US2003065189A1PendingUtilityA1
Processes for producing 4-substituted benzopyran derivatives
Assignee: CHUGAI PHARMACEUTICAL CO LTDPriority: Sep 30, 1998Filed: Aug 6, 2002Published: Apr 3, 2003
Est. expirySep 30, 2018(expired)· nominal 20-yr term from priority
C07D 311/58
46
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Claims
Abstract
Starting, for example, from 1-fluoro-2-fluoromethyl-3-butyn-2-yl 4-trifluoromethylphenyl ether, N-(2-cyanoethyl)-5-fluoro-4-fluoromethyl-4-(4-trifluoromethylphenoxy)-2-pentynamide is produced and then cyclized to synthesize 2,2-bis(fluoromethyl)-N-(2-cyanoethyl)-6-trifluoromethyl-2H-1-benzopyran-4-carboxamide. The invention processes for producing 4-substituted benzopyran derivatives involve fewer steps, feature greater safety and allow for easier purification than the prior art processes.
Claims
exact text as granted — not AI-modifiedWhat is claimed is
1 . A process for producing 4-substituted benzopyran derivatives represented by formula (G-VI)
where R 1 and R 2 , which may be the same or different, represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted lower alkoxycarbonyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted arylsulfonyl group, a halogen atom, a nitro group, a cyano group or NY a Y b , where Y a and Y b , which may be the same or different, each represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxycarbonyl group, an acyl group, an optionally substituted lower alkylsulfonyl group or an optionally substituted arylsulfonyl group or, when taken together with the nitrogen atom to which they are bound, may form a 3- to 8-membered ring or, when taken together, represent a substituent ═N═O—N═;
R 3 and R 4 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group or, when taken together with the carbon atom to which they are bound, represent a polymethylene group or a substituent forming a heterocycle, provided that R 3 and R 4 are not both a hydrogen atom;
R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group;
the process comprising any one of the schemes (1), (2), (3), (4), and (5) containing a plurality of steps as indicated below, namely,
(1): (1-1)→(1-2)→(1-3)→(1-4)→(1-5);
(2): (3-1)→(3-2);
(3): (4-1)→(4-2);
(4): (a-1)→(a-2)→(b-1)→(b-2)→(1-5); and
(5): (a-1)→(a-2)→(d-1)→(d-2)→(d-3);
(1-1) the step of reacting a compound of formula (II)
where X and Y, which may be the same or different, represent a leaving group such as a halogen atom, an optionally substituted lower alkylsulfonyloxy group or an arylsulfonyloxy group; R 1 and R 2 have the same meanings as defined above with an olefin of formula (III)
where R 3 and R 4 have the same meanings as defined above to give a compound of formula (IV)
where Y, R 1 , R 2 , R 3 and R 4 have the same meanings as defined above;
(1-2) the step of reacting the resulting compound formula (IV) with a halogenating agent to give a compound of formula (V)
where Y, R 1 , R 2 , R 3 , R 4 and Hal have the same meanings as defined above;
(1-3) the step of reacting the resulting compound of formula (V) with a base to give a compound of formula (VI)
where Y, R 1 , R 2 , R 3 , R 4 and Hal have the same meanings as defined above; (1-4) the step of reacting the resulting compound of formula (VI) with a base to give a 4-halobenzopyran of formula (I)
where Y, R 1 , R 2 , R 3 , R 4 and Hal have the same meanings as defined above;
(1-5) the step of reacting the compound of formula (I) with carbon monoxide and a compound of formula (G-III)
R 5 R 6 NH (G-III)
where R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group in the presence of a metal to give a 4-substituted benzopyran derivative of formula (G-VI);
(3-1) the step of reacting a compound of formula (G-I)
where R 1 , R 2 , R 3 and R 4 have the same meanings as defined above with carbon dioxide in the presence of a base to give a compound of formula (G-II)
where R 1 , R 2 , R 3 and R 4 have the same meanings as defined above or a salt thereof;
(3-2) the step of reacting the resulting compound of formula (G-II) or salt thereof with a compound of formula (G-III)
R 5 R 6 NH (G-III)
where R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group to give a 4-substituted benzopyran derivative of formula (G-VI);
(4-1) the step of reacting a compound of formula (G-I)
where R 1 , R 2 , R 3 and R 4 have the same meanings as defined above with a compound of formula (G-IVa)
where R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group or a compound of formula (G-IVb)
R 6a NCO (G-IVb)
where R 6a represents an optionally substituted lower alkyl group in the presence of a base to give a compound of formula (G-V)
where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the same meanings as defined above;
(4-2) the step of subjecting the resulting compound of formula (G-V) to a thermal cyclization reaction to give a 4-substituted benzopyran derivative of formula (G-VI);
(a-1) the step of reacting an alcohol of formula (C-I)
where R 3 and R 4 have the same meanings as defined above with a compound of formula (C-II) or (C-III)
R 7 SO 2 Cl (C-II) (R 7 SO 2 ) 2 O (C-III)
where R 7 represents an optionally substituted alkyl group or an optionally substituted aryl group in the presence of a base to give a compound of formula (C-IV)
where R 7 , R 3 and R 4 have the same meanings as defined above;
(a-2) the step of reacting the compound of formula (C-IV) with a compound of formula (C-V)
where R 1 and R 2 have the same meanings as defined above, in the presence of a base and a monovalent or divalent copper salt to give a compound of formula (C-VI)
where R 1 , R 2 , R 3 and R 4 have the same meanings as defined above;
(b-1) the step of subjecting the compound of formula (C-VI) which is the end product of step (a-2) to a halogenation reaction to give a compound of formula (D-II)
where R 1 , R 2 , R 3 and R 4 have the same meanings as defined above and Hal represents a halogen atom;
(b-2) the step of subjecting the compound of formula (D-II) to a thermal cyclization reaction to give a 4-halobenzopyran derivative of formula (I)
where R 1 , R 2 , R 3 , R 4 and Hal have the same meanings as defined above;
(d-1) the step of reacting the compound of formula (C-VI), which is the end product of step (a-2), with a compound of formula (H-II)
O═C(OR 8 ) 2 (H-II)
or a compound of formula (H-III)
ClC═O(OR 8 ) (H-III)
where R 8 represents an optionally substituted lower alkyl group to give a compound of formula (H-IV)
where R 1 , R 2 , R 3 , R 4 and R 8 have the same meanings as defined above;
(d-2) the step of subjecting the compound of formula (H-IV) to a thermal cyclization reaction to give a compound of formula (H-V)
where R 1 , R 2 , R 3 , R 4 and R 8 have the same meanings as defined above;
(d-3) the step of hydrolyzing the resulting compound of formula (H-V) and then subjecting the hydrolyzate to dehydrative condensation with a compound of formula (G-III)
R 5 R 6 NH (G-III)
where R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group, to give a 4-substituted benzopyran derivative of formula (G-VI) set forth above.
2 . A process for producing 4-substituted benzopyran derivatives represented by formula (G-VIa)
where R 1a represents a lower perfluoroalkyl group, a nitro group or a cyano group;
R 3a and R 4a , which may be the same or different, represent a hydrogen atom, an optionally substituted lower alkyl group or, when taken together with the carbon atom to which they are bound, represent a polymethylene group or a substituent forming a heterocycle, provided that R 3a and R 4a are not both a hydrogen atom;
R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group;
the process comprising scheme (1a) containing a plurality of steps as indicated below, namely, (1a) (1a-1)→(1a-2)→(1a-3)→(1a-4)→(1a-5); and (1a-1) the step of reacting a compound of formula (IIa)
where X and Y which may be the same or different represent a leaving group;
R 1a has the same meaning as defined above with an olefin of formula (IIIa)
where R 3a and R 4a have the same meanings as defined above to give a compound of formula (IVa)
where Y, R 1a , R 3a and R 4a have the same meanings as defined above;
(1a-2) the step of reacting the resulting compound of formula (IVa) with a halogenating agent to give a compound of formula (Va)
where Y, R 1a , R 3a and R 4a have the same meanings as defined above, and Hal represents a halogen atom;
(1a-3) the step of reacting the resulting compound of formula (Va) with a base to give a compound of formula (VIa)
where Y, R 1a , R 3a , R 4a and Hal have the same meanings as defined above;
(1a-4) the step of reacting the resulting compound of formula (VIa) with a base to give a compound of formula (Ia)
where R 1a , R 3a , R 4a and Hal have the same meanings as defined above;
(Ia-5) the step of reacting the resulting compound of formula (Ia) with carbon monoxide and a compound of formula (G-III)
R 5 R 6 NH (G-III)
where R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group, in the presence of a metal to give a 4-substituted benzopyran derivative of formula (G-VIa) set forth above
where R 1a , R 3a , R 4a , R 5 and R 6 have the same meanings as defined above.
3 . A process for producing 4-substituted benzopyran derivatives represented by formula (G-VIb)
where R 1b represents a lower perfluoroalkyl group;
R 3b and R 4b , which may be the same or different, represent a hydrogen atom, an optionally substituted lower alkyl group or, when taken together with the carbon atom to which they are bound, represent a polymethylene group, provided that R 3b and R 4b are not both a hydrogen atom;
R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group by scheme (1b) containing a plurality of steps as indicated below, namely, (1b) (1b-1)→(1b-2)→(1b-3)→(1b-4)→(1b-5); and (1b-1) the step of reacting a compound of formula (IIb)
where X and Y, which may be the same or different, represent a leaving group;
R 1b has the same meaning as defined above, with an olefin of formula (IIIb)
where R 3b and R 4b have the same meanings as defined above, to give a compound of formula (IVb)
where Y, R 1b , R 3b and R 4b have the same meanings as defined above;
(1b-2) the step of reacting the resulting compound of formula (IVb) with a halogenating agent to give a compound of formula (Vb)
where Y, R 1b , R 3b and R 4b have the same meanings as defined above, and Hal represents a halogen atom;
(1b-3) the step of reacting the resulting compound of formula (Vb) with a base to give a compound of formula (VIb)
where Y, R 1b , R 3b , R 4b and Hal have the same meanings as defined above;
(1b-4) the step of reacting the resulting compound of formula (VIb) with a base to give a compound of formula (Ib)
where R 1b , R 3b , R 4b and Hal have the same meanings as defined above;
(Ib-5) the step of reacting the resulting compound of formula (Ib) with carbon monoxide and a compound of formula (G-III)
R 5 R 6 NH (G-III)
where R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group, in the presence of a metal to give a 4-substituted benzopyran derivative of formula (G-VIb)
where R 1b , R 3b , R 4b , R 5 and R 6 have the same meanings as defined above.
4 . A process for producing 4-substituted benzopyran derivatives represented by formula (G-VIc)
where R 1b represents a lower perfluoroalkyl group;
R 3c and R 4c , which are the same, represent a lower alkyl group or a lower fluoroalkyl group;
R 5c represents a hydrogen atom and R 6 represents an optionally substituted lower alkyl group;
the process comprising scheme 1c containing a plurality of steps as indicated below:
(1c) (1c-1)→(1c-2)→(1c-3)→(1c-4)→(1c-5);
(1c-1) the step of reacting a compound of formula (IIb)
where X and Y, which may be the same or different, represent a leaving group;
R 1b has the same meaning as defined above, with an olefin of formula (IIIc)
where R 3c and R 4c have the same meanings as defined above, to give a compound of formula (IVc)
where Y, R 1b , R 3c and R 4c have the same meanings as defined above;
(1c-2) the step of reacting the resulting compound of formula (IVc) with a halogenating agent to give a compound of formula (Vc)
where Y, R 1b , R 3c and R 4c have the same meanings as defined above, and Hal represents a halogen atom;
(1c-3) the step of reacting the resulting compound of formula (Vc) with a base to give a compound of formula (VIc)
where Y, R 1b , R 3c and R 4c have the same meanings as defined above, and Hal represents a halogen atom;
(1c-4) the step of reacting the resulting compound of formula (VIc) with a base to give a compound of formula (Ic)
where R 1b , R 3c , R 4c and Hal have the same meanings as defined above;
(Ic-5) the step of reacting the resulting compound of formula (Ic) with carbon monoxide and a compound of formula (G-IIIc)
R 5c R 6a NH (G-IIIc)
where R 5c represents a hydrogen atom and R 6a represents an optionally substituted lower alkyl group, in the presence of a metal to give a 4-substituted benzopyran derivative of formula (G-VIc).
5 . A process for producing 4-substituted benzopyran derivatives represented by formula (G-VId)
where R 1b represents a lower perfluoroalkyl group;
R 5c represents a hydrogen atom; and R 6b represents a lower alkyl group which may optionally have a cyano group, by scheme (id) containing a plurality of steps as indicated below:
(1d) (1d-1)→(1d-2)→(1d-3)→(1d-4)→(1d-S); and
(1d-1) the step of reacting a compound of formula (IId)
where X and Y, which may be the same or different, represent a leaving group;
R 1b has the same meaning as defined above, with an olefin of formula (IIId)
to give a compound of formula (IVd)
where Y and R 1b have the same meanings as defined above;
(1d-2) the step of reacting the resulting compound of formula (IVd) with a halogenating agent to give a compound of formula (Vd)
where Y and R 1b have the same meanings as defined above, and Hal represents a halogen atom;
(1d-3) the step of reacting the resulting compound of formula (Vd) with a base to give a compound of formula (VId)
where Y, R 1b and Hal have the same meanings as defined above;
(1d-4) the step of reacting the resulting compound of formula (VId) with a base to give a 4-halobenzopyran derivative of formula (Id)
where R 1b and Hal have the same meanings as defined above;
(Id-5) the step of reacting the resulting compound of formula (Id) with carbon monoxide and a compound of formula (G-IIId)
R 5c R 6b NH (G-IIId)
where R 5c represents a hydrogen atom and R 6b represents a lower alkyl group which may optionally have a cyano group, in the presence of a metal to give a 4-substituted benzopyran derivative of formula (G-VId) set forth above.
6 . A process for producing 4-substituted benzopyran derivatives represented by formula (G-VIe)
where R 1e represents a trifluoromethyl group or a pentafluoroethyl group;
R 5c represents a hydrogen atom;
R 6d represents a cyanoethyl group;
by scheme (1e) containing a plurality of steps as indicated below:
(1e) (1e-1)→(1e-2)→(1e-3)→(1e-4)→(1e-5); and
(1e-1) the step of reacting a compound of formula (IIe)
where R 1e has the same meaning as defined above with an olefin of formula (IIId)
to give a compound of formula (IVe)
where R 1e has the same meaning as defined above;
(1e-2) the step of reacting the resulting compound of formula (IVe) with a halogenating agent to give a compound of formula (Ve)
where R 1e has the same meaning as defined above; Hal represents a halogen atom;
(1e-3) the step of reacting the resulting compound of formula (Ve) with a base to give a compound of formula (VIe)
where R 1e and Hal have the same meanings as defined above;
(1e-4) the step of reacting the resulting compound of formula (VIe) with a base to give a 4-halobenzopyran derivative of formula (Ie)
where R 1e and Hal have the same meanings as defined above;
(1e-5) the step of reacting the resulting compound of formula (Ie) with carbon monoxide and a compound of formula (G-IIIe)
R 5c R 6d NH (G-IIIe)
where R 5c represents a hydrogen atom and R 6d represents a cyanoethyl group, in the presence of a metal to give a 4-substituted benzopyran derivative of formula (G-VIe) set forth above.
7 . A process according to scheme (3) or (4) recited in claim 1 for producing 4-substituted benzopyran derivatives represented by formula (G-VIg)
where R 1g and R 2g , which may be the same or different, represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted lower alkoxycarbonyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted arylsulfonyl group, a halogen atom, a nitro group, a cyano group or NY a Y b where Y a and Y b , which may be the same or different, each represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxycarbonyl group, an acyl group, an optionally substituted lower alkylsulfonyl group or an optionally substituted arylsulfonyl group or, when taken together with the nitrogen atom to which they are bound, may form a 3- to 8-membered ring;
R 3g and R 4g , which may be the same or different, represent a hydrogen atom or an optionally substituted α-haloalkyl group, provided that they are not both a hydrogen atom;
R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group; the process comprising the steps of:
reacting an alcohol of formula (C-Ig)
where R 3g and R 4g have the same meanings as defined above with a compound of formula (C-II) or (C-III)
R 7 SO 2 Cl (C-II) (R 7 SO 2 ) 2 O (C-III)
where R 7 represents an optionally substituted alkyl group or an optionally substituted aryl group in the presence of a base to give a compound of formula (C-IVg)
where R 7 , R 3g and R 4g have the same meanings as defined above;
reacting the compound of formula (C-IVg) with a compound of formula (C-Vg)
where R 1g and R 2g have the same meanings as defined above in the presence of a base and a monovalent or divalent copper salt to give a compound of formula (G-Ig)
where R 1g , R 2g , R 3g and R 4g have the same meanings as defined above;
reacting the compound of formula (G-Ig) with carbon dioxide in the presence of a base to give a compound of formula (G-IIg)
where R 1g , R 2g , R 3g and R 4g have the same meanings as defined above or a salt thereof;
reacting the compound of formula (G-IIg) or salt thereof with a compound of formula (G-III)
R 5 R 6 NH (G-III)
where R 5 and R 6 which may be the same or different represent a hydrogen atom or an optionally substituted lower alkyl group to give a compound of formula (G-Vg)
where R 1g , R 2g , R 3g , R 4g , R 5 and R 6 have the same meanings as defined above;
or alternatively reacting the compound of formula
where R 1g , R 2g , R 3g and R 4g have the same meanings as defined above with a compound of formula (G-IVa)
where R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group or a compound of formula (G-IVb)
R 6a NCO (G-IVb)
where R 6a represents an optionally substituted lower alkyl group in the presence of a base to give a compound of formula (G-Vg)
where R 1g , R 2g , R 3g , R 4g , R 5 and R 6 have the same meanings as defined above; and
subjecting the compound of formula (G-Vg) to a thermal cyclization reaction.
8 . A process according to scheme (3) recited in claim 1 for producing 4-substituted benzopyran derivatives represented by formula (G-VIh)
wherein R 1 and R 2 in formula (G-VI), which may be the same or different, represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted lower alkoxycarbonyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted arylsulfonyl group, a halogen atom, a nitro group, a cyano group or NY a Y b where Y a and Y b , which may be the same or different, each represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxycarbonyl group, an acyl group, an optionally substituted lower alkylsulfonyl group or an optionally substituted arylsulfonyl group or, when taken together, may form a 3- to 8-membered ring);
R 3 and R 4 each represent a fluoromethyl group; and
R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group.
9 . The process according to scheme (3) recited in claim 1 for producing 4-substituted benzopyran derivatives represented by formula (G-VIi)
wherein R 1 in formula (G-VI) represents a 6-trifluoromethyl group or a 6-pentafluoroethyl group;
R 2 represents a hydrogen atom;
R 3 and R 4 each represent a fluoromethyl group; and
R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group.
10 . The process according to scheme (3) recited in claim 1 for producing 4-substituted benzopyran derivatives represented by formula (G-VIj)
wherein R 1 in formula (G-VI) represents a 6-trifluoromethyl group or a 6-pentafluoroethyl group;
R 2 represents a hydrogen atom;
R 3 and R 4 each represent a fluoromethyl group; and
R 5 represents a hydrogen atom and R 6 represents a 2-cyanoethyl group.
11 . A process for producing 4-substituted benzopyran derivatives represented by formula (G-VIg)
where R 1g and R 2g , which may be the same or different, represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted lower alkoxycarbonyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted arylsulfonyl group, a halogen atom, a nitro group, a cyano group or NY a Y b where Y a and Y b , which may be the same or different, each represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxycarbonyl group, an acyl group, an optionally substituted lower alkylsulfonyl group or an optionally substituted arylsulfonyl group or, when taken together with the nitrogen atom to which they are bound, may form a 3- to 8-membered ring;
R 3g and R 4g , which may be the same or different, represent a hydrogen atom or an optionally substituted α-haloalkyl group, provided that they are not both a hydrogen atom;
R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group, wherein a compound represented by formula (G-Vk)
where R 1g , R 2g , R 3g , R 4g , R 5 and R 6 have the same meanings as defined above is subjected to a thermal cyclization reaction.
12 . A process according to claim 11 for producing 4-substituted benzopyran derivatives represented by formula (G-VII)
wherein R 1g and R 2g in formula (G-VIg), which may be the same or different, represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted lower alkoxycarbonyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted arylsulfonyl group, a halogen atom, a nitro group, a cyano group or NY a Y b where Y a and Y b , which may be the same or different, each represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxycarbonyl group, an acyl group, an optionally substituted lower alkylsulfonyl group or an optionally substituted arylsulfonyl group or, when taken together with the nitrogen atom to which they are bound, may form a 3- to 8-membered ring;
R 3g and R 4g each represent a fluoromethyl group;
R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group.
13 . A process according to claim 11 for producing 4-substituted benzopyran derivatives represented by formula (G-VIm)
wherein R 1g in formula (G-VIg) represents a 6-trifluoromethyl group or a 6-pentafluoroethyl group;
R 2g represents a hydrogen atom;
R 3g and R 4g each represent a fluoromethyl group; and
R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group.
14 . A process according to claim 11 for producing 4-substituted benzopyran derivatives represented by formula (G-VIn)
wherein R 1g in formula (G-VIg) represents a 6-trifluoromethyl group or a 6-pentafluoroethyl group;
R 2g represents a hydrogen atom;
R 3g and R 4g each represent a fluoromethyl group; and
R 5 represents a hydrogen atom and R 6 represents a 2-cyanoethyl group.
15 . A process according to scheme (5) or (6) recited in claim 1 for producing 4-substituted benzopyran derivatives represented by formula (Iz)
where R 1g and R 2g , which may be the same or different, represent a hydrogen atom, an optionally substituted lower alkyl group, a halogen atom, an optionally substituted lower alkoxy group, NY a Y b (here Y a and Y b , which may be the same or different, each represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxycarbonyl group, an acyl group, an optionally substituted lower alkylsulfonyl group or an optionally substituted arylsulfonyl group or, when taken together with the nitrogen atom to which they are bound, may form a 3- to 8-membered ring, a nitro group, a cyano group, an optionally substituted lower alkoxycarbonyl group, an optionally substituted lower alkylsulfonyl group or an optionally substituted arylsulfonyl group; Hal represents a halogen atom the process comprising:
reacting an alcohol of formula (C-Ia)
with a compound of formula (C-II) or (C-III)
R 7 SO 2 Cl (C-II) (R 7 SO 2 ) 2 O (C-III)
where R 7 represents an optionally substituted lower alkyl group or an optionally substituted aryl group in the presence of a base to give a compound of formula (C-IVa)
where R 7 has the same meaning as defined above;
reacting the compound of formula (C-IVa) with a compound of formula (C-Vg)
where R 1g and R 2g have the same meanings as defined above in the presence of a base and a monovalent or divalent copper salt to give a compound of formula (G-VIa)
where R 1g and R 2g have the same meanings as defined above;
subjecting the compound of formula (G-VIa) to a halogenation reaction to give a compound of formula (D-IIa)
where R 1g , R 2g and Hal have the same meanings as defined above; and
subjecting the compound of formula (D-IIa) to a thermal cyclization reaction.
16 . A process according to scheme (5) or (6) recited in claim 1 for producing 4-substituted benzopyran derivatives represented by formula (Iy)
where R 1 in formula (I) represents a 6-trifluoromethyl group or a 6-pentafluoroethyl group;
R 2 represents a hydrogen atom;
R 3 and R 4 both represent a fluoromethyl group; X is a bromine atom, the process comprising:
reacting an alcohol of formula (C-Ia)
with a compound of formula (C-II) or (C-III)
R 7 SO 2 Cl (C-II) (R 7 SO 2 ) 2 O (C-III)
where R 7 represents an optionally substituted lower alkyl group or an optionally substituted aryl group in the presence of a base to give a compound of formula (C-IVa)
where R 7 has the same meaning as defined above;
reacting the compound of formula (C-IVa) with a 4-substituted phenol derivative of formula (C-Va)
where R 1e has the same meaning as defined above in the presence of a base and a monovalent or divalent copper salt to give a compound of formula (G-VIb)
where R 1e has the same meaning as defined above;
subjecting the compound of formula (G-VIb) to bromination reaction to give a compound of formula (D-IIb)
where R 1e has the same meaning as defined above; and
subjecting the compound of formula (D-IIb) to a thermal cyclization reaction.
17 . A process according to scheme (5) or (6) recited in claim 1 for producing 4-substituted benzopyran derivatives represented by formula (G-VIz)
wherein R 1 in formula (G-VI) represents a 6-trifluoromethyl group or a 6-pentafluoroethyl group;
R 2 represents a hydrogen atom;
R 3 and R 4 each represents a fluoromethyl group; and
R 5 and R 6 , which may be the same or different, represent a hydrogen atom or an optionally substituted lower alkyl group.
18 . A process according to scheme (5) or (6) recited in claim 1 for producing 4-substituted benzopyran derivatives represented by formula (G-VIy)
wherein R 1 in formula (G-VI) represents a 6-trifluoromethyl group or a 6-pentafluoroethyl group; R 2 represents a hydrogen atom;
R 3 and R 4 each represents a fluoromethyl group; and
R 5 represents a hydrogen atom and R 6 represents a 2-cyanoethyl group.
19 . A process according to scheme (5) or (6) in claim 1 , comprising reacting a compound of formula (C-IVb)
as obtained by reacting methanesulfonyl chloride of formula (C-II) where R 7 is a methyl group with a compound of formula (C-I) where R 3 and R 4 are each a fluoromethyl group.
20 . A process according to scheme (5) or (6) in claim 1 , comprising reacting a compound of formula (C-IVc)
where Tol represents a tolyl group that is obtained by reacting p-toluenesulfonyl chloride of formula (C-II) where R 7 is a p-tolyl group with a compound of formula (C-I) where R 3 and R 4 are each a fluoromethyl group in the presence of a base.
21 . A process according to scheme (5) or (6) recited in claim 1 , comprising reacting a compound of formula (C-VIb)
where R 1e has the same meaning as defined above that is obtained by reacting a compound of formula (C-Va)
where R 1e has the same meaning as defined above;
R 1 in formula (C-V) is a 4-trifluoromethyl group or a 4-pentafluoroethyl group; and
R 2 is a hydrogen atom with a compound of formula (C-IVb) or (C-IVc)
wherein Tol represents a p-tolyl group.
22 . A process according to scheme (5) or (6) recited in claim 1 , comprising reacting a compound of formula (D-IIb)
where R 1e has the same meaning as defined above that is obtained by brominating a compound of formula (C-VIb)
where R 1e has the same meaning as defined above;
R 1 in formula (C-VI) is a 4-trifluoromethyl group or a 4-pentafluoroethyl group;
R 2 is a hydrogen atom; and
R 3 and R 4 are both a fluoromethyl group).
23 . A process according to scheme (5) or (6) recited in claim 1 , comprising reacting a 4-bromobenzopyran derivative of formula (Iq)
where R 1e has the same meaning as defined above that is obtained by subjecting a compound of formula (D-IIb)
where R 1e has the same meaning as defined above;
R 1 in formula (D-II) is a 4-trifluoromethyl group or a 4-pentafluoroethyl group;
R 2 is a hydrogen atom; and
R 3 and R 4 are both a fluoromethyl group; and
X is a bromine atom to a thermal cyclization reaction.
24 . The process according to claim 2 wherein the leaving group is a halogen atom, an optionally substituted lower alkylsulfonyloxy group, or an arylsulfonyloxy group
25 . The process according to claim 3 wherein the leaving group is a halogen atom, an optionally substituted lower alkylsulfonyloxy group, or an arylsulfonyloxy group
26 . The process accdroing to claim 4 wherein the leaving group is a halogen atom, an optionally substituted lower alkylsulfonyloxy group, or an arylsulfonyloxy group
27 . The process according to claim 5 wherein the leaving group is a halogen atom, an optionally substituted lower alkylsulfonyloxy group, or an arylsulfonyloxy group.
28 . The process according to scheme (4) recited in claim 1 for producing 4-substituted benzopyran derivatives represented by formula (G-VIh)
wherein R 1 and R 2 in formula (G-VI) which may be the same or different represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted lower alkoxycarbonyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted arylsulfonyl group, a halogen atom, a nitro group, a cyano group or NY a Y b where Y a and Y b which may be the same or different each represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxycarbonyl group, an acyl group, an optionally substituted lower alkylsulfonyl group or an optionally substituted arylsulfonyl group or, when taken together, may form a 3- to 8-membered ring; R 3 and R 4 each represent a fluoromethyl group; and R 5 and R 6 which may be the same or different represent a hydrogen atom or an optionally substituted lower alkyl group.
29 . The process according to claim 7 for producing 4-substituted benzopyran derivatives represented by formula (G-VIh)
wherein R 1 and R 2 in formula (G-VI) which may be the same or different represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group, an optionally substituted lower alkoxycarbonyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted arylsulfonyl group, a halogen atom, a nitro group, a cyano group or NY a Y b where Y a and Y b which may be the same or different each represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxycarbonyl group, an acyl group, an optionally substituted lower alkylsulfonyl group or an optionally substituted arylsulfonyl group or, when taken together, may form a 3- to 8-membered ring; R 3 and R 4 each represent a fluoromethyl group; and R 5 and R 6 which may be the same or different represent a hydrogen atom or an optionally substituted lower alkyl group.
30 . The process according to scheme (4) recited in claim 1 for producing 4-substutited benzopyran derivatives represented by formula (G-VIi)
wherein R 1 in formula (G-VI) represents a 6-trifluoromethyl group or a 6-pentafluoroethyl group; R 2 represents a hydrogen atom; R 3 and R 4 each represent a fluoromethyl group; and R 5 and R 6 which may be the same or different represent a hydrogen atom or an optionally substituted lower alkyl group.
31 . The process according to claim 7 for producing 4-substituted benzopyran derivatives represented by formula (G-VIi)
wherein R 1 in formula (G-VI) represents a 6-trifluoromethyl group or a 6-pentafluoroethyl group; R 2 represents a hydrogen atom; R 3 and R 4 each represent a fluoromethyl group; and R 5 and R 6 which may be the same or different represent a hydrogen atom or an optionally substituted lower alkyl group.
32 . The process according to scheme (4) recited in claim 1 for producing 4-substituted benzopyran derivatives represented by formula (G-VIj)
wherein R 1 in formula (G-VI) represents a 6-trifluoromethyl group or a 6-pentafluoroethyl group; R 2 represents a hydrogen atom; R 3 and R 4 each represent a fluoromethyl group; and R 5 represents a hydrogen atom and R 6 represents a 2-cyanoethyl group.
33 . The process according to claim 7 for producing 4-substituted benzopyran derivatives represented by formula (G-VIj)
wherein R 1 in formula (G-VI) represents a 6-trifluoromethyl group or a 6-pentafluoroethyl group; R 2 represents a hydrogen atom; R 3 and R 4 each represent a fluoromethyl group; and R 5 represents a hydrogen atom and R 6 represents a 2-cyanoethyl group.Cited by (0)
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