EP4352065A1

EP4352065A1 - Process for producing biotin intermediate

Info

Publication number: EP4352065A1
Application number: EP21944658.0A
Authority: EP
Inventors: Werner Bonrath; Bo Gao; Kun Peng; Qiong-mei ZHANG
Original assignee: DSM IP Assets BV
Current assignee: DSM IP Assets BV
Priority date: 2021-06-11
Filing date: 2021-06-11
Publication date: 2024-04-17
Also published as: EP4352065A4; CN117440956A; WO2022257152A1; CN117440956B

Abstract

Provided is an improved process for producing a biotin intermediate compound (I) with low cost and high yield and/or selectivity, 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; R3 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 and uses 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 more importantly reduces cost by avoiding expensive catalysts and reagents and provides high yield 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 an amide solvent,
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 may be a metal cyanide such as sodium cyanide (NaCN) , potassium cyanide (KCN) , zinc cyanide and copper cyanide. Preferably, the cyanide is 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 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, benzoyl or acetyl.
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.
In another embodiment of the present invention, R ₁ is H, R ₂ is phenyl, R ₃ is benzyl, R ₄ is benzoyl, bistrifluoromethylmethyl or acetyl, 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 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 10 mL, per 1 mole of the compound of formula (II) .
Preferably, in the present invention, the reaction is carried out in the absence of a catalyst. Optionally, the present invention may also be carried out in the presence of a catalyst. The catalyst may be 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.
In the present invention, an auxiliary reagent may be added into the reaction. Examples of the suitable auxiliary reagent include but are not limited to ammonium chloride, potassium iodide, tetrabutylammonium bromide, 18‐Crown‐6, 4‐Dimethylaminopyridine, and acetic anhydride, and mixture thereof.
The reaction of the process of the present invention may be carried out at the temperature of from 0℃to 200℃, preferably from 10℃ to 180℃, more preferably 20℃ to 150℃, such as 50℃ to 120℃ such as 50 ℃, 60 ℃, 80 ℃, 100 ℃ or 120℃, and the most preferably 60℃ to 80℃.
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 avoids expensive cyanide reagents and catalysts and provides high yield and/or selectivity.
The present invention will be further illustrated by the following examples.
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 group.
Example 1
Compound 1 (150 mg, 0.46 mmol) , KCN (59.8 mg, 2 eq. ) and formamide (2.5 mL) were placed in a 10 mL Schlenk tube. The mixture was stirred at the condition as shown in Table 1 to obtain the desired compound 2. NMR analyzed the conversion and the selectivity with the results as shown in Table 1.
Table 1

Entries	Condition	Conversion	selectivity
1	60℃, for 6h	34%	99.9%
2	80℃, for 3h	68 %	89.3 %
3	120℃, for 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 10 mL Schlenk tube. The mixture was stirred at 60℃ for 7 hours to obtain the desired compound 2. NMR analysis show the conversion is 24%and the selectivity is 99%.
Examples 3
Compound 3 (150 mg, 0.407 mmol) , KCN (53 mg, 2 eq. ) and formamide (2.5 mL) were placed in a 10 mL Schlenk tube. The mixture was stirred at the condition as shown in Table 2 to obtain the desired compound 2. NMR analyzed the conversion and the selectivity with the results as shown in Table 2.
Table 2

Entries	Condition	Conversion	selectivity
5	80℃, for 1.5h	99 %	62.4%
6	60℃, for 2h	99 %	55.1%
7	40℃, for 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 10 mL Schlenk tube. The mixture was stirred at 40℃ for 22 hours to obtain the desired compound 2. NMR analysis show the conversion is 100%and the selectivity is 65.4%.
Example 5
Compound 1 (150 mg, 0.46 mmol) , NaCN (45 mg, 2 eq. ) and formamide (5 mL) were placed in a 10 mL Schlenk tube. The mixture was stirred at 60℃ for 7 hours to obtain the desired compound 2. NMR shows the conversion is 26 %and the selectivity is 99.9%.
Comparison Examples
Compound 3 (150 mg, 0.407 mmol) , KCN (53 mg, 2 eq. ) and a solvent (2.5 mL) as shown in Table 3 were placed in a 10 mL Schlenk tube. The mixture was stirred at 80℃ overnight to obtain the desired compound 2. NMR analyzed the conversion and the selectivity with the results as shown in Table 3.
Table 3

Entries	solvents	Conversion	selectivity
11	dimethylformamide	95%	10.3%
12	dimethylsulfoxide	100%	18.1%

Claims

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 an amide solvent,

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.
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.
The process of claim 1, wherein the cyanide is sodium cyanide (NaCN) or potassium cyanide (KCN) .
The process of claim 1, wherein the amide solvent is preferably formamide or acetamide.
The process of claim 1, wherein R ₁ is H and R ₂ is phenyl.
The process of claim 1, wherein R ₃ is preferably tert‐butyl or benzyl, optionally substituted by one or more substituents, more preferably, R ₃ is benzyl.
The process of claim 1, wherein R ₄ is preferably H, methyl, ethyl, trifluoromethyl, bistrifluoromethylmethyl, trimethylsilyl (‐TMS) , formyl, acetyl, propionyl, benzoyl, 4‐nitrobenzoyl, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, phenylsulfonyl, toluenesulfonyl or benzylsulfonyl.
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 H, X is S, and Y is O.
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, bistrifluoromethylmethyl or acetyl, X is S, and Y is O.
The process of any one of claims 1‐9, 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) .
The process of any one of claims 1‐9, wherein the solvent is 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 10 mL, per 1 mole of the compound of formula (II) .
The process of any one of claims 1‐9, wherein the reaction is carried out in the absence of a catalyst.
A process for producing (+) ‐biotin which comprises the process for producing the compound of formula (I) according to any one of claims 1‐12.