Process for preparing xanthine phosphodiesterase V inhibitors and precursors thereof

1. A method for producing a compound having the following formula:

wherein,

R 1 , R 2 and R 3 are each independently selected from the group consisting of: H, C 1-15 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, C 3-15 cycloalkyl, aryl, heteroaryl, —OR 5 , —C(O)OR 5 , —C(O)R 5 , —C(O)N(R 5 ) 2 , —NHC(O)R 5 and —NHC(O)OR 5 , wherein R 5 is H or C 1-15 alkyl;

provided that R 2 and R 3 are not both —H;

R 4 is C 1-12 alkyl, C 3-15 cycloalkyl, C 3-15 cycloalkenyl, heterocycloalkyl, aryl or heteroaryl;

wherein R 1 , R 2 , R 3 and R 4 are optionally substituted with one or more moieties independently selected from the group consisting of: C 1-15 alkyl, C 3-15 cycloalkyl, C 2-15 alkenyl, C 3-15 cycloalkenyl, C 2-15 alkynyl, aryl, heteroaryl, heterocycloalkyl, halo, nitro, oximino, acetate, propionate, pivaloyl, —OC(O)R 5 , —NC(O)R 5 or —SC(O)R 5 , —OR 50 , —NR 50 R 51 , —C(O)OR 50 , —C(O)R 50 , —SO 0-2 R 50 , —SO 2 NR 50 R 51 , NR 52 SO 2 R 50 , ═C(R 50 R 51 ), ═NOR 50 , ═NCN, ═C(halo) 2 —C(O)N(R 50 R 51 ), —OC(O)R 50 , —OC(O)N(R 50 R 51 ), —N(R 52 )C(O)(R 50 ), —(R 52 )C(O)OR 50 and —(R 52 )C(O)N(R 50 R 51 ), wherein R 5 is H or C 1-12 alkyl and wherein R 50 , R 51 and R 52 are each independently selected from the group consisting of: H, Cf 1-6 alkyl, C 3-6 cycloalkyl, C 4-6 heterocycloalkyl, heteroaryl, and aryl;

Hal is a halogen atom;

the method comprising:

a) forming a dihalogenated Compound 7 from compound 6:

 wherein Hal is selected to be the same halogen moiety for each occurrence; and

b) reacting a Compound 7 with Compound 8, R 4 NH 2 , and a base, to form a compound of structure 9:

wherein,

L is selected to be R 3 .

2. A method for producing Compound 5AK without separation or purification of intermediate products, said method comprising:

(a) reacting Compound 2 with Compound 1A to form Compound 3A:

b) reacting Compound 3A with a base in an alcoholic solvent to form Compound 4A:

c) reacting Compound 4A with a N-ethyl urethane and a potassium alkoxide in an ethereal solvent to form Compound 5AK:

wherein,

Et is CH 3 CH 2 —;

Me is CH 3 —; and

R 53 is H or C 1-12 alkyl.

3. The method of claim 2 wherein,

the base is 5–20 mol % NaOEt or KOtBu, and

the alcoholic solvent is ethanol.

4. The method of claim 2 wherein,

the N-ethylurethane is EtNCO 2 Et;

the potassium alkoxide is KOtBu; and

the ethereal solvent is diglyme.

5. The method of claim 1 wherein Compound 6 is Compound 6A and Compound 7 is Compound 7A, and said halogen is selected to be bromine, said method comprising forming a dibrominated compound from compound using N-bromosuccinimide, acetonitrile as a solvent, and sulfuric acid as a catalyst:

wherein,

MeCN is acetonitrile;

NBS is N-bromosuccinimide,

Me is CH 3 —; and

OAc is acetate.

6. The method of claim 1 wherein Compound 7 is Compound 7A, Compound 8 is Compound 8A. Compound 9 is Compound 9A and the base is sodium bicarbonate, wherein the reaction is carried out in the presence of N,N-dimethyl acetamide as a solvent:

wherein,

DMA is N,N-dimethyl acetamide

Me is CH 3 —; and

OAc is acetate.

7. The method of claim 1 wherein Compound 9 is Compound 9A, and further comprises the step of preparing Compound 13A by treating compound 9A with tetrabutylammonium hydroxide, the addition of which is followed by the addition of methanol:

wherein,

n-Bu 4 NOH is tetrabutylammonium hydroxide;

Me is CH 3 —; and

OAc is acetate.