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 B ₆ .

Various processes for the preparation of oxazole compounds have been developed. One preferred process in industry is from alanine and oxalic acid in ethanol 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, the oxidant iodosobenzene is highly flammable and has explosion risk. In addition, 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-C ₆ 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 "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" or "substituent" as used refers to lower alkyl, lower alkoxyl, hydroxyl, halo, -NH ₂ , -N0 ₂ , cyano or isocyano.

In the present invention, a compound represented by a formula or a name also cover stereoisomers thereof, including diastereomers and enantiomers, such as cis/trans-isomers or E/Z-isomers.

In the first aspect of the present invention, it provides a process for producing a compound of formula (I), comprising reacting a compound of formula (II) with a compound of formula (III) to produce the compound of formula (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, R ₂ and R ₃ , together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, lower alkyl, lower alkoxyl, aryl, or NR ₄ R ₄ ' (wherein R and R ' are dependently H or lower alkyl), optionally substituted by one or more substituents; or R', Ri, R ₂ and R ₃ , together with the carbon they connect, form carbon monoxide (Cº0).

Preferably, R is H or Ci-C ₆ 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, R ₂ and R ₃ , together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, Ci-C ₆ lower alkyl, Ci-C ₆ lower alkoxyl, aryl, or NR ₄ R ₄ ' (wherein R and R ' are dependently H or Ci-C ₆ 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 NR ₄ R ₄ ' (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 NR ₄ R ₄ ' (wherein R and R ' are dependently H, methyl or ethyl), optionally substituted by one or more substituents. More preferably, R', Ri, R ₂ and R ₃ , together with the carbon they connect, form carbon monoxide (C=0).

In one embodiment,

R is H, methyl, ethyl or phenyl; and any two of Ri, R ₂ and R ₃ , together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methoxyl, ethoxyl, or NR R ' (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, R ₂ and R ₃ , together with the carbon they connect, form a carbonyl group, and the rest one is hydroxyl, methoxyl, ethoxyl, -NH ₂ or -NHCH ₃ .

In the present invention, the compound of formula (I) and (II) may be in a form of any salt of formula (G) and (IG) respectively: wherein R is defined as above, and X and Y are dependently a metal element such as alkali metal elements (lithium (Li), sodium (Na), potassium (K), and cesium (Cs)), or alkaline-earth metal elements (beryllium (Be), magnesium (Mg), calcium (Ca), and barium (Ba)), or Iron (ll/lll); or ammonium (NH ) or substituted ammonium. Preferably, X and Y are dependently Na or K.

In the process of the present invention, the compound of formula (III) may be added in an amount of from 0.01 mols to 20 moles, preferably from 0.05 moles to 15 moles, more preferably from 0.1 mole to 10 moles such as 0.2, 0.5, 0.8, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 and 10 moles, per 1 mole of the compound of formula (II).

The process of the present invention may be carried out in the presence of a solvent. The solvent may be an inorganic solvent such as liquid ammonia, or an organic solvent including but not limited to alkane such as pentane, hexane, heptane, cyclopentane and cyclohexane, aromatic hydrocarbon such as benzene and toluene, ester such as methyl formate and ethyl formate, alcohol such as ethanol, ether such as methyl tert-butyl ether (TBME) and cyclopentyl methyl ether, tertiary amine such as N,N-diethylaniline, triethylamine and tributylamine, amide such as dimethylformamide (DMF), diethylformamide (DEF) and dibutylformamide (DBF), acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), or mixture thereof.

More preferably, the solvent is liquid ammonia, toluene, THF, heptane, acetonitrile, methyl formate, N,N- diethylaniline, triethylamine, TBME, cyclopentyl methyl ether, toluene, ethanol, or mixture thereof. The most preferably, the solvent is liquid ammonia, toluene, heptane, acetonitrile, methyl formate, TBME, or mixture thereof.

In one embodiment, the compound of formula (III) is methyl formate, and the solvent is selected from the group consisting of liquid ammonia, heptane, acetonitrile, methyl formate, N,N-diethylaniline, triethylamine, TBME, cyclopentyl methyl ether and toluene, and mixture thereof.

In another embodiment, the compound of formula (III) is ethyl formate, and the solvent is selected from the group consisting of liquid ammonia, toluene, THF and heptane, and mixture thereof.

In the process of the present invention, the solvent may be added in an amount of from 0.05 mL to 10 mL, preferably from 0.1 mL to 9 mL, more preferably from 0.15 mL to 5 mL such as 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 2, 3, 4 and 5 mL, per 1 mmol of the compound of formula (II).

The reaction of the present invention may be carried out at the temperature from -50°C to 110°C, preferably from -40°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, under a pressure at 1-20 bar, preferably 2-15 bar, more preferably 3-10 bar such as 3, 4, 5, 6, 7, 8, 9 and 10 bar. 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.

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 (I la) with a strong base such as sodium methoxide, sodium ethoxide, sodium hydride (NaH) and sodium amide.

Wherein Ri is as defined above.

Alternatively, the compound of formula (II) maybe produced from nitriles such as acetonitrile as disclosed in US 5187297 A.

The inventor of the present invention surprisingly discovered that the compound of formula (I) according to the present invention is new. Accordingly, in the second aspect of the present invention, it provides a compound of formula (I),

Wherein R is defined as above.

As described above, the compound of formula (I) according to the present invention can be used for producing oxazole compounds. As a result, the whole process for producing oxazole compounds avoid toxic and unsafe reagents while providing high yield and high selectivity.

In the third aspect of the present invention, it provides a process for producing an oxazole compound comprising the step of producing the compound of formula (I) as defined 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.

¹ H 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

2

A dried four necked round bottom flask was charged with liquid ammonia (50 mL, 2.05 mol, 18.4 eq). After the flask was flushed with argon, iron nitrate nonahydrate (32 mg, 0.078 mmol, 0.0007 eq) was added. Then, potassium (4.36 g, 112 mmol, 1.0 eq) was added at -50°C and stirred for 30 mins at -40°C to -50°C. At the same temperature anhydrous acetonitrile (10.07 g, 245 mmol, 2.2 eq) was added dropwise in 15 mins and anhydrous acetonitrile (35 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 (12.56 g, 93% yield).

Example 4

A dried four necked round bottom flask was charged with liquid ammonia (50 mL, 2.05 mol, 16 eq) and anhydrous heptane (5 mL, 34.1 mmol, 0.26 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 heptane (35 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.

Heptane (30 mL) was added to the grey suspension, and then ethyl formate (11.69 g, 154.8 mmol, 1.2 eq) dissolved in anhydrous heptane (20 mL) was added dropwise to the grey suspension during 20 mins. The reaction mixture was stirred for 2 hours to obtain a grey and thick suspension. N-butyl acetate (100 mL) was added and the mixture was filtrated over a paper filter (7 cm diameter) to obtain a filter cake containing compound 3 (19.30 g, 83 w/w% purity, 93% yield). ^J H 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 5

2 3

A dried autoclave was charged at -40°C to -50°C with liquid ammonia (887 mL, 36 mol, 46 eq) and iron nitrate nonahydrate (210 mg, 0.97 mmol, 0.001 eq). Then sodium (18.0 g, 783 mmol, 1.0 eq) was added, and the reaction mixture stirred for 30 min at -40°C to -50°C until complete cessation of hydrogen evolution. The reaction mixture was heated to 20°C over a period of 45 min, whereas a pressure of 8 bar formed. At the same temperature anhydrous acetonitrile (64.2 g, 1,564 mmol, 2.0 eq) was pumped over a period of 15 min, and the reaction mixture was stirred for 150 min. Ethyl formate (71.7 g, 949 mmol, 1.2 eq) was pumped over a period of 60 min and the reaction mixture was stirred for 8 h. All volatiles were evaporated to obtain compound 3 (76.8 g, 582 mmol, 74% yield).

Example 6

Ethyl formate (2.14 g, 29 mmol, 1.2 eq) was added dropwise to compound 2 (2.50 g, 24 mmol, 1.0 eq) obtained according to the same procedures of Example 2 in 20 min. The reaction mixture was stirred for 1.5 hours to obtain a grey slurry. TBME (30 mL) was added. Then, the mixture was filtrated over a paper filter to obtain a filter cake containing compound 3 (2.60 g, 82% yield).

Example 7

Ethyl formate (2.14 g, 29 mmol, 1.2 eq) was added dropwise to the grey suspension obtained according to the same procedures of Example 2 (2.50 g, 24 mmol, 1.0 eq) in 20 min. The reaction mixture was stirred for 1.5 hours to obtain a grey and thick suspension. TBME (30 mL) was added. Then, the mixture was filtrated over a paper filter (4.5 cm diameter) to obtain a filter cake containing compound 3 (2.65 g, 83% yield).

Example 8

2

3

Ethyl formate (10.49 g, 142 mmol, 1.1 eq) dissolved in acetonitrile (20 mL) was added dropwise to the grey suspension obtained according to the same procedures of Example 2 (13.43 g, 129 mmol, 1.0 eq) 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 (15.84 g, 93% yield).

Example 9

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).

Example 10

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) obtained 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 11

2 3

Methyl formate (9.28 g, 155 mmol, 1.2 eq) dissolved in heptane (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 heptane 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 (15.46 g, 91% yield).

Example 12

2

3 Methyl formate (8.51 g, 142 mmol, 1.1 eq) dissolved in acetonitrile (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 acetonitrile in 15 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 (15.98 g, 94% yield).

Example 13

2

3

Methyl formate (8.51 g, 142 mmol, 1.1 eq) dissolved in N,N-diethylaniline (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 N,N-diethylaniline in 20 min and stirred for 10 min. Afterwards, additional methyl formate (47.0 g, 183 mmol, 6.1 eq) was added. The reaction mixture was stirred over night to obtain a grey 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 (11.44 g, 67.2% yield).

Example 14

2 3

Methyl formate (8.51 g, 142 mmol, 1.1 eq) dissolved in triethylamine (20 mL) was added dropwise to the grey suspension (13.43g, 129 mmol, 1.0 eq) obtained according to the same procedures as Example 2 except that toluene was replaced with triethylamine in 20 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 (13.97 g, 82% yield).

Example 15

Methyl formate (9.28 g, 155 mmol, 1.2 eq) dissolved in TBME (20 mL) was added dropwise to the grey suspension (13.43g, 129 mmol, 1.0 eq) obtained according to the same procedures as Example 2 except that toluene was replaced with TBME (13.43g, 129 mmol, 1.0 eq) 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 16

©

© Na cyclopentyl methyl ether

2 3

Methyl formate (9.28 g, 155 mmol, 1.2 eq) dissolved in cyclopentyl methyl ether (20 mL) was added dropwise to the grey suspension (13.43g, 129 mmol, 1.0 eq) obtained according to the same procedures as Example 2 except that toluene was replaced with cyclopentyl methyl ether 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 (13.47 g, 79% yield).

Example 17

Dimethyl formamide (6.95 g, 95 mmol, 3 eq) dissolved in toluene (5 mL) was added dropwise to the grey suspension obtained according to the same procedures of Example 2 (3.3g, 31.7 mmol, 1.0 eq) 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 18

Carbon monoxide (50 bar overpressure) was added to ethanol (10 mL) and the filter cake obtained according to the same procedures of Example 2 (347 mg, 3.33 mmol, 1.0 eq). 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 19

The filter cake obtained according to the same procedures of Example 9 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).

To a solution of the compound 4 (220 mg, 2.0 mmol) in dried 1,2-dichloroethane (20 mL) was added BF ₃ -Et ₂ 0 (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 NaHC0 ₃ , and then extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 and concentrated by the rotary evaporator. The crude product was purified by flash column chromatography to give the compound 5 (140 mg, 65% yield).