Process for production of biotin intermediates

Abstract

The present invention provides an improved process for the production of biotin intermediate compound (I) or a stereoisomer thereof or a mixture thereof with higher yield and selectivity in a more efficient manner compared to the prior art: # imgabs0 # wherein: R1 and R2 are each lower alkyl independently of one another, optionally substituted by one or more substituents, and optionally substituted by one or more substituents, and R1 and R2 are each lower alkyl independently of one another, optionally substituted by one or more substituents, optionally substituted by one or more substituents, optionally substituted by one or more substituents, optionally substituted by one or more substituents, and optionally substituted by one or more substituents; or R1 and R2 together with the carbon atom to which they are attached form a lower cycloalkyl group optionally substituted by one or more substituents; r3 is H or a protecting group suitable for a nitrogen atom; and X and Y are each independently of one another O or S.

Description

Technical Field

[0001] The present invention relates to a process for producing an important biotin intermediate. Background Art

[0002] D-biotin, also known as vitamin H, is mainly used in the fields of medicine and health, nutritional supplements, feed additives, cosmetics and beverages. The molecular structure of D-biotin is shown below:

[0003]

[0004] Since the Swiss company Roche first introduced industrially synthesized D-biotin in 1949, its synthesis method has been extensively studied worldwide. To date, many general synthetic routes have been reported. However, most industrial methods for D-biotin use thiolactone compounds (a) to produce intermediate compounds (b), which are then converted into compounds (c) by catalytic hydrogenation and finally converted into D-biotin (see US 3,740,416).

[0005]

[0006] A known method for producing a thiolactone compound (a) comprises: step a) using L-cysteine ​​or L-serine as a raw material to produce an intermediate compound (d), step b) converting the intermediate compound (d) into a dicyclic cyanohydantoin (e) in two steps, and step c) finally converting the dicyclic cyanohydantoin (e) into compound (a) in another two steps (see US Pat. No. 5,095,118 A).

[0007]

[0008] In the above method, step b) is critical, but it has two steps and uses expensive catalysts and reagents. In addition, the solubility of compound (d) in the system is low. Therefore, this method is ineffective for industry.

[0009] Therefore, there remains a need for a method for producing biotin intermediate compounds with improved efficiency. Summary of the invention

[0010] The present invention provides an improved method for producing a biotin intermediate compound (I), or a stereoisomer thereof, or a stereoisomer mixture thereof.

[0011]

[0012] in:

[0013] R1 and R2 are each independently lower alkyl, optionally substituted by one or more substituents, or

[0014] R1 and R2 together with the carbon atoms to which they are attached form a lower cycloalkyl group, optionally substituted with one or more substituents;

[0015] R3 is H or a suitable protecting group for the nitrogen atom; and

[0016] X and Y are each independently O or S.

[0017] According to the process of the present invention, the compound of formula (I) can be produced in a more efficient manner with higher yield and selectivity compared to the prior art. DETAILED DESCRIPTION

[0018] In the present invention, the term "lower alkyl" as used herein refers to a C1-C 10 Alkyl, that is, a branched or unbranched, cyclic or non-cyclic saturated hydrocarbon containing 1 to 10 carbon atoms. Preferably, "low alkyl" is selected from the group consisting of 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, "low alkyl" is methyl or ethyl.

[0019] In the present invention, the term "lower cycloalkyl" as used herein refers to a C3-C 10 Cycloalkyl, i.e., monocyclic, bicyclic or spirocyclic aliphatic hydrocarbon groups having 3 to 10 carbon atoms, may optionally contain one or more alkenylene groups as part of the ring structure. Preferably, low cycloalkyl is C3-C7 cycloalkyl or C5-C6 cycloalkyl. Examples of low cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, etc. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0020] In the present invention, the "protecting group" may be selected from the group consisting of tert-butyl, benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 4-methylbenzyl, allyl, methallyl, crotyl, methoxymethyl, trimethylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl.

[0021] In the present invention, the term "lower alkoxy" as used refers to a structure represented by (lower alkyl)-O-, wherein lower alkyl is as defined herein.

[0022] In the present invention, the term "halo" as used refers to iodide, bromide, chloride and fluoride, preferably bromide or iodide, more preferably bromide.

[0023] In the present invention, the term "substituent" as used herein means lower alkyl, lower alkoxy, hydroxy, halo, -NH2, -NO2, cyano and / or isocyano.

[0024] In the present invention, the structure of the compound formula of the present invention This means that the group R is oriented away from the viewer compared to the chiral carbon to which it is attached.

[0025] In the present invention, the structure of the compound formula of the present invention This means that the group R' is oriented closer to the viewer than the chiral carbon to which it is attached.

[0026] In the present invention, the symbols used in the compound formula of the present invention are It means that the attached group is attached to the chiral carbon in the S- and / or R-configuration according to the Cahn-Ingold-Prelog priority rules.

[0027] In particular, the present invention also provides a method for producing a compound of formula (I) or a stereoisomer thereof or a stereoisomeric mixture thereof, which comprises reacting a compound of formula (II) or a stereoisomer thereof or a stereoisomeric mixture thereof with a cyanide to obtain a compound of formula (I) or a stereoisomer thereof or a stereoisomeric mixture thereof,

[0028]

[0029] wherein R1, R2, R3, X and Y are each non-independently as defined above.

[0030] In the present invention, R1 and R2 are each independently preferably a C1-C6 alkyl group, optionally substituted by one or more substituents, and more preferably, R1 is a methyl group and R2 is also a methyl group.

[0031] In the present invention, the protecting group may be one of tert-butyl, benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 4-methylbenzyl, allyl, methallyl, crotyl, methoxymethyl, trimethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

[0032] In the present invention, R3 is preferably tert-butyl or benzyl, optionally substituted by one or more substituents, more preferably, R3 is benzyl.

[0033] In one embodiment of the present invention, R1 is methyl, R2 is methyl, R3 is benzyl, X is S, and Y is O.

[0034] In another embodiment of the present invention, R1 and R2 together with the carbon atoms to which they are attached form a C3-C7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, R3 is benzyl, X is S, and Y is O.

[0035] In the present invention, the stereoisomer of the compound of formula (II) may be a compound of formula (IIa) or (IIb):

[0036]

[0037] wherein R1, R2, R3, X and Y are each non-independently as defined above.

[0038] Preferably, the stereoisomer of the compound of formula (II) is a compound of formula (IIa') or (IIb'):

[0039]

[0040] In this method, the cyanide can be a metal cyanide such as sodium cyanide (NaCN), potassium cyanide (KCN), zinc cyanide, copper cyanide, sodium ferrocyanide and potassium ferrocyanide; or a cyanosilane such as trimethylsilyl cyanide (TMSCN), acetone cyanohydrin, tert-butyldimethylsilyl cyanide and β-trimethylsilyl propionitrile.

[0041] In the method, the cyanide is preferably selected from the group consisting of metal cyanides such as sodium cyanide, potassium cyanide, zinc cyanide and copper cyanide, more preferably selected from the group consisting of sodium cyanide and potassium cyanide.

[0042] In this method, the reaction can be carried out in a solvent. Examples of solvents include, but are not limited to, amides such as formamide and acetamide; alkanes such as cyclohexane; alkyl halides such as chloroform, dichloromethane (DCM), 1,1,2,2-tetrachloroethane and 1-chloro-2-methylbutane; alkanoic acids such as dimethyl carbonate (DMC); nitriles such as acetonitrile (ACN) and benzonitrile; aromatic alkanes such as toluene; and ethers such as tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether; sulfones such as sulfolane; and mixtures thereof. Preferably, the solvent is an amide such as formamide and acetamide.

[0043] More preferably, in this process, the cyanide is selected from metal cyanides such as sodium cyanide, potassium cyanide, zinc cyanide and copper cyanide, more preferably from sodium cyanide and potassium cyanide, and an amide such as formamide and acetamide is used as solvent.

[0044] In the method, a catalyst is optionally used. The catalyst may be selected from the group consisting of 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), lanthanide trifluoromethanesulfonates such as ytterbium trifluoromethanesulfonate (Yb(OTf)3 ), scandium trifluoromethanesulfonate (Sc(OTf)3) and neodymium trifluoromethanesulfonate (Nd(OTf)3)), silver trifluoromethanesulfonate (AgOTf), bismuth trifluoromethanesulfonate (Bi(OTf)3) and hafnium trifluoromethanesulfonate (Hf(OTf)4); indium halides, such as indium bromide (InBr3) and indium iodide (InI3); bis(trifluoromethanesulfonyl imide) silver (AgNTf2); bis(trifluoromethanesulfonyl imide) lithium (LiNTf2); and trifluoromethanesulfonyl imide; or mixtures thereof.

[0045] In this process, when the cyanide is a cyanosilane, such as trimethylsilylcyanide (TMSCN), methyldiisopropylsilylcyanide, acetone cyanohydrin, tert-butyldimethylsilylcyanide and β-trimethylsilylpropionitrile, preferably a catalyst as defined above is used.

[0046] In this method, the cyanide may be added in an amount of 1 mol to 20 mol, preferably 1.5 mol to 15 mol, more preferably 2 mol to 10 mol, per 1 mol of the compound of formula (II) or its stereoisomer or its stereoisomeric mixture.

[0047] In this method, the solvent may be used in the reaction in an amount of 0.1 L to 20 L, preferably 0.5 L to 15 L, more preferably 1.2 L to 10 L, per 1 mol of the compound of formula (II) or its stereoisomer or its stereoisomeric mixture.

[0048] In this method, the catalyst may be added in an amount of 0.01 mol to 1 mol, preferably 0.05 mol to 0.8 mol, more preferably 0.1 mol to 0.5 mol, per 1 mol of the compound of formula (II) or its stereoisomer or its stereoisomeric mixture.

[0049] The reaction of the method can be carried out at a temperature of 0°C to 150°C, preferably 10°C to 100°C, more preferably 20°C to 80°C (such as 30°C, 40°C, 50°C, 60°C or 70°C), and most preferably 20°C to 60°C.

[0050] Surprisingly, the inventors of the present invention have found that the compound of formula (II) has an increased solubility in amide solvents and therefore the reaction can be carried out at a higher concentration of the compound of formula (II) or its stereoisomer or stereoisomeric mixture thereof.

[0051] Therefore, the method is preferably carried out in an amide solvent such as formamide and acetamide. More preferably, in the method of the present invention, the amide solvent is used in an amount of 0.1L to 3L, more preferably 0.25L to 2.5L, further preferably 0.5L to 2L (such as 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5 and 2.0L) per 1mol of the compound of formula (II) or its stereoisomer or its stereoisomer mixture.

[0052] Most preferably, in this method, the cyanide is selected from metal cyanides such as sodium cyanide, potassium cyanide, zinc cyanide and copper cyanide, sodium ferrocyanide, potassium ferrocyanide; more preferably selected from sodium cyanide and potassium cyanide, and amides such as formamide and acetamide are used as solvent in an amount of 0.1L to 3L, more preferably 0.25L to 2.5L, further preferably 0.5L to 2L (such as 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5 and 2.0L) per 1 mol of the compound of formula (II) or its stereoisomer or its stereoisomer mixture.

[0053] The obtained compound of formula (I) can be separated and / or purified by methods well known in the art and used in the next step of preparing (+)-biotin. Therefore, the present invention also provides a method for producing (+)-biotin, which includes a method for producing a compound of formula (I) as described herein.

[0054] The method of the present application uses a compound of formula (II), or a stereoisomer thereof, or a stereoisomeric mixture thereof, which has good solubility in the reaction system, so the method can be run at a high concentration, thereby providing improved efficiency.

[0055] The present invention further provides intermediate compounds of formula (III) or stereoisomers thereof or stereoisomeric mixtures thereof which are surprisingly novel:

[0056]

[0057] wherein R1, R2, R3, X and Y are each independently as defined above, and R4 is OH or CN.

[0058] The present invention will be further illustrated by the following examples.

[0059] Example

[0060] In the following examples of the present application, "Bn" is benzyl and "CN" is cyano.

[0061] Example 1

[0062]

[0063] L-cysteine ​​hydrochloride (50.0 g, 98.0% purity, 311 mmol) was added to acetone (518 mL) under nitrogen. The reaction mixture was kept under reflux for 18 hours. After cooling to room temperature, the mixture was filtered to obtain 48.7 g of compound 1 as a solid (81.4% yield, >99.0% purity).

[0064]

[0065] Compound 1 (10.0 g, >99.0% purity, 50.6 mmol) and sodium cyanate (3.29 g, 50.6 mmol) were added to acetic acid (84 mL). The reaction mixture was stirred at room temperature for 18 hours. After removing the solvent, water (10 mL) was added. The mixture was stirred for 1 hour and then filtered. The resulting filter cake was washed with water (15 mL) and dried to produce 6.39 g of compound 2 as a white solid (62.0% yield, 90.7% purity).

[0066]

[0067] Benzyl bromide (16.6 g, 97.0 mmol) was added to a mixture of compound 2 (17.9 g, 91.7% purity, 88.2 mmol), K2CO3 (13.4 g, 97.0 mmol) and DMF (294 mL). The mixture was stirred at room temperature for 3 hours. After all compound 2 was consumed by checking by LCMS, the reaction mixture was filtered. The resulting mixture was then extracted with ethyl acetate (300 mL) and water (300 mL). The aqueous phase was further extracted with ethyl acetate (150 mL × 3), and the organic phase was washed with saturated NH4Cl (150 mL × 2) and saturated NaCl (150 mL × 2). The organic phases were combined and dried with Na2SO4. The solvent was removed to obtain 30 g of crude compound 3 (97.8% yield, 79.4% purity).

[0068]

[0069] Compound 3 (30.0 g, 99.2% purity, 108 mmol) and methanol (360 mL) were added to a 1 L reactor. The resulting suspension was cooled to 0 ° C. NaBH4 (8.48 g, 96.0% purity, 215 mmol) was added at a temperature below 5 ° C. After stirring for 3 hours, the mixture was warmed to room temperature. When the reaction was completed by LCMS, water (540 mL) was added to quench the reaction at 0 ° C. The filter cake was washed with water (20 mL) and dried by crystallization and filtration to obtain 25.3 g of compound 4 as a white solid (82.5% yield, 97.7% purity).

[0070] Example 2

[0071]

[0072] Compound 4 (15.0 g, 97.7% purity, 52.6 mmol), KCN (7.02 g, 108 mmol) and formamide (90 mL) were added to a 250 mL three-necked flask. The mixture was heated to 40 ° C and maintained for 7 hours. After cooling to room temperature, the mixture was extracted with water (90 mL) and ethyl acetate (90 mL). The aqueous phase was further extracted with ethyl acetate (90 mL × 3), and the organic phases were combined, washed with water (90 ml × 2) and saturated NaCl (150 mL × 2), and then dried with Na2SO4. The solvent was removed by a rotary evaporator to obtain 17.1 g of crude compound 5 (20% conversion, > 99% selectivity, by HPLC).

[0073] Example 3

[0074]

[0075] Under nitrogen protection, compound 4 (7.68g, 97.7% purity, 26.9mmol), TMSCN (13.8g, 96.0% purity, 134mmol) and DCM (90mL) are placed in a 250mL three-necked flask. Under stirring, TMSOTf (595mg, 2.68mmol) is added. The reaction mixture is kept at room temperature overnight. The solvent is removed by a rotary evaporator to obtain 9.70g of crude compound 5, which is a solid (74.2% yield, 74.3% purity).

[0076] Example 4

[0077]

[0078] Compound 4 (150.0 mg, 97.7% purity, 0.53 mmol), KCN (70.18 mg, 1.08 mmol) and formamide in the amounts shown in Table 1 were placed in a 10 mL Schlenk tube. The mixture was stirred at 40° C. for 7 hours to produce Compound 5. The conversion of the reaction and the selectivity determined by NMR are shown in Table 1.

[0079] Table 1

[0080] entry Formamide (mL) Conversion rate Selectivity 1 2.5 23％ ＞99％ 2 1.5 28％ ＞99％ 3 0.9 24％ ＞99％ 4 0.7 27％ ＞99％

[0081] Example 5

[0082]

[0083] The crude compound 5 (9.70 g, 74.3% purity, 25.1 mmol) was hydrolyzed with 10% aqueous KOH solution (94 mL) and ethanol (94 mL) at 80°C for 2-4 hours. The ethanol was then removed and a 37% aqueous HCl solution was added to adjust the pH of the mixture to about 1. The resulting mixture was heated to 55-60°C. After 3 hours, the mixture was filtered, and the filter cake was washed with water (10 mL) and dried to give 6.77 g of compound 7 (90.0% yield, 88.7% purity).

[0084]

[0085] At room temperature, under nitrogen, compound 7 (8.0g, 99.0% purity, 30mmol) and sodium acetate (2.5g, 30mmol) are added to a 250mL three-necked flask equipped with a magnetic stirrer. DMF (75mL) and acetic anhydride (15.0g, 150mmol) are added. The mixture is heated to 150°C for 4 hours. After cooling to room temperature, ethyl acetate (75mL) and water (75mL) are added for extraction. The aqueous phase is further extracted with ethyl acetate (75mL×3), and the organic phase is washed with saturated NH4Cl (50mL×2) and saturated NaCl (50mL×2). The organic phases are combined and dried with Na2SO4. After removing the solvent, 2.4g crude compound 8 (23.0% yield, 72.0% purity) is obtained.

[0086]

[0087] At room temperature, compound 8 (77.0 mg, 72.0% purity, 223 μmol) and K2CO3 (33.9 mg, 246 μmol) were added to a 10 mL flask equipped with a magnetic stirrer. DMF (2.5 ml) and benzyl bromide (106 μL, 200 μmol) were added. The mixture was kept at 150° C. for 5 hours to obtain thiolactone. The yield was about 7.0% by HPLC.

Claims

1. A method for producing a compound of formula (I) or its stereoisomer or its stereoisomeric mixture, the method comprising reacting a compound of formula (II) or its stereoisomer or its stereoisomeric mixture with cyanide to obtain the compound of formula (I) or its stereoisomer or its stereoisomeric mixture, in: R1 and R2 are each independently lower alkyl, optionally substituted by one or more substituents, or R1 and R2 together with the carbon atoms to which they are attached form a lower cycloalkyl group, optionally substituted with one or more substituents; R3 is H or a suitable protecting group for the nitrogen atom; and X and Y are each independently O or S.

2. The method according to claim 1, wherein the cyanide is selected from the group consisting of: metal cyanides such as sodium cyanide (NaCN), potassium cyanide (KCN), zinc cyanide, copper cyanide, sodium ferrocyanide and potassium ferrocyanide; and cyanosilanes such as trimethylsilyl cyanide (TMSCN), acetone cyanohydrin, tert-butyldimethylsilyl cyanide and β-trimethylsilyl propionitrile.

3. The method according to claim 1, wherein the reaction is carried out in a solvent selected from the group consisting of: amides, such as formamide and acetamide; alkanes, such as cyclohexane; halogenated alkanes, such as chloroform, dichloromethane (DCM), 1,1,2,2-tetrachloroethane and 1-chloro-2-methylbutane; alkanoic acids, such as dimethyl carbonate (DMC); nitriles, such as acetonitrile (ACN) and benzonitrile; aromatic alkanes, such as toluene; and ethers, such as tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether; sulfones, such as sulfolane; and mixtures thereof.

4. The method according to claim 3, wherein the solvent is used in an amount of 0.1 L to 20 L, preferably 0.5 L to 15 L, more preferably 1.2 L to 10 L, per 1 mol of the compound of formula (II) or its stereoisomer or its stereoisomeric mixture.

5. The process according to claim 1, wherein the cyanide is selected from metal cyanides such as sodium cyanide, potassium cyanide, zinc cyanide and copper cyanide, more preferably selected from sodium cyanide and potassium cyanide, and an amide such as formamide and acetamide is used as a solvent.

6. The method according to claim 1, wherein a catalyst is used and the catalyst is selected from the group consisting of: 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), lanthanide trifluoromethanesulfonates such as trifluoromethanesulfonate (TMSOTf); Ytterbium methanesulfonate (Yb(OTf)3), scandium trifluoromethanesulfonate (Sc(OTf)3) and neodymium trifluoromethanesulfonate (Nd(OTf)3)), silver trifluoromethanesulfonate (AgOTf), bismuth trifluoromethanesulfonate (Bi(OTf)3) and hafnium trifluoromethanesulfonate (Hf(OTf)4); indium halides, such as indium bromide (InBr3) and indium iodide (InI3); silver bis(trifluoromethanesulfonyl imide) (AgNTf2); lithium bis(trifluoromethanesulfonyl imide) (LiNTf2); and trifluoromethanesulfonyl imide; or mixtures thereof.

7. The method according to any one of claims 1 to 6, wherein the amide solvent is used in an amount of 0.1 L to 3 L, more preferably 0.25 L to 2.5 L, further preferably 0.5 L to 2 L per 1 mol of the compound of formula (II) or its stereoisomer or its stereoisomeric mixture.

8. The method according to any one of claims 1 to 6, wherein the cyanide is selected from metal cyanides such as sodium cyanide, potassium cyanide, zinc cyanide and copper cyanide, sodium ferrocyanide, potassium ferrocyanide; more preferably selected from sodium cyanide and potassium cyanide, and amides such as formamide and acetamide are used as solvent in an amount of 0.1 L to 3 L, more preferably 0.25 L to 2.5 L, and further preferably 0.5 L to 2 L per 1 mol of the compound of formula (II) or its stereoisomer or its stereoisomer mixture.

9. A method for producing (+)-biotin, the method comprising the method for producing a compound of formula (I) according to any one of claims 1 to 8.

10. A compound of formula (III), or a stereoisomer thereof, or a stereoisomeric mixture thereof: in: R1 and R2 are each independently lower alkyl, optionally substituted by one or more substituents, or R1 and R2 together with the carbon atoms to which they are attached form a lower cycloalkyl group, optionally substituted with one or more substituents; R3 is H or a protecting group suitable for the nitrogen atom; R4 is OH or CN; and X and Y are each independently O or S.

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