US3740416A - (+)-cis - 1,3-dibenzyl-hexahydro-1h-thieno-(3,4-d)imidazoles - 2,4-dione, and process for tis preparation - Google Patents

(+)-cis - 1,3-dibenzyl-hexahydro-1h-thieno-(3,4-d)imidazoles - 2,4-dione, and process for tis preparation Download PDF

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Publication number
US3740416A
US3740416A US00090477A US3740416DA US3740416A US 3740416 A US3740416 A US 3740416A US 00090477 A US00090477 A US 00090477A US 3740416D A US3740416D A US 3740416DA US 3740416 A US3740416 A US 3740416A
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cis
dibenzyl
hexahydro
thieno
dione
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US00090477A
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M Gerecke
J Zimmermann
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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F Hoffmann La Roche AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • the invention relates to the optically active thiolactone of the formula 2 R- 1 3N-R A 6a 321 wherein the rings A and B are cis-linked and R is benzyl.
  • the invention relates to optically active compounds of the following formulas, of which the Formulas III, IV, IX, X, XII and XIII have the absolute configuration of biotin in the positions 3a and 6a and the Formulas V, VI, XIV, XV and XVI have the ab- XII XIII
  • R is as previously described; R is lower alkyl of 1-4 carbon atoms, and R is benzyl or lower alkyl of 1-4 carbon atoms.
  • the invention relates to processes for the preparation of )-biotin.
  • the invention relates to the optically active (+)-thiolactone of the formula wherein rings A and B are cis-linked, and R is as described above, is reacted at an elevated temperature with a salt of a thio derivative of a carboxylic acid.
  • R is benzyl, with cholesterol or with cyclohexanol into the corresponding half-esters of the formulas wherein R is as previously described and R is cyclohexyl or chloesteryl, separating the diastereomeric cholesterol half-esters from each other 'by fractional crystallization of their triethylamine salts or resolving the enantiomeric cyclohexyl half-esters from each other by fractional crystallization of their ephedrine salts, and converting the salts of the desired antipode, i.e., the antipode, or the desired diastereomer, i.e., the (+)-diastereomer, thus obtained into the (+)-lactone of Formula a.
  • the conversion of the trione of Formula a by means of cholesterol or by means of cyclohexanol into the corresponding half-esters of Formulas b and c is expediently carried out in an inert organic solvent, preferably in an aromatic hydrocarbon, and at an elevated temperature, preferably at the reflux temperature of the reaction mixture.
  • the separation of the racemic or diastereomeric halfesters of Formulas b and c with triethylamine or with ephedrine is expediently effected in a lower alkanol such as ethanol or isopropanol, or in a lower ketone such as acetone, at a temperature in the range of about 40 C. to about the boiling temperature of the reaction mixture.
  • a lower alkanol such as ethanol or isopropanol
  • a lower ketone such as acetone
  • the salts of the desired antipode or the desired diastereomer thus obtained can be directly converted into of (+)-biotin, the carboxybutyl side-chain is introduced to the (+)-thiolactone and the benzyl groups are split 01f.
  • the (+)-thiolactone is understood to be that antipode which is dextrorotatory in chloroform.
  • the racemic lactone of the Formula II used as starting material is a known substance and can be prepared according to known methods. For example, it can be obtained by reacting cis-bis-benzylaminosuccinic acid with phosgene in the presence of alkali, treating the reaction product with a dehydrating agent and, thereafter reducing the resulting product.
  • optically active (+)-lactone which can also be used as the starting material, is a new substance and can, for example, be prepared by converting the trione of the formula 0 R- N-R the +)-1actone of Formula II by means of lithium borohydride in an inert organic solvent.
  • racemic lactone of Formula II is used as the starting material in the process of the invention, there is obtained the racemic thiolactone of Formula I, and, when the optically active (+)-lactone of Formula II is used as the starting material, there is obtained the optically active (+)-thiolactone of Formula I.
  • reaction of the lactone of Formula II that is, both the racemate and the optically active (+)-form
  • a salt of a thio derivative of a carboxylic acid is expediently effected in an inert organic solvent and at a temperature in the range of about 100 C. to about 200 C., preferably in the range of about 140 C. to about 185 C.
  • solvents there are expediently used high-boiling solvents, especially high-boiling amides, tert. amines, ethers, and the like.
  • high-boiling solvents especially high-boiling amides, tert. amines, ethers, and the like.
  • Exemplary of such solvents are diethylaniline, collidine, lutidine, phenyl ethyl ether and,
  • I preferably, dimethylacetamide, dimethylformamide, quinoline, and the like.
  • solvents with a lower boiling point such as, perhaps, carbon disulfide or cyclic ethers such as tetrahydrofuran or dioxane, or tert.
  • amines such as pyridine, triethylamine, and the like, can also be 7 used, in such case the reaction expediently is carried out under pressure.
  • the reaction can also be carried out without solvent in the melt.
  • reaction is expediently carried out under an atmosphere of an inert gas, for example, under nitrogen.
  • salts of a thio derivative of a carboxylic acid there can be used salts of strong bases, for example, alkali or alkaline earth metal salts and, preferably, sodium or potassium salts.
  • the carboxylic acid moiety is not critical. Both aliphatic and aromatic carboxylic acids can be used as long as they are stable above C.
  • Preferred salts of thio derivatives of carboxylic acids are the sodium and potassium salts of thioacetic acid, thiobenzoic acid,
  • Potassium thioacetate is particularly preferred.
  • the +)-thiolactone of Formula I is converted by a Grignard reaction into the optically active compound of Formula HI.
  • the conversion of this compound into that of Formula IV is effected :by means of a dehydrating agent, for example, glacial acetic acid, or a dilute mineral acid, such as dilute sulfuric acid.
  • the compound of Formula IV is converted by catalytic hydrogenation using, for example, Raney-nickel as the catalyst into the compound of Formula V.
  • the alkoxy groups are split from this compound by, for example, hydrobromic acid to yield the compound of Formula VI.
  • the compound of Formula VI is converted by treatment with an alkali metal dialkyl malonate such as sodium diethyl malonate into 75 the compound of Formula VII.
  • the compound of Formula VII is saponified and, after decarboxylation and debenzylation, there is obtained (+)-biotin of Formula VIII.
  • (+)-thiolactone of Formula I is converted by a Grignard reaction and subsequent treatment with carbon dioxide into the optically active compound of Formula IX.
  • the conversion of the compound of Formula IX into that of Formula X is etfected by means of a dehydrating agent such as, for example, glacial acetic or a dilute mineral acid, for example, dilute sulfuric acid.
  • the compound of Formula X is converted by catalytic hydrogenation using, for example, Raney-nickel as the catalyst into the compound of Formula XI.
  • By debenzylation of the compound of Formula XI there is obtained (+)-biotin of Formula VIII.
  • the compound of Formula XIII is converted by catalytic hydrogenation using, for example, Raney-nickel as the catalyst, into the compound of Formula XIV.
  • the conversion of the compound of Formula XIV into the compound of Formula XV is eflected by treatment with hydrobromic acid in glacial acetic.
  • the transformation of the compound of Formula XV into the compound of Formula XVI is effected by means of an alkali metal cyanide, for example, sodium cyanide.
  • the compound of Formula XVI is converted into (+)-biotin of Formula VIII by saponification and debenzylation.
  • the (-l-) cis-l,3-dibenzyl-hexahydro-lH-furo[3,4-d] imidazole-2,4-dione used as the starting material can be prepared as follows:
  • reaction product is taken up in benzene and dilute hydrochloric acid, and the organic phase is washed neutral with water.
  • benzene is removed by distillation under vacuum and the residue crystallized from 25 ml. of isopropanol. There is obtained a first portion of 1.52 g. and,
  • the mixture is allowed to cool to room temperature over a period of 2 hours, and then with ice-cooling, 22 ml. of water and 5.5 ml. of concentrated hydrochloric acid are added. The layers are separated. The aqueous phase is again extracted with toluene and the organic extracts are repeatedly washed with water. The combined toluene extracts are diluted with 25 ml. of methanol, made alkaline (pH 11) with 28% aqueous sodium hydroxide solution and allowed to stand at room temperature for 30 minutes. The reaction mixture is treated with water. The aqueous phase is separated and repeatedly extracted with toluene.
  • EXAMPLE 13 Preparation of )-bi0tin 11.0 g. of magnesium are covered with 70 ml. of diethyl ether and 70 ml. of toluene. A solution containing 24.9 g. of 1,2-dibromoethane in 36 ml. of diethyl ether is then added dropwise with cooling over a period of about 20 minutes. Temperature of the reaction mixture is 20 to 28 C. After 45 minutes, a solution of 16.9 g. of 1,4-dichlorobutane in 36 ml. of diethyl ether and 75 ml. of toluene is added dropwise over a period of 25 minutes. The mixture is stirred for an additional 105 minutes.
  • the glacial acetic is removed by distillation under vacuum. The residue is dissolved in toluene and evaporated under vacuum.
  • the residual, oily cis-1,3-dibenzyl-4-(4 carboxybutylidene)-hexahydro-1H- thieno[3,4-d]imidazol-2-one which is dextrorotatory in chloroform is dissolved in 80 ml. of methanol and hydrogenated in the presence of Raney-nickel at 3540 C. under 38 to 40 atmospheres of hydrogen pressure.
  • the catalyst is removed by filtration, and the filtrate is evaporated, whereby there are obtained 10.3 g. of oily crude N,N-dibenzyl-biotin, which is levorotatory in chloroform.
  • Gerecke et al. (Gerecke, Zimmermann and Aschwanden), I-Ielv. Chim. Acta, 1970, vol. 53, pages 991-9 (July 10, 1970).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
US00090477A 1969-11-29 1970-11-17 (+)-cis - 1,3-dibenzyl-hexahydro-1h-thieno-(3,4-d)imidazoles - 2,4-dione, and process for tis preparation Expired - Lifetime US3740416A (en)

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CH1777369A CH556867A (de) 1969-11-29 1969-11-29 Verfahren zur herstellung eines racemischen oder optisch aktiven thiolactons.

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US3740416A true US3740416A (en) 1973-06-19

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US (1) US3740416A (ja)
JP (1) JPS5327279B1 (ja)
BE (1) BE759513A (ja)
CA (1) CA982591A (ja)
CH (1) CH556867A (ja)
DK (1) DK154563C (ja)
FR (1) FR2077540B1 (ja)
GB (2) GB1320799A (ja)
NL (1) NL156140B (ja)
SE (1) SE391928B (ja)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4054740A (en) * 1974-12-24 1977-10-18 Hoffmann-La Roche Inc. Hydroxybiotin
US4130713A (en) * 1977-08-05 1978-12-19 Hoffmann-La Roche Inc. Biotin intermediates
US4189586A (en) * 1977-08-05 1980-02-19 Hoffmann-La Roche Inc. Preparation of biotin
US4228295A (en) * 1977-02-23 1980-10-14 Hoffmann-La Roche Inc. Novel cycloheptathiophene intermediates for the synthesis of biotin
US4245104A (en) * 1978-12-01 1981-01-13 Hoffmann-La Roche Inc. Isoxazolines and isoxazolidines
US4247704A (en) * 1979-05-29 1981-01-27 Hoffmann-La Roche Inc. Hexahydro thieno imadazole intermediates for the synthesis of biotin
US4284557A (en) * 1979-05-29 1981-08-18 Hoffmann-La Roche Inc. Intermediate racemates for the preparation of biotin and a process for their preparation
EP0036030A1 (en) * 1980-03-14 1981-09-23 Sumitomo Chemical Company, Limited Process for preparing biotin
US4320056A (en) * 1980-05-15 1982-03-16 Hoffmann-La Roche Inc. Certain thia-diazatricyclo[3,3,3,08,11 ]tridecanes, and their preparation
US4337345A (en) * 1977-08-05 1982-06-29 Hoffmann-La Roche Inc. Preparation of biotin via thieno [3,2c] isoxazoles
US4382031A (en) * 1981-03-12 1983-05-03 Hoffmann-La Roche Inc. Intermediates for the preparation of biotin
US4537973A (en) * 1980-03-12 1985-08-27 Sumitomo Chemical Company, Limited Process for preparing biotin
US5235065A (en) * 1991-03-06 1993-08-10 Merck Patent Gesellschaft Mit Beschrankter Haftung Process for the preparation of a d-(+)-biotin intermediate
US5708185A (en) * 1995-12-26 1998-01-13 Sumitomo Chemical Company, Limited Process for producing 1-hydroxythienoimidazole carboxylic acid and thienoimidazole carboxylic acid
US20030004357A1 (en) * 2000-01-14 2003-01-02 Ulrich Koop Reaction of carbonyl compounds with organometallic reagents
CN101096372B (zh) * 2007-01-24 2010-09-29 绍兴文理学院 硫内酯的合成工艺
CN103554129A (zh) * 2013-10-09 2014-02-05 安徽泰格维生素实业有限公司 一种生物素中间体硫酮的制备方法
CN103788112A (zh) * 2012-11-02 2014-05-14 菏泽市方明制药有限公司 一种苄基生物素脱苄制备生物素的方法
CN102268007B (zh) * 2010-02-09 2015-11-25 浙江新和成股份有限公司 双苄生物素衍生物的制备方法
CN107973806A (zh) * 2016-10-21 2018-05-01 大丰海嘉诺药业有限公司 一种制备d-生物素溴盐中间体的方法
WO2021224295A1 (en) 2020-05-07 2021-11-11 Dsm Ip Assets B.V. A process for producing d-biotin intermediates

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK43985A (da) * 1984-03-09 1985-09-10 Hoffmann La Roche Fremgangsmaade til fremstilling af heterocycliske forbindelser
TW200300676A (en) 2001-12-04 2003-06-16 Tanabe Seiyaku Co Biotin intermediate and its production
WO2020110831A1 (ja) * 2018-11-28 2020-06-04 株式会社トクヤマ チオラクトン誘導体の製造方法
JP7229434B1 (ja) * 2021-06-11 2023-02-27 株式会社トクヤマ ヒドロキシチエノイミダゾール誘導体、ビニルスルフィド誘導体、ｎ－ブチリデンスルフィド誘導体、及び飽和直鎖炭化水素置換チエノイミダゾール誘導体の製造方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK71723C (da) * 1946-05-31 1950-11-20 Hoffmann La Roche Fremgangsmåde til fremstilling af d,1-biotin.
DK81470C (da) * 1947-07-24 1956-07-30 Hoffmann La Roche Fremgangsmåde til fremstilling af d- og l-biotin.
DK73837C (da) * 1947-07-24 1952-03-03 Hoffmann La Roche Fremgangsmåde til fremstilling af biotin eller homologe biotinforbindelser.

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4054740A (en) * 1974-12-24 1977-10-18 Hoffmann-La Roche Inc. Hydroxybiotin
US4228295A (en) * 1977-02-23 1980-10-14 Hoffmann-La Roche Inc. Novel cycloheptathiophene intermediates for the synthesis of biotin
US4130713A (en) * 1977-08-05 1978-12-19 Hoffmann-La Roche Inc. Biotin intermediates
US4189586A (en) * 1977-08-05 1980-02-19 Hoffmann-La Roche Inc. Preparation of biotin
US4337345A (en) * 1977-08-05 1982-06-29 Hoffmann-La Roche Inc. Preparation of biotin via thieno [3,2c] isoxazoles
US4245104A (en) * 1978-12-01 1981-01-13 Hoffmann-La Roche Inc. Isoxazolines and isoxazolidines
US4247704A (en) * 1979-05-29 1981-01-27 Hoffmann-La Roche Inc. Hexahydro thieno imadazole intermediates for the synthesis of biotin
US4284557A (en) * 1979-05-29 1981-08-18 Hoffmann-La Roche Inc. Intermediate racemates for the preparation of biotin and a process for their preparation
US4537973A (en) * 1980-03-12 1985-08-27 Sumitomo Chemical Company, Limited Process for preparing biotin
EP0036030A1 (en) * 1980-03-14 1981-09-23 Sumitomo Chemical Company, Limited Process for preparing biotin
US4320056A (en) * 1980-05-15 1982-03-16 Hoffmann-La Roche Inc. Certain thia-diazatricyclo[3,3,3,08,11 ]tridecanes, and their preparation
US4382031A (en) * 1981-03-12 1983-05-03 Hoffmann-La Roche Inc. Intermediates for the preparation of biotin
US5235065A (en) * 1991-03-06 1993-08-10 Merck Patent Gesellschaft Mit Beschrankter Haftung Process for the preparation of a d-(+)-biotin intermediate
US5708185A (en) * 1995-12-26 1998-01-13 Sumitomo Chemical Company, Limited Process for producing 1-hydroxythienoimidazole carboxylic acid and thienoimidazole carboxylic acid
EP0781775A3 (en) * 1995-12-26 1998-02-04 Sumitomo Chemical Company, Limited Process for producing 1-hydroxythienoimidazole carboxylic acid and thienoimidazole carboxylic acid
US20030004357A1 (en) * 2000-01-14 2003-01-02 Ulrich Koop Reaction of carbonyl compounds with organometallic reagents
US7098344B2 (en) * 2000-01-14 2006-08-29 Merck Patent Gmbh Reaction of carbonyl compounds with organometallic reagents
CN101096372B (zh) * 2007-01-24 2010-09-29 绍兴文理学院 硫内酯的合成工艺
CN102268007B (zh) * 2010-02-09 2015-11-25 浙江新和成股份有限公司 双苄生物素衍生物的制备方法
CN103788112A (zh) * 2012-11-02 2014-05-14 菏泽市方明制药有限公司 一种苄基生物素脱苄制备生物素的方法
CN103788112B (zh) * 2012-11-02 2016-03-09 菏泽市方明制药有限公司 一种苄基生物素脱苄制备生物素的方法
CN103554129A (zh) * 2013-10-09 2014-02-05 安徽泰格维生素实业有限公司 一种生物素中间体硫酮的制备方法
CN103554129B (zh) * 2013-10-09 2016-03-23 安徽泰格维生素实业有限公司 一种生物素中间体硫酮的制备方法
CN107973806A (zh) * 2016-10-21 2018-05-01 大丰海嘉诺药业有限公司 一种制备d-生物素溴盐中间体的方法
WO2021224295A1 (en) 2020-05-07 2021-11-11 Dsm Ip Assets B.V. A process for producing d-biotin intermediates

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Publication number Publication date
NL156140B (nl) 1978-03-15
JPS5327279B1 (ja) 1978-08-07
FR2077540A1 (ja) 1971-10-29
BE759513A (fr) 1971-05-27
CH556867A (de) 1974-12-13
NL7015567A (ja) 1971-06-02
SE391928B (sv) 1977-03-07
GB1320799A (en) 1973-06-20
DK154563B (da) 1988-11-28
CA982591A (en) 1976-01-27
DK154563C (da) 1989-04-17
DE2058234A1 (de) 1971-06-09
GB1320798A (en) 1973-06-20
DE2058234B2 (de) 1977-02-17
FR2077540B1 (ja) 1975-12-12

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