Astrazeneca Ab

Astra Zeneca U.k. Limited

Mark Purdie

Philip O'Keefe

Brian Springthorpe

Mark Furber

James Francis McCabe

Lilian Alcaraz

James Gair Ford

Lyn Powell

Simon Mark Pointon

Jane Withnall

Anne O'Kearney-McMullan

James Francis Mccabe

Anne O'kearney-Mcmullan

Philip O'keefe

The present invention relates to chemical processes useful in the manufacture of the compound 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (the active entity within AZD0530), to intermediates useful in the manufacture of that compound and to processes for the manufacture of those intermediates. The invention also relates to particular crystalline forms of that compound such as a difumarate salt and a trihydrate and to pharmaceutical compositions containing such crystalline forms.

Crystalline forms of 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline

The invention provides compounds of formula (I): wherein: X is CH, O, S(O)or NR; Y is a bond, CH, NR, CHNH, CHNHC(O), CH(OH), CH(NHCOR), CH(NHSOR), CHO or CHS; Z is C(O), or when Y is a bond Z can also be S(O); Ris optionally substituted aryl, optionally substituted heterocyclyl or Ccycloalkyl fused to a benzene ring; and R, R, R, R, R, Rand R, R, R, R, R, Rand Rare as defined herein; are modulators of chemokine (especially CCR3) activity (for use in, for example, treating asthma). The invention also provides a process for making 4-(3,4-dichlorophenoxy)piperidine, which is useful as an intermediate for making certain compounds of the invention.

Chemical compounds

A salt of substituted or unsubstituted methylene bisphosphonic acid of formula I 

Salts of substituted methylene bisphosphonic acids

The present invention concerns a process for preparing 4-(hydroxy)-[1,4']bipiperidinyl-1&#x2032;-carboxylic acid tert-butyl ester, comprising hydrogenating a mixture of 4-hydroxypiperidine and 1-tert-butoxycarbonyl-4-piperidone in a suitable solvent, in the presence of a suitable catalyst and at a suitable pressure.

Process for preparing 4-(hydroxy)-[1,4']bipiperidinyl-l'carboxylic acid tert-butyl ester

A process for the preparation of salts of substituted or unsubstituted methylene bisphosphonic acids by hydrolysing the corresponding acid ester with hydrochloric acid, removing water from the acid azeotropically prior to addition of an amine or a base to produce the resultant salt in good yield.

Process for preparing methylene bisphosphonic and salts

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Loughborough, United Kingdom

Mark Purdie