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US 2004/0106808 A1Published application
Processes for preparing calanolide a and intermediates thereof
OwnerShiro Terashima, Kenichi Koyakumaruinventors
Life of this patent
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Abstract
The present invention provides a production method of Calanolide A according to the following method 1 wherein each symbol is as defined in the specification, as a more convenient and industrially practical method for the synthesis of Calanolide A from an easily available starting material.
Claims32
A production method of Calanolide A, which comprises
- (a) a step of reacting phloroglucinol (I)
- 27
- or a hydrate thereof, with a β-ketoester represented by the formula (II)
- 28
- wherein R1 is an alkyl group optionally having substituent(s), a cycloalkyl group optionally having substituent(s) or an aryl group optionally having substituent(s), in the presence of an acid catalyst to give 5,7-dihydroxy-4-propylcoumarin (III)
- 29
- (b) a step of reacting 5,7-dihydroxy-4-propylcoumarin (III) with an acylating agent represented by the formula (IV)
- 30
- wherein X1 is an alkoxyl group optionally having substituent(s), a cycloalkyloxy group optionally having substituent(s), an aryloxy group optionally having substituent(s), an acyloxy group optionally having substituent(s), an alkoxycarbonyloxy group optionally having substituent(s), a substituted amino group, a substituted sulfonyloxy group, a substituted phosphonyloxy group or a halogen atom to give 5-hydroxy-7-{(2-methyl)-2-butenoyloxy}-4-propylcoumarin (V).
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- (c) a step of subjecting 5-hydroxy-7-{(2-methyl)-2-butenoyloxy}-4-propylcoumarin (V) to an intramolecular rearrangement reaction to give 5,7-dihydroxy-8-{(2-methyl)-2-butenoyl}-4-propylcoumarin (VI)
- 32
- (d) a step of reacting 5,7-dihydroxy-8-{(2-methyl)-2-butenoyl}-4-propylcoumarin (VI) with 3-methyl-2-butenal to give 12-oxocalanolide A (VII)
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- (e) a step of reducing 12-oxocalanolide A (VII) to give Calanolide A (VIII).
12 more elements
5-Hydroxy-7-{(2-methyl)-2-butenoyloxy}-4-propylcoumarin (V)
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A production method of 5-hydroxy-7-{(2-methyl)-2-butenoyloxy}-4-propylcoumarin (V)
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- which comprises reacting 5,7-dihydroxy-4-propylcoumarin (III)
- 36
- with an acylating agent represented by the formula (IV)
- 37
- wherein X1 is an alkoxyl group optionally having substituent(s), a cycloalkyloxy group optionally having substituent(s), an aryloxy group optionally having substituent(s), an acyloxy group optionally having substituent(s), an alkoxycarbonyloxy group optionally having substituent(s), a substituted amino group, a substituted sulfonyloxy group, a substituted phosphonyloxy group or a halogen atom.
3 more elements
A production method of 5,7-dihydroxy-8-{(2-methyl)-2-butenoyl}-4-propylcoumarin (VI)
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- which comprises subjecting 5-hydroxy-7-{(2-methyl)-2-, butenoyloxy}-4-propylcoumarin (V)
- 39
- to an intramolecular rearrangement reaction.
1 more element
A production method of 12-oxocalanolide A (VII)
- 40
- which comprises reacting 5,7-dihydroxy-8-{(2-methyl)-2-butenoyl}-4-propylcoumarin (VI)
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- with 3-methyl-2-butenal.
1 more element
A production method of 12-oxocalanolide A (VII)
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- which comprises reacting 2,3-trans-dihydro-6-hydroxy-2,3-dimethyl-7-propyl-1H,9H-benzo[1,2-b:3,4-b′]dipyran-1,9-dione (IX)
- 43
- with 3-methyl-2-butenal.
1 more element
A production method of Calanolide A, which comprises
- (a) a step of reacting phloroglucinol (I)
- 44
- or a hydrate thereof with a p-ketoester represented by the formula (II)
- 45
- wherein R1 is an alkyl group optionally having substituent(s), a cycloalkyl group optionally having substituent(s) or an aryl group optionally having substituent(s), in the presence of an acid catalyst to give 5,7-dihydroxy-4-propylcoumarin (III)
- 46
- (h) a step of reacting 5,7-dihydroxy-4-propylcoumarin (III) with an acylating agent represented by the formula (X)
- 47
- wherein X2 is an alkoxyl group optionally having substituent(s), a cycloalkyloxy group optionally having substituent(s), an aryloxy group optionally having substituent(s), an acyloxy group optionally having substituent(s), an alkoxycarbonyloxy group optionally having substituent(s), a substituted amino group, a substituted sulfonyloxy group, a substituted phosphonyloxy group or a halogen atom, to give 5,7-dihydroxy-8-propionyl-4-propylcoumarin (XI)
- 48
- (i) a step of reacting 5,7-dihydroxy-8-propionyl-4-propylcoumarin (XI) with 3-methyl-2-butenal to give 5-hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (XII)
- 49
- (j) a step of reacting 5-hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]-dipyran-8-one (XII) with an acetal of acetaldehyde represented by the formula (XIII)
- 50
- wherein two R2 conveniently having the same superscript may be the same group or different groups, an alkyl group optionally having substituent(s), a cycloalkyl group optionally having substituent(s) or an aryl group optionally having substituent(s), or two R2 may be joined to form a ring structure, in the presence of an acid catalyst to give 12-oxocalanolide A (VII)
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- (e) a step of reducing 12-oxocalanolide A (VII) to give Calanolide A (VIII)
- 52
15 more elements
A production method of 5-hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (XII)
- 53
- which comprises reacting 5,7-dihydroxy-8-propionyl-4-propylcoumarin (XI)
- 54
- with 3-methyl-2-butenal.
1 more element
A production method of 12-oxocalanolide A, which comprises
- (k) a step of obtaining 5-hydroxy-2,2-dimethyl-6-{(2-methyl)-2-butenoyl}-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]-dipyran-8-one (XIV)
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- from 10,11-cis-dihydro-6,6,10,11-tetramethyl-4-propyl-2H,6H,12H-benzo[1,2-b:3,4-b′:5,6-b″]tripyran-2,12-dione (VII′)
- 56
- by the use of a base, and
- (l) a step of subjecting 5-hydroxy-2,2-dimethyl-6-{(2-methyl)-2-butenoyl}-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (XIV) to a intramolecular cyclization reaction to give 12-oxocalanolide A (VII)
- 57
4 more elements
(deleted)
A production method of 5-hydroxy-2,2-dimethyl-6-{(2-methyl)-2-butenoyl}-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (XIV)
- 58
- which comprises treating 10,11-dihydro-6,6,10,11-tetramethyl-4-propyl-2H,6H,12H-benzo[1,2-b:3,4-b′:5,6-b″]tripyran-2,12-dione (VII″)
- 59
- with a base.
1 more element
A production method of 12-oxocalanolide A (VII)
- 60
- which comprises reacting an acid with 10,11-cis-dihydro-6,6,10,11-tetramethyl-4-propyl-2H,6H,12H-benzo[1,2-b:3,4-b′:5,6-b″]tripyran-2,12-dione (VII′)
- 61
Dependencies are inferred from the claim text.