EP4352064A1 - Process for producing biotin intermediate - Google Patents

Process for producing biotin intermediate

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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
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German (de)
French (fr)
Inventor
Werner Bonrath
Bo Gao
Kun Peng
Qiong-mei ZHANG
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DSM IP Assets BV
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DSM IP Assets BV
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Publication date
Application filed by DSM IP Assets BV filed Critical DSM IP Assets BV
Publication of EP4352064A1 publication Critical patent/EP4352064A1/en
Pending legal-status Critical Current

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    • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Provided an improved process for producing a biotin intermediate compound (I) with low cost and high yield, Wherein: 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; and X and Y are each independently of one another O or S.

Description

    [Title established by the ISA under Rule 37.2] PROCESS FOR PRODUCING BIOTIN INTERMEDIATE Technical Field
  • The present invention is related to a process for producing an important biotin intermediate.
    • Background of the Invention
  • 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:
  • Since the debut of industrially synthetized D-biotin of a Swiss company Roche in 1949, the synthesis methods have been still undergone many researches in the world. To date, many about total synthesis routes have been reported. Yet, the most industrial process for D-biotin uses thiolactone compounds (a) to produce the intermediate compound (b) which is then converted by catalytic hydrogenation to the compound (c) and finally to the D-biotin (see US 3,740,416) .
  • 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)
  • In the above process, the 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.
  • Accordingly, there is still demand in a process for producing the biotin intermediate compound (I) with improved cost, yield and/or selectivity.
  • Summary of the Invention
  • The present invention provides an improved process for producing a biotin intermediate compound (I) ,
  • Wherein:
  • 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; and
  • 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.
    • Detailed Description of the Invention
  • In the present invention, the term “lower alkyl” as used refers to C 1-C 10 alkyl, i.e., branched or unbranched, cyclic or non-cyclic, saturated hydrocarbon comprising 1-10 carbon atoms. Preferably, 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.
  • In the present invention, the term “aryl” as used refers to a carbocyclic aromatic system containing one ring, or two or three rings fused together where in the ring atoms are all carbon. The term “aryl” includes, but is not limited to groups such as phenyl, benzyl, xylyl and naphthalenyl.
  • In the present invention, the term “lower cycloalkyl” as used 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.
  • In the present invention, the term “lower aralkyl” as used refers to an aryl attached to the parent molecular moiety through a lower alkyl, wherein the aryl and the lower alkyl are defined herein.
  • In the present invention, the term “acyl” as used refers to a structure represented by R-C (=O) -wherein R is lower alkyl or aryl as defined herein.
  • In the present invention, the term “lower silyl” as used refers to a structure represented by R 1R 2R 3Si-wherein R 1, R 2 and R 3 are each independently of one another lower alkyl or aryl as defined herein.
  • In the present invention, the term “lower alkyl sulfonyl” as used refers to a structure represented by (lower alkyl) -S (=O)  2-wherein the lower alkyl is as defined herein.
  • In the present invention, the term “arylsulfonyl” as used refers to a structure represented by aryl-S (=O)  2-wherein the aryl is as defined herein.
  • In the present invention, the term “lower aralkyl sulfonyl” as used refers to a structure represented by (lower aralkyl) -S (=O)  2-wherein the lower aralkyl is as defined herein.
  • In the present invention, the term “lower alkoxyl” as used refers to the structure represented by (lower alkyl) -O-, wherein the lower alkyl is as defined herein.
  • In the present invention, the term “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.
  • In the present invention, the term “halide” as used is meant to include iodide, bromide, chloride and fluoride, and preferably bromide or iodide, and more preferably bromide.
  • In the present invention, the term “substituent” or “substituents” as used refers to lower alkyl, lower alkoxyl, hydroxyl, halo, -NH 2, -NO 2, cyano and/or isocyano.
  • In the present invention, 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,
  • Wherein:
  • 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; and
  • X and Y are each independently of one another O or S.
  • In the present invention, the cyanide is a cyanosilane such as trimethylsilyl cyanide (TMSCN) and β-trimethylsilylpropionitrile. Preferably, the cyanide is TMSCN.
  • In the present invention, 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 2SiOTf) , 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 trifluoromethanesulfonate (AgOTf) and bismuth trifluoromethanesulfonate (Bi (OTf)  3) , indium halide such as indium bromide (InBr 3) and indium iodide  (InI 3) , sliver bis (trifluoromethane sulfonimide) (AgNTf 2) , and trifluoromethansulfonimide, or mixture thereof.
  • The catalyst is preferably HOTf, TMSOTf, t-BuMe 2SiOTf, 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.
  • In the present invention, 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.
  • In the present invention, 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.
  • In the present invention, R 3 is preferably tert-butyl or benzyl, optionally substituted by one or more substituents, more preferably, R 3 is benzyl.
  • In the present invention, R 4 is preferably H, methyl, ethyl, trifluoromethyl, bistrifluoromethylmethyl, trimethylsilyl (-TMS) , formyl, acetyl, propionyl, benzoyl, 4-nitrobenzoyl, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, phenylsulfonyl, toluenesulfonyl or benzylsulfonyl. More preferably, R 4 is H, acetyl, propionyl, benzoyl, toluenesulfonyl, bistrifluoromethylmethyl or trifluoromethanesulfonyl. The most preferably, R 4 is H, acetyl or -TMS.
  • In one embodiment of the present invention, R 1 is H, R 2 is phenyl, R 3 is benzyl, R 4 is H, X is S, and Y is O.
  • The stereoisomer of the present invention includes enantiomers and diastereomers. For example, the compound of the formula (I) has the following stereoisomers:
  • and the compound of formula (II) has the following stereoisomers:
  • Wherein R 4 is defined as above.
  • More particularly, the compound of the formula (I) is one of the following stereoisomers:
  • More particularly, the compound of the formula (II) is one of the following stereoisomers:
  • In the process of the present invention, 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) .
  • In the process of the present invention, 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. Examples of the 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.
  • In the present invention, 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℃ to 200℃, preferably from 0℃ to 100℃, more preferably 10℃ to 50℃, 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.
  • The present invention will be further illustrated by the following examples.
  • Examples
  • In the following examples of the present application, “Ph” is phenyl, ” Bn” is benzyl, “TMS” is trimethylsilyl, “CN” is cyano group, and “tBu” is tert-butyl.
  • Examples 1
  • Compound 1 (302 mg, purity 94.32%, 0.87 mmol) was placed in a 10 mL Schlenk tube. DCM (4 mL) and TMSCN (0.224 mL, purity 96%, 2 eq. ) were added. A catalyst (0.1 eq. ) as shown in Table 1 was mixed with DCM (1 mL) and then the mixture was added in 10 mins. The mixture was stirred for 8 hours at room temperature to obtain the compound 2. The NMR yields are shown in Table 1.
  • Table 1
  • Entries Catalysts NMR yield
    1 TMSOTf >99%
    2 Zn (OTf)  2 92.6 %
    3 Fe (OTf)  3 52.1 %
    4 Cu (OTf)  2 76.9 %
    5 AgOTf 84.7 %
    6 Bi (OTf)  3 59.9 %
    7 t-BuMe 2SiOTf 93.4 %
    8 InBr 3 93.5 %
    9 AgNTf 2 50.0 %
    10 HOTf 84.7 %
    11 Trifluoromethansulfonimide >99%
  • Examples 2
  • Compound 1 (302 mg, purity 94.32%, 0.87 mmol) was placed in a 10 mL Schlenk tube. A solvent (4 mL) as shown in Table 2 and TMSCN (0.224 mL, purity 96%, 2 eq. ) were added. TMSOTf (19.73 mg 0.1 eq. ) was mixed with the solvent (1 mL) and then the mixture was added in 10 mins. The mixture was stirred for 8 hours at room temperature to obtain the compound 2. The NMR yields are shown in Table 2.
  • Table 2
  • Entries Solvents NMR yield
    12 ACN >99%
    13 1-chloro-2-methylbutane 95.2 %
    14 toluene 76.3 %
    15 cyclohexane 86.2 %
    16 CHCl 2CHCl 2 92.6 %
    17 CHCl 3 94.3 %
    18 DMC 40.8 %
    19 Benzonitrile 95.7%
    20 THF 64.5%
  • Examples 3
  • Compound 3 (100 mg, 0.251 mmol) was placed in a 10 mL Schlenk tube. DCM (1.3 mL) and TMSCN (0.033 mL, purity 96%, 1 eq. ) were added. TMSOTf (5.58 mg, 0.1 eq. ) was mixed with DCM (0.33mL) and then the mixture was added in 10 mins. The mixture was stirred for 2 days at room temperature to obtain the compound 2. The NMR yields is about 94.3%.
  • Example 5
  • Compound 4 (110 mg, 0.2985 mmol) was placed in a 10 mL Schlenk tube. DCM (1.5 mL) and TMSCN (0.078 mL, purity 96%, 2 eq. ) were added. TMSOTf (6.76 mg, 0.1 eq. ) was mixed with DCM (0.5 mL) and then the mixture was added in 10 mins. The mixture was stirred overnight at room temperature to obtain the compound 2. The NMR yields is about 95.2%.
  • Examples 4
  • Compound 5 (64 mg, 0.219 mmol) was placed in a 10 mL Schlenk tube. DCM (1 mL) and TMSCN (0.06 mL, purity 96%, 2 eq. ) were added. TMSOTf (5 mg, 0.1 eq. ) was mixed with DCM (0.25mL) and then the mixture was added in 10 mins. The mixture was stirred overnight at room temperature to obtain the compound 2. The NMR yields is about 70.6%.
  • Comparison Example
  • Compound 1 (302 mg, purity 94.32%, 0.87 mmol) was placed in a 10 mL Schlenk tube. DCM (4 mL) and TMSCN (0.224 mL, purity 96%, 2 eq. ) were added. FeCl 3 (14.40 mg, 0.1 eq. ) was mixed with DCM (1 mL) and then the mixture was added in 10 mins. The mixture was stirred for 8 hours at room temperature. NMR shows no desired product generated.

Claims (13)

  1. 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,
    Wherein:
    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; and
    X and Y are each independently of one another O or S.
  2. The process of claim 1, wherein 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 2SiOTf) , 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 trifluoromethanesulfonate (AgOTf) and bismuth trifluoromethanesulfonate (Bi (OTf)  3) , indium halide such as indium bromide (InBr 3) and indium iodide (InI 3) , sliver bis (trifluoromethane sulfonimide) (AgNTf 2) , and trifluoromethansulfonimide, or mixture thereof.
  3. The process of claim 1, wherein the cyanide is a cyanosilane such as trimethylsilyl cyanide (TMSCN) and β-trimethylsilylpropionitrile.
  4. The process of any one of claims 1-3, wherein R 1 is H and R 2 is phenyl.
  5. The process of any one of claims 1-3, wherein R 3 is preferably tert-butyl or benzyl, optionally substituted by one or more substituents.
  6. The process of any one of claims 1-3, wherein R 4 is H, methyl, ethyl, trifluoromethyl, bistrifluoromethylmethyl, trimethylsilyl (-TMS) , formyl, acetyl, propionyl, benzoyl, 4-nitrobenzoyl, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, phenylsulfonyl, toluenesulfonyl or benzylsulfonyl.
  7. The process of claim 6, wherein R 4 is R 4 is H, acetyl or -TMS.
  8. The process of any one of claims 1-3, wherein R 1 is H, R 2 is phenyl, R 3 is benzyl, R 4 is H, X is S, and Y is O.
  9. The process of any one of claims 1-8, wherein the cyanide is 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) .
  10. The process of any one of claims 1-8, wherein the catalyst is 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) .
  11. The process of any one of claims 1-8, wherein the reaction is carried out in a solvent.
  12. The process of claim 11, wherein the solvent is selected from the group consisting of 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.
  13. A process for producing (+) -biotin which comprises the process for producing the compound of formula (I) according to any one of claims 1-12.
EP21944657.2A 2021-06-11 2021-06-11 Process for producing biotin intermediate Pending EP4352064A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3776385D1 (en) * 1986-04-19 1992-03-12 Merck Patent Gmbh METHOD FOR PRODUCING D - (+) - BIOTIN.
DE3928263A1 (en) * 1989-08-26 1991-02-28 Merck Patent Gmbh METHOD FOR PRODUCING 7-CYAN-7,7A-DIHYDRO-1H, 3H-IMIDAZOLE (1,5-C) THIAZOL-5 (6H) -ONES
DE4024692A1 (en) * 1990-08-03 1992-02-06 Merck Patent Gmbh METHOD FOR PRODUCING CYANHYDANTOINES
DE4116157A1 (en) * 1991-05-17 1992-11-19 Merck Patent Gmbh METHOD FOR PRODUCING IMIDAZOTHIAZOLONE DERIVATIVES
FR2972453B1 (en) * 2011-03-09 2013-11-29 Minakem NOVEL PROCESS FOR THE SYNTHESIS OF METHYL (1R, 2S, 5S) -6,6-DIMETHYL-3-AZABICYCLO [3.1.0] HEXANE-2-CARBOXYLATE OR ONE OF ITS SALTS
CN111620903A (en) * 2020-06-17 2020-09-04 安徽贝克联合制药有限公司 C-nucleoside analogue, preparation method and application of nitrile-containing C-nucleoside compound for synthesizing Rudexilvir

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