Taro Pharmaceuticals U.s.a., Inc.

Taro Pharmaceutical Industries Limited

Wael Baidossi

Daniella Gutman

Shimon Chernyak

Rosa L Cyjon

Sorin Bercovici

Simon Cherniak

Terese Soudah

The present invention provides a process for the preparation of a stable polymorph III of Atovaquone exhibiting characteristic peaks (expressed in degrees 20&#xb1;0.2&#xb0;&#x3b8;) at about 6.9, 9.6, 14.1, 14.7, 17.0, 18.5, 19.1, 19.9, 20.3, 22.0, 22.6, 23.2, 24.2, 26.8, and 28.5, which comprises: (a) providing a sample of Atovaquone particles; (b) heating the sample of Atovaquone particles at a minimal temperature of between 140&#xb0; C. to 160&#xb0; C. depending on the particle size of the sample; and (c) cooling the sample to obtain the stable polymorphic form of Atovaquone.

Process for the preparation of a stable polymorphic form of Atovaquone

The present invention is related to a novel synthetic procedure that provides a simple, safe and commercially valuable method for the preparation of 2-phenyl-1,3-propanediol. The process for the preparation of 2-phenyl-1,3-propanediol involves reducing diethyl phenylmalonate with sodium borohydride (NaBH) in the presence of an alkali metal dihydrogen phosphate buffer or the hydrate thereof.

Process for the preparation of 2-phenyl-1,3-propanediol

The present invention provides a method of preparing a 4-(arylmethyl)amino-1H-imidazo(4,5-c)quinoline of formula (4) by reacting an arylmethylamine of formula (3) with a 4-chloro-1H-imidazo(4,5-c)quinoline of formula (2). The present invention further provides a method of preparing an acid addition salt of formula (5) comprising the step of hydrolyzing a 4-(arylmethyl)amino-1H-imidazo(4,5-c)quinoline of formula (4) with a strong acid, HX. The present invention further provides a method of preparing a 4-amino-1H-imidazo(4,5-c)quinoline of formula (1) comprising the step of treating an acid addition salt of formula (5) with a base.

[object Object]

The present invention provides a method of preparing a 5H-dibenz[b,f]azepine-5-carboxamide of formula (1) wherein R, R, R, and Rare independently selected from the group consisting of hydrogen, halogen, nitro, cyano, carboxyl, A, &#x2014;CO(A), &#x2014;OCO(A), &#x2014;O(A), &#x2014;N(A), &#x2014;CON(A), and &#x2014;COO(A), wherein A is selected from the group consisting of C-Calkyl, C-Ccycloalkyl, C-Calkenyl, C-Ccycloalkenyl, C-Calkynyl, and C-Caryl, wherein the two A groups of &#x2014;N(A)and &#x2014;CON(A)can be the same or different, and wherein Rand Rcan together form a bond; comprising reacting a 5H-dibenz[b,f]azepine of formula (2) with a) a cyanate salt selected from the group consisting of alkali metal cyanate salts and alkaline-earth metal cyanate salts, and b) a salt of an amino compound having no N&#x2014;H bonds, wherein the salt has a K(25&#xb0; C.) of at least about 10&#xd7;10.

Method of preparing a 5H-dibenz(b,f)azepine-5-carboxamide

The present invention provides a method of preparing a 5H-dibenz[b,f]azepine-5-carboxamide of formula (1) wherein R, R, R, and Rare independently selected from the group consisting of hydrogen, halogen, nitro, cyano, carboxyl, A, &#x2014;CO(A), &#x2014;OCO(A), &#x2014;O(A), &#x2014;N(A), &#x2014;CON(A), and &#x2014;COO(A), wherein A is selected from the group consisting of C&#x2013;Calkyl, C&#x2013;Ccycloalkyl, C&#x2013;Calkenyl, C&#x2013;Ccycloalkenyl, C&#x2013;Calkynyl, and C&#x2013;Caryl, wherein the two A groups of &#x2014;N(A)and &#x2014;CON(A)can be the same or different, and wherein Rand Rcan together form a bond; comprising reacting a 5H-dibenz[b,f]azepine of formula (2) with a) a cyanate salt selected from the group consisting of alkali metal cyanate salts and alkaline-earth metal cyanate salts, and b) a salt of an amino compound having no N&#x2014;H bonds, wherein the salt has a K(25&#xb0; C.) of at least about 10&#xd7;10.

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Hamesholash, Israel

Wael Baidossi