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US 2003/0199690 A1Published application
Process for synthesis of D1 receptor antagonists
AssigneeSchering Corporation
InventorsVilas H. Dahanukar, Jeffrey M. Eckert, Dinesh Gala, Brian Lucas, Doris P. Schumacher, Ilia Zavialov
Life of this patent
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Abstract
In one embodiment, the present invention describes the synthesis of a compound of formula 1 and intermediates therefor.
Claims36
A process for preparing a compound of formula I:
- 26
- where X1 is Cl or F and Y is selected from the group consisting of malonate, oxalate, sulfonate, phosphate and hydrochloride ions, is prepared from a compound of formula II:
- 27
- where Q has the formula
- 28
- or —CH(OR)2, where R is C1-C6 alkyl and wherein X is an anion selected from the group consisting of:
- halide ion,
- BF4−,
- CH3C6H4SO3−,
- C6H5SO3−,
- CH3SO3−,
- CF3SO3−,
- PO43−,
- phosphonate of the formula (R1O)2P(O)O− where R1 is an alkyl or aryl group,
- a group of the formula (OR1)PO− where R1 is an alkyl or aryl group, and
- a group of the formula (R2)2(O)PO−, where R2═OR, O-aryl, NR2, and SR:
- said process comprising:
- (a) reacting the compound of formula II with an organometallic reagent of formula III:
- 29
- where X1 is Cl or F, where M is selected from the group consisting of Co, Ni, Mg, Zn, Ti, Ce, Mn and Cu;
- and L is selected from the group consisting of Br, Cl, CN, acetate and acetyl acetate, p being a number ranging from 1 to 3 depending on the valence of M;
- in the presence of a metal salt of the formula CuZm (m is 1 or 2) or in the presence of a copper salt-lithium chloride complex of formula, CuZn.dLiCl (n is 1 or 2, d ranges from 1 to 4), where Z is selected from the group consisting of cyanide, halide, acetate, acetyl acetonate, benzoyl benzoate, trifluoroacetate, thiophenoxide, phenylacetylide, thiocyanate, tetrafluoroborate, trifluoromethanesulfonate and trifluoroacetylacetonate,
- followed by treatment with acid HY, to form a compound of formula IV:
- 30
- where X1 and Y are as defined as above;
- b) cyclizing and reducing the compound of formula IV to form a compound of formula V;
- 31
- and
- (c) deprotecting the compound of formula V to form the compound of formula I.
26 more elements
A process for preparing the compound of formula IV:
- 40
- said process comprising:
- (i) reacting a compound of formula VI
- 41
- with an alkyllithium and an aziridinium forming reagent in a solvent to form a compound of formula II:
- 42
- wherein:
- Q has the formula
- 43
- or —CH(OR)2 where R is C1-C6 alkyl and X is selected from the group consisting of:
- halide ion,
- BF4−,
- CH3C6H4SO3−,
- C6H5SO3−,
- CH3SO3−,
- CF3SO3−,
- PO4 3−,
- phosphonate of the formula (R1O)2P(O)O− where R1 is an alkyl or aryl group,
- a group of the formula (OR1)PO− where R1 is an alkyl or aryl group, and
- a group of the formula (R2)2(O)PO−, where R2═OR, O-aryl, NR2, and SR, and
- (ii) reacting said compound of formula II with an organometallic reagent and a metal salt reagent to form the compound of formula IV.
18 more elements
A compound of formula
- 45
- formed by a process of
- reacting a compound of formula II:
- 46
- where Q has the formula
- 47
- or —CH(OR)2, where R is C1-C6 alkyl and wherein X is an anion selected from the group consisting of:
- halide ion,
- BF4−,
- CH3C6H4SO3−,
- C6H5SO3−,
- CH3SO3−,
- CF3SO3−,
- PO43−,
- phosphonate of the formula (R1O)2P(O)O− where R1 is an alkyl or aryl group,
- a group of the formula (OR1)PO− where R1 is an alkyl or aryl group, and
- a group of the formula (R2)2(O)PO−, where R2═OR, O-aryl, NR2, and SR:
- with an organometallic reagent of formula III:
- 48
- where X1 is Cl or F, where M is selected from the group consisting of Co, Ni, Mg, Zn, Ti, Ce, Mn and Cu;
- and L is selected from the group consisting of Br, Cl, CN, acetate and acetyl acetate, p being a number 1-3 depending on M;
- in the presence of a metal salt of the formula CuZm (m is 1 or 2) or in the presence of a copper salt-lithium chloride complex of formula, CuZn.dLiCl (n is 1 or 2, d ranges from 1 to 4), where Z is selected from the group consisting of cyanide, halide, acetate, acetyl acetonate, benzoyl benzoate, trifluoroacetate, thiophenoxide, phenylacetylide, thiocyanate, tetrafluoroborate, trifluoromethanesulfonate and trifluoroacetylacetonate,
- followed by treatment with acid HY, to form a compound of formula IV.
20 more elements
An anime of formula IX
- 51
- wherein X is an anion selected from the group consisting of:
- halide ion,
- BF4−,
- CH3C6H4SO3−,
- C6H5SO3−,
- CH3SO3−,
- CF3SO3−,
- PO43−,
- phosphonate of the formula (R1O)2P(O)O− where R1 is an alkyl or aryl group,
- a group of the formula (OR1)PO− where R1 is an alkyl or aryl group, and
- a group of the formula (R2)2(O)PO−, where R2═OR, O-aryl, NR2, and SR.
9 more elements
An amine of formula X
- 52
- wherein X is an anion selected from the group consisting of:
- halide ion,
- BF4−,
- CH3C6H4SO3−,
- C6H5SO3−,
- CH3SO3−,
- CF3SO3−,
- PO43−,
- phosphonate of the formula (R1O)2P(O)O− where R1 is an alkyl or aryl group,
- a group of the formula (OR1)PO− where R1 is an alkyl or aryl group, and
- a group of the formula (R2)2(O)PO−, where R2═OR, O-aryl, NR2, and SR.
9 more elements
A process which comprises reacting the compound of formula II
- 53
- where Q has the formula
- 54
- or —CH(OR)2, where R is C1-C6 alkyl and wherein X is an anion selected from the group consisting of:
- PO43−,
- phosphonate of the formula (R1O)2P(O)O− where R1 is an alkyl or aryl group,
- a group of the formula (OR1)PO− where R1 is an alkyl or aryl group, and
- a group of the formula (R2)2(O)PO−, where R2═OR, O-aryl, NR2, and SR:
- with an organometallic reagent of formula III:
- 55
- where X1 is Cl or F, where M is selected from the group consisting of Co, Ni, Mg, Zn, Ti, Ce, Mn and Cu;
- and L is selected from the group consisting of Br, Cl, CN, acetate and acetyl acetate, p being a number ranging from 1 to 3 depending on the valence of M;
- in the presence of a metal salt of the formula CuZm (m is 1 or 2) or in the presence of a copper salt-lithium chloride complex of formula, CuZn.dLiCl (n is 1 or 2, d ranges from 1 to 4), where Z is selected from the group consisting of cyanide, halide, acetate, acetyl acetonate, benzoyl benzoate, trifluoroacetate, thiophenoxide, phenylacetylide, thiocyanate, tetrafluoroborate, trifluoromethanesulfonate and trifluoroacetylacetonate,
- followed by treatment with acid HY, to form a compound of formula IV:
- 56
- where X1 and Y are as defined as above.
13 more elements
Dependencies are inferred from the claim text.