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US 2001/0036653 A1Published application
Stereo-specific synthesis of shimikic acid derivatives with improved efficiency
AssigneeHoffmann-La Roche Inc.
InventorsHans Iding, Beat Wirz, Ulrich Zutter
Life of this patent
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Abstract
The invention provides a multistep synthesis for the preparation of 4,5-diamino shikimic acid derivatives of formula 1 starting from an isophthalic acid derivative of formula 2 4,5-Diamino shikimic acid derivatives are potent inhibitors of viral neuraminidase.
Claims25
A process for preparing a 4,5 diamino shikimic acid derivitive having formula 1a
- 37
- wherein
- R1 is an optionally substituted alkyl group,
- R2 is an alkyl group and
- R3 and R4, independent of each other are H or a substituent of an amino group, with the proviso that both R3 and R4 are not H
- comprising:
- hydrogenating an isophthalic acid derivative of formula II,
- 38
- wherein R1 and R2 are as above and
- R5 is H or lower alky, therebyforming an all-cis-cyclohexane dicarboxylate of formula III,
- 39
- wherein R1, R2 and R5 are as above;
- selecting a stereo-selective hydrolysis and dealkylation sequence from the group consisting of a) in the case when R5=H, stereo-selectively hydrolyzing said all-cis-cyclohexane dicarboxylate of formula (III), forming said (S)- or (R)-cyclohexane monoacid of formula IVa or IVb, b) in the case where R5=lower alkyl, stereo-selectively hydrolyzing said all-cis cyclohexane dicarboxylate of formula III forming said (S)- or (R)-alkoxy cyclohexane monoacid of formula IVa or IVb then dealkylating said alkoxy all-cis-cyclohexane dicarboxylate, forming said all cis-cyclohexane dicarboxylate of formula III and c) if R5=lower alkyl, dealkylating said alkoxy all-cis-cyclohexane dicarboxylate of formula (III), then stereo-selectively hydrolyzing said all-cis cyclohexane dicarboxylate of formula III thereby forming said (S)- or (R)-cyclohexane mono acid of the formulae IVa or IVb,
- 40
- wherein R1 and R2 are as above;
- converting the cyclohexane monoacid of formula (IVa) to an oxazolidinone of the formula Va
- 41
- wherein R1 and R2 are as above;
- transforming said oxazolidinone of formula (Va) into a cyclohexenol of formula VIa,
- 42
- wherein R1 and R are as above and R6 is an amino protecting group;
- converting said cyclohexenol of formula (VIa) to an azide of formula VIIa,
- 43
- wherein R1, R2 and R6 are as above;
- reducing and acylating said azide of formula (VIIa) forming the respective acylated amine of the formula VIIIa,
- 44
- wherein R1, R2, R3, R4 and R6 are as above;
- and
- removing the amino protecting group R6 thereby forming said 4,5-diamino shikimic acid derivative of formula (Ia).
26 more elements
A process for the preparation of an isophthalic acid derivative of the formula II
- 45
- wherein R1 is an optionally substituted alkyl group,
- R is an alkyl group and
- R3 and R4, independent of each other are H or a substituent of an amino group,
- with the proviso that both R3and R4are not H
- R5 is H or lower alkyl comprising:
- converting a dialkoxyphenol of the formula X to
- 46
- a trialkoxybenzene of the formula XI;
- 47
- halogenating said trialkoxybenzene to a dihalotrialkoxybenzene of the formula XII
- 48
- wherein X stands for a halogen atom;
- and
- carbonylating said dihaloalkoxybenzene thereby forming said product of formula II.
12 more elements
A process for the preparation of an all-cis-cyclohexane dicarboxylate derivative of formula III
- 49
- wherein R1 is an optionally substituted alkyl group,
- R2 is an alkyl group and
- R3 and R4, independent of each other are H or a substituent of an amino group,
- with the proviso that both R3and R4 are not H,
- R5 is H or lower alkyl comprising:
- hydrogenating an isophthalic acid derivative of the formula II
- 50
- wherein R1 is an optionally substituted alkyl group,
- R2 is an alkyl group and
- R5 is H or lower alkyl.
8 more elements
A process for the preselected preparation of the (S)- or (R)-cyclohexane monoacid having the formula IVa or IVb
- 51
- wherein R1 is an optionally substituted alkyl group,
- R2 is an alkyl group comprising:
- stereo-selectively hydrolyzing an all-cis-cyclohexane dicarboxylate of the formula III
- 52
- wherein,
- if R5=H, stereo-selectively hydrolyzed or, if R5=lower alkyl, either dealkylated first and then stereo-selectively hydrolyzed or stereo-selectively hydrolyzed first and then dealkylated.
4 more elements
A compound of the formula II
- 53
- wherein R1 is an optionally substituted alkyl group,
- R2 is an alkyl group and
- R5 is H or lower alkyl
1 more element
A compound of formula III
- 54
- wherein R1 is an optionally substituted alkyl group,
- R is an alkyl group and
- R5 is H or lower alkyl.
1 more element
A compound of the formulae IVa or IVb.
- 55
- wherein R1 is an optionally substituted alkyl group and
- R2 is an alkyl group.
A compound of the formulae Va or Vb
- 56
- wherein R1 is an optionally substituted alkyl group and
- R2 is an alkyl group.
A compound of the formulae VIa or VIb
- 57
- wherein R1 is an optionally substituted alkyl group,
- R2 is an alkyl group and R6 is an amino protecting group.
A compound of the formulae VIIa or VIIb
- 58
- wherein R1 is an optionally substituted alkyl group.
- R2 is an alkyl group and R6 is an amino protecting group.
Dependencies are inferred from the claim text.