(IO)  Patent No.:  US 7,495,101 B2  Feb.24,2009  (45)  Date of Patent:  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  (51)  Int. Cl.  (52)  U.S. Cl.  .......................................  546/115;  546/116  (58)  Field of Classification Search  ................. 546/115,  546/116  See application file for complete search history.  21 Claims, No Drawings  (56)  References Cited  U.S. PATENT DOCUMENTS  (57)  ABSTRACT  OTHER PUBLICATIONS  FOREIGN PATENT DOCUMENTS  C07D  471102  (2006.01)  C07D  491102  (2006.01)  C07D  498102  (2006.01)  (65)  Prior Publication Data  3,296,275 A  3,822,274 A  l/ 1967 Schaeren  7/1974 Harris et al.  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.  Primary Examiner-Janet  L Andres  Assistant Examiner-Niloofar  Rahmani  (74)  Attorney, Agent, or Firm-Nixon  & Vanderhye P.C.  * cited by examiner  International Search Report.  WO  WO 2004/058775  7/2004  Nov. 19, 2003  (DE)  ................................ 103 53 999  (30)  Foreign Application Priority Data  US 2007 /0072254 Al  Mar. 29, 2007  3,250,778 A  *  5/1966 Kimel et al. .................. 546/15  US007495101B2 