Synthesis of 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one
AssigneeRoche Colorado Corporation
InventorsMichael P. Fleming, Yeun-Kwei Han, Lewis M. Hodges, David A. Johnston, Roger P. Micheli, Kurt Puentener, Chris R. Roberts, Michelangelo Scalone, Mark A. Schwindt, Rober J. Topping
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Abstract
The present invention relates to a novel process for producing a δ-lactone of the formula: 1 using an acyl halide of the formula: 2 wherein R1, R2 R3 and X are described herein, as well as novel intermediates. In particular, the present invention relates to a process for enantioselectively producing the (R)-δ-lactone.
Claims48
A process for the preparation of a δ-lactone of the formula:
- 47
- said process comprising contacting an α-halo ester of the formula:
- 48
- with a reactive species generating reagent selected from the group consisting of Grignard reagents, magnesium, magnesium-sodium mixtures, samarium, manganese, and mixtures thereof under conditions sufficient to produce said δ-lactone,
- wherein
- R1 is C1-C20 alkyl;
- R2 is H or C1-C10 alkyl;
- Y is a halide;
- and
- Z is nitrile, ester, amide, hydroxylamino amide, acid halide, anhydride, carboxyl carbonate or carboxyl haloformate.
A process for producing (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one comprising contacting an α-halo ester of the formula:
- 52
- with a reactive species generating reagent selected from the group consisting of Grignard reagents, magnesium, magnesium-sodium mixtures, samarium, manganese, and mixtures thereof under conditions sufficient to produce said (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one,
- wherein
- Z is nitrile or a moiety of the formula —C(═O)W;
- W is C1-C6 alkoxide, C6-C20 aryloxide, C7-C20 arylalkoxide, halide, C1-C6 carboxylate or a moiety of the formula —NR3R4;
- each of R3 and R4 is independently C1-C6 akyl, C6-C20 aryl, C7-C20 arylalkyl, C1-C6 alkoxide, C6-C20 aryloxide, C7-C20 arylalkoxide or R3 and R4 together form a moiety of the formula —(CR5R6)a—Q—(CR7R8)b—;
- each of R5, R6, R7 and R8 is independently H or C1-C6 alkyl, C6-C20 aryl, C7-C20 arylalkyl;
- Q is O, NR9 or S;
- R9 is H, an amine protecting group, C1-C6 alkyl, C6-C20 aryl or C7-C20 arylalkyl;
- and
- each of a and b is independently an integer from 1 to 4.
A process for producing (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one comprising:
- (a) enantioselectively reducing a β-keto compound of the formula:
- 56
- to produce a (R)-β-hydroxy compound of the formula:
- 57
- (b) contacting said (R)-β-hydroxy compound with an α-halo activated carbonyl compound of the formula:
- 58
- in the presence of a base under conditions sufficient to produce an α-halo ester of the formula:
- 59
- (c) contacting said α-halo ester with a reactive species generating reagent selected from the group consisting of Grignard reagents, metal and mixtures thereof under conditions sufficient to produce said (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one,
- wherein
- Z is nitrile or a moiety of the formula —C(═O)W;
- W is C1-C6 alkoxide, C6-C20 aryloxide, C7-C20 arylalkoxide, halide, C1-C6 carboxylate or a moiety of the formula —NR3R4;
- each of R3 and R4 is independently C1-C6 alkyl, C6-C20 aryl, C7-C20 arylalkyl, C1-C6 alkoxide, C6-C20 aryloxide, C7-C20 arylalkoxide or R3 and R4 together form a moiety of the formula —(CR5R6)a—Q—(CR7R8)b—;
- each of R5, R6, R7 and R8 is independently H or C1-C6 alkyl, C6-C20 aryl, C7-C20 arylalkyl;
- Q is O, NR9 or S;
- X is Br or Cl;
- R9 is H, an amine protecting group, C1-C6 alkyl, C6-C20 aryl or C7-C20 arylalkyl;
- and
- each of a and b is independently an integer from 1 to 4.
A compound of the formula:
- 60
- or its corresponding enolate of the formula:
- 61
- wherein
- R1 is C1-C20 alkyl;
- R2 is H or C1-C10 alkyl;
- X is a halide;
- and
- Z is nitrile, ester, amide, hydroxyamino amide, acid halide, anhydride, carboxyl carbonate or carboxyl haloformate.
A process for producing β-ketoester of the formula:
- 64
- comprising the steps of:
- (a) contacting an alkyl acetoacetate of the formula CH3C(═O)CH2C(═O)OR10, with a magnesium alkoxide under conditions sufficient to produce a magnesium salt of said alkyl acetoacetate and a first alcohol and removing at least a portion of said first alcohol;
- (b) contacting said alkyl acetoacetate magnesium salt with an alkyl acyl halide of the formula R1C(═O)X, under conditions sufficient to produce a tricarbonyl compound of the formula R1C(═O)CH[C(═O)CH3]C(═O)OR10;
- and
- (c) contacting said tricarbonyl compound with a second alcohol under conditions sufficient to produce said β-ketoester,
- wherein
- X is a halide;
- R1 is C1-C20 alkyl;
- and
- R10 is C1-C6 alkyl, C6-C20 aryl or C7-C20 arylalkyl.
Dependencies are inferred from the claim text.