WO2018189108A1

WO2018189108A1 - A process for preparation of an imidazothiazolone compound

Info

Publication number: WO2018189108A1
Application number: PCT/EP2018/059022
Authority: WO
Inventors: Werner Bonrath; Jonathan Alan Medlock; Kun Peng; Lei Zhang; Zhibin Zhu
Original assignee: Dsm Ip Assets B.V.
Priority date: 2017-04-12
Filing date: 2018-04-09
Publication date: 2018-10-18
Also published as: CN110506045A; CN110506045B

Abstract

The application provides a modified process for the preparation of an imidazothiazolone of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof, wherein R1 is C1-10 alkyl or aryl, preferably phenyl; R2 is a protective group which is suitable for a nitrogen atom, preferably benzyl, optionally substituted by one or more C1-4 alkyl or C1-4-alkoxy, which comprises the following steps: a) Reacting a compound of formula (II) with a compound of formula (III) in a first solvent; and b) Removing the first solvent and refluxing the reaction mixture in a second solvent to obtain the compound of formula (I).

Description

A PROCESS FOR PREPARATION OF AN IMIDAZOTHIAZOLONE COMPOUND

Technical field

The application is related to a new process for the preparation of an imidazothiazolone compound, an important intermediate for the preparation of biotin.

Background of the Invention

Biotin (Vitamin H) is one of the B-complex group of vitamins and has immense commercial importance in the area of animal health and nutrition. It is one of the biocatalysts of the reversible metabolic reactions of carbon dioxide transport in micro and macro organisms. It is used in poultry feeds of rapid growth of chicks and healthy hatching of eggs. Biotin avidin complex finds a vital role in the area of biochemistry.

To date, a number of synthetic routes of biotin have been reported. Of the various approaches described toward biotin synthesis, cysteine has attracted a great deal of attention in recent years. As shown in below process, a thiazolidine derivative 1 can be derived from L-cysteine and then react with isocyanate to obtain an imidazothiazolone compound 2, a very important intermediate which can be converted to biotin. (see: US 5,095,118)

L-Cysteine 2

One process for the preparation of the imidazothiazolone compound 2 includes reacting the thiazolidine derivative 1 derived from L-cysteine with benzyl isocyanate. However, the process uses solvents of glacial acetic acid and acetic anhydride, which are corrosive to equipment once mixing with the produced water in the reaction, and thus not suitable for industry, (see: CN 102010434 A)

A modified process for the preparation of the imidazothiazolone compound 2 uses THF, instead of glacial acetic acid and acetic anhydride, as solvent but has to use concentrated hydrochloric acid in the reaction. It is also not suitable for industry because of the strong corrosive acid, (see: WO 2015049700 Al)

Another modified process includes reacting the thiazolidine derivative 1 with benzaldehyde in the presence of phosphorus oxychloride which is toxic and thus the process is not good.

Therefore, there is strong demand for a new process for the preparation of an imidazothiazolone compound in the industry of biotin synthesis.

Summary of the Invention

The application provides a new process for the preparation of an imidazothiazolone of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof,

Wherein Ri is Quo alkyl or aryl, preferably phenyl; R2 is a protective group which is suitable for a nitrogen atom, preferably benzyl, optionally substituted by one or more C1-4 alkyl or Ci-₄-alkoxy, which comprises the following steps:

a) Reacting a compound of formula (II) with a compound of formula (III) in a first solvent; and b) Removing the first solvent and refluxing the reaction mixture in a second solvent to obtain the compound of formula (I).

The process of the present application avoids any strong acid or toxic materials in the reaction, has short reaction time, and provides high yield and selectiveness.

Detailed description of the Invention

In the application, the term "alkyl" refers to unsubstituted or substituted straight- or branched- chain hydrocarbon groups having 1-20 carbon atoms, preferably 1-7 carbon atoms. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, neopentyl, hexyl, isohexyl, heptyl, octyl and the like. Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more of the following groups: halo, cycloalkyl, alkoxy or aryl.

In the application, the term "cycloalkyl" refers to optionally substituted monocyclic aliphatic hydrocarbon groups of 3-6 carbon atoms, which may be substituted by one or more substituents, such as alkyl, alkoxy or halo.

In the application, the term "alkoxy" refers to alkyl-O-.

In the application, the term "aryl" refers to a phenyl group, which may optionally be substituted by 1-4 substituents, such as optionally substituted alkyl, cycloalkyl, halo or alkoxy.

The term "halogen", "halide" or "halo" refers to fluorine, chlorine, bromine and iodine.

The application provides a process for the preparation of an imidazothiazolone of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof,

(II) (III) (I)

Wherein Ri is Quo alkyl or aryl, preferably phenyl, R2 is a protective group which is suitable for a nitrogen atom, preferably benzyl, optionally substituted by one or more C1-4 alkyl or Ci-₄-alkoxy, which comprises the following steps:

The stereoisomer of the compound of formula (I) includes enantiomers and diastereomers. Preferably, the compound of the formula (I) is the following stereoisomer of formula (Γ) or formula (I"):

In the reaction of the step a), the compound of formula (III) may be added in an amount of 0.8-4 moles, preferably 1-3 moles, more preferably 1.2-3 moles, per mole of the compound of formula (II).

The first solvent in the step a) may be any one suitable for the reaction. Preferably, the first solvent is THF. The first solvent may be added in an amount of from 1 L to 3.5 L, preferably from 1.5 L to 3 L, more preferably 2 L to 2.6 L, per mole of the compound of formula (II).

The reaction of the step a) may be carried out under the temperature of from 40 °C to 70 °C, preferably from 50 °C to 65 °C, more preferably from 55 °C to 60 °C, and the most preferably 60 °C.

The second solvent in the step b) may be any solvent suitable for the reaction, preferably those forming azeotrope with water in the reaction, such as toluene. The second solvent may be added into the reaction mixture in an amount of from 2 L to 7 L, preferably from 3 L to 6 L, more preferably 4 L to 5.5 L, per mole of the compound of formula (II).

Preferably, the process of the present application is carried out in one pot. In one embodiment, the process of the present application is carried out in the presence of a catalyst. Preferably, the catalyst is added in the step b). The catalyst may be any catalyst known in the art. Preferably the catalyst is a solid acid catalyst.

Examples of the sold acid catalyst include but are not limited to silica based solid acids, such as silica supported aluminium chloride (lluminium silicate, Montmorillonite K-10, and KSF ), silica supported boron trifluoride (Silica-BF₃), silica supported zinc salts (ZnBr₂/SiC>₂), silica supported perchloric acid (HCI0₄-SiC>₂), silica supported sulfuric acid, silica supported sulfonic acids (SA-SBA- 15-p, Fe₃0₄@-Si0₂-S0₃H, Fe₃0₄-SBA-S0₃H, SBSSA, SBNPSA), silica supported heteropolyacids, and silica supported ionic liquids (Immobilized IL); zeolite based solid acids, such as ZSM-5; polymer based solid acids, such as linear and cross-linked polymer based solid acids (Ps-AICI₃, Ps-FeCI₃, Ps- AI(OTf)3, PVPP-BF3, and PSSA ), biopolymer based solid acids, and ion-exchange resin based solid acids (Amberlyst-15, Amberlyst-35, Nafion SAC-13, Nafion^®NR50, Amberlite, and DR-2030); hydroxyapatite based solid acids, such as ZnC -HAP and SnC -HAP; zirconia based solid acids, such as ZAF; carbon based solid acids, such as CSC-Star, CSC-Star-SOsAIC , CSC-Star-Glu-IL.2, CMK-5-SO3H, Carbon-SC>3H and Fe30₄@C.

The compound of formula (II) may be synthesized by known processes, such as the process disclosed in the Chinese patent publication CN 101735242.

The process of the present application avoids any strong acid in the reaction, has short reaction time, and provides high yield and selectiveness. In addition, the water produced in the process can be removed by refluxing and the solid acid catalyst can be easily isolated from the reaction by simple filtration for recycle. Accordingly, the process of the present application is cost effective.

The invention of the present application will be further illustrated by the following examples.

Examples

Exam le 1

1 2 3

In a 100 mL two-necked round bottom flask filled with nitrogen, the compound 1 (0.85 g, 3.90 mmol) and anhydrous THF (7.5 mL) were added. To the suspension, a solution of compound 2 (0.63 g, 4.68 mmol) in anhydrous THF (2.5 mL) was added dropwise over a period of 20 minutes at 0 °C and stirred for further 1 h at 60 °C. The solvent was removed under vacuum. In a 100 mL single- necked round bottom flask with Dean-Stark trap, the residue and activated solid acid DR-2030 (0.43 g) in toluene (20 mL) was refluxed for 1 h. The mixture was filtered and the filtration was concentrated under vacuum. The residue was purified by Biotage to obtain compound 3 (1.184 g, isolated yield: 94%; NMR yield from reaction mixture: 95.69%).

Exam le 2

1 2 3

In a 100 mLtwo-necked round bottom flask filled with nitrogen, the compound 1 (1.0 g, 4.59 mmol) and anhydrous THF (7.5 mL) were added. To the suspension, a solution of compound 2 (0.74 g, 5.50 mmol) in anhydrous THF (2.5 mL) was added dropwise over a period of 20 minutes at 0 °C and stirred for further 1 h at 60 °C. The solvent was removed under vacuum. In a 100 mL single-necked round bottom flask with Dean-Stark trap, the residue and solid acid ZSM-5 (0.50 g) in toluene (20 mL) was refluxed for 1 h. The mixture was filtered and the filtration was concentrated under vacuum to obtain compound 3 (1.34 g, QNMR yield: 85.2%).

Exam le 3

In a 100 mLtwo-necked round bottom flask filled with nitrogen, the compound 1 (1.0 g, 4.59 mmol) and anhydrous THF (7.5 mL) were added. To the suspension, a solution of compound 2 (0.74 g, 5.50 mmol) in anhydrous THF (2.5 mL) was added dropwise over a period of 20 minutes at 0 °C and stirred for further lh at 60 °C. The solvent was removed under vacuum. In a 100 mL single-necked round bottom flask with Dean-Stark trap, the residue and solid acid Montmorllonite K-10 (0.50 g) in toluene (20 mL) was refluxed for lh. The mixture was filtered and the filtration was concentrated under vacuum to obtain compound 3 (1.41 g, QNMR yield: 87.5%).

Example 4

1

In a 100 mL two-necked round bottom flask filled with nitrogen, the compound 1 (0.50 g, 2.30 mmol) and anhydrous THF (6.0 mL) were added. To the suspension, a solution of compound 2 (0.37 g, 2.76 mmol) in anhydrous THF (2.0 mL) was added dropwise over a period of 20 minutes at 0°C and stirred for further 1 h at 60 °C. The solvent was removed under vacuum. In a 100 mL single- necked round bottom flask with Dean-Stark trap, the residue and solid acid Aluminium silicate (0.25 g) in toluene (10 mL) was refluxed for lh. The mixture was filtered and the filtration was concentrated under vacuum to obtain compound 3 (0.85 g, QNMR yield: 83.5%).

Example 5

1 2 3

In a 100 mLtwo-necked round bottom flask filled with nitrogen, the compound 1 (1.0 g, 4.59 mmol) and anhydrous THF (7.5 mL) were added. To the suspension, a solution of compound 2 (0.74 g, 5.50 mmol) in anhydrous THF (2.5 mL) was added dropwise over a period of 20 minutes at 0 °C and stirred for further 1 h at 60 °C. The solvent was removed under vacuum. In a 100 mL single-necked round bottom flask with Dean-Stark trap, the residue in toluene (20 mL) was refluxed for lh. The mixture was filtered and the filtration was concentrated under vacuum to obtain compound 3 (1.76 g, QNMR yield: 87.0%).

Exam le 6

1 2 3

In a 100 mLtwo-necked round bottom flask filled with nitrogen, the compound 1 (1.0 g, 4.59 mmol) and anhydrous THF (7.5 mL) was added. To the suspension, a solution of compound 2 (2.57 g, 19.08 mmol) in anhydrous THF (2.5 mL) was added dropwise over a period of 20 minutes at 0 °C and stirred for further 1 h at 60 °C. The solvent was removed under vacuum. In a 100 mL single-necked round bottom flask with Dean-Stark trap, the residue and activated solid acid DR-2030 (0.50 g) in toluene (20 mL) was refluxed for 1 h. The mixture was filtered and the filtration was concentrated under vacuum to obtain compound 3 (3.6 g, QNMR yield: 80.8%).

4 2 5

In a 100 mL two-necked round bottom flask filled with nitrogen, the compound 4 (0.80 g, 3.33 mmol) and anhydrous THF (7.5 mL) was added. To the suspension, a solution of compound 2 (0.54 g, 4.00 mmol) in anhydrous THF (2.5 mL) was added dropwise over a period of 20 minutes at 0 °C and stirred for further 1 h at 60 °C. The solvent was removed under vacuum. In a 100 mL single- necked round bottom flask with Dean-Stark trap, the residue and activated solid acid DR-2030 (0.4 g) in toluene (20 mL) was refluxed for lh. The mixture was filtered and the filtration was concentrated under vacuum to obtain compound 5 (1.24 g, QNMR yield: 82.75%).

Claims

1. A process for the preparation of an imidazothiazolone of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof,

(ID (ill) (I)

c) Reacting a compound of formula (II) with a compound of formula (III) in a first solvent; and d) Removing the first solvent and refluxing the reaction mixture in a second solvent to obtain the compound of formula (I).

2. The process of claim 1, wherein the stereoisomer of the compound of formula (I) is the stereoisomer of formula (Γ) or formula ( ):

3. The process of claim 1 or 2, wherein in the reaction of the step a) the compound of formula (III) is added in an amount of 0.8-4 moles, preferably 1-3 moles, more preferably 1.2-3 moles, per mole of the compound of formula (II).

4. The process of claim 1 or 2, wherein the first solvent is THF.

5. The process of claim 1 or 2, wherein the second solvent is a solvent forming azeotrope with water in the reaction, such as toluene.

6. The process of claim 1 or 2, which is carried out in one pot.

7. The process of claim 1 or 2, which is carried out in the presence of a catalyst.

8. The process of claim 7, wherein the catalyst is a solid acid catalyst.

9. The process of claim 8, wherein the catalyst is selected from the group consisting of silica based solid acids, such as silica supported aluminium chloride (lluminium silicate, Montmorillonite K-10, and KSF ), silica supported boron trifluoride (Silica-BFs), silica supported zinc salts (ZnBr2/SiC>2), silica supported perchloric acid (HCI0₄-SiC>2), silica supported sulfuric acid, silica supported sulfonic acids (SA-SBA-15-p, Fe₃0₄@-SiC>₂-S0₃H, Fe₃0₄-SBA-S0₃H, SBSSA, SBNPSA), silica supported heteropolyacids, and silica supported ionic liquids (Immobilized IL); zeolite based solid acids, such as ZSM-5; polymer based solid acids, such as linear and cross-linked polymer based solid acids (Ps- AICI₃, Ps-FeCI₃, Ps-AI(OTf)₃, PVPP-BF₃, and PSSA ), biopolymer based solid acids, and ion-exchange resin based solid acids (Amberlyst-15, Amberlyst-35, Nation SAC-13, Nafion^®NR50, Amberlite, and DR-2030); hydroxyapatite based solid acids, such as ZnC -HAP and SnC -HAP; zirconia based solid acids, such as ZAF; carbon based solid acids, such as CSC-Star, CSC-Star-S0₃AICl2, CSC-Star-Glu-IL.2, CMK-5-S0₃H, Carbon-S0₃H and Fe₃0₄@C.

10. The process of any one of claims 7-9, wherein the catalyst is added in the step b).