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# c12) United States Patent 

# Fischesser et al. 

# (54) MANUFACTURE OF VITAMIN B$_{6 }$ 

(75) Inventors: Jocelyn Fischesser, Wittenheim (FR); Helmut Fritsch, Liirrach (DE); Andrew George Gum, Rixheim (FR); Reinhard Karge, Staufen (DE); Ralf Keuper, Liirrach (DE) 

(73) Assignee: DSM IP Assets B.V., Heerlen (NL) 

( *) Notice: Subject to any disclaimer, the term ofthis patent is extended or adjusted under 35 U.S.C. 154(b) by 250 days. 

(21) Appl. No.: 10/579,836 

(22) PCT Filed: Nov. 9, 2004 

(86) PCT No.: PCT /EP2004/012655 § 371 (c)(l), (2), ( 4) Date: Jun.8,2006 

(87) PCT Pub. No.: WO2005/049618 PCT Pub. Date: Jun. 2, 2005 

## (65) Prior Publication Data 

US 2007 /0072254 Al Mar. 29, 2007 

## (30) Foreign Application Priority Data 

Nov. 19, 2003 (DE) ................................ 103 53 999 

(51) Int. Cl. 

<img src='content_image/937971.jpg'>

(52) U.S. Cl. ....................................... 546/115; 546/116 

(58) Field of Classification Search ................. 546/115, 546/116 See application file for complete search history. 

## (56) References Cited 

3,250,778 A * 5/1966 Kimel et al. .................. 546/15 

## U.S. PATENT DOCUMENTS 

<img src='content_image/937986.jpg'>

# (IO) Patent No.: US 7,495,101 B2 

# Feb.24,2009 (45) Date of Patent: 

<img src='content_image/937973.jpg'>

## FOREIGN PATENT DOCUMENTS 

WO WO 2004/058775 7/2004 

International Search Report. 

* cited by examiner 

Primary Examiner-Janet L Andres 

Assistant Examiner-Niloofar Rahmani 

(74) Attorney, Agent, or Firm-Nixon & Vanderhye P.C. 

## (57) ABSTRACT 

A process for manufacturing a 3-unsubstituted, 3-monosub› stituted or 3,3-disubstituted 9-acyloxy-l ,5-dihydro-8-meth› ylpyrido[3,4-e] [1,3]dioxepin (I) and optionally for manufac› turing pyridoxine involves performing an addition reaction between a 4-methyl-5-alkoxy-oxazole (II) and a 2-unsubsti› tuted, 2-monosubstituted or 2,2-disubstituted 4, 7-dihydro-(1, 3 )-dioxepin (III) in the substantial absence of a solvent and a catalyst to give a product mixture consisting essentially of the appropriate Diels-Alder adduct (IV) in a major proportion and the appropriate 3-unsubstituted, 3-monosubstituted or 3,3-disubstituted 1,5-dihydro-8-methylpyrido[3,4-e] [1,3]di› oxepin 9-ol (V) in a minor proportion, removal of a substan› tial proportion of the unreacted oxazole and dioxapin starting materials from the product mixture by distillation under reduced pressure, addition of a substantially anhydrous organic acid to said product mixture and rearrangement of the Diels-Alder adduct IV to further V in the presence of said substantially anhydrous organic acid with removal of the generated alkanol by distillation under reduced pressure, and acylation of the resultingly enriched quantity of V with an added carboxylic acid anhydride to produce the desired I, and optionally converting this so-manufactured acy lation product I to pyridoxine by acid hydrolysis for achieving deprotection and deacylatiom. Pyridoxine is a well known form of vitamin B$_{6 }$ with well established utility. 

US007495101B2 

## OTHER PUBLICATIONS 

## 21 Claims, No Drawings 

