This application is a 371 of PCT/JP01/06145 filed Jul. 16, 2001.
The present invention relates to production methods of intermediates for 1-substituted-1,2,3-triazole compounds having an inhibitory action on growth factor receptor tyrosine kinases (especially HER2) useful as pharmaceutical agents.
As a production method of an intermediate for a 1-substituted-1,2,3-triazole compound having a tyrosine kinase inhibitory action, for example, there is mentioned a method comprising condensing compound (1) of the following formula and compound (2) of the following formula in the presence of a base in a solvent inert to the reaction (e.g., aromatic hydrocarbons such as benzene, toluene, xylene etc., ethers such as tetrahydrofuran, dioxane etc., ketones such as acetone, 2-butanone etc., halogenated hydrocarbons such as chloroform, dichloromethane etc., N,N-dimethylformamide, dimethyl sulfoxide, and a mixed solvent of these) to give the objective compound (3) (JP-A-11-60571, WO 98/03505): 
wherein W1 is a leaving group, R0 is an optionally substituted aromatic heterocyclic group, X1 is an oxygen atom, an optionally oxidized sulfur atom, xe2x80x94C(=O)xe2x80x94or xe2x80x94CH(OH)xe2x80x94, Y1 is CH or N, ml is an integer of 0 to 10, n1 is an integer of 1 to 5, the cyclic group 
is an optionally substituted aromatic azole group and the ring A1 may be further substituted.
In addition, as a production method of a 1-alkyl-1,2,3-triazole compound, for example, there is mentioned a method comprising reacting the compound (b2) of the following formula and the compound (b3) of the following formula in the presence or absence of a base (JP-A-5-170763): 
wherein R1, R2, R3, R4 and R8 are the same or different and each is a hydrogen atom or a lower alkyl group, R2 and R3 in combination may form, together with the carbon atoms to which they are bonded, a cyclopentane ring or a cyclohexane ring, R5, R6 and R7 are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted by halogen atom(s) or a lower alkoxy group optionally substituted by halogen atom(s), Y2 is a halogen atom, a lower alkyl sulfonyloxy group or an aryl sulfonyloxy group, and R9 is a 5 or 6-membered heterocyclic group having 1 to 3 nitrogen atom(s), and wherein a 1H-1,2,4-triazole group is excluded and the heterocyclic group is optionally substituted by 1 to 3, the same or different halogen atom(s), lower alkyl group(s) or lower alkoxy group(s).
The aforementioned conventional production methods pose problems in that they show low reaction selectivity, and therefore, a low yield. A method using a silver salt of 1H-1,2,3-triazole shows fine selectivity but requires expensive starting materials. Therefore, there is a demand for an industrially advantageous production method of an intermediate for a 1-substituted-1,2,3-triazole compound having an inhibitory action on growth factor receptor tyrosine kinases (especially HER2).
As a production method for obtaining a 1,2,3-triazole compound useful as a starting material of pharmaceutical agents or an intermediate for printing, image processing agents, by the use of a hydrazone derivative, there is known, for example, a method comprising reacting compound (c1) of the following formula and compound (c2) under neutral or basic conditions to give compound (3) (JP-A-8-53425): 
In the above formulas, R1c is a lower alkyl group optionally substituted by halogen atom(s), a phenyl group wherein benzene ring is optionally substituted by at least one substituent selected from halogen atom, lower alkyl group and lower alkoxy group, a benzyl group wherein benzene ring is optionally substituted by at least one substituent selected from halogen atom, lower alkyl group and lower alkoxy group, a lower alkylamino group wherein alkyl group is optionally substituted by halogen atom, a phenylamino group wherein benzene ring is optionally substituted by at least one substituent selected from halogen atom, lower alkyl group and lower alkoxy group, an ammonium group that forms a salt with an inorganic acid or a carboxyl group that forms a salt with ammonia; X is a halogen atom; R2c and R3c are each a hydrogen atom or a lower alkyl group optionally substituted by halogen atom(s); and R4c is a lower alkyl group optionally substituted by halogen atom(s) or a phenyl group wherein benzene ring is optionally substituted by at least one substituent selected from halogen atom, lower alkyl group and lower alkoxy group.
As a production method of an amine compound such as the above-mentioned compound (c1), there is known a method comprising reacting phthalimide butyryl chloride and chlorobenzene in the presence of anhydrous aluminum chloride, and treating the obtained 4-chloro-4-phthalimide butyrophenone with acetic acid and hydrochloric acid to give 4-chloro-4-aminobutyrophenone hydrochloride [Journal of Medicinal Chemistry (J. Med. Chem.), vol. 9, pp. 945-949 (1966)].
The conventional production method for obtaining the aforementioned compound (c3) showed lower yield from the compound (c1). A conventional production method for obtaining an amine compound, such as compound (c1), poses a problem in that it requires many steps. Therefore, there is a demand for an industrially advantageous production method of an intermediate for a 1-substituted-1,2,3-triazole compound having an inhibitory action on growth factor receptor tyrosine kinase (especially, HER2).
The present inventors have studied various production methods of 1-substituted-1,2,3-triazole derivatives, and first found that a reaction in a secondary or tertiary alcohol in the presence of a base or a reaction in the absence of a base unexpectedly results in the selective production of the objective 1-substituted-1,2,3-triazole derivative in a high yield, and that this production method is fully satisfactory on an industrial scale, based on which they intensively investigated and completed the present invention.
They have also found that a reaction of an alkylamine compound and a hydrazone derivative, followed by a treatment with a base, unexpectedly results in the selective production of the objective 1-substituted-1,2,3-triazole derivative in a high yield, and that this production method is fully satisfactory on an industrial scale, based on which they intensively investigated and completed the present invention.
Further, the present inventors have found that a production method via a protected 4-hydroxymethyloxazole compound as an intermediate unexpectedly results in the production of the objective product in a high yield, and that this production method is fully satisfactory on an industrial scale, based on which they intensively investigated and completed the present invention.
Accordingly, the present invention provides the following.
1. A method for producing a compound of the formula: 
wherein
Ra1 and Ra2 are each a hydrogen atom, a substituted hydroxy, a substituted thiol, a substituted amino, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl;
Ra3 is a group of the formula: 
xe2x80x83wherein Ra4 and Ra5 are each a hydrogen atom, an optionally substituted hydroxy, an optionally substituted thiol, an optionally substituted amino, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl, or Ra4 and Ra5 in combination form oxo, Ra6 is an optionally substituted aromatic group, and ma is an integer of 0 to 10; or
two or three from Ra1, Ra2 and Ra3 form an optionally substituted ring, together with the adjacent carbon atom; and
Ra7 and Ra8 are each a hydrogen atom, a halogen, an optionally substituted hydroxy, an optionally substituted thiol, an optionally substituted amino, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl,
which method comprises reacting a compound of the formula: 
wherein Xa is a leaving group and other symbols are as defined above, or a salt thereof [hereinafter to be also referred briefly to as compound (aII)] and a compound of the formula: 
wherein each symbol is as defined above, or a salt thereof,
(1) in a secondary or tertiary alcohol in the presence of a base, or
(2) in the absence of a base.
2. The production method of the aforementioned 1, which comprises reaction in a secondary or tertiary alcohol in the presence of a base.
3. The production method of the aforementioned 1, which comprises reaction in a tertiary alcohol in the presence of a base.
4. The production method of 1 above, wherein Ra1 is a hydrogen atom.
5. The production method of 1 above, wherein Ra1 and Ra2 are each a hydrogen atom.
6. The production method of 1 above, wherein Ra3 is a group of the formula: 
wherein each symbol is as defined in the aforementioned 1.
7. The production method of 6 above, wherein Ra4 and Ra5 are each a hydrogen atom.
8. The production method of 6 above, wherein Ra6 is an optionally substituted phenyl.
9. The production method of 6 above, wherein ma is 3.
10. The production method of 1 above, wherein Ra7 and Ra8 are each a hydrogen atom.
11. A salt of a compound of the formula: 
12. A compound of the formula: 
wherein Xaxe2x80x2 is a halogen atom, OSO2Ra or OCORa wherein Ra is an optionally substituted hydrocarbon group [hereinafter to be referred to as compound (aIIa)].
13. A method for producing compound (aIIa), which comprises reacting a compound of the formula: 
wherein Ma is a hydrogen atom, an alkali metal atom or an alkaline earth metal atom [hereinafter to be referred to as compound (aIIxe2x80x2)], and 1) thionyl halide [hereinafter to be referred to as compound (aa)], 2) oxalyl halide [hereinafter to be referred to as compound (ab)], 3) a compound of the formula:
RaSO2Xa or (RaSO2)2O
wherein Ra is an optionally substituted hydrocarbon group and Xa is a leaving group [hereinafter to be referred to as compound (ac)] or 4) a compound of the formula:
RaCOXa or (RaCO)2O
wherein Ra and Xa are as defined above [hereinafter to be referred to as compound (ad)] under basic conditions.
14. A compound of the formula: 
or a salt thereof [hereinafter to be also referred to as compound (aIe)].
15. The production method of the aforementioned 1 wherein Ra1, Ra2, Ra7 and Ra8 are each a hydrogen atom and Ra3 is 3-[4-(t-butoxyphenyl)]propyl.
16. A method for producing a compound of the formula: 
which comprises reacting a compound of the formula: 
wherein Ma is a hydrogen atom, an alkaline metal atom or an alkaline earth metal atom, and 1) thionyl halide, 2) oxalyl halide, 3) a compound of the formula:
RaSO2Xa or (RaSO2)2O
wherein Ra is an optionally substituted hydrocarbon group and Xa is a leaving group or 4) a compound of the formula:
RaCOXa or (RaCO)2O
wherein Ra and Xa are as defined above, under basic conditions to give a compound of the formula: 
wherein Xaxe2x80x2 is a halogen atom, OSO2Ra or OCORa wherein Ra is as defined above, and reacting this compound with a compound of the formula: 
or a salt thereof, (1) in the presence of a base in a secondary or tertiary alcohol, or
(2) in the absence of a base to give a compound of the formula: 
and deprotecting this compound.
17. A method for producing a compound of the formula: 
which comprises deprotecting a compound of the formula: 
18. A method for producing a compound of the formula: 
which comprises deprotecting a compound of the formula: 
19. A method for producing a compound of the formula: 
wherein Rb1, Rb2 and Rb3 are each a hydrogen atom, an optionally substituted hydroxy, an optionally substituted thiol, an optionally substituted amino, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl, or two or three from Rb1, Rb2 and Rb3 form, together with the adjacent carbon atom, an optionally substituted ring, and Rb4 and Rb5 are each a hydrogen atom, an optionally substituted hydroxy, an optionally substituted thiol, an optionally substituted amino, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl, and Rb6 is an optionally substituted alkyl or an optionally substituted phenyl, or a salt thereof [hereinafter to be also referred to as compound (bI)], which comprises reacting a compound of the formula: 
wherein each symbol is as defined above, or a salt thereof [hereinafter to be also referred to as compound (bII)] and a compound of the formula: 
wherein Xb1 and Xb2 are each a halogen, and Rb4, Rb5 and Rb6 are as defined above, or a salt thereof, [hereinafter also to be referred to as compound (bIII)] and treating the reaction mixture with a base.
20. The production method of 19 above, wherein Rb1 is a hydrogen atom.
21. The production method of 19 above, wherein Rb1 and Rb2 are each a hydrogen atom.
22. The production method of the aforementioned 19, wherein Rb3 is a group of the formula: 
wherein Rb7 and Rb8 are each a hydrogen atom, an optionally substituted hydroxy, an optionally substituted thiol, an optionally substituted amino, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl, or Rb7 and Rb8 in combination form oxo, Rb9 is an optionally substituted aromatic group, and mb is an integer of 0 to 10.
23. The production method of 22 above wherein Rb7 and Rb8 are each a hydrogen atom, Rb9 is an optionally substituted phenyl, and mb is 3.
24. The production method of 23 above wherein Rb1 and Rb2 are each a hydrogen atom.
25. The production method of 19 above wherein Rb4 and Rb5 are each a hydrogen atom.
26. The production method of 19 above wherein Rb6 is a phenyl substituted by alkyl.
27. A method for producing a compound of the formula: 
wherein, Rb10 is an optionally substituted amino, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an acyl, Rb11 is a substituent, nb is an integer of 0 to 4, and Rb12 is an optionally substituted alkylene, an optionally substituted alkenylene or an optionally substituted alkynylene, or a salt thereof, which comprises reacting a compound of the formula: 
wherein each symbol is as defined above, or a salt thereof [hereinafter to be also referred to as compound (bIV)] and a compound of the formula:
HOOCxe2x80x94Rb12xe2x80x94NH2xe2x80x83xe2x80x83(bV)
wherein Rb12 is as defined above, a salt thereof or a reactive derivative thereof [hereinafter to be also referred to as compound (bV)].
28. A method for producing a compound of the formula: 
wherein each symbol is as defined above, or a salt thereof [hereinafter to be also referred to as compound (bVII)], which comprises reacting compound (bIV) and compound (bV), and reducing the obtained compound (bVI) or a salt thereof.
29. A method for producing a compound of the formula: 
wherein each symbol is as defined above, or a salt thereof [hereinafter to be also referred to as compound (bVIII)], which comprises reacting compound (bIV) and compound (bV), reducing the obtained compound (bVI) or a salt thereof, reacting the obtained compound (bVII) and compound (bIII), and treating the reaction mixture with a base.
30. The production method of 29 above, wherein Rb4 and Rb5 are each a hydrogen atom, Rb10 is a C1-3 alkyl, Rb12 is a trimethylene and nb is 0.
31. A trifluoromethanesulfonate of a compound of the formula: 
wherein Rb12xe2x80x2 is trimethylene and other symbols are as defined in the aforementioned 27.
32. A method for producing a compound of the formula: 
wherein Arc is an optionally substituted aromatic group, Rc1 and Rc2 are each a hydrogen atom or a lower alkyl, Rc3 and Rc4 are each a hydrogen atom or a lower alkyl, Yc is C, S or SO and Rc5 is a hydrogen atom, a lower alkyl, an optionally substituted phenyl, an optionally substituted benzyloxy or an optionally substituted benzylamino, or a salt thereof [hereinafter to be also referred to as compound (cIV)], which comprises reacting a reaction mixture of a compound of the formula: 
wherein each symbol is as defined above, or a salt thereof [hereinafter to be also referred to as compound (cI)] and a compound of the formula: 
wherein Xc1 and Xc2 are each a halogen, and other symbols are as defined above, or a salt thereof [hereinafter to be also referred to as compound (cII)] with a compound of the formula: 
wherein Mc is a hydrogen atom or a metal, and other symbols are as defined above, or a salt thereof [hereinafter to be also referred to as compound (cIII)].
33. The production method of 32 above, wherein Arc is 4-trifluoromethylphenyl.
34. The production method of 32 above, wherein Rc1, Rc2, Rc3 and Rc4 are each a hydrogen atom and Rc5 is methyl.
36. A method for producing a compound of the formula: 
wherein each symbol is as defined above, or a salt thereof [hereinafter to be also referred to as compound (cVII)], which comprises subjecting compound (cIV) to hydrolysis or catalytic reduction, subjecting the obtained compound of the formula: 
wherein each symbol is as defined above, or a salt thereof [hereinafter to be also referred to as compound (cV)] to sulfonylation or halogenation, and reacting the compound with a compound of the formula: 
wherein nc is an integer of 1 to 10, or a salt thereof [hereinafter to be also referred to as compound (cVI)].
37. The production method of 36 above, wherein Arc is 4-trifluoromethylphenyl.
38. The production method of 36 above, wherein Rc1, Rc2, Rc3 and Rc4 are each a hydrogen atom, Rc5 is methyl and nc is 4.
39. A method for producing compound (cVII) or a salt thereof, which comprises reacting a reaction mixture of compound (cI) and compound (cII) with compound (cIII), subjecting the resulting compound to hydrolysis or catalytic reduction, subjecting the obtained compound (cV) to sulfonylation or halogenation, and reacting the compound with compound (cVI).
40. The production method of 39 above, wherein Arc is 4-trifluoromethylphenyl.
41. The production method of 39 above, wherein Rc1, Rc2, Rc3 and Rc4 are each a hydrogen atom, Rc5 is methyl and nc is 4.
42. A method for producing a compound of the formula: 
wherein each symbol is defined above, or a salt thereof, which comprises subjecting a reaction mixture of a compound of the formula: 
wherein each symbol is as defined in the aforementioned 32 or a salt thereof and compound (cII) or a salt thereof to hydrolysis, subjecting the obtained compound of the formula: 
wherein each symbol is as defined above or a salt thereof to sulfonylation or halogenation, and reacting the resulting compound with compound (cVI) or a salt thereof.
43. A method for producing compound (cVIIa) or a salt thereof, which comprises reacting a reaction mixture of compound (cIa) or a salt thereof and compound (cII) or a salt thereof with compound (cVI) or a salt thereof.
44. A compound of the formula: 
45. A method for producing compound (cVIIa) or a salt thereof, which comprises subjecting the compound (cVa) or a salt thereof to sulfonylation or halogenation, and reacting the resulting compound with compound (cVI) or a salt thereof.
46. 1-[4-[4-[[2-[(E)-2-[4-(Trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole.
47. The crystal of the aforementioned 46, having characteristic peaks at diffraction angles of about 6.98, 14.02, 17.56, 21.10 and 24.70 degrees in powder X-ray diffraction.
48. A pharmaceutical composition comprising the crystal of the aforementioned 46.
USPTO Backgrounds
USPTO Backgrounds