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US4876350A Expired / Lapsed US ⏱️ 0.0 years remaining

Process for the production of (+) biotin

Assignee: Lonza AG
•
Filing: 1987-12-16
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Granted: 1989-10-24
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Expires: 2007-12-16
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Abstract

Abstract Process for the production of (+) biotin. A compound of the formula: ##STR1## wherein R 1 is e.g., an (R)-1-phenylalkyl group, and R 2 is, e.g., hydrogen. The desired diastereomer of the formula: ##STR2## is separated out. If R 2 is H, a protective group is introduced by reaction with, e.g., an aliphatic acid chloride. The diastereomer is converted by reaction with a thiocarboxylic acid salt derivative into the corresponding thiolacetone, which is reacted with a Grignard reactant and subsequently water is split off. Alternatively, the corresponding thiolacetone is reacted with a compound of the formula: (C.sub.6 H.sub.5).sub.3 P.sup.⊕ (CH.sub.2).sub.4 COOR 3 .X.sup.⊖ wherein R 3 is, e.g., H, and X is a halogen atom, in the presence of a base to provide a compound of the formula: ##STR3## Such compound is catalytically hydrogenated and then converted into (+) biotin by cleavage of the protective groups.

Inventors

  • 👤 John McGarrity
  • 👤 Leander Tenud

Bibliographic Details

Application Number —
Jurisdiction US
Data Source google_patents
Last Synchronized 2026-11-08 03:05
CPC Classifications
C; C07; C07D; C07D495/00; C07D495/02; C07D495/04; Y; Y02; Y02P; Y02P20/00; Y02P20/50; Y02P20/55

Claims Analysis

Total Claims: 18
Claim 1
Independent Claim 259 words
Process for the production of (+) biotin, comprising catalytically hydrogenating a compound of the formula: ##STR23## wherein R 1 is an (R)- or (S)-1-phenylalkyl group, an (R)- or (S)-1-alkoxycarbonyl-1-phenylmethyl group or an (R)- or (S)-1-aryloxycarbonyl-1-phenylmethyl group, and R 2 is hydrogen, a substituted or unsubstituted alkanoyl group, an unsubstituted or a substituted benzoyl group, a substituted or an unsubstituted benzyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aryloxyalkyl group, an alkoxyalkyl group, a pyranyl group, an unsubstituted or substituted benzenesulfonyl group, an alkylsulfonyl group, a diarylphosphinyl group, a dialkoxyphosphinyl group or a trialkylsilyl group, with hydrogen, separating the desired diastereomer of the formula: ##STR24## if R 2 is H, introducing a protective group by reaction with aliphatic or aromatic acid chlorides, aliphatic or aromatic carboxylic acid anhydrides, haloformic acid alkyl esters, benzyl halides, 1-alkoxyalkyl halides, enol ethers, aromatic or aliphatic sulfonic acid halides, diarylphosphinic acid halides, phosphoric acid dialkyl ester chlorides, trialkylsilyl halides or trialkylsilyl acetamides, converting the diastereomer by a further reaction with a thiocarboxylic acid salt derivative into the corresponding thiolactone, reacting the corresponding thiolactone with a Grignard reagent and subsequently splitting off of water or with a compound of the formula: (C.sub.6 H.sub.5).sub.3 P.sup.⊕ (CH.sub.2).sub.4 COOR.sub.3.X.sup.⊖ III wherein R 3 is H or alkyl with 1 to 4 C atoms and X is a halogen atom, in the presence of a base to a compound of the formula: ##STR25## where R 3 has the above-mentioned meaning, catalytically hydrogenating said compound and then converting said catalytically-hydrogenated compound into (+) biotin by cleavage of the protective groups.
Claim 2
Dependent Claim 259 words
Process for the production of (+) biotin, comprising catalytically hydrogenating a compound of the formula: ##STR23## wherein R 1 is an (R)- or (S)-1-phenylalkyl group, an (R)- or (S)-1-alkoxycarbonyl-1-phenylmethyl group or an (R)- or (S)-1-aryloxycarbonyl-1-phenylmethyl group, and R 2 is hydrogen, a substituted or unsubstituted alkanoyl group, an unsubstituted or a substituted benzoyl group, a substituted or an unsubstituted benzyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aryloxyalkyl group, an alkoxyalkyl group, a pyranyl group, an unsubstituted or substituted benzenesulfonyl group, an alkylsulfonyl group, a diarylphosphinyl group, a dialkoxyphosphinyl group or a trialkylsilyl group, with hydrogen, separating the desired diastereomer of the formula: ##STR24## if R 2 is H, introducing a protective group by reaction with aliphatic or aromatic acid chlorides, aliphatic or aromatic carboxylic acid anhydrides, haloformic acid alkyl esters, benzyl halides, 1-alkoxyalkyl halides, enol ethers, aromatic or aliphatic sulfonic acid halides, diarylphosphinic acid halides, phosphoric acid dialkyl ester chlorides, trialkylsilyl halides or trialkylsilyl acetamides, converting the diastereomer by a further reaction with a thiocarboxylic acid salt derivative into the corresponding thiolactone, reacting the corresponding thiolactone with a Grignard reagent and subsequently splitting off of water or with a compound of the formula: (C.sub.6 H.sub.5).sub.3 P.sup.⊕ (CH.sub.2).sub.4 COOR.sub.3.X.sup.⊖ III wherein R 3 is H or alkyl with 1 to 4 C atoms and X is a halogen atom, in the presence of a base to a compound of the formula: ##STR25## where R 3 has the above-mentioned meaning, catalytically hydrogenating said compound and then converting said catalytically-hydrogenated compound into (+) biotin by cleavage of the protective groups.
Claim 3
Dependent Claim 57 words
Process according to claim 1 wherein platinum, palladium, rhodium, or ruthenium catalyst on support materials such as carbon, aluminum oxide, aluminum silicate, silicon dioxide, calcium carbonate, or a homogeneous catalyst, consisting of rhodium or iridium with triphenylphosphine or cyclooactadiene as the ligands is used as the hydrogenation catalyst for the hydrogenation of compound I to compound II.
Claim 4
Dependent Claim 24 words
Process according to claim 2 wherein rhodium on aluminum oxide is used as the hydrogenation catalyst for hydrogenation from compound I to compound II.
Claim 5
Dependent Claim 14 words
Process according to claim 3 wherein compound II has position 3aS-configuration and position 6aR-configuration.
Claim 6
Dependent Claim 27 words
Process according to claim 4 wherein an alkaline-earth or alkali thiocarboxylic acid salt of an aliphatic or aromatic carboxylic acid is used as the thiocarboxylic acid derivative.
Claim 7
Dependent Claim 15 words
Process according to claim 5 wherein alkalithioacetate is used as the thiocarboxylic acid salt derivative.
Claim 8
Dependent Claim 44 words
Process according to claim 6 wherein the Grignard reagent takes place with a Grignard compound of the formula: XMg--(CH.sub.2).sub.4 --MgX where X is chlorine or bromine, with subsequent treatment with CO 2 and then splitting off of water in the presence of an acid.
Claim 9
Dependent Claim 58 words
Process according to claim 7 wherein compound III is converted to compound IV in the presence of an alkylalkali metal, an alkali metal hydride, or a compound of the formula: ##STR26## wherein Y is an alkali metal, an alkali metal oxide, an alkali metal alkylamide, an alkali metal amide, an alkali metal hydroxide or an alkali metal carbonate.
Claim 10
Dependent Claim 46 words
Process according to claim 8 wherein the hydrogenation of compound IV is performed in the presence of a palladium, platinum, rhodium, ruthenium or nickel catalyst or one of said catalysts, on a support material such as carbon, aluminum oxide, aluminum silicate, silicon dioxide or calcium carbonate.
Claim 11
Dependent Claim 19 words
Process according to claim 9 wherein the cleavage of the protective groups takes place by treatment with an acid.
Claim 12
Dependent Claim 14 words
Process according to claim 1 wherein compound II has position 3aS-configuration and position 6aR-configuration.
Claim 13
Dependent Claim 27 words
Process according to claim 1 wherein an alkaline-earth or alkali thiocarboxylic acid salt of an aliphatic or aromatic carboxylic acid is used as the thiocarboxylic acid derivative.
Claim 14
Dependent Claim 15 words
Process according to claim 1 wherein alkalithioacetate is used as the thiocarboxylic acid salt derivative.
Claim 15
Dependent Claim 44 words
Process according to claim 1 wherein the Grignard reagent takes place with a Grignard compound of the formula: XMg--(CH.sub.2).sub.4 --MgX wherein X is chlorine or bromine, with subsequent treatment with CO 2 and then splitting off of water in the presence of an acid.
Claim 16
Dependent Claim 57 words
Process according to claim 1 wherein compound III is converted to Compound IV in the presence of an alkylalkali metal, an alkali metal hydride or a compound of the formula: ##STR27## wherein Y is an alkali metal, an alkali metal oxide, an alkali metal alkylamide, an alkali metal amide, an alkali hydroxide or an alkali metal carbonate.
Claim 17
Dependent Claim 41 words
Process according to claim 1 wherein the hydrogenation of compound IV is performed in the presence of a palladium, platinum, rhodium, ruthenium or nickel catalyst, or one of said catalysts on carbon, aluminum oxide, aluminum silicate, silicon dioxide or calcium carbonate.
Claim 18
Dependent Claim 17 words
Process according to claim 1 wherein cleavage of the protective groups takes place by treatment with acids.

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