Process for the preparation of quinazolinones

• US 6,175,009 B1
• Filed: 11/18/1999
• Issued: 01/16/2001
• Est. Priority Date: 11/18/1999
• Status: Expired due to Fees

• Current Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Original Assignee: DuPont Performance Elastomers L (Bristol-Myers Squibb Company)
• Inventors: Storace, Louis, Magnus, Nicholas Andrew, Confalone, Pasquale Nicholas
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Liu, Hong
• Application Number:
  US09/442,598
• Time in Patent Office: 425 Days
• Field of Search: 544/286, 544/285
• US Class Current: 544/285
• CPC Class Codes: C07D 239/80 Oxygen atoms

Abstract

The present invention relates generally to an asymmetric synthesis of 4,4-disubstituted-3,4-dihydro-2(1H)-quinazolinones, and intermediates thereof. The target compounds are useful for the treatment of human immunodeficiency virus (HIV) as an inhibitor of reverse transcriptase.

Claims

1. A process for the preparation of a compound of formula (I):

wherein;

R¹ is C_1-3 alkyl substituted with 1-7 halogen;

R² is selected from C_1-5 alkyl substituted with 1-2 R⁴, C_2-5 alkenyl substituted with 1-2 R⁴, C_2-5 alkynyl substituted with 1 R⁴, and OR^2a;

R^2a is C_1-4 alkyl;

R^3a is H;

R^3b is selected from H, C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, I, and NR⁵R^5a;

R^3c is selected from H, C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, I, and NR⁵R^5a;

R^3d is selected from H, C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, I, and NR⁵R^5a;

alternatively, R^3a and R^3b combine to form —

OCH₂O—

;

R⁴ is selected from C_3-5 cycloalkyl substituted with 0-2 R^4a, phenyl substituted with 0-5 R^4a, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 R^4a;

R^4a is selected from C_1-3 alkyl, Cl, Br, F, I, OCH₃, SCH₃, and NR⁵R^5a; and

R⁵ and R^5a are independently selected from H and C_1-3 alkyl;

the process comprising;

step (1), contacting a compound of formula (II);

 

or a salt form or a hydrate of the salt form thereof;

with an isocyanate of formula (III);

wherein;

R^8a is selected from methyl, ethyl, propyl, and isopropyl;

R⁸ is selected from phenyl substituted with 0-3 R⁹, and naphthyl substituted with 0-3 R⁹; and

R⁹ is selected from C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, and I;

 

to form a compound of formula (II-a);

 

or a salt form thereof;

step (1-i), cyclizing the compound of formula (II-a) to form a compound of formula (IV);

step (2), dehydrating the compound of formula (IV) to form a compound of formula (V);

step (2-i), contacting the compound of formula (V) with a nucleophile of formula (VI);

 

R²—

M 

 

(VI)

 

wherein M is a metal counterion;

to form a compound of formula (VII);

 

or a salt form thereof; and

step (3), ionizing the compound of formula (VII) to form a compound of formula (I), or a pharmaceutically acceptable salt form thereof.

2. The process according to claim 1, wherein:

R¹ is CF₃;

R² is selected from ethene substituted with cyclopropyl and ethyne substituted with cyclopropyl;

R^3a is H;

R^3b is Cl;

R^3c and R^3d are H;

R^8a is CH₃;

R⁸ is phenyl;

M is a counter ion selected from Li⁺, Na⁺, K⁺, CuCl⁺, CuBr⁺, MgCl⁺, MgI⁺, and MgBr⁺; and

wherein;

step (1) comprises contacting the compound of formula (II) with the isocyanate of formula (III) in the presence of a first strong acid;

step (1-i) comprises cyclizing the compound of formula (II-a) by heating the compound of formula (II-a) to a temperature in the range of about 50°

C. to about 70°

C.;

step (2) comprises dehydrating the compound of formula (IV) by contacting the compound of formula (IV) with at least one equivalent of a dehydrating agent in the presence of suitable amount of a base;

step (2-i) comprises contacting the compound of formula (V) with the nucleophile of formula (VI) by adding the nucleophile of formula (VI) to the compound of formula (V) at a suitable temperature to form the compound of formula (VII); and

step (3) comprises ionizing the compound of formula (VII) by contacting the compound of formula (VII) with a second strong acid to form a compound of formula (I) or a pharmaceutically acceptable salt form thereof.

3. The process according to claim 2, wherein:

the first strong acid is selected from trifluoroacetic acid, formic acid, methanesulfonic acid, nitric acid, sulfuric acid, hydrochloric acid;

trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethyl silyl cyanide, triisopropylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triethylsilyl chloride, and trimethylsilyl trifluoromethanesulfonate;

the dehydrating agent is selected from methanesulfonyl chloride, thionyl chloride, acetyl chloride, and triphenylphosphine;

the amount of base in step (2) is in the range of about 2 to about 7 molar equivalents and the base is selected from triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, pyridine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, tetramethylethylenediamine, and N,N-dimethylaminopyridine;

the suitable temperature to form the compound of formula (VII) is less than 0°

C.; and

the second strong acid is selected from trifluoroacetic acid, formic acid, and methanesulfonic acid.

4. The process according to claim 3, wherein

the first strong acid is hydrochloric acid, the dehydrating agent is thionyl chloride, the base is triethylamine, and the second strong acid is formic acid.

5. The process according to claim 3, wherein the first strong acid is trimethylsilyl chloride.

6. The process according to claim 3, wherein the base is N-methylmorpholine.

7. The process according to claim 3, wherein:

the first strong acid is trimethylsilyl chloride, the dehydrating agent is thionyl chloride, the base is N-methylmorpholine, and the second strong acid is formic acid.

8. A process for the preparation of a compound of formula (VII):

or a salt form thereof;

wherein;

R¹ is C_1-3 alkyl substituted with 1-7 halogen;

R² is selected from C_1-5 alkyl substituted with 1-2 R⁴, C_2-5 alkenyl substituted with 1-2 R⁴, C_2-5 alkynyl substituted with 1 R⁴, and OR^2a;

R^2a is selected from C_1-4 alkyl;

R^3a is H;

R^3b is selected from H, C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, I, and NR⁵R^5a;

R^3c is selected from H, C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, I, and NR⁵R^5a;

R^3d is selected from H, C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, I, and NR⁵R^5a;

alternatively, R^3a and R^3b combine to form —

OCH₂O—

;

R⁴ is selected from C_3-5 cycloalkyl substituted with 0-2 R^4a, phenyl substituted with 0-5 R^4a, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 R^4a;

R^4a is selected from C_1-3 alkyl, Cl, Br, F, I, OCH₃, SCH₃, and NR⁵R^5a;

R⁵ and R^5a are independently selected from H and C_1-3 alkyl;

R^8a is selected from methyl, ethyl, propyl, and isopropyl;

R⁸ is selected from phenyl substituted with 0-3 R⁹, and naphthyl substituted with 0-3 R⁹; and

R⁹ is selected from C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, and I;

the process comprising;

step (2), dehydrating a compound of formula (IV)

 

to form a compound of formula (V);

step (2-i), contacting the compound of formula (V) with a nucleophile of formula (VI);

 

R²—

M 

 

(VI)

 

wherein M is a metal counterion;

to form a compound of formula (VII).

9. The process according to claim 8, wherein:

R¹ is CF₃;

R² is selected from ethene substituted with cyclopropyl and ethyne substituted with cyclopropyl;

R^3a is H;

R^3b is Cl;

R^3c and R^3d are H;

R^8a is CH₃;

R⁸ is phenyl; and

M is selected from Li⁺, Na⁺, K⁺, CuCl⁺, CuBr⁺, MgCl⁺, MgI⁺ and MgBr⁺.

10. The process according to claim 8, wherein the process is carried out in a suitable solvent, and further comprising crystallizing the compound of formula (VII) by contacting the suitable solvent with a crystallization solvent.

11. The process according to claim 8, wherein:

step (2) comprises dehydrating the compound of formula (IV) by contacting the compound of formula (IV) with at least one equivalent of a dehydrating agent in the presence of a suitable amount of base to form a compound of formula (V); and

step (2-i) comprises contacting the compound of formula (V) with the nucleophile of formula (VI) by adding the nucleophile of formula (VI) to the compound of formula (V) at a suitable temperature to form the compound of formula (VII).

12. The process according to claim 8, wherein:

step (2) further comprises;

a) contacting the compound of formula (IV) with at least one equivalent of a dehydrating agent in the presence of a base to form a compound of formula (V) and a precipitated amine salt of the base; and

b) separating the precipitated amine salt of the base from the compound of formula (V).

13. The process according to claim 8, wherein:

step (2) further comprises;

a) contacting the compound of formula (IV) with at least one equivalent of a dehydrating agent in the presence of a base to form a compound of formula (V) and a precipitated amine salt of the base; and

b) separating the precipitated amine salt of the base from the compound of formula (V) by filtration.

14. The process according to claim 11, wherein:

R¹ is CF₃;

R² is selected from ethene substituted with cyclopropyl and ethyne substituted with cyclopropyl;

R^3a is H;

R^3b is Cl;

R^3c and R^3d are H;

R^8a is CH₃;

R⁸ is phenyl; and

M is selected from Li⁺ and MgCl⁺.

15. The process according to claim 14, wherein:

the dehydrating agent is selected from methanesulfonyl chloride, thionyl chloride, acetyl chloride, and triphenylphosphine;

the amount of base is in the range of about 2 to about 7 molar equivalents and is selected from triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, pyridine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, tetramethylethylenediamine, and N,N-dimethylaminopyridine; and

the suitable temperature to form the compound of formula (VII) is less than 0°

C.

16. The process according to claim 8, further comprises:

step (3), ionizing the compound of formula (VII) to form a compound of formula (I);

or a pharmaceutically acceptable salt form thereof.

17. The process according to claim 16, wherein step (3) comprises contacting the compound of formula (VII) with a strong acid selected from trifluoroacetic acid, formic acid, and methanesulfonic acid to form a compound of formula (I) or a pharmaceutically acceptable salt form thereof.

18. The process according to claim 8, wherein the compound of formula (IV) is prepared by the process comprising:

step (1), contacting a compound of formula (II);

 

or a salt form or a hydrate of the salt form thereof;

with an isocyanate of formula (III);

 

to form a compound of formula (II-a);

 

or a salt form thereof; and

step (1-i), cyclizing the compound of formula (II-a) to form a compound of formula (IV).

19. The process according to claim 18, wherein:

R¹ is CF₃;

R² is selected from ethene substituted with cyclopropyl, and ethyne substituted with cyclopropyl;

R^3a is H;

R^3b is Cl;

R^3c and R^3d are H;

R^8a is CH₃;

R⁸ is phenyl;

M is MgCl⁺ or Li⁺; and

the compound of formula (II) is the hydrate of the hydrochloride salt.

20. The process according to claim 19, wherein step (1-i) comprises cyclizing the compound of formula (II-a) by heating the compound of formula (II-a) to a temperature in the range of about 50°

C. to about 70°

C.

21. The process according to claim 18, wherein step (1) comprises contacting the compound of formula(II) with the isocyanate of formula (III) in the presence of an acid selected from hydroiodic acid, hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, toluenesulfonic acid, benzene sulfonic acid, trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethyl silyl cyanide, triisopropylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triethylsilyl chloride, and trimethylsilyl trifluoromethanesulfonate.

22. A process for the preparation of a compound of formula (I):

wherein;

R¹ is selected from C_1-3 alkyl substituted with 1-7 halogen, and C_2-5 alkynyl substituted with 1 R⁴;

R² is selected from CF₃, C_1-5 alkyl substituted with 1-2 R⁴, C_2-5 alkenyl substituted with 1-2 R⁴, C_2-5 alkynyl substituted with 1 R⁴, and OR^2a;

R^2a is selected from C_1-4 alkyl;

R^3a is H;

R^3b is selected from H, C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, I, and NR⁵R^5a;

R^3c is selected from H, C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, I, and NR⁵R^5a;

R^3d is selected from H, C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, I, and NR⁵R^5a;

alternatively, R^3a and R^3b combine to form —

OCH₂O—

;

R⁴ is selected from C_3-5 cycloalkyl substituted with 0-2 R^4a, phenyl substituted with 0-5 R^4a, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 R^4a;

R^4a is selected from C_1-3 alkyl, Cl, Br, F, I, OCH₃, SCH₃, and NR⁵R^5a; and

R⁵ and R^5a are independently selected from H and C_1-3 alkyl;

the process comprising;

step (1), contacting a compound of formula (II);

 

or a salt form or a hydrate of the salt form thereof;

with an isocyanate of formula (III);

wherein;

R^8a is selected from methyl, ethyl, propyl, and isopropyl;

R⁸ is selected from phenyl substituted with 0-3 R⁹, and naphthyl substituted with 0-3 R⁹; and

R⁹ is selected from C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, and I;

to form a compound of formula (II-a);

 

or a salt form thereof;

step (1-i), cyclizing the compound of formula (II-a) to form a compound of formula (IV);

step (2), dehydrating the compound of formula (IV);

to form a compound of formula (V);

(2-i) contacting the compound of formula (V) with a nucleophile of formula (VI);

 

wherein M is a metal counterion;

to form a compound of formula (VII);

 

or a salt form thereof; and

step (3), ionizing the compound of formula (VII) to form a compound of formula (I), or a pharmaceutically acceptable salt form thereof.

23. A compound of formula (IV):

wherein;

R¹ is C_1-3 alkyl substituted with 1-7 halogen;

R² is selected from C_1-5 alkyl substituted with 1-2 R⁴, C_2-5 alkenyl substituted with 1-2 R⁴, C_2-5 alkynyl substituted with 1 R⁴, and OR^2a;

R^2a is selected from C_1-4 alkyl;

R^3a is H;

R^3b is selected from H, C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, I, and NR⁵R^5a;

R^3c is selected from H, C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, I, and NR⁵R^5a;

R^3d is selected from H, C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, I, and NR⁵R^5a;

alternatively, R^3a and R^3b combine to form —

OCH₂O—

;

R⁴ is selected from C_3-5 cycloalkyl substituted with 0-2 R^4a, phenyl substituted with 0-5 R^4a, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 R^4a;

R^4a is selected from C_1-3 alkyl, Cl, Br, F, I, OCH₃, SCH₃, and NR⁵R^5a;

R⁵ and R^5a are independently selected from H and C_1-3 alkyl;

R^8a is selected from methyl, ethyl, propyl, and isopropyl;

R⁸ is selected from phenyl substituted with 0-3 R⁹, and naphthyl substituted with 0-3 R⁹; and

R⁹ is selected from C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, and I.

24. The compound of formula (VII):

or a salt form thereof;

wherein;

R¹ is C_1-3 alkyl substituted with 1-7 halogen;

R² is selected from C_1-5 alkyl substituted with 1-2 R⁴, C_2-5 alkenyl substituted with 1-2 R⁴, C_2-5 alkynyl substituted with 1 R⁴, and OR^2a;

R^2a is selected from C_1-4 alkyl;

R^3a is H;

R^3b is selected from H, C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, I, and NR⁵R^5a;

R^3c is selected from H, C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, I, and NR⁵R^5a;

R^3d is selected from H, C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, I, and NR⁵R^5a;

alternatively, R^3a and R^3b combine to form —

OCH₂O—

;

R⁴ is selected from C_3-5 cycloalkyl substituted with 0-2 R^4a, phenyl substituted with 0-5 R^4a, and a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from O, N, and S, substituted with 0-2 R^4a;

R^4a is selected from C_1-3 alkyl, Cl, Br, F, I, OCH₃, SCH₃, and NR⁵R^5a;

R⁵ and R^5a are independently selected from H and C_1-3 alkyl;

R^8a is selected from methyl, ethyl, propyl, and isopropyl;

R⁸ is selected from phenyl substituted with 0-3 R⁹, and naphthyl substituted with 0-3 R⁹; and

R⁹ is selected from C_1-4 alkyl, C_1-4 alkoxy, F, Cl, Br, and I.

25. The compound according to claim 24, wherein the compound of formula (VII) is (VII-i):

or a salt form thereof.