Process for the production of biotin intermediates

Abstract

This invention provides an improved process for the low-cost, high-yield and / or high-selectivity production of biotin intermediate compound (I), wherein: R1 and R2 are each independently H, lower alkyl, lower cycloalkyl, aryl or lower aralkyl, optionally substituted by one or more substituents; R3 is H or a protecting group suitable for the nitrogen atom; and X and Y are each independently O or S.

Description

Technical Field

[0001] This invention relates to a process for producing important biotin intermediates. Background Technology

[0002] D-Biotin, also known as Vitamin H, is mainly used in medicine, nutritional fortification, feed additives, cosmetics, and beverages. The molecular structure of D-Biotin is as follows:

[0003]

[0004] Since the industrial synthesis of D-biotin by Roche in Switzerland in 1949, the synthetic method has been the subject of much research worldwide. To date, numerous information regarding the overall synthetic routes has been reported. However, most industrial processes for D-biotin use a thiolactone compound (a) to produce an intermediate compound (b), which is then converted to compound (c) via catalytic hydrogenation, ultimately yielding D-biotin. (See US 3,740,416)

[0005]

[0006] Known processes for producing compound (a) include: a) producing an optically active hydantoin from L-cysteine ​​or L-serine, and then converting it into an intermediate compound (IX); b) converting the intermediate compound (IX) into a bicyclic cyanohydantoin (I) in two steps; and c) finally converting the bicyclic cyanohydantoin (I) into compound (a) in two more steps. (See US 5,095,118A)

[0007]

[0008] In the above process, step b) is crucial, but it involves two steps and uses expensive catalysts and reagents. Therefore, this process is not yet industrially feasible.

[0009] Therefore, there is still a need for a process with improved cost, yield and / or selectivity for the production of biotin intermediate compounds (I). Summary of the Invention

[0010] This invention provides a process for producing biotin intermediate compound (I).

[0011]

[0012] in:

[0013] R1 and R2 are each independently H, a lower alkyl group, a lower cycloalkyl group, an aryl group, or a lower aralkyl group, and may be optionally substituted by one or more substituents;

[0014] R3 is H or a protecting group suitable for the nitrogen atom; and

[0015] X and Y can be either O or S independently.

[0016] The process of this application reduces the number of steps in producing compound (I), and more importantly, reduces costs by avoiding the use of expensive catalysts and reagents, while providing high yield and / or high selectivity. Detailed Implementation

[0017] In this invention, the term "lower alkyl" refers to C1-C 10 Alkyl groups are branched or straight-chain, cyclic or acyclic saturated hydrocarbons containing 1-10 carbon atoms. Preferably, "lower alkyl groups" are C1-C6 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, isodel, tert-decyl, and cyclodecyl. More preferably, "lower alkyl groups" are methyl or ethyl.

[0018] In this invention, the term "aryl" refers to a carbocyclic aromatic system containing one, two, or three rings fused together, wherein all ring atoms are carbon atoms. The term "aryl" includes, but is not limited to, groups such as phenyl, benzyl, xylyl, and naphthyl.

[0019] In this invention, the term "lower cycloalkyl" as used refers to a saturated monocyclic, bicyclic, or tricyclic group, wherein all ring atoms in the ring system are carbon atoms, and each cyclic segment contains 3 to 12 carbon ring members. One lower cycloalkyl group has 5 to 7 carbon atoms. Examples of lower cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.

[0020] In this invention, the term "lower aryl alkyl" as used refers to an aryl group attached to a parent molecule segment via a lower alkyl group, wherein the aryl group and the lower alkyl group are as defined herein.

[0021] In this invention, the term "acyl" as used refers to a structure represented by RC (=O)-, where R is a lower alkyl or aryl group as defined herein.

[0022] In this invention, the term "lower silane" as used refers to silane derived from R 1 R 2 R 3 The structure represented by Si, where R 1 R 2 and R3 Each is independently a lower alkyl or aryl group as defined herein.

[0023] In this 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.

[0024] In this invention, the term "arylsulfonyl" as used refers to the structure represented by aryl-S(=O)2-, wherein the aryl group is as defined herein.

[0025] In this invention, the term "lower aralkyl sulfonyl" as used refers to a structure represented by (lower aralkyl)-S(=O)2-, wherein the lower aralkyl group is as defined herein.

[0026] In this invention, the term “lower alkoxy” as used refers to the structure represented by (lower alkyl)-O-, wherein the lower alkyl is as defined herein.

[0027] In this invention, the term "halogen" or "halogen" as used refers to a group of elements including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), preferably Cl or Br.

[0028] In this invention, the term "halogen" as used means including iodides, bromides, chlorides and fluorides, preferably bromides or iodides, more preferably bromides.

[0029] In this invention, the term "substituent" as used refers to lower alkyl, lower alkoxy, hydroxy, halogen, -NH2, -NO2, cyano and / or isocyano.

[0030] In this invention, the symbols used in the compound formulas of this invention are... This refers to the linking group being attached to a chiral carbon in an S- and / or R- configuration.

[0031] This invention provides a process for producing a compound of formula (I) or a stereoisomer thereof or a mixture thereof, comprising reacting a compound of formula (II) or a stereoisomer thereof or a mixture thereof with a cyanide in the presence of an amide solvent.

[0032]

[0033] in:

[0034] R1 and R2 are each independently H, a lower alkyl group, a lower cycloalkyl group, an aryl group, or a lower aralkyl group, and may be optionally substituted by one or more substituents;

[0035] R3 is H or a protecting group suitable for nitrogen atoms;

[0036] R4 is H, a lower alkyl group, a lower silyl group, an acyl group, a lower alkyl sulfonyl group, an aryl sulfonyl group, or a lower arylalkyl sulfonyl group, optionally substituted with one or more substituents, and

[0037] X and Y can be either O or S independently.

[0038] In this invention, the cyanide can be a metal cyanide, such as sodium cyanide (NaCN), potassium cyanide (KCN), zinc cyanide, and copper cyanide. The cyanide is preferably sodium cyanide or potassium cyanide.

[0039] In this invention, the amide solvent is preferably formamide or acetamide. More preferably, the amide solvent is formamide.

[0040] In this invention, the protecting group may be tert-butyl, benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 4-methylbenzyl, allyl, methylallyl, crotonyl, methoxymethyl, trimethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

[0041] In this invention, R1 and R2 are each preferably H, C1-C6 alkyl, phenyl or benzyl, optionally substituted by one or more substituents, more preferably R1 is H and R2 is phenyl.

[0042] In this invention, R3 is preferably tert-butyl or benzyl, optionally substituted by one or more substituents, and more preferably R3 is benzyl.

[0043] In this invention, R4 is preferably H, methyl, ethyl, trifluoromethyl, bis(trifluoromethyl)methyl, trimethylsilyl (-TMS), formyl, acetyl, propionyl, benzoyl, 4-nitrobenzoyl, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, phenylsulfonyl, toluenesulfonyl, or benzylsulfonyl. More preferably, R4 is H, acetyl, propionyl, benzoyl, toluenesulfonyl, bis(trifluoromethyl)methyl, or trifluoromethanesulfonyl. Most preferably, R4 is H, benzoyl, or acetyl.

[0044] In one embodiment of the present invention, R1 is H, R2 is phenyl, R3 is benzyl, R4 is H, X is S, and Y is O.

[0045] In another embodiment of the present invention, R1 is H, R2 is phenyl, R3 is benzyl, R4 is benzoyl, bis(trifluoromethyl)methyl or acetyl, X is S and Y is O.

[0046] The stereoisomers of the present invention include enantiomers and diastereomers. For example, the compound of formula (I) has the following stereoisomers:

[0047]

[0048] Furthermore, the compound of formula (II) has the following stereoisomers:

[0049]

[0050] R4 is defined as above.

[0051] More specifically, the compound of formula (I) is one of the following stereoisomers:

[0052]

[0053] More specifically, the compound of formula (II) is one of the following stereoisomers:

[0054]

[0055] In the process of the present invention, the amount of cyanide added can be from 1 mole to 20 moles per mole of compound (II), preferably from 1.5 moles to 15 moles, and more preferably from 2 moles to 10 moles.

[0056] In this invention, the amount of solvent used in the reaction can be from 1 mL to 30 mL per mole of compound (II), preferably from 2 mL to 20 mL, and more preferably from 2 mL to 10 mL.

[0057] In this invention, the reaction is preferably carried out in the absence of a catalyst. Of course, this invention can also be carried out in the presence of a catalyst. The catalyst may be selected from: trifluoromethanesulfonic acid (HOTf); trifluoromethanesulfonates, such as trimethylsilyl trifluoromethanesulfonate (TMSOTf) and tert-butyldimethylsilyl trifluoromethanesulfonate (t-BuMe2SiOTf); trifluoromethanesulfonates, 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 halides, such as indium bromide (InBr3) and indium iodide (InI3); bis(trifluoromethanesulfonylimide)silver (AgNTf2) and trifluoromethanesulfonylimide; or mixtures thereof.

[0058] In this invention, auxiliary reagents may be added to the reaction. Examples of suitable auxiliary reagents include, but are not limited to, ammonium chloride, potassium iodide, tetrabutylammonium bromide, 18-crown ether-6, 4-dimethylaminopyridine, acetic anhydride, and mixtures thereof.

[0059] The reaction of the process of the present invention can be carried out at a temperature of 0°C to 200°C, preferably 10°C to 180°C, more preferably 20°C to 150°C, for example 50°C to 120°C, such as 50°C, 60°C, 80°C, 100°C or 120°C, and most preferably 60°C to 80°C.

[0060] The obtained compound of formula (I) can be isolated and / or purified using processes known in the art and used to prepare (+)-biotin. Therefore, the present invention also provides a process for producing (+)-biotin, comprising the process for producing the compound of formula (I) described herein.

[0061] The process of this invention avoids expensive cyanide reagents and catalysts, and provides high yield and / or high selectivity.

[0062] The following examples will further illustrate the present invention.

[0063] Example

[0064] In the following embodiments of this application, "Ph" is phenyl, "Et" is ethyl, "Bn" is benzyl, "Ac" is acetyl, and "CN" is cyano.

[0065] Example 1

[0066]

[0067] 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 under the conditions shown in Table 1 to obtain the desired compound 2. The conversion and selectivity were analyzed by NMR, and the results are shown in Table 1.

[0068] Table 1

[0069] project condition Conversion rate Selective 1 60℃,6h 34％ 99.9％ 2 80℃,3h 68％ 89.3％ 3 120℃,1h 100％ 68.3％

[0070] Example 2

[0071]

[0072] 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 °C for 7 hours to obtain the desired compound 2. NMR analysis showed a conversion of 24% and a selectivity of 99%.

[0073] Example 3

[0074]

[0075] 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 under the conditions shown in Table 2 to obtain the desired compound 2. The conversion and selectivity were analyzed by NMR, and the results are shown in Table 2.

[0076] Table 2

[0077] project condition Conversion rate Selective 5 80℃,1.5h 99％ 62.4％ 6 60℃,2h 99％ 55.1％ 7 40℃,5.5h 99％ 50.7％

[0078] Example 4

[0079]

[0080] 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 °C for 22 hours to obtain the desired compound 2. NMR analysis showed a conversion of 100% and a selectivity of 65.4%.

[0081] Example 5

[0082]

[0083] 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 °C for 7 hours to obtain the desired compound 2. NMR analysis showed a conversion of 26% and a selectivity of 99.9%.

[0084] Comparative Example

[0085]

[0086] 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 10 mL Schlenk tube. The mixture was stirred overnight at 80 °C to obtain the desired compound 2. The conversion and selectivity were analyzed by NMR, and the results are shown in Table 3.

[0087] Table 3

[0088] project solvent Conversion rate Selective 11 dimethylformamide 95％ 10.3％ 12 Dimethyl sulfoxide 100％ 18.1％

Claims

1. A process for producing a compound of formula (I) or a stereoisomer thereof or a mixture of stereoisomers thereof, comprising reacting a compound of formula (II) or a stereoisomer thereof or a mixture of stereoisomers thereof with a cyanide in the presence of an amide solvent, ###0001### (I) (II) wherein: R1 and R2 are each independently H, lower alkyl, lower cycloalkyl, aryl or lower aralkyl, optionally substituted with one or more substituents; R3 is H or a protecting group suitable for a nitrogen atom; R4 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, wherein the cyanide is a metal cyanide; wherein the amide solvent is a formamide or an acetamide; and wherein: "substituent" means lower alkyl, lower alkoxy, hydroxy, halo, -NH2, -NO2, cyano and / or isocyano; "lower alkoxy" means a structure represented by (lower alkyl)-O-, wherein lower alkyl is as defined above; "lower cycloalkyl" means a saturated monocyclic, bicyclic or tricyclic ring radical wherein the ring atoms of the ring system are all carbon atoms, and each ring fragment contains from 3 to 12 carbon atom ring members; "aryl" means a carbocyclic aromatic ring system containing one ring, or two or three rings fused together, wherein the ring atoms are all carbon atoms; "lower aralkyl" means an aryl group attached to the parent molecular moiety through a lower alkyl group, wherein lower alkyl and aryl are as defined above; "lower alkylsulfonyl" means a structure represented by (lower alkyl)-S(=0)2-, wherein lower alkyl is as defined above; and "lower aralkylsulfonyl" means a structure represented by (lower aralkyl)-S(=0)2-, wherein lower aralkyl is as defined above.

2. The process according to claim 1, wherein the metal cyanide is selected from the group consisting of sodium cyanide (NaCN), potassium cyanide (KCN), zinc cyanide and copper cyanide.

3. The process according to claim 1, wherein the metal cyanide is sodium cyanide (NaCN) or potassium cyanide (KCN).

4. The process according to claim 1, wherein R1 is H and R2 is phenyl.

5. The process according to claim 1, wherein R3 is t-butyl or benzyl, optionally substituted with one or more substituents.

6. The process according to claim 1, wherein R3 is benzyl.

7. The process according to claim 1, wherein R4 is H, methyl, ethyl, trifluoromethyl, bistrifluoromethylmethyl, trimethylsilyl (-TMS), formyl, acetyl, propionyl, benzoyl, 4-nitrobenzoyl, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, phenylsulfonyl, toluenesulfonyl or benzylsulfonyl.

8. The process according to any one of claims 1 to 7, wherein R1 is H, R2 is phenyl, R3 is benzyl, R4 is H, X is S and Y is O.

9. The process according to any one of claims 1 to 7, wherein R1 is H, R2 is phenyl, R3 is benzyl, R4 is benzoyl, bistrifluoromethylmethyl or acetyl, X is S and Y is O. ​ "lower alkyl" means a C1-C10 10 alkyl, i.e. a branched or straight chain, cyclic or acyclic, saturated hydrocarbon comprising 1-10 carbon atoms; ​ ​ ​ "Lower alkyl" means a straight or branched carbon chain radical. The term "lower alkyl" as used herein includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, isohexyl and the like. 1 R 2 R 3 Si- represents a structure wherein R 1 , R 2 and R 3 are each independently lower alkyl or aryl as defined above. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 10. The process according to any one of claims 1 to 7, wherein the cyanide is added in an amount of 1 mole to 20 moles per 1 mole of compound of formula (II).

11. The process according to any one of claims 1 to 7, wherein the cyanide is added in an amount of 1.5 moles to 15 moles per 1 mole of compound of formula (II).

12. The process according to any one of claims 1 to 7, wherein the cyanide is added in an amount of 2 moles to 10 moles per 1 mole of compound of formula (II).

13. The process according to any one of claims 1 to 7, wherein the solvent is used in the reaction in an amount of 1 mL to 30 mL per 1 mole of compound of formula (II).

14. The process according to any one of claims 1 to 7, wherein the solvent is used in the reaction in an amount of 2 mL to 20 mL per 1 mole of compound of formula (II).

15. The process according to any one of claims 1 to 7, wherein the solvent is used in the reaction in an amount of 2 mL to 10 mL per 1 mole of compound of formula (II).

16. The process according to any one of claims 1 to 7, wherein the reaction is carried out without a catalyst.

17. 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 to 16.

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