Claims for Patent: 6,828,120

Summary for Patent: 6,828,120

Title:	Process to prepare 11.beta., 17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dione 21-acetate
Abstract:	The present invention is a novel process for the transformation of 17.alpha.-hydroxy-6.alpha.-methylpregn-4-ene-3,20-dione 17-acetate (I) ##STR1## to 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) ##STR2##
Inventor(s):	Pearlman; Bruce Allen (Kalamazoo, MI), White; Michael J. (Portage, MI), Gilbert; Ivan G. (Kalamazoo, MI)
Assignee:	Pharmacia and Upjohn Company (Kalamazoo, MI)
Application Number:	10/172,479
Patent Claims:	1. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) which comprises: (1) contacting 17.alpha.-hydroxy-6.alpha.-methylpregn-4-ene-3,20-dione 17-acetate (I) with a .DELTA..sup.1 -dehydrogenase to produce 17.alpha.-hydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dione 17 acetate (II); (2) contacting 17.alpha.-hydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dione 17 acetate (II) with a 11.beta.-hydroxylase to produce 11.beta.,17.alpha.-dihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dione 17-acetate (III); (3) hydrolyzing the 11.beta.,17.alpha.-dihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dione 17-acetate (III) to produce11.beta.,17.alpha.-dihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-d ione (IV); (4) contacting 11.beta.,17.alpha.-dihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dione (IV) with iodine, a catalyst, a mild base to produce 11.beta.,17.alpha.-dihydroxy-21-diiodo-6.alpha.-methylpregna-1,4-diene-3,2 0-dione (V) and (5) contacting 11.beta.,17.alpha.-dihydroxy-21-diiodo-6.alpha.-methylpregna-1,4-diene-3,2 0-dione (V) with a salt of acetic acid. 2. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 1 where the contacting with the .DELTA..sup.1 -dehydrogenase is with .DELTA..sup.1 -dehydrogenase of A. simplex. 3. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 2 where the .DELTA..sup.1 -dehydrogenase of A. simplex is used as fermentation, whole cell concentrate, whole cells, cell free or immobilized cells. 4. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 3 where the .DELTA..sup.1 -dehydrogenase of A. simplex is used by whole cell concentrate. 5. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 2 where the .DELTA..sup.1 -dehydrogenation is conducted in the presence of catalyase. 6. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 2 where the .DELTA..sup.1 -dehydrogenation is conducted in the presence of an exogenous electron acceptor. 7. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 6 where the exogenous electron acceptor is selected from the group consisting of menadione, menadione bisulfilte, 1,4-naphthoquinone, phenazine methosulfate, phenazine ethosulfate and vitamin K-type compounds. 8. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 7 where the exogenous electron acceptor is menadione. 9. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 2 where the .DELTA..sup.1 -dehydrogenation is conducted in the presence of water-immiscible organic solvent. 10. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 9 where the water-immiscible organic solvent is selected from the group consisting of toluene, xylene, benzene, heptane, methylene chloride, n-octanol, carbon tetrachloride and higher n-alcohols or mixtures thereof. 11. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 10 where the water-immiscible organic solvent is a mixture of methylene chloride and toluene. 12. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 1 where the 11.beta.-hydroxylase is of C. lunata. 13. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 12 where the 11.beta.-hydroxylase is of C. lunata by fermentation, cell concentrate, whole cells or cell free reaction. 14. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 13 where the 11.beta.-hydroxylase is of C. lunata by fermentation. 15. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 12 where the C. lunata is cultured in the presence of a detergent. 16. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 15 where the detergent is a non-ionic detergent selected from the group consisting of ethoxylated alcohols, ethoxylated fatty acids, ethoxylated fatty esters and oils, ethoxylated alkyl phenols, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene ethers, polyethylene glycol ethers of alkyl phenols, polyethylene glycol ethers, of primary alcohols and polyethylene glycol ethers of secondary alcohols. 17. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 16 where the non-ionic detergent is an ethoxylated alkyl phenol. 18. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 17 where the ethoxylated alkyl phenol is octylphenoxy polyethoxy ethanol. 19. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 12 where C. lunata is cultured in the presence of a natural oil. 20. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 19 where the natural oil is selected from the group consisting of soybean oil, castor oil, corn oil, cottonseed oil, lard oil, linseed oil, olive oil, peanut oil, rape seed oil and safflower seed oil. 21. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 20 where the natural oil is soybean oil. 22. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 12 using a timed nitrate addition. 23. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 22 where the source of nitrate is selected from the group consisting of ammonium nitrate, aluminum nitrate, calcium nitrate, sodium nitrate, barium nitrate, potassium nitrate, cupric nitrate, cesium nitrate, magnesium nitrate, manganese nitrate, ferric nitrate, zinc nitrate, cobalt nitrate, lithium nitrate and nitric acid. 24. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 23 where the source of nitrate is ammonium nitrate. 25. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 12 which uses a temperature shift. 26. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 25 where the temperature shift is from about 28.degree. to about 37.degree.. 27. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 1 where the hydrolyzing is performed with a base selected from the group consisting of carbonate, hydroxide or C.sub.1 -C.sub.4 alkoxide. 28. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 27 where the base is selected from the group consisting of carbonate in methanol, hydroxide in aqueous methanol or methoxide. 29. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 28 where the base is methoxide. 30. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 27 where more than one equivalent of base is used. 31. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 1 where the product of step (3) is contacted with iodine in the presence of base and bromide ion. 32. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 31 where the base is selected from the group consisting of hydroxide, C.sub.1 -C.sub.4 alkoxide. 33. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 32 where the base is hydroxide. 34. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 31 where the bromide is present in a catalytic amount. 35. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 1 where the product of step (4) is contacted with CH.sub.3 --COO.sup.--. 36. A process for the preparation of 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) according to claim 1 where the 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dion e 21-acetate (VI) produced contains not more than 0.1% of any impurity.

Details for Patent 6,828,120

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Aimmune Therapeutics, Inc.	PALFORZIA	peanut (arachis hypogaea) allergen powder-dnfp	Powder	125696	January 31, 2020		2022-06-14