CN117440956A - Process for the production of biotin intermediates - Google Patents

Process for the production of biotin intermediates Download PDF

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Publication number
CN117440956A
CN117440956A CN202180099065.4A CN202180099065A CN117440956A CN 117440956 A CN117440956 A CN 117440956A CN 202180099065 A CN202180099065 A CN 202180099065A CN 117440956 A CN117440956 A CN 117440956A
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Prior art keywords
cyanide
compound
formula
benzyl
present
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Chinese (zh)
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维尔纳·邦拉蒂
高搏
彭坤
张琼梅
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DSM IP Assets BV
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DSM IP Assets BV
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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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The present invention provides an improved process for the low cost, high yield and/or high selectivity production of a biotin intermediate compound (I), wherein: r is R 1 And R is 2 Each independently is H, lower alkyl, lower cycloalkyl, aryl, or lower aralkyl, optionally substituted with one or more substituents; r is R 3 Is H or a protecting group suitable for nitrogen atoms; and X and Y are each independently O or S.

Description

Process for the production of biotin intermediates
Technical Field
The present invention relates to a process for the production of important biotin intermediates.
Background
D-biotin, also known as vitamin H, is mainly used in the fields of medicine and health, nutrition enhancers, feed additives, cosmetics, beverages and the like. The molecular structural formula of D-biotin is as follows:
since the advent of industrial synthesis of D-biotin by Roche, switzerland, 1949, the synthesis method has been under much research worldwide. To date, a number of information about the overall synthetic route has been reported. However, most commercial processes of D-biotin use a thiolactone compound (a) to produce an intermediate compound (b), which is then converted into a compound (c) by catalytic hydrogenation, to finally obtain D-biotin. (see US 3,740,416)
Known processes for producing the above compound (a) include: a) Producing optically active hydantoin (hydantoin) from L-cysteine or L-serine, and then converting it into intermediate compound (IX); b) Converting the intermediate compound (IX) into the dicyclo-cyanohydantoin (I) in two steps; c) The dicyclo-cyanohydantoin (I) is finally converted into the compound (a) in two steps. (see US 5,095,118A)
In the above process, step b) is critical, but it has two steps and uses expensive catalysts and reagents. Therefore, the process is not yet industrially perfect.
Thus, there remains a need for a process for the production of biotin intermediate compound (I) with improved cost, yield and/or selectivity.
Disclosure of Invention
The present invention provides a process for the production of a biotin intermediate compound (I),
wherein:
R 1 and R is 2 Each independently is H, lower alkyl, lower cycloalkyl, aryl, or lower aralkyl, optionally substituted with one or more substituents;
R 3 is H or a protecting group suitable for nitrogen atoms; and is also provided with
X and Y are each independently O or S.
The process of the present application reduces the steps in the production of the compounds of formula (I) and, more importantly, reduces costs by avoiding the use of expensive catalysts and reagents and provides high yields and/or high selectivities.
Detailed Description
In the present invention, the term "lower alkyl" as used herein means C 1 -C 10 Alkyl, i.e. branched or straight chain, cyclic or acyclic saturated hydrocarbons containing from 1 to 10 carbon atoms. Preferably, "lower alkyl" is C 1 -C 6 Alkyl groups including, but not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, isopentyl, 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, "lower alkyl" is methyl or ethyl.
In the present invention, the term "aryl" is used to refer to a carbocyclic aromatic system containing one ring, or two or three rings fused together, wherein the ring atoms are carbon atoms. The term "aryl" includes, but is not limited to, groups such as phenyl, benzyl, xylyl, and naphthyl.
In the present invention, the term "lower cycloalkyl" is used to refer to a saturated monocyclic, bicyclic or tricyclic group wherein the ring atoms of the ring system are carbon atoms and each cyclic fragment contains 3 to 12 carbon atom ring members. Wherein one lower cycloalkyl has 5 to 7 carbon atoms. Examples of lower cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.
In the present invention, the term "lower aralkyl" as used herein refers to an aryl group attached to the parent molecular moiety through a lower alkyl group, wherein aryl and lower alkyl are as defined herein.
In the present invention, the term "acyl" as used herein refers to a structure represented by r—c (=o) -wherein R is a lower alkyl or aryl group as defined herein.
In the present invention, the term "lower silane group" as used herein means a group consisting of R 1 R 2 R 3 Si-, wherein R 1 、R 2 And R is 3 Each independently is a lower alkyl or aryl group as defined herein.
In the present invention, the term "lower alkylsulfonyl" used means a compound consisting of (lower alkyl) -S (=o) 2 -a structure represented, wherein lower alkyl is as defined herein.
In the present invention, the term "arylsulfonyl" as used herein refers to aryl-S (=o) 2 -a represented structure wherein aryl is as defined herein.
In the present invention, the term "lower aralkylsulfonyl" as used herein means a compound prepared from (lower aralkyl) -S (=o) 2 -a structure represented wherein lower aralkyl is as defined herein.
In the present invention, the term "lower alkoxy" as used herein refers to the structure represented by (lower alkyl) -O-, wherein lower alkyl is as defined herein.
In the present invention, the term "halogen" or "halogen" as used herein refers to a group of elements including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), preferably Cl or Br.
In the present invention, the term "halide" as used is meant to include iodide, bromide, chloride and fluoride, preferably bromide or iodide, more preferably bromide.
In the present invention, the term "substituent" as used herein means lower alkyl, lower alkoxy, hydroxy, halo, -NH 2 、-NO 2 Cyano and/or isocyano.
In the present invention, the symbols used in the formulae of the compounds of the present inventionMeaning that the linking group is attached to the chiral carbon in the S-and/or R-configuration.
The present invention provides a process for the production of a compound of formula (I) or a stereoisomer or a mixture of its stereoisomers, comprising reacting a compound of formula (II) or a stereoisomer or a mixture of its stereoisomers with cyanide in the presence of an amide solvent,
wherein:
R 1 and R is 2 Each independently is H, lower alkyl, lower cycloalkyl, aryl, or lower aralkyl, optionally substituted with one or more substituents;
R 3 is H or a protecting group suitable for nitrogen atoms;
R 4 is H, lower alkyl, lower silyl, acyl, lower alkylsulfonyl, arylsulfonyl or lower aralkylsulfonyl, optionally substituted with one or more substituents, and
x and Y are each independently O or S.
In the present invention, cyanide may be metal cyanide such as sodium cyanide (NaCN), potassium cyanide (KCN), zinc cyanide, and copper cyanide. The cyanide is preferably sodium cyanide or potassium cyanide.
In the present invention, the amide solvent is preferably formamide or acetamide. More preferably, the amide solvent is formamide.
In the present invention, the protecting group may be t-butyl, benzyl, 4-methoxybenzyl, 3, 4-dimethoxybenzyl, 4-methylbenzyl, allyl, methallyl, crotyl, methoxymethyl, trimethylsilyl, t-butyldimethylsilyl or t-butyldiphenylsilyl.
In the present invention, R 1 And R is 2 Each independently is preferably H, C 1 -C 6 Alkyl, or phenyl or benzyl, optionally substituted with one or more substituents, more preferably R 1 Is H, R 2 Is phenyl.
In the present invention, R 3 Preferably tert-butyl or benzyl, optionally substituted with one or more substituents, more preferably R 3 Is benzyl.
In the present invention, R 4 Preferably H, methyl, ethyl, trifluoromethyl, bistrifluoromethyl, trimethylsilyl (-TMS), formyl, acetyl, propionyl, benzoyl, 4-nitrobenzoyl, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, phenylsulfonyl, toluenesulfonyl or benzylsulfonyl. More preferably, R 4 Is H, acetyl, propionyl, benzoyl, tosyl, bistrifluoromethyl or trifluoromethanesulfonyl. Most preferably, R 4 Is H, benzoyl or acetyl.
In one embodiment of the invention, R 1 Is H, R 2 Is phenyl, R 3 Is benzyl, R 4 And is H, X is S, Y is O.
In another embodiment of the invention, R 1 Is H, R 2 Is phenyl, R 3 Is benzyl, R 4 Is benzoyl, bistrifluoromethyl or acetyl, X is S, Y is O.
Stereoisomers of the invention include enantiomers and diastereomers. For example, the compounds of formula (I) have the following stereoisomers:
and the compound of formula (II) has the following stereoisomers:
wherein R is 4 As defined above.
More specifically, the compound of formula (I) is one of the following stereoisomers:
more specifically, the compound of formula (II) is one of the following stereoisomers:
in the process of the present invention, the cyanide may be added in an amount of 1 to 20 moles, preferably 1.5 to 15 moles, more preferably 2 to 10 moles, per 1 mole of the compound of formula (II).
In the present invention, the solvent may be used in an amount of 1mL to 30mL, preferably 2mL to 20mL, more preferably 2mL to 10mL per 1 mol of the compound of formula (II).
In the present invention, the reaction is preferably carried out in the absence of a catalyst. Of course, the invention can also be carried out in the presence of a catalyst. The catalyst may be selected from: trifluoromethanesulfonic acid (HOTf); triflate esters, e.g. trimethylsilyl triflate (TMSOTF) and t-butyldimethylsilyl triflate (t-BuMe) 2 SiOTf; triflate salts, e.g. zinc triflate (Zn (OTf) 2 ) Ferric triflate (Fe (OTf) 3 ) Copper triflate (Cu (OTf) 2 ) Ytterbium triflate (Yb (OTf) 3 ) Scandium triflate (Sc (OTf)) 3 ) Silver triflate (AgOTf) and bismuth triflate (Bi (OTf) 3 ) The method comprises the steps of carrying out a first treatment on the surface of the Indium halides, e.g. indium bromide (InBr) 3 ) And indium iodide (InI) 3 ) The method comprises the steps of carrying out a first treatment on the surface of the Bis (trifluoromethanesulfonyl imide) silver (AgNTf 2 ) And trifluoromethanesulfonyl imide; or mixtures thereof.
In the present invention, an auxiliary reagent may be added to the reaction. Examples of suitable auxiliary agents include, but are not limited to, ammonium chloride, potassium iodide, tetrabutylammonium bromide, 18-crown-6, 4-dimethylaminopyridine, acetic anhydride and mixtures thereof.
The reaction of the process of the present invention may be carried out at a temperature of from 0 ℃ to 200 ℃, preferably from 10 ℃ to 180 ℃, more preferably from 20 ℃ to 150 ℃, for example from 50 ℃ to 120 ℃, such as 50 ℃, 60 ℃, 80 ℃, 100 ℃ or 120 ℃, most preferably from 60 ℃ to 80 ℃.
The resulting compound of formula (I) can be isolated and/or purified by processes well known in the art and used to prepare (+) -biotin. Accordingly, the present invention also provides a process for the production of (+) -biotin which comprises the process for the production of a compound of formula (I) as described herein.
The process of the present invention avoids expensive cyanide reagents and catalysts and provides high yields and/or high selectivities.
The following examples will further illustrate the invention.
Examples
In the following examples of the present application, "Ph" is phenyl, "Et" is ethyl, "Bn" is benzyl, "Ac" is acetyl, and "CN" is cyano.
Example 1
Compound 1 (150 mg,0.46 mmol), KCN (59.8 mg,2 eq.) and formamide (2.5 mL) were placed in a 10mL Schlenk tube. The mixture was stirred under the conditions shown in table 1 to give the desired compound 2. The conversion and selectivity were analyzed by NMR and the results are shown in table 1.
TABLE 1
Project Conditions (conditions) Conversion rate Selectivity of
1 60℃,6h 34％ 99.9％
2 80℃,3h 68％ 89.3％
3 120℃,1h 100％ 68.3％
Example 2
Compound 1 (150 mg,0.46 mmol), KCN (300 mg,10 eq.) and formamide (5 mL) were placed in a 10mL Schlenk tube. The mixture was stirred at 60 ℃ for 7 hours to give the desired compound 2.NMR analysis showed 24% conversion and 99% selectivity.
Example 3
Compound 3 (150 mg,0.407 mmol), KCN (53 mg,2 eq.) and formamide (2.5 mL) were placed in a 10mL Schlenk tube. The mixture was stirred under the conditions shown in table 2 to give the desired compound 2. The conversion and selectivity were analyzed by NMR and the results are shown in table 2.
TABLE 2
Project Conditions (conditions) Conversion rate Selectivity of
5 80℃,1.5h 99％ 62.4％
6 60℃,2h 99％ 55.1％
7 40℃,5.5h 99％ 50.7％
Example 4
Compound 4 (70 mg,0.163 mmol), KCN (21 mg,2 eq.) and formamide (1.3 mL) were placed in a 10mL Schlenk tube. The mixture was stirred at 40 ℃ for 22 hours to give the desired compound 2.NMR analysis showed 100% conversion and 65.4% selectivity.
Example 5
Compound 1 (150 mg,0.46 mmo), naCN (45 mg,2 eq.) and formamide (5 mL) were placed in a 10mL Schlenk tube. The mixture was stirred at 60 ℃ for 7 hours to give the desired compound 2.NMR analysis showed 26% conversion and 99.9% selectivity.
Comparative example
Compound 3 (150 mg,0.407 mmol), KCN (53 mg,2 eq.) and the solvent shown in Table 3 (2.5 mL) were placed in a 10mL Schlenk tube. The mixture was stirred at 80 ℃ overnight to give the desired compound 2. The conversion and selectivity were analyzed by NMR and the results are shown in table 3.
TABLE 3 Table 3
Project Solvent(s) Conversion rate Selectivity of
11 Dimethylformamide 95％ 10.3％
12 Dimethyl sulfoxide 100％ 18.1％

Claims (13)

1. A process for producing a compound of formula (I) or a stereoisomer thereof or a mixture of its stereoisomers, comprising reacting a compound of formula (II) or a stereoisomer thereof or a mixture of its stereoisomers with cyanide in the presence of an amide solvent,
wherein:
R 1 and R is 2 Each independently is H, lower alkyl, lower cycloalkyl, aryl, or lower aralkyl, optionally substituted with one or more substituents;
R 3 is H or a protecting group suitable for nitrogen atoms;
R 4 is H, lower alkyl, lower silyl, acyl, lower alkylsulfonyl, arylsulfonyl or lower aralkylsulfonyl, optionally substituted with one or more substituents, and
x and Y are each independently O or S.
2. The process of claim 1, wherein the cyanide is a metal cyanide such as sodium cyanide (NaCN), potassium cyanide (KCN), zinc cyanide, and copper cyanide.
3. The process of claim 1, wherein the cyanide is sodium cyanide (NaCN) or potassium cyanide (KCN).
4. The process according to claim 1, wherein the amide solvent is preferably formamide or acetamide.
5. The process of claim 1, wherein R 1 Is H, R 2 Is phenyl.
6. The process of claim 1, wherein R 3 Preferably tert-butyl or benzyl, optionally substituted with one or more substituents, more preferably R 3 Is benzyl.
7. The process of claim 1, wherein R 4 Preferably H, methyl, ethyl, trifluoromethyl, bistrifluoromethyl, trimethylsilyl (-TMS), formyl, acetyl, propionyl, benzoyl, 4-nitrobenzoyl, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, phenylsulfonyl, toluenesulfonyl or benzylsulfonyl.
8. The process of any one of claims 1-7, wherein R 1 Is H, R 2 Is phenyl, R 3 Is benzyl, R 4 And is H, X is S, Y is O.
9. The process of any one of claims 1-7, wherein R 1 Is H, R 2 Is phenyl, R 3 Is benzyl, R 4 Is benzoyl, bistrifluoromethyl or acetyl, X is S, Y is O.
10. The process according to any one of claims 1-9, wherein the cyanide is added in an amount of 1 to 20 moles, preferably 1.5 to 15 moles, more preferably 2 to 10 moles per 1 mole of the compound of formula (II).
11. The process according to any one of claims 1-9, wherein the solvent is used in the reaction in an amount of 1mL to 30mL, preferably 2mL to 20mL, more preferably 2mL to 10mL per 1 mole of the compound of formula (II).
12. The process of any one of claims 1-9, wherein the reaction is performed in the absence of a catalyst.
13. Process for the production of (+) -biotin comprising a process for the production of a compound of formula (I) according to any one of claims 1-12.
CN202180099065.4A 2021-06-11 2021-06-11 Process for the production of biotin intermediates Pending CN117440956A (en)

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Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4024692A1 (en) * 1990-08-03 1992-02-06 Merck Patent Gmbh METHOD FOR PRODUCING CYANHYDANTOINES
CN104829627A (en) * 2015-05-08 2015-08-12 东南大学 Chiral hexahydrofuro [2,3-b] furan-3-methylamine, and preparation method and application thereof
US20230069104A1 (en) * 2019-06-28 2023-03-02 Kymera Therapeutics, Inc. Irak degraders and uses thereof

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