PROCESSES FOR PRODUCING DECITABINE

• US 20100249394A1
• Filed: 03/25/2010
• Published: 09/30/2010
• Est. Priority Date: 03/26/2009
• Status: Abandoned Application

• Current Assignee: Albemarle Corporation
• Original Assignee: Albemarle Corporation
• Inventors: Liu, Yunqi, Lambeth, Gregory H., Nixon, Brian W.
• Application Number:
  US12/731,760
• Publication Number:
  US 20100249394A1
• Time in Patent Office: Days
• US Class Current: 536/28.300
• CPC Class Codes: C07H 19/12 Triazine radicals

Abstract

New processes for producing decitabine are provided.

Claims

1. A process comprising:

(a) combining at least 2-deoxy-D-ribose and methanol to yield a first combination, wherein the amount of methanol is at least about 4 grams per gram of the 2-deoxy-D-ribose and the methanol is substantially anhydrous;

(b) cooling the first combination to about 25°

C. to about −

20°

C.;

(c) combining at least an acyl halide and at least a portion of the first combination to yield a second combination;

(d) maintaining the second combination at about 25°

C. to about −

20°

C. for about 30 minutes to about 240 minutes;

(e) combining at least a first volatile tertiary amine and at least a portion of the second combination to yield a first product comprising 1-O-methyl-2-deoxy-D-ribofuranose and methanol;

(f) removing substantially all of the methanol from the first product, yielding a substantially methanol-free first product;

(g) combining at least a substantially anhydrous Solvent A, a Catalyst A, a second volatile tertiary amine, and at least a portion of the substantially methanol-free first product to yield a third combination;

(h) combining at least p-chlorobenzoyl chloride and at least a portion of the third combination to yield a fourth combination;

(i) stirring the fourth combination for about 2 hours to about 6 hours at about 10°

C. to about 40°

C.;

(j) filtering the fourth combination to yield a filtrate and a filter cake;

(k) collecting the filtrate;

(l) rinsing the filter cake with at least a substantially anhydrous rinsing solvent;

(m) combining at least acetic acid, at least a portion of the filtrate, and at least a portion of the used rinsing solvent to yield a fifth combination;

(n) combining at least HCl gas and at least a portion of the fifth combination at about −

10°

C. to about 25°

C. to yield a sixth combination;

(o) stirring the sixth combination;

(p) collecting a second product comprising 1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-alpha-D-ribofuranosyl-chloride from the sixth combination;

(q) drying the second product to yield at least 1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-alpha-D-ribofuranosyl-chloride;

(r) yielding beta;

alpha anomers of 4-amino-1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-D-ribofuranosyl-1,3,5-triazin-2(1H)-one from at least the 1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-alpha-D-ribofuranosyl-chloride; and

(s) yielding decitabine from at least the beta;

alpha anomers of 4-amino-1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-D-ribofuranosyl-1,3,5-triazin-2(1H)-one.

3. A process according to claim 1 or 2, wherein yielding beta:

alpha anomers of 4-amino-1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-D-ribofuranosyl-1,3,5-triazin-2(1H)-one from at least the 1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-alpha-D-ribofuranosyl-chloride comprises;

(a) combining at least 5-azacytosine, hexamethyldisalazane and a Catalyst B in the presence of a first inert gas to yield a first intermediate product comprising 2-[(trimethylsilypamino]-4-[(trimethylsilyl)oxy]-s-triazine;

(b) stirring and heating the first intermediate product to at least about 60°

C.;

(c) stirring the first intermediate product while maintaining the first intermediate product at at least about 60°

C.;

(d) removing at least a portion of unreacted hexamethyldisalazane from the first intermediate product;

(e) combining at least a substantially anhydrous first Solvent B and at least a portion of the first intermediate product;

(f) removing at least a portion of the first Solvent B from the first intermediate product;

(g) combining at least a portion of the first intermediate product and at least a substantially anhydrous second Solvent B to yield a second intermediate product comprising 2-[(trimethylsilypamino]-4-[(trimethylsilypoxy]-s-triazine,

(h) combining at least a substantially anhydrous third Solvent B and at least a portion of the 1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-alpha-D-ribofuranosyl-chloride to yield a first intermediate combination;

(i) cooling the first intermediate combination to at least about 25°

C. to about −

10°

C. while stirring;

(j) combining at least the following to yield a second intermediate combination;

at least a portion of the first intermediate combination and at least a portion of the second intermediate product;

(k) combining at least a Catalyst C, a substantially anhydrous fourth Solvent B, and at least a portion of the second intermediate combination to yield a third intermediate combination;

(l) stirring the third intermediate combination at about −

10°

C. to about 25°

C. in the presence of a second inert gas;

(m) combining at least the third intermediate combination and a fifth Solvent B to yield a fourth intermediate combination;

(n) combining at least the following to form a fifth intermediate combination;

(i) either (a) a weak base such as saturated aqueous sodium bicarbonate to adjust the pH of the fourth intermediate combination to about 6 to about 8, or (b) water, methanol, or solid NaHCO₃, (ii) water or brine, and (iii) at least a portion, e.g., substantially all, or all, of the fourth intermediate combination; and

(o) yielding at least beta;

alpha anomers of 4-amino-1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-D-ribofuranosyl-1,3,5-triazin-2(1 H)-one from the fifth intermediate combination.

4. A process according to claim 1 or 2, wherein yielding beta:

alpha anomers of 4-amino-1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-D-ribofuranosyl-1,3,5-triazin-2(1H)-one from at least the 1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-alpha-D-ribofuranosyl-chloride comprises;

(a) combining at least 5-azacytosine, hexamethyldisalazane and a Catalyst B in the presence of a first inert gas to yield a first intermediate product comprising 2-[(trimethylsilypamino]-4-[(trimethylsilyl)oxy]-s-triazine;

(b) stirring and heating the first intermediate product to at least about 60°

C.;

(c) stirring the first intermediate product while maintaining the first intermediate product at at least about 60°

C.;

(d) removing at least a portion of unreacted hexamethyldisalazane from the first intermediate product;

(e) combining at least a substantially anhydrous first Solvent B, at least a portion of the 1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-alpha-D-ribofuranosyl-chloride, and at least a portion of the first intermediate product to yield a first intermediate combination;

(f) combining at least a Catalyst C, a substantially anhydrous second Solvent B, and at least a portion of the first intermediate combination to yield a second intermediate combination;

(g) stirring the second intermediate combination at about −

10°

C. to about 25°

C.;

(h) combining at least a weak base and the second intermediate combination to adjust the pH of the second intermediate combination to about 6 to about 8;

(i) yielding from the second intermediate combination at least a composition comprising one or more organic compounds; and

(j) yielding from the composition at least beta;

alpha anomers of 4-amino-1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-D-ribofuranosyl-1,3,5-triazin-2(1H)-one.

5. A process according to claim 1 or 2 wherein yielding decitabine from at least the beta:

alpha anomers of 4-amino-1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-D-ribofuranosyl-1,3,5-triazin-2(1H)-one comprises;

(a) combining at least substantially anhydrous methanol, an inert gas, and at least a portion of the beta;

alpha anomers of 4-amino-1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-D-ribofuranosyl-1,3,5-triazin-2(1H)-one to yield a penultimate combination;

(b) combining at least NaOMe in methanol and at least a portion of the penultimate combination while stirring to yield a final combination;

(c) yielding a solid from the final combination; and

(d) rinsing the solid with a substantially anhydrous final rinse solvent to yield decitabine.

6. A process according to claim 1 or 2 wherein yielding decitabine from at least the beta:

alpha anomers of 4-amino-1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-D-ribofuranosyl-1,3,5-triazin-2(1H)-one comprises;

(a) combining at least substantially anhydrous methanol, an inert gas, and at least a portion of the beta;

alpha anomers of 4-amino-1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-D-ribofuranosyl-1,3,5-triazin-2(1H)-one to yield a penultimate combination;

(b) combining at least NaOMe in methanol and at least a portion of the penultimate combination while stirring to yield a final combination;

(c) stirring the final combination for about 1 to about 4 hours at ambient temperature;

(d) cooling the final combination to about 25°

C. to about 0°

C. and maintaining at about 25°

C. to about 0°

C. for about 30 minutes to about 60 minutes;

(e) yielding a solid from the final combination;

(f) rinsing the solid with a final rinse solvent; and

(g) drying the solid to yield decitabine.

2. A process comprising:

(a) combining at least 1-O-methyl-3,5-di-O-p-chlorobenzoyl-2-deoxy-alpha/beta-D-ribose, acetic acid, an acyl halide, and a substantially anhydrous solvent to yield a first combination;

(b) while stirring and in the presence of an inert gas, feeding gaseous HCl to the first combination at about −

10°

C. to about 25°

C. to yield a second combination comprising 1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-alpha-D-ribofuranosyl-chloride;

(c) stirring the second combination at about −

10°

C. to about 25°

C.;

(d) yielding from the second combination a product comprising 1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-alpha-D-ribofuranosyl-chloride;

(e) rinsing the product with a rinse;

(f) drying the product to yield at least 1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-alpha-D-ribofuranosyl-chloride;

(g) yielding beta;

alpha anomers of 4-amino-1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-D-ribofuranosyl-1,3,5-triazin-2(1H)-one from at least the 1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-alpha-D-ribofuranosyl-chloride; and

(h) yielding decitabine from at least the beta;

alpha anomers of 4-amino-1-[3,5-di-O-(p-chlorobenzoyl)]-2-deoxy-D-ribofuranosyl-1,3,5-triazin-2(1H)-one.