EP4136066A1

EP4136066A1 - A process for preparation of substituted enamine compounds

Info

Publication number: EP4136066A1
Application number: EP21717374.9A
Authority: EP
Inventors: Werner Bonrath; Le DAI; Xixiang DAI; Qiangqiang LIU; Marc-André Mueller; Kun Peng; Liuhai WU; Lei Zhang; Zili Zhang
Original assignee: DSM IP Assets BV
Current assignee: DSM IP Assets BV
Priority date: 2020-04-17
Filing date: 2021-04-01
Publication date: 2023-02-22
Also published as: CN115397807A; WO2021209269A1; CN118993936A; CN115397807B

Abstract

The present invention provides a substituted enamine compound of formula (I), and a process for producing oxazole compounds from the compound of formula (I). According to the processes of the present invention, it can produce substituted enamine compounds with high yield and selectivity while avoiding toxic or unsafe reagents for producing oxazole compounds. wherein R is H, lower alkyl or aryl, optionally substituted by one or more substituents.

Description

A process for preparation of substituted enamine compounds

Technical Field

The present invention is related to a new process for producing substituted enamine compounds.

Background of the Invention

Oxazole compounds represent a vast class of heterocyclic aromatic organic compounds. Oxazole compounds have become increasingly important because of biological activities and their use as intermediates for the preparation of new biological materials. The wide range of biological activities of oxazole compounds includes anti-inflammatory, analgesic, antibacterial, antifungal, hypoglycemic, antiproliferative, anti-tuberculosis, muscle relaxant and HIV inhibitor activity. In addition, oxazole derivatives are important intermediates for preparation of biological compounds such as vitamin B₆.

Various processes for the preparation of oxazole compounds have been developed. One preferred process in industry is from alanine and oxalic acid in EtOH carried out by azeotropic distillation with benzene. Following this concept, the ring closure reaction to obtain 5-ethoxy-4-methyloxazole can also be carried out using phosgene or triphosgene, which is toxic and not environment friendly (see CN 104725262 B, CN 102898321 A and CN 105985297 A)

In recent years, one attractive process is direct cyclodehydration of acyloxy enamines because acyloxy enamines have been introduced early N-atom and installed the carboxylic acids. It was reported that acyloxy enamines can be synthesized by intermolecular oxidative coupling of an enamine compound with carboxylic acid by using iodosobenzene as the oxidant. However, oxidant iodosobenzene is highly flammable and has explosion risk. In addition, oxidant iodosobenzene is not soluble in solvents and thus results in unstable yields of the process (see Xin Liu et al., Org. Lett., Vol. 14, No. 21, 2012).

Therefore, there is still demand of a new process for the preparation of substituted enamines, which can be converted to oxazole compounds, in industry.

Summary of the Invention The present invention provides a substituted enamine compound of formula (I), which can be converted to an oxazole compound, wherein R is H, lower alkyl or aryl, optionally substituted by one or more substituents.

The present invention also provides a process for producing the compound of formula (I) and a process for producing oxazole compounds from the compound of formula (I).

According to the processes of the present invention, it can produce substituted enamine compounds with high yield and selectivity, while avoiding toxic or unsafe reagents for producing oxazole compounds.

Detailed Description of the Invention

In the present invention, the term "lower alkyl" as used refers to Ci-Cio alkyl, i.e., branched or unbranched, cyclic or non-cyclic, saturated hydrocarbon comprising 1-10 carbon atoms. Preferably, the "lower alkyl" is Ci-C₆ alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert- butyl, cyclobutyl, pentyl, iso-pentyl, 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, the "lower alkyl" is methyl or ethyl.

In the present invention, the term "aryl" as used refers to aromatic hydrocarbon such as phenyl, benzyl, xylyl and naphthalenyl.

In the present invention, the term "lower alkoxyl" as used refers to the structure represented by (lower alkyl)-0-, wherein the lower alkyl is defined as above.

In the present invention, the term "carbonyl group" as used refers to the structure represented by -(C=0)-. In the present invention, the term "halo" or "halogen" as used refers to a group of elements including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), preferably refers to Cl or Br.

In the present invention, the term "substituents" as used refers to lower alkyl, lower alkoxyl, hydroxyl, halo, -NH₂, -N0₂, cyano or isocyano.

In the first aspect of the present invention, it provides a process for producing a compound of formula (I), comprising: a) reacting a compound of formula (II) with a compound of formula (III) to produce a compound of formula (la); and b) converting the compound of formula (la) into the compound of formula (I),

(la) (I) wherein

R is H, lower alkyl or aryl, optionally substituted by one or more substituents; and

R' is H; and any two of Ri, R₂ and R₃, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, lower alkyl, lower alkoxyl, aryl, or NR₄R₄' (wherein R₄ and R₄' are dependently H or lower alkyl), optionally substituted by one or more substituents; or R', Ri, R₂ and R₃, together with the carbon they connect, form carbon monoxide (Cº0).

Preferably, R is H or Ci-Ce alkyl, optionally substituted by one or more substituents. More preferably, R is H, methyl, ethyl, propyl or butyl, optionally substituted by one or more substituents. The most preferably, R is H or methyl.

Preferably, any two of Ri, R₂ and R₃, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, Ci-C₆ lower alkyl, Ci-C₆ lower alkoxyl, aryl, or NR₄R₄' (wherein R and R ' are dependently H or Ci-C₆ lower alkyl), optionally substituted by one or more substituents. More preferably, the rest one is hydroxyl, methyl, ethyl, propyl, butyl, methoxyl, ethoxyl, propoxyl, butoxyl, or NR₄R₄' (wherein R and R ' are dependently H, methyl, ethyl, propyl or butyl), optionally substituted by one or more substituents. The most preferably, the rest one is hydroxyl, methoxyl, ethoxyl, or NR₄R₄' (wherein R and R ' are dependently H, methyl or ethyl), optionally substituted by one or more substituents.

More preferably, R', Ri, R₂ and R₃, together with the carbon they connect, form carbon monoxide (Cº0).

In one embodiment,

R is H, methyl, ethyl or phenyl; and any two of Ri, R₂ and R₃, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methoxyl, ethoxyl, or NR₄R₄' (wherein R and R ' are dependently H, methyl or ethyl).

In another embodiment,

R is H, methyl, ethyl or phenyl; and

The compound of formula (III) is carbon monoxide.

In one preferable embodiment,

R is H or methyl; and any two of Ri, R₂ and R₃, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methoxyl, ethoxyl, -NH₂ or -NHCH₃.

In the present invention, the compound of formula (la) and (II) may be in a form of any salt of formula (la') and (IG) respectively:

(la ) (II·) wherein R is defined as above, and X and Y are dependently a metal element such as alkali metal elements (lithium (Li), sodium (Na), postassium (K), rubidium (Rb), caesium (Cs) and francium (Fr)); or alkaline-earth metal elements (beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba) and radium (Ra)); and Iron (ll/lll), nickel and cobalt. Preferably, X is Na or K.

In the step a) of the process of the present invention, the compound of formula (III) may be added in an amount of from 0.01 moles to 20 moles, preferably from 0.05 moles to 15 moles, more preferably from 0.1 mole to 10 moles, per 1 mole of the compound of formula (II).

The step a) of the process of the present invention may be carried out in the presence of a solvent. The solvent preferably is a polar organic solvent such as toluene, tetrahydrofuran (THF), methyl tert-butyl ether (TBME), alcohol (i.e., ethanol) and benzene, or mixture thereof.

The reaction of the step a) of the present invention may be carried out at the temperature from -30°C to 110°C, preferably from -20°C to 100°C, more preferably from -10°C to 50°C such as -10, -5, 0, 10, 15, 20, 25, 30, 35, 40, 45 and 50°C. After the reaction finishes, the obtained compound of formula (la) may be used to the next step b) directly or purified by known process such as crystallization and/or filtration.

In the step b) of the process of the present application, the compound of formula (la) may be converted into the compound of formula (I) by any suitable way, for example, by adding water, an acid, an acidic salt or an alcohol. The Examples of the acid include but are not limited to organic acid such as formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, tartaric acid, fumaric acid and maleic acid; inorganic acid such as hydrochloric acid, sulfonic acid, phosphoric acid, nitric acid, nitrous acid, chloric acid, hypochlorous acid, perchloric acid, sulfonic acid, hydrobromic acid and hydrofluoric acid; and acidic resin such as sulfonic acid resin. The examples of the acidic salt include but are not limited to ammonium chloride, monopotassium phosphate, monosodium phosphate, sodium hydrogen sulfate and potassium hydrogen sulfate. The examples of the alcohol include but are not limited to methanol, ethanol and phenol.

In one embodiment, the compound of formula (la) is converted into the desired compound of formula (I) by adding an acid as defined above. The acid may be added in an amount of from 0.1 mol to 10 mol, preferably from 0.5 mol to 8 mol, more preferably from 1 mol to 5 mol such as 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 and 10 mol, per 1 mol of the compound of formula (la). In an alternative embodiment, the compound of formula (la) is converted into the desired compound of formula (I) by adding water. The water may be added in an amount of from 10 mL to 1000 mL, preferably from 18 mL to 500 mL, more preferably from 20 mL to 100 mL, per 1 mol of the compound of formula (la).

In the step b) of the process of the present application, a solvent may be used when necessary. Example of the suitable solvent include but are not limited to ethyl acetate, ethyl butyrate, butyl acetate, tetrahydrofuran, toluene, 1,4-dioxane, 2,5-dimethyltetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diethyl ether, acetonitrile, methyl tert-butyl ether, and mixture thereof.

The step b) of the process of the present invention may be carried out at the temperature from 0°C to 50°C, preferably from 10°C to 40°C, such as 10, 15, 20, 25, 30, 35 and 40°C. After the reaction finishes, the obtained compound of formula (I) may be directly used for industrial application, or purified by known process such as extraction, crystallization and/or filtration.

In the process of the present application, the reaction mixture of the step a) containing the compound of formula (la) is preferably used to the step b) directly without isolation and purification. In such case, the process of the present application may be carried out in one pot.

Accordingly, the present invention also provides a one-pot process for the preparation of the compound of formula (I), which comprises adding the compound of formula (II) as defined above, the compound of formula (III) as defined above, optionally the solvent as defined above, and water or an acid or an acidic salt or an alcohol as defined above into one pot for reaction to obtain the compound of formula (I).

The compound of formula (II) may be prepared by any process known in the art in-situ or ex-situ, for example, by treating the compound of formula (lla) with a strong base such as sodium (Na), Sodium hydride (NaH) or sodium amide.

Wherein Ri is as defined above.

Alternatively, the compounnd of formula (II) may be produced from nitriles as disclosed in US 5187297 A. The processes of the present invention avoid toxic and unsafe reagents while providing high yield and high selectivity. In addition, the obtained products of the processes of the present invention can be used for producing oxazole compounds directly without any purification.

In the second aspect of the present invention, it provides a process for producing an oxazole compound comprising the step for producing the compound of formula (la) and/or the compound of formula (I) as described above. The process of the present invention avoids toxic phosphate reagents and saves steps compared to the processes known in the art and thus provides a new process.

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

Examples

Example 1

1 2

A dried four necked round bottom flask was charged with liquid ammonia (15 mL, 0.615 mol, 11 eq). After the flask was flushed with argon, sodium (1.5 g, 65 mmol, 1.1 eq) was added and stirred for 30 mins at - 40°C to -50°C. At the same temperature compound 1 (4.85 g, 59 mmol, 1 eq) in THF (20 mL) was added dropwise in 15 mins. Then the reaction mixture was warmed to room temperature in 1 hour and stirred for additional 1 hour to obtain a white suspension of the compound 2.

¹H NMR of f/Z-isomers of compound 2 (400 MHz, DMSO) d (ppm): 1.74 (3H) (46.7%), 1.53 (3H) (53.3%).

Example 2

2 A dried four necked round bottom flask was charged with liquid ammonia (50 mL, 2.05 mol, 16 eq). After the flask was flushed with argon, iron nitrate nonahydrate (35 mg, 0.087 mmol, 0.00067 eq) was added. Then sodium (2.96 g, 129 mmol, 1.0 eq) was added and stirred for 30 mins at -40°C to -50°C. At the same temperature anhydrous acetonitrile (11.65 g, 283 mmol, 2.2 eq) was added dropwise in 15 mins and anhydrous toluene (40 mL) was added immediately. The reaction mixture was warmed to room temperature in 1 hour and stirred for additional 1 hour to obtain a grey suspension.

This suspension was filtrated over a paper filter (7 cm diameter) and washed with TBME (200 mL) to obtain filter cake containing the compound 2 (19.40 g, 67.1wt% purity, 97% yield).

Example 3

Ethyl formate (10.71 g, 142 mmol, 1.1 eq) dissolved in anhydrous toluene (20 mL) was added dropwise to the grey suspension (13.43 g, 129 mmol, 1.0 eq) obtained according to the same procedures of Example 2 in 20 mins. The reaction mixture was stirred overnight to obtain a grey and thick suspension. TBME (100 mL) was added and the mixture was filtrated over a paper filter (7 cm diameter) to obtain a filter cake containing compound 3 (49.68 g, 31.6wt% purity, 92% yield).

NMR of E -isomer of compound 3 (400 MHz, DMSO) d (ppm): 8.81 (1H), 3.73 (1H), 1.82 (1H).

NMR of Z-isomer of compound 3 (400 MHz, DMSO) d (ppm): 8.58 (1H), 4.21 (1H), 1.93 (3H).

Example 4

Ethyl formate (4.82 g, 65 mmol, 0.5 eq) dissolved in THF (10 mL) was added dropwise to the grey suspension (13.43 g, 129 mmol, 1.0 eq) according to the same procedures of Example 2 except that toluene was replaced with THF in 20 mins. The reaction mixture was stirred overnight to obtain a grey and thick suspension. TBME (100 mL) was added and the mixture was filtrated over a paper filter (7 cm diameter) to obtain a filter cake containing compound 3 (7.40 g, 82% yield).

Example 5

Methyl formate (9.28 g, 155 mmol, 1.2 eq) dissolved in TBME (20 mL) was added dropwise to the grey suspension (13.43 g, 129 mmol, 1.0 eq) obtained according to the same procedures of Example 2 except that toluene was replaced with TBME in 30 min. The reaction mixture was stirred over night to obtain a white and thick suspension. TBME (100 mL) was added. Then, the mixture was filtrated over a paper filter (7 cm diameter) to obtain a filter cake containing compound 3 (15.19 g, 89% yield).

Example 6

2 3

Dimethyl formamide (6.95 g, 95 mmol, 3 eq) dissolved in toluene (5 mL) was added dropwise to the grey suspension (3.3 g, 31.7 mmol, 1.0 eq) obtained according to the same procedures of Example 2 in 10 min. The reaction mixture was stirred for 3 days at 40°Cto obtain a white suspension. TBME (50 mL) was added. Then, the mixture was filtrated over a paper filter (4 cm diameter) to obtain a filter cake containing compound 3 (1.98 g, 47% yield).

Example 7

2 3 Carbon monoxide (50 bar overpressure) was added to ethanol (10 mL) and the filter cake (347 mg, 3.33 mmol, 1.0 eq) obtained according to the same procedures of Example 2. The reaction mixture was shaked over 19 h at 70°C to obtain a yellow suspension. TBME (20 mL) was added. Then, the mixture was filtrated over a paper filter (2 cm diameter) to obtain a filter cake containing compound 3 (248 mg, 56% yield).

Example 8

3 4

The filter cake obtained according to Example 3 was loaded in a four necked round bottom flask under argon atmosphere. Butyl acetate (100 mL) was added and acetic acid (7.75 g, 129 mmol, 1.0 eq) was added dropwise in 5 mins. The reaction mixture was stirred for 30 mins at room temperature and then filtered over a paper filter (7 cm diameter). The filtrate was dried at 45°C (2 mbar) to produce a colorless oil which crystallized slowly to obtain the compound 4 (13.22 g, 98.8wt% purity, 92% yield).

NMR of Z-isomer of compound 4 (400 MHz, DMSO) d (ppm): 10.20 (1H), 8.43 (1H), 4.90 (1H), 2.15 (3H). H NMR of f-isomer of compound 4 (400 MHz, DMSO) d (ppm): 10.40 (1H), 8.81 - 8.14 (1H), 6.37 - 4.78 (1H), 2.39 -1.97 (3H).

Example 9

3 4

The filter cake obtained according to Example 3 was loaded in a four necked round bottom flask under argon atmosphere. Butyl acetate (50 mL) was added and H₂0 (20 mL) was added dropwise in 5 mins. The reaction mixture was stirred for 10 mins at room temperature and then extracted with butyl acetate (50 mL x 3). The organic phase was dried at 45°C (2 mbar) to produce a colorless oil which crystallized slowly to obtain the compound 4 (7.0 g, 53% yield based on acetonitrile).

Example 10

1 4

A dried round bottom flask was charged with THF (250 mL). After the flask was flushed with argon, NaH (40 g, 1000 mmol, 2 eq) was added. Then the mixture of compound 1 (41.1 g, 500 mmol, 1 eq) and ethyl formate (71.4 g, 1000 mmol, 2 eq) in THF (250 mL) was added dropwise in 30 min and stirred at room temperature for 5 hours. Acetic acid (60.1 g, 1000 mmol, 2 eq) was added dropwise in 5 mins. The reaction mixture was stirred for 30 mins at room temperature and then filtered over a paper filter (7 cm diameter). The filtrate was dried at 45°C (2 mbar) to produce a colorless oil which crystallized slowly to obtain the compound 4 (45.2 g, 82% yield).

Example 11

4 5

To a solution of the compound 4 (220 mg, 2.0 mmol) in dried 1,2-dichloroethane (20 mL) was added BF₃-Et₂0 (4.0 mmol, 2.0 eq). The reaction mixture was heated to reflux, and then phenyliodine(lll) diacetate (838 mg, 2.6 mmol, 1.3 eq) was added in one portion rapidly. After stirring under refluxing condition for 0.5-3 hours, the reaction mixture was cooled down to room temperature, quenched with saturated aqueous NaHC0₃, and then extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous l\la₂SC>₄ and concentrated by the rotary evaporator. The crude product was purified by flash column chromatography to give the compound 5 (140 mg, 65% yield).

Claims

1. A process for producing a compound of formula (I), comprising: a) reacting a compound of formula (II) with a compound of formula (III) to produce a compound of formula (la); and b) converting the compound of formula (la) into the compound of formula (I), wherein

R' is H; and any two of Ri, R₂ and R₃, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, lower alkyl, lower alkoxyl, aryl, or NR R ' (wherein R and R ' are dependently H or lower alkyl), optionally substituted by one or more substituents; or R', Ri, R₂ and R₃, together with the carbon they connect, form carbon monoxide (Cº0).

2. The process of claim 1, wherein R is H, methyl, ethyl, propyl or butyl, optionally substituted by one or more substituents.

3. The process of claim 1, wherein any two of Ri, R₂ and R₃, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methyl, ethyl, propyl, butyl, methoxyl, ethoxyl, propoxyl, butoxyl, or NR R ' (wherein R and R ' are dependently H, methyl, ethyl, propyl or butyl), optionally substituted by one or more substituents.

4. The process of claim 1, wherein R', Ri, R₂ and R₃, together with the carbon they connect, form carbon monoxide (Cº0).

5. The process of claim 1, wherein R is H, methyl, ethyl or phenyl; and any two of Ri, R₂ and R₃, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methoxyl, ethoxyl, or NR4R4' (wherein R and R ' are dependently H, methyl or ethyl).

6. The process of claim 1, wherein R is H, methyl, ethyl or phenyl; and the compound of formula (III) is carbon monoxide.

7. The process of claim 1, wherein R is H or methyl; and any two of Ri, R₂ and R₃, together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methoxyl, ethoxyl, -NH₂ or -NHCH₃.

8. The process of claim 1, wherein the compound of formula (la) and (II) are in a form of any salt of formula (la') and (IG) respectively:

(la ) (II·) wherein R is defined as any one of claims 1-7, and X and Y are dependently a metal element such as alkali metal elements (lithium (Li), sodium (Na), postassium (K), rubidium (Rb), caesium (Cs) and francium (Fr)); or alkaline-earth metal elements (beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba) and radium (Ra)); and Iron (ll/lll), nickel and cobalt.

9. The process of any one of claims 1-8, wherein the step a) of the process is carried out in the presence of a solvent.

10. The process of claim 9, wherein the solvent is a polar organic solvent such as toluene, tetrahydrofuran (THF), methyl tert-butyl ether (TBME), alcohol (i.e., ethanol) and benzene, or mixture thereof.

11. The process of any one of claims 1-8, wherein in the step b) the compound of formula (la) is converted into the compound of formula (I) by adding water, an acid, an acidic salt or an alcohol.

12. The process of any one of claims 1-8, wherein in the step b) the compound of formula (la) is converted into the compound of formula (I) by adding an acid selected from the group consisting of organic acid such as formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, tartaric acid, fumaric acid and maleic acid; inorganic acid such as hydrochloric acid, sulfonic acid, phosphoric acid, nitric acid, nitrous acid, chloric acid, hypochlorous acid, perchloric acid, sulfonic acid, hydrobromic acid and hydrofluoric acid; and acidic resin such as sulfonic acid resin.

13. The process of any one of claims 1-8, wherein in the step b) a solvent is used.

14. The process of claim 13, wherein the solvent is selected from the group consisting of ethyl acetate, ethyl butyrate, butyl acetate, tetrahydrofuran, toluene, 1,4-dioxane, 2,5-dimethyltetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diethyl ether, acetonitrile, methyl tert-butyl ether, and mixture thereof.

15. The process of any one of claims 1-8, wherein the process is carried out in one pot.

16. The process of any one of claims 1-8, wherein the compound of formula (II) is prepared in-situ.

17. A process for producing an oxazole compound comprising the step for producing the compound of formula (la) and/or the compound of formula (I) according to any one of claims 1-16.

18. A compound of formula (I) or a salt thereof, wherein R is H, lower alkyl or aryl, optionally substituted by one or more substituents.

19. The compound of claim 18, wherein R is H, methyl, ethyl, propyl or butyl, optionally substituted by one or more substituents.

20. The compound of claim 18 or 19, wherein the salt is a compound of formula (la') wherein R is defined as claims 18 or 19, and X is a metal element such as alkali metal elements (lithium (Li), sodium (Na), postassium (K), rubidium (Rb), caesium (Cs) and francium (Fr)); or alkaline-earth metal elements (beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba) and radium (Ra)); and Iron (ll/lll), nickel and cobalt.