Patent GB-782267-A (GB)
Title: A process for the manufacture of pyrophosphoric and phosphonic acid derivatives
Inventor: ATHERTON FRANK RATCLIFFE
IPC: C07F9/38
Filed: 1954-05-07
Abstract: Anhydrides of phosphoric acid monoesters, anhydrides of phosphonic acids, and mixed anhydrides of phosphoric acid monoesters and phosphonic acids, and salts thereof, are obtained by reacting a phosphoric acid monoester or a phosphonic acid with an imino chloride in the presence of two equivalents of a suitable base and treating the product with a monobasic salt of a phosphoric acid or with either the free phosphoric acid monoester or the free phosphonic acid, (preferably, in the case where the free acid or acid ester is used, in the presence of a further equivalent of a base, which base may be present during the said imino-chloride reaction step) and, if desired, converting the product into the free acid or further salts. The imino chlorides used in the process are those of the general formula (A) (Cl)C=N-B, wherein A and B are organic radicals which are inert under the reaction conditions and wherein A is attached to the carbon atom through a tertiary carbon atom.  The preferred imino chlorides are N-alkylbenzimino chlorides.  Suitable bases for use in the process are alkali and alkaline earth metal hydroxides or tertiary amines, e.g. tertiary alkyl or cycloalkyl amines.  The base should generally be a strong base but when symmetrical products are required either a weak base (e.g. pyridine) or a strong base can be used.  A weak base can be used in addition to the base used as reactant, e.g. when the weak base is used as a solvent for the reaction mixture.  The process need only be carried out in two steps when an asymmetrical product is being prepared.  When a symmetrical product is required the process may be carried out by reacting a phosphoric acid monoester or a phosphonic acid with a monobasic salt of the phosphoric acid monoester or of the phosphonic acid or with the free monoester or phosphonic acid in the presence of the imino chloride and of two or three equivalents of a suitable base.  The products are of the type <FORM:0782267/IV (a)/1> wherein m and n are 0 or 1 and may differ from each other and R1 and R11 are aryl or alkyl groups which may contain substituents, e.g. aryl or heterocyclic or hydroxyl substituents, as in the case where R1OH and/or R11OH from which R1 and/or R11 are derived, is benzyl alcohol, riboflavin, adenosine or other nucleoside, or a sugar, and R1 and R11 may be the same or different.  Where the starting materials contain reactive hydroxyl groups in the organic part of the molecule the said groups should be protected, e.g. by acylation, alkylation, or acetal formation.  The conversion of the products into the free acids may be effected by treatment with a mineral acid or by passage through a cationic exchange resin in its hydrogen form and the further salts may be produced from the free acid by treatment with the appropriate base or from the salt product by double decomposition.  During the process the imino chloride is converted into the corresponding amide which may be reconverted to the imino chloride by reacting with phosphorus pentachloride or thionyl chloride and the imino chloride can thus be used again.  Examples are given for the production of (a) symmetrical pyrophosphoric acid diphenyl ester from phenyl phosphoric acid using pyridine as solvent and triethylamine as base, the imino chloride used being N-sec.-butyl-, N-methyl-, N-ethyl-, N-isopropyl-, or N-cyclohexyl-benzimino-chloride or by using pyridine alone as base and solvent and N-sec.-butyl-benzimino chloride as the imino chloride; (b) symmetrical pyrophosphoric acid di-(naphthyl-(2)) ester from naphthyl-(2)-phosphoric acid using the solvent, base and imino chlorides as for product (a); (c) phenylphosphonic anhydride from phenylphosphonic acid, the reaction being carried out in pyridine, acetonitrile or a -picoline and with the same base and iminochlorides as for product (a); (d) benzylphosphonic anhydride by replacing the phenyl phosphoric acid used for product (a) with benzyl phosphonic acid; (e) naphthyl-(2)-phosphoric phenylphosphonic anhydride from phenylphosphonic acid in the first stage and naphthyl - (2) - phosphoric acid in the second stage. Each of the products (a) to (e) is recovered in the form of its bis-(S-benzyl-isothiouronium salt). In another example P1,P2-diadenosine-51 pyrophosphate is obtained from adenosine-51-phosphate using dimethyl-octylamine as the base, dimethyl formamide as solvent and either N-sec.-butyl-, or N-phenylbenziminochloride as the imino chloride.