of a noble metal catalyst and may be further modified in that 2-acyl-3-carbamyl-4-methyl-novobiosyl chloride is prepared by acylating 3-carbomyl-4-methylnovobiose which can be prepared by the process described and claimed in Specification 853,592 to produce 1, 2-diacyl-3-carbamyl-4-methylnovobiose and reacting this compound with hydrogen chloride under anhydrous conditions.  In all the processes referred to above, coumarin compounds of the formula: <FORM:0856816/IV(b)/8> wherein R1 represents hydrogen or an acyl group, may exist and react as chromone compounds of the formula : <FORM:0856816/IV(b)/9> Detailed examples are given.  1, 2 - Diacyl - 3 - carbamyl - 4 - methyl - novobiose of the formula : <FORM:0856816/IV(b)/100> wherein R represents an acyl radical, is prepared by acylating 3-carbamyl-4-methyl-novobiose. 2-Acyl-3-carbamyl-4-methyl-novobiosyl chloride of the formula: <FORM:0856816/IV(b)/111> wherein R represents an acyl radical, is prepared by treating 1, 2-diacyl-3-carbamyl-4-methyl-novobiose with hydrogen chloride under anhydrous conditions  Ethyl 3-(g , g -dimethylallyl)-4-hydroxybenzoate is prepared by reacting ethyl p-hydroxybenzoate and g , g -dimethylallyl bromide in the presence of sodium. 3-(g ,g - dimethylallyl)-4-hydroxybenzoic acid is prepared by hydrolysing the above ester.  3-(3-Methylbutyl)-4-hydroxybenzoic acid is prepared by hydrogenating ethyl 3-(g , g -dimethylallyl)-4-hydroxybenzoate in the presence of platinum oxide and hydrolysing the resulting ethyl 3-(3-methylbutyl)-4-hydroxybenzoate.  Specifications 821,819 and 821,820 also are referred to.