Process for producing biotin intermediates

Abstract

This invention provides an improved process for the low-cost, high-yield production of biotin intermediate compound (I), wherein: R1 and R2 are each independently H, a lower alkyl, a lower cycloalkyl, an aryl, or a 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 requires expensive catalysts and reagents. Therefore, this process is not yet industrially viable.

[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 described in this application reduces the number of steps required to produce the (I) compound, lowers costs by avoiding expensive catalysts, and provides high yields and / or high selectivity. Detailed Implementation

[0017] In this invention, the term "lower alkyl" as used 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" as used refers to a carbocyclic aromatic system containing one ring, or two or three rings fused together, wherein all atoms in the ring are carbon. 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 group of lower cycloalkyl groups 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 R1 R 2 and R 3 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 a 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 a catalyst.

[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 is a cyanosilane, such as trimethylsilyl cyanide (TMSCN) and β-trimethylsilylpropionitrile. Preferably, the cyanide is TMSCN.

[0039] In this invention, the catalyst is 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.

[0040] Preferably, the catalyst is HOTf, TMSOTf, t-BuMe2SiOTf, Zn(OTf)2, Fe(OTf)3, Cu(OTf)2, Yb(OTf)3, Sc(OTf)3, AgOTf, Bi(OTf)3, InBr3, InI3, AgNTf2, or trifluoromethanesulfonylimide, or a mixture thereof. More preferably, the catalyst is HOTf, TMSOTf, Zn(OTf)2, Cu(OTf)2, AgOTf, InBr3, or trifluoromethanesulfonylimide, or a mixture thereof. Most preferably, the catalyst is TMSOTf.

[0041] 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.

[0042] 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.

[0043] In this invention, R3 is preferably tert-butyl or benzyl, optionally substituted by one or more substituents, and more preferably R3 is benzyl.

[0044] 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, acetyl, or -TMS.

[0045] 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.

[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 the process of the present invention, the amount of catalyst added can be from 0.01 moles to 1 mole per 1 mole of compound (II), preferably from 0.05 moles to 0.8 moles, and more preferably from 0.1 moles to 0.5 moles.

[0057] The reactions in the process of this invention can be carried out in a solvent or a mixture thereof. Examples of suitable solvents include, but are not limited to, alkanes such as cyclohexane; haloalkanes such as chloroform, dichloromethane (DCM), 1,1,2,2-tetrachloroethane and 1-chloro-2-methylbutane; alkanic acids such as dimethyl carbonate (DMC); nitriles such as acetonitrile (ACN) and benzonitrile; aromatic hydrocarbons such as toluene; cyclic ethers such as tetrahydrofuran (THF); and mixtures thereof.

[0058] 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 7 mL.

[0059] The reaction of the process of the present invention can be carried out at a temperature of -50°C to 200°C, preferably 0°C to 100°C, more preferably 10°C to 50°C, and most preferably room temperature.

[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] Compared with existing processes, the process of this application simplifies operation, avoids expensive catalysts, and improves the yield of compound (I).

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

[0063] Example

[0064] In the following embodiments of this application, "Ph" is phenyl, "Bn" is benzyl, "TMS" is trimethylsilyl, "CN" is cyano, and "tBu" is tert-butyl.

[0065] Example 1

[0066]

[0067] Compound 1 (302 mg, 94.32% purity, 0.87 mmol) was placed in a 10 mL Schlenk tube. DCM (4 mL) and TMSCN (0.224 mL, 96% purity, 2 eq.) were added. The catalyst (0.1 eq.) shown in Table 1 was mixed with DCM (1 mL), and then the mixture was added over 10 minutes. The mixture was stirred at room temperature for 8 hours to give compound 2. The NMR yields are shown in Table 1.

[0068] Table 1

[0069]

[0070]

[0071] Example 2

[0072]

[0073] Compound 1 (302 mg, 94.32% purity, 0.87 mmol) was placed in a 10 mL Schlenk tube. The solvent (4 mL) and TMSCN (0.224 mL, 96% purity, 2 eq.) shown in Table 2 were added. TMSOTf (19.73 mg, 0.1 eq.) was mixed with the solvent (1 mL), and then added over 10 minutes. The mixture was stirred at room temperature for 8 hours to give compound 2. The NMR yields are shown in Table 2.

[0074] Table 2

[0075] Projects solvent NMR yield 12 ACN >99％ 13 1-Chloro-2-methylbutane 95.2％ 14 Toluene 76.3％ 15 Cyclohexane 86.2％ 16 <![CDATA[CHCl2CHCl2]]> 92.6％ 17 <![CDATA[CHCl3]]> 94.3％ 18 DMC 40.8％ 19 Benzonitrile 95.7％ 20 THF 64.5％

[0076] Example 3

[0077]

[0078] Compound 3 (100 mg, 0.251 mmol) was placed in a 10 mL Schlenk tube. DCM (1.3 mL) and TMSCN (0.033 mL, 96% purity, 1 eq.) were added. TMSOTf (5.58 mg, 0.1 eq.) was mixed with DCM (0.33 mL), and then the mixture was added over 10 minutes. The mixture was stirred at room temperature for 2 days to give compound 2. The NMR yield was approximately 94.3%.

[0079] Example 5

[0080]

[0081] Compound 4 (110 mg, 0.2985 mmol) was placed in a 10 mL Schlenk tube. DCM (1.5 mL) and TMSCN (0.078 mL, 96% purity, 2 eq.) were added. TMSOTf (6.76 mg, 0.1 eq.) was mixed with DCM (0.5 mL), and then the mixture was added over 10 minutes. The mixture was stirred overnight at room temperature to give compound 2. The NMR yield was approximately 95.2%.

[0082] Example 4

[0083]

[0084] Compound 5 (64 mg, 0.219 mmol) was placed in a 10 mL Schlenk tube. DCM (1 mL) and TMSCN (0.06 mL, 96% purity, 2 eq.) were added. TMSOTf (5 mg, 0.1 eq.) was mixed with DCM (0.25 mL), and then the mixture was added over 10 minutes. The mixture was stirred overnight at room temperature to give compound 2. The NMR yield was approximately 70.6%.

[0085] Comparative Example

[0086]

[0087] Compound 1 (302 mg, 94.32% purity, 0.87 mmol) was placed in a 10 mL Schlenk tube. DCM (4 mL) and TMSCN (0.224 mL, 96% purity, 2 eq.) were added. FeCl3 (14.40 mg, 0.1 eq.) was mixed with DCM (1 mL), and then the mixture was added over 10 minutes. The mixture was stirred at room temperature for 8 hours. NMR showed no formation of the desired product.

Claims

1. 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 a catalyst. in: R1 and R2 are each independently H, a lower alkyl group, a lower cycloalkyl group, an aryl group, or a lower aralkyl group, optionally substituted by one or more substituents selected from lower alkyl groups, lower alkoxy groups, halogens, -NH2, -NO2, cyano and / or isocyano groups; R3 is H or a protecting group suitable for nitrogen atoms; R4 is H, and X and Y are each independently O or S. "Lower alkyl groups" refer to branched or straight-chain saturated hydrocarbons containing 1-10 carbon atoms. "Lower cycloalkyl" refers to saturated monocyclic, bicyclic, or tricyclic groups in which all ring atoms in the ring system are carbon atoms, and each cyclic segment contains 3 to 12 carbon ring members. "Lower aryl group" refers to an aryl group that is attached to a parent molecule segment via a lower alkyl group. "Lower alkoxy" is represented by (lower alkyl)-O-. The catalyst is: trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl trifluoromethanesulfonate, zinc trifluoromethanesulfonate, iron trifluoromethanesulfonate, copper trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, scandium trifluoromethanesulfonate, silver trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, indium bromide, indium iodide, bis(trifluoromethanesulfonylimide)silver, trifluoromethanesulfonylimide; or any mixture thereof, and The reaction is carried out in a solvent, said solvent being: cyclohexane, chloroform, dichloromethane, 1,1,2,2-tetrachloroethane, 1-chloro-2-methylbutane, dimethyl carbonate, acetonitrile, benzonitrile, toluene, tetrahydrofuran, and any mixture thereof.

2. The process according to claim 1, wherein the cyanide is cyanosilane.

3. The process according to claim 1, wherein the cyanide is trimethylsilyl cyanide or β-trimethylsilyl propionitrile.

4. The process according to any one of claims 1-3, wherein R1 is H and R2 is phenyl.

5. The process according to any one of claims 1-3, wherein R3 is tert-butyl or benzyl, optionally substituted with one or more substituents selected from lower alkyl, lower alkoxy and / or -NO2.

6. The process according to any one of claims 1-3, wherein R1 is H, R2 is phenyl, R3 is benzyl, X is S, and Y is O.

7. The process according to any one of claims 1-3, wherein the amount of cyanide added is from 1 mole to 20 moles per mole of compound (II).

8. The process according to any one of claims 1-3, wherein the amount of cyanide added is 1.5 to 15 moles per mole of compound (II).

9. The process according to any one of claims 1-3, wherein the amount of cyanide added is from 2 to 10 moles per mole of compound (II).

10. The process according to any one of claims 1-3, wherein the amount of catalyst added is from 0.01 moles to 1 mole per 1 mole of compound (II).

11. The process according to any one of claims 1-3, wherein the amount of catalyst added is from 0.05 moles to 0.8 moles per mole of compound (II).

12. The process according to any one of claims 1-3, wherein the amount of catalyst added is from 0.1 mole to 0.5 mole per mole of compound (II).

13. A process for producing (+)-biotin, comprising the process for producing compound (I) according to any one of claims 1-12.

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