Method for synthesizing diaryl-substituted heterocyclic compounds, including tetrahydrofurans

• US 6,255,498 B1
• Filed: 10/16/1998
• Issued: 07/03/2001
• Est. Priority Date: 10/16/1998
• Status: Expired due to Fees

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Chorghade, Mukund S., Rao, Vemuri Venkata Kiran, Rao, Alla Verkata Rama, Prasad, Anegondi Sreenivasa, Islam, Amin ul
• Primary Examiner(s): OWENS, AMELIA A
• Application Number:
  US09/173,918
• Time in Patent Office: 991 Days
• Field of Search: 549/80, 549/429, 546/268.1
• US Class Current: 549/429
• CPC Class Codes: C07C 319/20 by reactions not involving the formation of sulfide groups
• CPC Class Codes: C07C 323/19 with singly-bound oxygen atoms bound to acyclic carbon atoms of the carbon skeleton
• CPC Class Codes: C07C 45/63 by introduction of halogen; by substitution of halogen atoms by other halogen atoms
• CPC Class Codes: C07C 45/71 being hydroxy groups
• CPC Class Codes: C07C 49/84 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07D 307/12 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 307/14 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/16 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

A method is provided for synthesizing diaryl-substituted heterocyclic compounds, particularly 2,5-diaryl-substituted tetrahydrofurans and tetrahydrothiophenes. Methods for synthesizing starting materials and intermediates are provided as well. An important application of the invention is in the synthesis of CMI-392, (±) trans-2-[5-(N′-methyl-N′-hydroxyureidyl-methyl)-3-methoxy-4-p-chlorophenylthioethoxyphenyl]-5-(3,4,5-thrimethoxyphenyl)-tetrahydrofuran, a highly effective agent in treating inflammatory and immune disorders. The invention also encompasses novel compounds useful as starting materials and intermediates in the synthetic processes disclosed.

Claims

1. A process for preparing a compound having the structural formula (I)

in which Ar¹ and Ar² are selected from the group consisting of aryl, aralkyl, heteroaryl and heteroaralkyl, optionally substituted with 1 to 3 substituents, and Q is O or S, the process comprising:

(a) catalytically coupling a compound having the structure (II)

to a compound having the structure (III)

under reaction conditions effective to produce the diaryl-substituted dione or dithione intermediate (IV)

(b) treating compound with a reducing agent, thereby providing compound (V)

(c) effecting cyclization of compound (V), under acidic conditions, to produce cyclized intermediate (VI)

as a racemic mixture of cis and trans isomers; and

(d) isomerizing the cis isomer in the racemic mixture to give the trans isomer by dissolving the racemic mixture in a crystallization solvent, seeding the solvent with trans isomer, and cooling the mixture to promote crystallization, thereby effecting cis-trans isomerization.

2. The process of claim 1, wherein Q is O.

3. The process of claim 1, wherein Q is S.

4. The process of claim 1, wherein Ar¹ and Ar² are independently selected from the group consisting of phenyl and pyridinyl, either unsubstituted or substituted at least one substituent selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, —

OR¹, —

(CH₂)_nOR¹, —

O(CH₂)_nOR¹, —

SR¹, —

(CH₂)_n,SR¹, —

S(CH₂)_nSR¹, —

COOR¹, —

(CO)R¹, —

NR²R³, —

(CO)NR²R³, —

O(CO)NR²R³, and —

CN, wherein R¹, R² and R³ are independently hydrogen, alkyl or aryl, m is 1, 2 or 3, and n is an integer in the range of 1 to 6.

5. The process of claim 1, further comprising, after either or both of step (c) and step (d), chemically modifying Ar¹, Ar², or both Ar¹ and Ar² to produce Ar³ and where Ar³ is as defined for Ar¹.

6. A process for preparing a compound having the structural formula (Ia)

in which Ar¹ and Ar³ are selected from the group consisting of aryl, aralkyl, heteroaryl and heteroaralkyl, substituted with 1 to 3 substituents, and Q is O or S, the process comprising:

(a) catalytically coupling a compound having the structure (II)

to a compound having the structure (III)

in which Ar² is defined as for Ar¹ and Ar³, under conditions effective to produce the diaryl-substituted dione or dithione intermediate (IV)

(b) treating compound (IV) with a reducing agent, thereby providing compound (V)

(c) effecting cyclization of compound (V), under acidic conditions, to produce cyclized intermediate (VI)

as a racemic mixture of cis and trans isomers;

(d) chemically modifying Ar² to give Ar³, thus providing compound (VIa)

as a racemic mixture of cis and trans isomers; and

(e) isomerizing the cis isomer in the racemic mixture of (VIa) to give the trans isomer by dissolving the racemic mixture of (VIa) in a crystallization solvent seeding the solvent with trans (VIa), and cooling the mixture to promote crystallization, thereby effecting cis-trans isomerization.

7. The process of claim 6, wherein Ar¹ is

Ar² is

and Ar³ is

so that compound (Ia) is

wherein:

the W are independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, —

OR¹, —

(CH₂)_nOR¹, —

O(CH₂)_n—

OR¹, —

SR¹, —

(CH₂)_nSR¹, —

S(CH₂)_nSR¹,—

COOR¹, —

(CO)R¹, —

NR²R³, —

(CO)NR²R³, —

O(CO)NR²R³, and —

CN, wherein R¹, R² and R³ are independently hydrogen, alkyl or aryl m is 1, 2 or 3, and n is an integer in the range of 1 to 6;

X is defined as for W;

Y is

in which p is 2 or 3, q is 1, 2, 3 or 4, R⁴ is S or SO₂, and R⁵ is lower alkyl, lower alkoxy or halogen;

R is halogen or —

COOR′

wherein R′

is lower alkyl; and

Z is

in which r is 0 or 1, R⁶ is H or OH, R⁷ is H or OH, and R⁸ is lower alkyl.

8. The process of claim 7, wherein Q is O, Ar¹ is

Ar³ is

in which the * represent the points of binding and Hal is Cl or F.

9. A process for preparing a compound having the structural formula (I)

in which Ar¹ and Ar² are selected from the group consisting of aryl, aralkyl, heteroaryl and heteroaralkyl, optionally substituted with 1 to 3 substituents, and Q is O or S, the process comprising:

(a) treating the diaryl-substituted dione or dithione (IV)

with a reducing agent thereby providing compound (V)

(b) effecting cyclization of compound (V), under acidic conditions, to produce cyclized intermediate (VI)

as a racemic mixture of cis and trans isomers; and

(c) isomerizing the cis isomer in the racemic mixture to give the trans isomer by dissolving the racemic in a crystallization solvent, seeding the solvent with trans isomer, and cooling the mixture to promote crystallization, thereby effecting cis-trans isomerization.

10. The process of claim 9, wherein Q is O.

11. The process of claim 9, wherein Q is S.

12. The process of claim 9, wherein Ar¹ and Ar² are independently selected from the group consisting of phenyl and pyridinyl, either unsubstituted or substituted at least one substituent selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, —

OR¹, —

(C₂)_nOR¹, —

O(CH₂)_nOR¹, —

SR¹, —

(CH₂)_n, SR¹m —

S(CH₂)_nSR¹, —

COOR¹, —

(CO)R¹, —

NR²R³, —

(CO)NR²R³, —

O(CO)NR²R³, and —

CN, wherein R¹, R² and R³ are independently hydrogen, alkyl or aryl m is 1, 2 or 3, and n is an integer range of 1 to 6.

13. The process of claim 9, further comprising, after either or both of step (b) and step (c), chemically modifying Ar¹, Ar², or both Ar¹ and Ar² to produce Ar³ and where Ar³ is as defined for Ar¹.

14. A process for preparing a compound having the structural formula (Ia)

in which Ar¹ and Ar³ are selected from the group consisting of aryl, aralkyl, heteroaryl and heteroaralkyl, substituted with 1 to 3 substituents, and Q is O or S, the process comprising:

(a) treating the diaryl-substituted dione or dithione (IV)

in which Ar² is defined as for Ar¹ and Ar³, with a reducing agent, thereby providing compound (V)

(b) effecting cyclization of compound (V), under acidic conditions, to produce cyclized intermediate (VI)

as a racemic mixture of cis and trans isomers;

(c) chemically modifying Ar² to give Ar³, thus providing compound (VIa)

as a racemic mixture of cis and trans isomers; and

(d) isomerizing the cis isomer in the racemic mixture of (VIIa) to give the trans isomer by dissolving the racemic mixture of (VIa) in a crystallization solvent, seeding the solvent with trans (VIa), and cooling the mixture to promote crystallization, thereby effecting cis-trans isomerization.

15. The process of claim 14, wherein Ar¹ is

Ar² is

and Ar³ is

so that compound (Ia) is

wherein:

the W are independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, —

OR¹, —

(CH₂)_nOR¹, —

O(CH₂)_nOR¹, —

SR¹, —

(CH₂)_nSR¹, —

COOR¹, —

(CO)R¹, —

NR²R³, —

(CO)N²R³R, —

O(CO)NR²R³, and —

CN, wherein R¹, R² and R³ are independently hydrogen, or m is 1, 2 or 3, and n is an integer in the range of 1 to 6;

X is defined as for W;

Y is

in which p is 2 or 3, q is 1, 2, 3 or 4, R⁴ is S or SO₂, and R⁵ is lower alkyl, lower alkoxy or halogen;

R is halogen or —

COOR′

wherein R′

is lower alkyl, and

Z is

in which r is 0 or 1, R⁶ is H or OH, R⁷ is H or OH, and R⁸ is lower alkyl.

16. The process of claim 15, wherein Q is O, Ar¹ is

Ar³ is

in which the * represent points of binding and Hal is Cl or F.