Improved process for production of D-biotin intermediates

Abstract

The present invention provides a process for the production of a compound of formula (I) comprising catalytic hydrogenation of a compound of formula (II) to obtain a compound of formula (I) wherein the compound of formula (II) is nanofiltration prior to hydrogenation. According to the method of the invention, catalytic toxicants can be significantly reduced. # imgabs0 # wherein R1 and R1'are independently H, lower alkyl, aryl or acyl groups, optionally substituted by one or more substituents; and R2 is a lower alkyl group optionally substituted by a lower alkoxy group or a carboxy group.

Description

Technical Field

[0001] The present invention relates to a method for preparing a D-biotin intermediate. Background Art

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

[0003]

[0004] Since the first industrial synthesis of D-biotin by Swiss company Roche in 1949, this synthesis method has been studied in many fields around the world. So far, there have been many reports on the total synthesis approach. However, the most industrialized method for D-biotin is to use a thiolactone compound (a) to produce an intermediate compound (b), which is then converted into a compound (c) by catalytic hydrogenation, and finally converted into D-biotin. In the catalytic hydrogenation step, a hydrogen pressure of 40 atmospheres and a Raney nickel catalyst of 10% by weight are used (see US 3,740,416 A).

[0005]

[0006] The improved process for the catalytic hydrogenation of compound (b) uses 5 wt% palladium on carbon and a hydrogen pressure of 50 bar. However, the yield of compound (c) is as low as 72% (see US 4,876,350 A).

[0007] Furthermore, all of the above methods have the problem of catalytic poisons, which limits the efficiency of the reaction and makes high pressure and high catalyst dosage necessary in the reaction (see Masahiko Seki et al., Chem. Eur. J., 2004, 10, 6102-6110).

[0008] Therefore, there remains a need in industry for improved methods for producing intermediate compounds of biotin. Summary of the invention

[0009] The present invention provides an improved process for producing an intermediate compound of formula (I), the process comprising subjecting a compound of formula (II) to catalytic hydrogenation to obtain a compound of formula (I), wherein the compound of formula (II) is subjected to nanofiltration before hydrogenation,

[0010]

[0011] wherein R1 and R1' are independently H, lower alkyl, aryl or acyl groups, optionally substituted by one or more substituents; and R2 is lower alkyl optionally substituted by lower alkoxy or carboxyl groups.

[0012] According to the method of the present invention, catalytic poisons can be significantly reduced. Therefore, the compound of formula (II) can be hydrogenated to the compound of formula (I) in high yield, while at the same time the dosage of the catalyst can be reduced, making the method of the present invention more cost-effective than the prior art. DETAILED DESCRIPTION

[0013] In the present invention, the term "lower alkyl" as used herein refers to a C1-C 10 Alkyl, i.e., a branched or unbranched, cyclic or non-cyclic saturated hydrocarbon containing 1 to 10 carbon atoms. Preferably, "low alkyl" is a C1-C6 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, isopentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, tert-hexyl, and cyclohexyl. More preferably, "low alkyl" is methyl or ethyl.

[0014] In the present invention, the term "aryl" as used refers to an aromatic hydrocarbon, such as substituted and unsubstituted phenyl, benzyl, xylyl and naphthyl.

[0015] In the present invention, the term "acyl" as used refers to the structure R'-C(=O)-, wherein R' is H or lower alkyl.

[0016] 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 above.

[0017] In the present invention, the term "carboxyl" as used refers to the structure -C(=O)OH.

[0018] In the present invention, the term "halo" or "halogen" refers to a group of elements including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0019] In the present invention, the term "substituent / substituents" as used refers to C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, aryl, hydroxyl, halo, halide, -NH2, -NO2, cyano and / or isocyano.

[0020] The inventors of the present invention surprisingly found that using an additional pretreatment as described herein, the compound of formula (I) can be hydrogenated with higher yields while using lower amounts of catalyst.

[0021] Specifically, the present invention provides a method for producing a compound of formula (I), the method comprising catalytically hydrogenating a compound of formula (II) to obtain a compound of formula (I), wherein the compound of formula (II) is nanofiltered before hydrogenation,

[0022]

[0023] Where R 1、 R1' and R2 are independently as defined above.

[0024] Preferably, R1 and R1' are independently H, C1-C6 alkyl, aryl or C1-C6 acyl group, optionally substituted by one or more substituents. More preferably, R1 and R1' are independently H, methyl, ethyl, propyl, butyl, phenyl, benzyl, formyl, acetyl, optionally substituted by one or more substituents. Most preferably, R1 and R1' are independently H, benzyl or acetyl, optionally substituted by one or more substituents.

[0025] Preferably, R2 is a C1-C6 alkyl group optionally substituted by a C1-C6 alkoxy or carboxyl group. More preferably, R2 is a methyl, ethyl, propyl or butyl group optionally substituted by a methoxy or ethoxy or carboxyl group. Most preferably, R2 is an ethyl or propyl group substituted by a methoxy or carboxyl group.

[0026] In one embodiment, R1 and R1' are independently H, benzyl or acetyl; and R2 is ethyl or propyl substituted with methoxy.

[0027] In another embodiment, R1 and R1' are independently H, benzyl or acetyl; and R2 is ethyl or propyl substituted with a carboxyl group.

[0028] In the method of the present invention, nanofiltration is performed with a nanofiltration membrane having a molecular weight cutoff (MWCO) of 100 to 1000, preferably 200 to 800, more preferably 250 to 600. Preferably, the nanofiltration membrane is selected from polymer membranes and ceramic membranes. More preferably, the nanofiltration membrane is polymeric. Examples of commercial membranes are BORSIG OSN membranes oNF-1, oNF-2 and oNF-3 (Borsig Membrane Technology GmbH, Germany) and Evonik's trade name

[0029] In the method of the present invention, nanofiltration is carried out in an organic solvent. The organic solvent may be selected from the group consisting of alcohols (e.g. methanol and ethanol), esters (e.g. ethyl acetate (EtOAc)), and aromatic hydrocarbons (e.g. toluene). Preferably, the organic solvent is toluene.

[0030] Preferably, the nanofiltration in the method of the present invention is performed in cross-flow mode. Further preferably, the nanofiltration is performed in diafiltration mode.

[0031] In the process of the present invention, nanofiltration can be carried out at a temperature of 0°C to 50°C, preferably 10°C to 30°C, more preferably room temperature. It is preferred that the nanofiltration is carried out under elevated pressure, typically and preferably the pressure applied is 5 bar to 50 bar, more preferably 10 bar to 40 bar, for example 20 bar.

[0032] In the method of the present invention, the permeate obtained from the nanofiltration can be used for catalytic hydrogenation directly or after removing the solvent. Preferably, the compound of formula (II) is separated from the permeate before hydrogenation. The retentate obtained from the nanofiltration can be discarded or re-fed into the nanofiltration. Preferably, the retentate is re-fed into the nanofiltration.

[0033] In the method of the present invention, the catalytic hydrogenation of the compound of formula (II) can be carried out according to the disclosure of the prior art (eg, US Pat. No. 3,740,416 A and US Pat. No. 4,876,350 A).

[0034] In the process of the present invention, the catalyst used in the catalytic hydrogenation is preferably selected from the group consisting of palladium, palladium hydroxide, nickel, nickel alloys, platinum, ruthenium and / or rhodium supported on common support materials such as carbon, clay, etc. More preferably, in the presence or absence of a modifier (such as formic acid, formaldehyde, carbon monoxide), the catalyst is selected from palladium, palladium hydroxide and nickel alloys (such as Raney nickel).

[0035] In the process of the present invention, the catalyst is used in an amount of 0.01% to 1% by weight, preferably 0.05% to 0.8% by weight, more preferably 0.1% to 0.5% by weight, for example 0.1%, 0.12%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, and 0.6% by weight (calculated as the metal or metal hydroxide contained in the catalyst), based on the weight of the compound of formula (II).

[0036] In the process of the present invention, the compound of formula (II) is preferably produced by a Grignard reaction of a compound of formula (III),

[0037]

[0038] wherein R1 and R1' are independently as defined above.

[0039] The Grignard reaction of the compound of formula (III) can be carried out according to methods known in the art, such as the methods disclosed in US Pat. No. 3,740,416 A and US Pat. No. 5,847,152 A.

[0040] According to the process of the present invention, the compound of formula (II) can be hydrogenated to the compound of formula (I) in high yield even at a lower catalyst dosage, so the process of the present invention is more cost-effective than the prior art.

[0041] Based on the good results of the method of the present invention, it is expected by those skilled in the art that the catalytic poisons in the hydrogenation should be generated by the impurities contained in the raw materials of the compound of formula (I), rather than the sulfide fragments in the compound of formula (II). Therefore, the method of the present invention is also suitable for using storage materials of the compound of formula (II) containing impurities.

[0042] Furthermore, the process of the present invention can be run in a continuous manner.

[0043] The present invention also provides a method for producing (+)-biotin, said method comprising the method for producing a compound of formula (I) as described herein.

[0044] The method of the present invention is further illustrated by the following examples.

[0045] Example

[0046] General Process

[0047] Raw material preparation

[0048] In an embodiment according to the present invention, the starting material (3aS,6aR,E)-1,3-dibenzyl-4-(3-methoxypropylidene)tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-one ("THE") is prepared by Grignard addition according to the procedure described in US 3,740,416A, and the starting material (E)-5-((3aS,6aR)-1,3-dibenzyl-2-oxohexahydro-4H-thieno[3,4-d]imidazol-4-ylidene)pentanoic acid ("DbBTN") is prepared by Grignard addition according to the procedure described in US 5,847,152 A.

[0049] Nanofiltration

[0050] The raw material (THE or DbBTN) (1 g) was dissolved in an organic solvent (15 mL) and subjected to nanofiltration in cross-flow mode during 65 hours. During the nanofiltration, a specific pressure was applied at 25° C. After the nanofiltration, the permeate was collected and evaporated, and the obtained residue was subjected to a catalytic hydrogenation test.

[0051] Catalytic hydrogenation

[0052] In an autoclave, THE (1 g) was dissolved in MeOH (5 mL). A specific amount of catalyst Pd / C was added to the reaction mixture. After purging with nitrogen, the reaction mixture was stirred at 75 ° C under a hydrogen pressure of 30 bar. After 16 h, the reaction mixture was cooled to room temperature, hydrogen was released, and the reactor was purged with nitrogen. After all volatiles were evaporated, the yield of THA was determined by GC.

[0053]

[0054] DbBTN was hydrogenated to DhBTN according to the same procedure, except that the solvent was EtOH and the reaction temperature was 100° C. The yield was determined by qHPLC.

[0055]

[0056] Example 1: Catalytic hydrogenation of THE without nanofiltration pretreatment

[0057] THF obtained from the Grignard addition was hydrogenated according to the above method, and the results are shown in Table 1.

[0058] Table 1

[0059] entry Catalyst Pd (mg) THE (area %) THA (area %) 1 1.2 91.7 5.9 2 2.0 81.6 15.8 3 2.8 45.4 51.7 4 3.2 19.2 78.1 5 4.0 0.8 96.4

[0060] Example 2: Catalytic hydrogenation of THE using nanofiltration pretreatment

[0061] The same THE as in Example 1 was used to perform nanofiltration, and then the obtained THE was hydrogenated with Pd / C (1.2 mg Pd / 1 g THE) according to the above method. The nanofiltration conditions and hydrogenation results are shown in Table 2.

[0062] Table 2

[0063]

[0064] nd = not defined in the product data sheet.

[0065] Example 3: Catalytic hydrogenation of permeate and retentate from nanofiltration

[0066] The THE obtained from the Grignard addition was nanofiltered by using a toluene solution of Borsig oNF-1 at 10 bar at room temperature. The permeate THE and the obtained retentate were then hydrogenated separately with Pd / C (1.2 mg Pd / 1 g THE) according to the above procedure. The hydrogenation results are shown in Table 3.

[0067] Table 3

[0068] entry THE THE (area %) THA (area %) 2 Permeate 0 98.6 3 Retentate THE 95.7 0

[0069] Example 4: Catalytic hydrogenation of DhBTN.

[0070] According to the above procedure, DhBTN prepared by Grignard addition was hydrogenated with Pd / C without or with nanofiltration pretreatment. Nanofiltration of DhBTN was run at room temperature using a toluene solution of Borsig oNF-1 at 10 bar. The results are shown in Table 4.

[0071] Table 4

[0072]

Claims

1. A method for producing a compound of formula (I), comprising subjecting a compound of formula (II) to catalytic hydrogenation to obtain a compound of formula (I), wherein the compound of formula (II) is subjected to nanofiltration prior to the hydrogenation, wherein R1 and R1' are independently H, lower alkyl, aryl or acyl groups, optionally substituted by one or more substituents; and R2 is lower alkyl optionally substituted by lower alkoxy or carboxyl groups.

2. The method according to claim 1, wherein the nanofiltration is performed using a nanofiltration membrane having a molecular weight cut-off (MWCO) of 100 to 1000, preferably 200 to 800, more preferably 250 to 600.

3. The method according to claim 1, wherein the nanofiltration membrane is selected from polymer membranes and ceramic membranes, preferably selected from the group consisting of: BORSIG OSN membranes oNF-1, oNF-2 and oNF-3 (Borsig Membrane Technology GmbH, Germany) and Evonik's trade name 4. The method according to any one of claims 1 to 3, wherein the nanofiltration is carried out in an organic solvent selected from the group consisting of: alcohols, such as methanol and ethanol; esters, such as ethyl acetate (EtOAc); and aromatic hydrocarbons, such as toluene.

5. The method according to any one of claims 1 to 3, wherein the nanofiltration is performed in cross-flow mode.

6. The method according to any one of claims 1 to 5, wherein the nanofiltration is performed in diafiltration mode.

7. The process according to any one of claims 1 to 6, wherein the catalyst used in the catalytic hydrogenation is preferably selected from the group consisting of palladium, palladium hydroxide, nickel, nickel alloys, platinum, ruthenium and / or rhodium supported on common support materials such as carbon, clay, etc.

8. The process according to any one of claims 1 to 6, wherein the catalyst used in the catalytic hydrogenation is used in an amount of 0.01 to 1 wt %, preferably 0.05 to 0.8 wt %, more preferably 0.1 to 0.5 wt %, such as 0.1 wt %, 0.12 wt %, 0.15 wt %, 0.2 wt %, 0.25 wt %, 0.3 wt %, 0.35 wt %, 0.4 wt %, 0.45 wt %, 0.5 wt %, and 0.6 wt % (calculated as the metal or metal hydroxide contained in the catalyst), based on the weight of the compound of formula (II).

9. The process according to any one of claims 1 to 8, wherein the compound of formula (II) is preferably produced by a Grignard reaction of the compound of formula (III), wherein R1 and R1′ are independently as defined in claim 1.

10. The process according to any one of claims 1 to 9, wherein the process is run in a continuous manner.

11. A method for producing (+)-biotin, the method comprising the method for producing the compound of formula (I) according to any one of claims 1 to 10.

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