Manufacture of vitamin B6

• US 7,495,101 B2
• Filed: 11/09/2004
• Issued: 02/24/2009
• Est. Priority Date: 11/19/2003
• Status: Active Grant

• Current Assignee: DSM IP Assets BV (DSM-Firmenich AG)
• Original Assignee: DSM IP Assets BV (DSM-Firmenich AG)
• Inventors: Gum, Andrew George, Fritsch, Helmut, Keuper, Ralf, Karge, Reinhard, Fischesser, Jocelyn
• Primary Examiner(s): Andres; Janet L
• Assistant Examiner(s): Rahmani; Niloofar
• Application Number:
  US10/579,836
• Publication Number:
  US 20070072254A1
• Time in Patent Office: 1,568 Days
• Field of Search: 546/115, 546/116
• US Class Current: 546/115
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: Y02P 20/582 Recycling of unreacted starting or intermediate materials

Abstract

A process for manufacturing a 3-unsubstituted, 3-monosubstituted or 3,3-disubstituted 9-acyloxy-1,5-dihydro-8-methylpyrido[3,4-e] [1,3]dioxepin (I) and optionally for manufacturing pyridoxine involves performing an addition reaction between a 4-methyl-5-alkoxy-oxazole (II) and a 2-unsubstituted, 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]dioxepin 9-ol (V) in a minor proportion, removal of a substantial 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 acylation product I to pyridoxine by acid hydrolysis for achieving deprotection and deacylatiom. Pyridoxine is a well known form of vitamin B₆ with well established utility.

Claims

1. A process for manufacturing a 3-unsubstituted, 3-monosubstituted or 3,3-disubstituted 9-acyloxy-1-5-dihydro-8-methylpyrido [3,4-e] [1,3]dioxepin of general formula

2. The process according to claim 1, wherein the starting materials of formulae II and III are 5-ethoxy-4-methyl-oxazole (formula II, wherein R¹ is ethyl) and 2-isopropyl-4,7-dihydro-(1,3)-dioxepin (formula III, wherein R² is hydrogen and R³ is isopropyl), respectively.

3. The process according to claim 1, wherein the process step involving the reaction of the starting materials of formulae II and III is effected at temperatures from about 130°

C. to about 170°

C., preferably from about 145°

C. to about 160°

C.

4. The process according to claim 1, wherein the molar ratio of the dihydrodioxepin of the formula III to the 4-methyl-5-alkoxy-oxazole of the formula II in the reaction mixture is from about 0.5:

1 to about 5;

1, preferably from about 1;

1 to about 2;

1.

5. The process according to claim 1, wherein distillation under reduced pressure for the removal of a substantial proportion of the unreacted starting materials of the formulae II and III from the product mixture obtained after the first step is effected by at a pressure in the range from about 10 mbar (1 kPa) to about 100 mbar (10 kPa).

6. The process according to claim 1, wherein an organic acid with a pKa value of up to about 5, preferably a C_2-5-alkanoic acid or a corresponding mono- or multihalogenated C_2-5-alkanoic acid, most preferably acetic acid, is used as the substantially anhydrous organic acid for the rearrangement of the Diels-Alder adduct of the formula IV to further 3-unsubstituted, 3-monosubstituted or 3,3-disubstituted 1,5-dihydro-8-methylpyrido[3,4-e] [1,3]dioxepin-9-ol of the formula V.

7. The process according to claim 1, wherein the amount of substantially anhydrous organic acid added for the rearrangement of the Diels-Alder adduct is from about 0.01 to about 2.0 equivalents per equivalent of said adduct.

8. The process according to claim 1, wherein the temperature of the product mixture to which the substantially anhydrous acid is added for the rearrangement of the Diels-Alder adduct is from about 50°

C. to about 115°

C.

9. The process according to claim 1, wherein the rearrangement of the Diels-Alder adduct with distillation of the generated alcohol R¹OH is effected at a reduced pressure from about 300 mbar (30 kPa) to about 700 mbar (70 kPa).

10. The process according to claim 1, wherein the carboxylic acid anhydride used for the acylation of the methylpyrido[3,4-e] [1,3]dioxepin-9-ol of the formula V corresponds to the anhydride of the substantially anhydrous acid used in the previous process step, and is preferably acetic anhydride.

11. The process according to claim 1, wherein the amount of carboxylic acid anhydride employed for the acylation is from about 1.05 to about 2 equivalents per equivalent of the methylpyrido[3,4-e] [1,3]dioxepin-9-ol to be acylated.

12. The process according to claim 1, wherein the temperature at which the acylation is effected is from about 50°

C. to about 115°

C.

13. The process according to claim 1, wherein the process is carried out continuously for two or more steps.

14. The process according to claim 1, wherein the optional final step of converting the so manufactured acylation product of the formula I to pyridoxine is realized by procedures well known in the prior art and, depending on the type of acid involved in the acid hydrolysis, produces pyridoxine in the form of the appropriate acid salt.

15. The process according to claim 14, wherein pyridoxine hydrochloride is produced.

16. The process according to claim 1, wherein distillation under reduced pressure for the removal of a substantial proportion of the unreacted starting materials of the formulae II and III from the product mixture obtained after the first step is effected by at a pressure in the range from about 20 mbar (2 kPa) to about 50 mbar (5 kPa).

17. The process according to claim 1, wherein distillation under reduced pressure for the removal of a substantial proportion of the unreacted starting materials of the formulae II and III from the product mixture obtained after the first step is effected by at a pressure in the range from about 35 mbar (3.5 kPa) to about 45 mbar (4.5 kPa).

18. The process according to claim 1, wherein the amount of substantially anhydrous organic acid added for the rearrangement of the Diels-Alder adduct is from about 1 to about 1.5 equivalents per equivalent of said adduct.

19. The process according to claim 1, wherein the temperature of the product mixture to which the substantially anhydrous acid is added for the rearrangement of the Diels-Alder adduct is from about 70°

C. to about 90°

C.

20. The process according to claim 1, wherein the amount of carboxylic acid anhydride employed for the acylation is from about 1.1 to about 1.5 equivalents per equivalent of the methylpyrido[3,4-e] [1 ,3]dioxepin-9-ol to be acylated.

21. The process according to claim 1, wherein the temperature at which the acylation is effected is from about 70°

C. to about 90°

C.