EP4352064A1 - Verfahren zur herstellung eines biotinzwischenprodukts - Google Patents

Verfahren zur herstellung eines biotinzwischenprodukts

Info

Publication number
EP4352064A1
EP4352064A1 EP21944657.2A EP21944657A EP4352064A1 EP 4352064 A1 EP4352064 A1 EP 4352064A1 EP 21944657 A EP21944657 A EP 21944657A EP 4352064 A1 EP4352064 A1 EP 4352064A1
Authority
EP
European Patent Office
Prior art keywords
mol
trifluoromethanesulfonate
compound
otf
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21944657.2A
Other languages
English (en)
French (fr)
Inventor
Werner Bonrath
Bo Gao
Kun Peng
Qiong-mei ZHANG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DSM IP Assets BV
Original Assignee
DSM IP Assets BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by DSM IP Assets BV filed Critical DSM IP Assets BV
Publication of EP4352064A1 publication Critical patent/EP4352064A1/de
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—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
    • C07D495/02—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

Definitions

  • the present invention is related to a process for producing an important biotin intermediate.
  • the D-Biotin also known as Vitamin H, is mainly applied to the fields of medicine and sanitation, nutrition enhancer, feed additive, cosmetics and drinks, etc.
  • the molecular structural formula of the D-Biotin is shown as follows:
  • a known process for producing the above compound (a) comprises: a) L-cysteine or L-serine is used as raw material to produce an optically active hydantoin which is then converted to an intermediate compound (IX) , b) the intermediate compound (IX) is converted into a bicyclic cyanohydantoin (I) in two steps, and c) the bicyclic cyanohydantoin (I) is finally converted to the compound (a) in additional two steps. (see US 5,095,118 A)
  • step b) is critical but it has two steps with using expensive catalysts and reagents. As a result, the process is not good enough for industry.
  • the present invention provides an improved process for producing a biotin intermediate compound (I) ,
  • R 1 and R 2 are each independently of one another H, lower alkyl, lower cycloalkyl, aryl, or lower aralkyl, optionally substituted by one or more substituents;
  • R 3 is H, or a protective group which is suitable for a nitrogen atom
  • X and Y are each independently of one another O or S.
  • the process of the present application reduces the steps for producing the compound of formula (I) , and reduces cost by avoiding expensive catalysts and provides high yields and/or selectivity.
  • lower alkyl refers to C 1 -C 10 alkyl, i.e., branched or unbranched, cyclic or non-cyclic, saturated hydrocarbon comprising 1-10 carbon atoms.
  • the “lower alkyl” is C 1 -C 6 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, iso-pentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, tert-hexyl, cyclohexyl, octyl, isooctyl, tert-octyl, cyclooctyl, nonyl, isononyl, tert-nonyl, cyclononyl, decyl, isodecyl, tert-decyl, cyclodecyl. More preferably, the “lower alkyl” is methyl or ethyl.
  • aryl refers to a carbocyclic aromatic system containing one ring, or two or three rings fused together where in the ring atoms are all carbon.
  • aryl includes, but is not limited to groups such as phenyl, benzyl, xylyl and naphthalenyl.
  • lower cycloalkyl refers to a saturated monocyclic, bicyclic or tricyclic group wherein the ring atoms of the cyclic system are all carbon and wherein each cyclic moiety contains from 3 to 12 carbon atom ring members.
  • One group of lower cycloalkyl has from 5 to 7 carbon atoms. Examples of lower cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.
  • lower aralkyl refers to an aryl attached to the parent molecular moiety through a lower alkyl, wherein the aryl and the lower alkyl are defined herein.
  • lower silyl refers to a structure represented by R 1 R 2 R 3 Si-wherein R 1 , R 2 and R 3 are each independently of one another lower alkyl or aryl as defined herein.
  • lower alkoxyl refers to the structure represented by (lower alkyl) -O-, wherein the lower alkyl is as defined herein.
  • halo or “halogen” as used refers to a group of elements including fluorine (F) , chlorine (Cl) , bromine (Br) and iodine (I) , preferably refers to Cl or Br.
  • halide as used is meant to include iodide, bromide, chloride and fluoride, and preferably bromide or iodide, and more preferably bromide.
  • substituteduent or “substituents” as used refers to lower alkyl, lower alkoxyl, hydroxyl, halo, -NH 2 , -NO 2 , cyano and/or isocyano.
  • the symbol as used in the compound formulas of the present invention means the connected group is connected to a chiral carbon in S-and/or R-configuration.
  • the present invention provides a process for producing a compound of formula (I) , or a stereoisomer thereof, or a stereoisomeric mixture thereof, comprising reacting a compound of formula (II) , or a stereoisomer thereof, or a stereoisomeric mixture thereof, with a cyanide in the presence of a catalyst,
  • R 1 and R 2 are each independently of one another H, lower alkyl, lower cycloalkyl, aryl, or lower aralkyl, optionally substituted by one or more substituents;
  • R 3 is H, or a protective group which is suitable for a nitrogen atom
  • R 4 is H, lower alkyl, lower silyl, acyl, lower alkyl sulfonyl, arylsulfonyl, or lower aralkyl sulfonyl, optionally substituted by one or more substituents;
  • X and Y are each independently of one another O or S.
  • the cyanide is a cyanosilane such as trimethylsilyl cyanide (TMSCN) and ⁇ -trimethylsilylpropionitrile.
  • TMSCN trimethylsilyl cyanide
  • ⁇ -trimethylsilylpropionitrile Preferably, the cyanide is TMSCN.
  • the catalyst is selected from a group consisting of trifluoromethanesulfonic acid (HOTf) , trifluoromethanesulfonate esters such as trimethylsilyl trifluoromethanesulfonate (TMSOTf) and tert-butyldimethylsilyl trifluoromethanesulfonate (t-BuMe 2 SiOTf) , trifluoromethanesulfonate salts such as zinc trifluoromethanesulfonate (Zn (OTf) 2 ) , iron trifluoromethanesulfonate (Fe (OTf) 3 ) , copper trifluoromethanesulfonate (Cu (OTf) 2 ) , ytterbium trifluoromethanesulfonate (Yb (OTf) 3 ) , scandium trifluoromethanesulfonate (Sc (OTf) 3 ) , silver trifluoromethanesulf
  • the catalyst is preferably HOTf, TMSOTf, t-BuMe 2 SiOTf, Zn (OTf) 2 , Fe (OTf) 3 , Cu (OTf) 2 , Yb (OTf) 3 , Sc (OTf) 3 , AgOTf, Bi (OTf) 3 , InBr 3 , InI 3 , AgNTf 2 , or trifluoromethansulfonimide, or mixture thereof. More preferably, the catalyst is HOTf, TMSOTf, Zn (OTf) 2 , Cu (OTf) 2 , AgOTf, InBr 3 or trifluoromethansulfonimide, or mixture thereof. The most preferably, the catalyst is TMSOTf.
  • the protective group may be tert-butyl, benzyl, 4-methoxybenzyl, 3, 4-dimethoxybenzyl, 4-methylbenzyl, allyl, methallyl, crotyl, methoxymethyl, trimethylsilyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.
  • R 1 and R 2 are, each independently of one another, preferably H, C 1 -C 6 alkyl, or phenyl or benzyl, optionally substituted by one or more substituents, and more preferably R 1 is H and R 2 is phenyl.
  • R 3 is preferably tert-butyl or benzyl, optionally substituted by one or more substituents, more preferably, R 3 is benzyl.
  • R 4 is preferably H, methyl, ethyl, trifluoromethyl, bistrifluoromethylmethyl, trimethylsilyl (-TMS) , formyl, acetyl, propionyl, benzoyl, 4-nitrobenzoyl, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, phenylsulfonyl, toluenesulfonyl or benzylsulfonyl.
  • R 4 is H, acetyl, propionyl, benzoyl, toluenesulfonyl, bistrifluoromethylmethyl or trifluoromethanesulfonyl.
  • R 4 is H, acetyl or -TMS.
  • R 1 is H
  • R 2 is phenyl
  • R 3 is benzyl
  • R 4 is H
  • X is S
  • Y is O.
  • the stereoisomer of the present invention includes enantiomers and diastereomers.
  • the compound of the formula (I) has the following stereoisomers:
  • R 4 is defined as above.
  • the compound of the formula (I) is one of the following stereoisomers:
  • the compound of the formula (II) is one of the following stereoisomers:
  • the cyanide may be added in an amount of from 1 mol to 20 mol, preferably from 1.5 mol to 15 mol, more preferably from 2 mol to 10 mol, per 1 mole of the compound of formula (II) .
  • the catalyst may be added in an amount of from 0.01 mol to 1 mol, preferably from 0.05 mol to 0.8 mol, more preferably from 0.1 mol to 0.5 mol, per 1 mole of the compound of formula (II) .
  • the reaction of the process of the present invention may be carried out in a solvent, or mixture thereof.
  • suitable solvent include but are not limited to alkane such as cyclohexane, haloalkane such as chloroform, dichloromethane (DCM) , 1, 1, 2, 2-tetrachloroethane and 1-chloro-2-methylbutane, alkanoic acid such as dimethyl carbonate (DMC) , nitriles such as acetonitrile (ACN) and benzonitrile, aromatic alkane such as toluene, and cyclic ether such as tetrahydrofuran (THF) , and mixture thereof.
  • alkane such as cyclohexane
  • haloalkane such as chloroform, dichloromethane (DCM) , 1, 1, 2, 2-tetrachloroethane and 1-chloro-2-methylbutane
  • alkanoic acid such as dimethyl carbonate (DMC)
  • the solvent may be used in the reaction in an amount of from 1 mL to 30 mL, preferably from 2 mL to 20 mL, more preferably from 2 mL to 7 mL, per 1 mole of the compound of formula (II) .
  • the reaction of the process of the present invention may be carried out at the temperature of from -50°C to 200°C, preferably from 0°C to 100°C, more preferably 10°C to 50°C, the most preferably at room temperature.
  • the obtained compound of the formula (I) may be isolated and/or purified by a well-known process in the art and used for the preparation of (+) -biotin. Accordingly, the present invention also provides a process for producing (+) -biotin which comprises the process for producing the compound of formula (I) as described herein.
  • the process of the present application simplifies the operation, avoids expensive catalysts and improves yield of the compound of formula (I) compared to the process of prior art.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
EP21944657.2A 2021-06-11 2021-06-11 Verfahren zur herstellung eines biotinzwischenprodukts Pending EP4352064A1 (de)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/099884 WO2022257151A1 (en) 2021-06-11 2021-06-11 Process for producing biotin intermediate

Publications (1)

Publication Number Publication Date
EP4352064A1 true EP4352064A1 (de) 2024-04-17

Family

ID=84424510

Family Applications (1)

Application Number Title Priority Date Filing Date
EP21944657.2A Pending EP4352064A1 (de) 2021-06-11 2021-06-11 Verfahren zur herstellung eines biotinzwischenprodukts

Country Status (3)

Country Link
EP (1) EP4352064A1 (de)
CN (1) CN117440957A (de)
WO (1) WO2022257151A1 (de)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0242686B1 (de) * 1986-04-19 1992-01-29 MERCK PATENT GmbH Verfahren zur Herstellung von D-(+)-Biotin
DE3928263A1 (de) * 1989-08-26 1991-02-28 Merck Patent Gmbh Verfahren zur herstellung von 7-cyan-7,7a-dihydro-1h,3h-imidazol(1,5-c) thiazol-5(6h)-onen
DE4024692A1 (de) * 1990-08-03 1992-02-06 Merck Patent Gmbh Verfahren zur herstellung von cyanhydantoinen
DE4116157A1 (de) * 1991-05-17 1992-11-19 Merck Patent Gmbh Verfahren zur herstellung von imidazothiazolon-derivaten
FR2972453B1 (fr) * 2011-03-09 2013-11-29 Minakem Nouveau procede de synthese du (1r,2s,5s)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate de methyle ou de l'un de ses sels
CN111620903A (zh) * 2020-06-17 2020-09-04 安徽贝克联合制药有限公司 C-核苷类似物以及用于合成瑞德西韦合成的含腈c-核苷类化合物的制备方法及其应用

Also Published As

Publication number Publication date
WO2022257151A1 (en) 2022-12-15
CN117440957A (zh) 2024-01-23

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