Claims
- 1. A method of preparing a compound of the formula whereinR1 and R3 are methyl, R2 is hydrogen, R4 is —NHCO—R6, R6 is selected from the group consisting of C1-C12 alkyl, cyclo C3-C6 alkyl, cyclo C3-C6 alkyl C1-C3 alkyl, phenyl, naphthyl, phenyl C1-C4 alkyl, naphthyl C1-C4 alkyl, pyriolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C1-C8 alkyl, piperidyl C1-C8 alkyl, piperidino C1-C8 alkyl, morpholinyl C1-C8 allyl, morpholino C1-C8 alkyl, piperazinyl C1-C8 alkyl, pyrrolyl C1-C8 alkyl, imidazolyl C1-C8 alkyl, pyridyl C1-C8 alkyl (wherein any of the foregoing is unsubstituted or substituted with a C1-C4 alkyl, amino, hydroxy, di(C1-C4)alkylamino, C1-C4 aminoalkyl, C1-C4 alkoxy, carboxyl, C1-C4 alkoxycarbonyl, C1-C4 carboxyalkyl, C2-C5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C1-C4)alkylamino), —RASO3A, —RBPO3B where RA and RB are each alkylene and A and B are each alkali metal or hydrogen atom, —NR7R8 where R7 is selected from the group consisting of C1-C12 alkyl, cyclo C3-C6 alkyl, cyclo C3-C6 alkyl C1-C3 alkyl, phenyl, naphthyl, phenyl C1-C4 alkyl, and naphthyl C1-C4 alkyl (wherein any of the foregoing is optionally substituted with a C1-C4 alkyl, amino, hydroxy, di(C1-C4)alkylamino, C1-C4 aminoalkyl, C1-C4 alkoxy, carboxyl, C1-C4 alkoxycarbonyl, C1-C4 carboxyalkyl, C2-C5 acyloxy, phenyl, phenoxy, halogen, or phenyl (C1-C4)dialkylamino), and R8 is hydrogen atom or C1-C4 alkyl, or —R9—OCOR10 where R9 is alkylene and R10 is selected from the group consisting of C1-C12 alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C1-C8 alkyl, piperidyl C1-C8 alkyl, piperidino C1-C8 alkyl, morpholinyl C1-C8 alkyl, morpholino C1-C8 alkyl, piperazinyl C1-C8 alkyl, pyrrolyl C1-C8 alkyl, imidazolyl C1-C8 alkyl, pyridyl C1-C8 alkyl (wherein any of the foregoing is optionally substituted with a C1-C4 alkyl, amino, hydroxy, C1-C4 dialkylamino, C1-C4 aminoalkyl, C1-C4 alkoxy, carboxyl, C1-C4 alkoxycarbonyl, C1-C4 carboxyalkyl, C2-C5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C1-C4)alkylamino), and the remaining three of R1, R2, R3, or R4 may be the same or different and each is independently a hydrogen atom, a C1-C4 alkyl or a C1-C4 alkoxy, R5 is selected from the group consisting of C1-C12 alkyl, cyclo C3-C6 alkyl, cyclo C3-C6 alkyl C1-C3 alkyl, phenyl, naphthyl, phenyl C1-C4 alkyl, naphthyl C1-C4 alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C1-C8 alkyl, piperidyl C1-C8 alkyl, piperidino C1-C8 alkyl, morpholinyl C1-C8 alkyl, morpholino C1-C8 alkyl, piperazinyl C1-C8 alkyl, pyrrolyl C1-C8 alkyl, imidazolyl C1-C8 alkyl, pyridyl C1-C8 alkyl (wherein any of the foregoing is optionally substituted with a C1-C4 alkyl, amino, hydroxy, C1-C4 dialkylamino, C1-C4 aminoalkyl, C1-C4 alkoxy, carboxyl, C1-C4 alkoxycarbonyl, C1-C4 carboxyalkyl, C2-C5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C1-C4)alkylamino), an alkenyl, an alkynyl, a dialkylaminoacyloxyalkyl, —RDSO3D or —REPO3E where RD and RE are each alkylene and D and E are each alkali metal or hydrogen atom, and m is 1, said method comprising: providing 1-acetyl-5-bromo4,6dimethylindoline; introducing a nitro substituent to the 7- position of said 1-acetyl-5-bromo-4,dimethylindoline; reducing said nitro substituent to an amino substituent; converting said amino substituent to an amide group of the formula R6C(O)—, wherein R6 is as defined above, reductively removing the bromine atom at the 5-position; and removing the acetyl substituent at the 1-position and thereafter covalently bonding R5 to the indoline nitrogen at the 1-position.
- 2. The method of claim 1, wherein said amino substituent is converted to an amide group of the formula R6C(O)— by reacting said amino with an acid of the formula R6CO2H or an acid halide of the formula R6COX, wherein X is a halogen atom.
- 3. The method of claim 2, wherein X is chloride.
- 4. The method of claim 1, wherein said amino substituent is converted to an amide group of the formula R6C(O)— by converting said amino group to an isocyanate and reacting said isocyanate with an amine of the formula HNR7R8.
- 5. The method of claim 1, wherein said amino substituent is converted to an amide group of the formula R6C(O)— by reacting the amino group with an isocyanate of the formula R7—NCO.
- 6. The method of claim 1, wherein said acetyl is removed via base hydrolysis.
- 7. The method of claim 6, wherein said base is hydroxide ion.
- 8. The method of claim 1, wherein said R5 is covalently bonded to said indoline nitrogen by reacting said indoline nitrogen with a compound of the formula R5X, wherein X is a halogen atom.
- 9. The method of claim 8, wherein R5 is unsubstituted.
- 10. The method of claim 8, wherein R5 is substituted with alkyl, amino, hydroxy, dialkylamino, aminoalkyl, alkoxy, carboxyl, alkoxycarbonyl, carboxyalkyl, acyloxy, phenyl, phenoxy or halogen.
- 11. The method of claim 1, wherein said bromine atom at the 5-position is reductively removed in the presence of a catalyst.
- 12. The method of claim 11, wherein said catalyst is palladium.
- 13. The method of claim 1, wherein said nitro substituent is reduced to an amino substituent, and said bromine atom at the 5-position is reductively removed, in one step.
- 14. The method of claim 13, wherein said amino substituent is converted to an amide group of the formula R6C(O)—by reacting the amino at the 7-position with an acid halide of the formula R6COX, wherein X is a halogen atom.
- 15. The method of claim 14, wherein said amino substituent is converted to an amide group of the formula R6C(O)— by converting the amino at the 7-position to an isocyanate and reacting said isocyanate with an amine of the formula HNR7R8.
- 16. A method of preparing a compound of the formula whereinR1 and R3 are methyl, R2 is hydrogen, R4 is —NHCO—R6, R5 is acetyl, R6 is selected from the group consisting of C1-C12 alkyl, cyclo C3-C6 alkyl, cyclo C3-C6 alkyl C1-C3 alkyl, phenyl, naphthyl, phenyl C1-C4 alkyl, naphthyl C1-C4 alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C1-C8 alkyl, piperidyl C1-C8 alkyl, piperidino C1-C8 alkyl, morpholinyl C1-C8 alkyl, morpholino C1-C8 alkyl, piperazinyl C1-C8 alkyl, pyrrolyl C1-C8 alkyl, imidazolyl C1-C8 alkyl, pyridyl C1-C8 alkyl (wherein any of the foregoing is unsubstitated or substituted with a C1-C4 alkyl, amino, hydroxy, di(C1-C4)alkylamino, C1-C4 aminoalkyl, C1-C4 alkoxy, carboxyl, C1-C4 alkoxycarbonyl, C1-C4 carboxyalkyl, C2-C5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C1-C4)alkylamino), —RASO3A, —RBPO3B where RA and RB are each alkylene and A and B are each alkali metal or hydrogen atom, —NR7R8 where R7 is selected from the group consisting of C1-C12 alkyl, cyclo C3-C6 alkyl, cyclo C3-C6 alkyl C1-C3 alkyl, phenyl, naphthyl, phenyl C1-C4 alkyl, and naphthyl C1-C4 alkyl (wherein any of the foregoing is optionally substituted with a C1-C4 alkyl, amino, hydroxy, di(C1-C4)alkylamino, C1-C4 aminoalkyl, C1-C4 alkoxy, carboxyl, C1-C4 alkoxycarbonyl, C1-C4 carboxyalkyl, C2-C5 acyloxy, phenyl, phenoxy, halogen, or phenyl (C1-C4)dialkylamino), and R8 is hydrogen atom or C1-C4 alkyl, or —R9—OCOR10 where R9 is alkylene and R10 is selected from the group consisting of C1-C12 alkyl, pyrrolidinyl, piperidyl, piperidino, morpholinyl, morpholino, piperazinyl, pyrrolyl, imidazolyl, pyridyl, pyrrolidinyl C1-C8 alkyl, piperidyl C1-C8 alkyl, piperidino C1-C8 alkyl, morpholinyl C1-C8 alkyl, morpholino C1-C8 alkyl, piperazinyl C1-C8 alkyl, pyrrolyl C1-C8 alkyl, imidazolyl C1-C8 alkyl, pyridyl C1-C8 alkyl (wherein any of the foregoing is optionally substituted with a C1-C4 alkyl, amino, hydroxy, C1-C4 dialkylamino, C1-C4 aminoalkyl, C1-C4 alkoxy, carboxyl, C1-C4 alkoxycarbonyl, C1-C4 carboxyalkyl, C2-C5 acyloxy, phenyl, phenoxy, halogen, or phenyl di(C1-C4)alkylamino), and the remaining three of R1, R2, R3, or R4 may be the same or different and each is independently a hydrogen atom, a C1-C4 alkyl or a C1-C4 alkoxy, and m is 1, said method comprising:providing 1-acetyl-5-bromo4,6-dimethylindoline; introducing a nitro substituent to the 7-position of said 1-acetyl-5-bromo4,6-dimethylindoline; reducing said nitro substituent to an amino substituent; converting said amino substituent to an amide group of the formula R6C(O)—, wherein R6 is as defined above; and reductively removing the bromine atom at the 5-position.
Priority Claims (1)
Number |
Date |
Country |
Kind |
6-225166 |
Sep 1994 |
JP |
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Parent Case Info
This is a divisional of application Ser. No. 08/809,242, filed on Mar. 19, 1997 U.S. Pat. No. 5,990,150 which is a PCT/JP95/018 Sep. 26, 1995.
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