* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1999, vol. 38, # 8, p. 986 - 988
[2] Organic Letters, 2006, vol. 8, # 18, p. 4125 - 4128
[3] Patent: US2009/143346, 2009, A1, . Location in patent: Page/Page column 8
[4] Patent: WO2005/118549, 2005, A2, . Location in patent: Page/Page column 23
2
[ 77287-34-4 ]
[ 20485-39-6 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: at 120℃; Stage #2: for 6.5 h;
Example 7: Preparation of 4-methyloxazole-5-formic acid ethyl ester (OXE) A 500 mL-stirred reaction vessel with a 30 mm χ 30 cm Kerapak column was charged with 1 50.2 g formamide (98percent, 3.267 mole, 1 .60 eq. ) and 1 3.4 g sulphuric acid (98percent, 0.1 35 mole, 0.07 eq. ). The mixture was heated at p = 65 mbar to an inner temperature = 120° C. Then 400.2 g FOXE crude (88.6percent, 2.036 mole, 1 .00 eq. ) was added within 5 h.. A HCOOH/water mixture was distilled from the reaction mixture during the FOXE dosage time. After the end of the FOXE dosage HCOOH/water was further distilled of to complete the reaction. This was the case after additional 1 .5 h of reaction and distillation after the end of the FOXE addition. During the complete reaction an overall amount of 100.8 g HCOOH/water mixture (HCOOH 56.7percent, water 37.7percent) was distilled off. In the sump, 407.0 g OXE crude with precipitated ammonium sulphate was obtained. 400.5 g OXE crude with precipitated ammonium sulphate were filtered through a filter nutsch to get 6.0 g filter cake and 391 .5 g OXE crude (OXE 68.7percent) as the filtrate. Yield in filtrate: 86.5percent Washing of the reaction equipment with ethanol affords additional 5.4percent yield. Overall yield: 91 .9 percent Washing of the filter cake was done twice with 1 1 .0 g FOXE crude for each washing. After the washing 4.8 g filter cake which was free of OXE and 24.2 g filtrate (FOXE 76.9percent, OXE 2.0 percent) were obtained. The filtrate can be recycled. OXE yield saving: 0.6percent Overall OXE yield from FOXE: 92.5percent Overall OXE yield from EACA: 80.1percent The FOXE remaining in the filter cake was washed from 4.4 g filter cake with 18.5 g toluene. After the washing, 3.9 g filter cake were obtained, which was free of FOXE. The 18.8 g filtrate (FOXE 8.6percent) can be recycled. Example 8: Rectification to purified OXE To a thin film evaporator with a 50 cm χ 30 mm Kerapak column at a temperature of 1 10°C and at p = 5 mbar, 380.5 OXE crude was fed continuously. At the head of the column which is run at a reflux ratio of 0.2, 246.1 g OXE (OXE 89.8percent) was obtained as the distillate and as a sump 67.4 g high boiling impurities (OXE 0.6percent) was obtained. Also 37.4 g hold-up was collected after the experiment. Loss of OXE in the sump: 0.2 percent Overall yield of OXE purified from EACA: 80.0percent
EXAMPLE 1 Preparation of Ethyl 4-Methyl-5-Oxazolecarboxylate This compound was prepared according to the procedure described in French Pat. No. 1,543,853. A mixture of 50.0 g (0.337 moles) of ethyl chloroacetoacetate and 42.0 g (0.933 moles) of formamide was stirred at 120°-135° for 18 hr. Thereafter, the mixture was cooled using an ice bath to 10° C. 300 ml of 1 N K2 CO3 was added dropwise with gas evolution noted. After complete addition of K2 CO3 solution, the reaction mixture was stirred with 200 ml of benzene/ether (2:1) and saturated with NaCl. The insoluble material was filtered and the benzene/ether layer was separated and washed with water, dried (MgSO4) and concentrated under reduced pressure. The brown residue was distilled on a Kugelrohr to give 14.8 g of white solid, mp 31°-33° C.; yield 31percent; nmr (CDCl3) 8.0 (s,1H,C2 H), 44 (q, J=7 Hz, 2H,CH2), 2.5 (s,3H,CH3), 1.4 (t,3H,CH3).
With ammonium hydroxide; In water; at 20℃; for 10h;Autoclave;
In a 250 ml steel autoclave, 38.8 g OXE (0.25 mol) and 96.4 g ammonia solution (3.12 mol, 55% in water) were added and stirred for 10 h at 20C. The product OXA precipitated during the reaction. The suspension was cooled down to -16C and stirred for 7 h to obtain 31.3 g of off white to slightly yellow crystals with a purity of 98.3% (±1) (GC), yield 97.6% (±1.5).
97.5%Chromat.
With ammonia;ammonium chloride; at 30℃; under 6000.6 Torr; for 20h;Product distribution / selectivity;
9Examples 6 and 7: Preparation of 2 catalyzed with ammonium chloride. Influence of the excess of ammoniaExample 1 was repeated but the amount of ammonia was varied. The results are summarized in Table 3. For better comparison the results of Example 1 are incorporated in the table. Example 1 : Preparation of MOXA (2) catalyzed with ammonium chloride 59.5 g (3500 mMol) of liquid ammonia were added within 20 minutes under stirring (300 rpm) to a mixture of 44.2 g (250 mMol) of <strong>[20485-39-6]ethyl 4-methyloxazole-5-carboxylate</strong>, MOXE (1 ), and 0.67g (12.5 mMol) of ammonium chloride. The internal temperature was maintained between 10 C and 15 C during the addition of the reactant. The reaction mixture was heated to 30 C under 8 bara for about 20 hours, cooled down to 20 C, and the ammonia was evaporated under normal pressure within 2 hours. The reactor was purged three times with nitrogen. The crystals were filtered, washed with 20 ml of 2-propanol, and dried at 40 C, 20 mbar. The mother liquor was evaporated under reduced pressure (15 mbar, 40 C) and the residue was dried at 40 C, 20 mbar.Crude 2 was obtained with a purity of 99.4 % (1 H NMR) and a yield of 96.5 % based on 1.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃;
Experiment 21 g; Dess-Martin oxidation of the alcohol 5 afforded the desired aldehyde 6, contaminated by the starting material 4b'. 2 g of the crude aldehyde 5b was obtained and used directly for the core formation.
58%
With sodium tetrahydroborate; In ethanol; at 0 - 20℃; for 2h;Reflux;
Example A.9 Preparation of intermediate (12) The suitable ethyl oxazole-5-carboxylate derivative (1.1 g, 7.09 mmol, 1 eq) wasdissolved in EtOH (14 mL) and the mixture was cooled to 0C. NaBH4 (14.17 mmol, 2eq) was added portionwise while stirring, and then the mixture was allowed to warm to r.t.. After 2 hrs at reflux, the conversion was complete by TLC (95/5 DCM/MeOH). The mixture was cooled to 0C and 2N HC1 was added dropwise till gas evolution ceased (pH 5-6). The obtained suspension was concentrated at reduced pressure, and the residue waspurified by flash chromatography (Si02) using as eluent a mixture DCM/MeOH = 95/5. The pure intermediate (12) was obtained as colourless oil ( 0.46 g, yield 58%).
(Step 2) Production of 5-hydroxymethyl-4-methyl-oxazole To a suspension of lithium aluminum hydride (23 g) in tetrahydrofuran (700 mL), a solution of ethyl 4-methyl-oxazole-5-carboxylate (101.87 g) in tetrahydrofuran (100 mL) was added dropwise at -50 to -60 C. After stirring for 10 minutes, water (23 mL), 15% sodium hydroxide aqueous solution (23 mL), and water (69 mL) were successively added to the reaction mixture. After stirring at room temperature for 40 minutes, the organic layer was separated, dried over anhydrous sodium sulfate, and then concentrated to obtain the title compound (54.487 g) as a yellow solid.
With sodium tetrahydroborate; In methanol; at 20℃; for 1h;Inert atmosphere;
Ethyl 4 -methyloxazole-5-carboxylate (24.6 mmol) was dissolved in MeOH (30 mL) and sodium borohydride (73.4 mmol) was added portionwise. Addition gave gas evolution and warmed up the reaction mixture, no cooling or nitrogen was used. After stirring at room temperature for 1 hour, gas evolution had ceased and a second portion of sodium borohydride was added (13.2 mmol} and the reaction mixture was stirred for an additional 30 minutes. The solvent was then carefully removed by rotary evaporation. The residue was dissolved in water and DCM (20 mL each) and the layers separated. The aqueous phase was neutralized with 3 M aqueous HC1 and extracted with DCM (3 x 20 mL) . The combined organic layers were dried with sodium sulfate, filtered and concentrated. The product was purified by ISCO (EtOAc/heptanes gradient) to give the product as a colorless oil. NMR (300 MHz , CDC13) : delta 1.77 (t, 1H) , 2.21 (s, 3H) , 4.64 (s, 2H) , 7.77 (s, 1H) ppm.
(Step 1) Production of ethyl 4-methyl-oxazole-5-carboxylate To 2-chloroethyl acetoacetate (132.545 g) was added formamide (90 mL), and the mixture was stirred overnight at 120 C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was distilled under reduced pressure (bp 66 to 69 C. (100 to 150 Pa)) to obtain the title compound (68.976 g) as colorless crystals.
4-Methyl-oxazole-5-carboxylic acid A solution of 40.0 grams (0.243 mol, 1.0 eq) of 2-Chloro-3-oxo-butyric acid ethyl ester in 240 mL formic acid (99%) was stirred at room temperature in a 500 mL round bottom flask equipped with a H2O condenser. To this solution was added 80.0 grams (1.27 mmol, 5.2 eq) of ammonium formate. The solution was then heated to reflux for five hours. After cooling to room temperature, the solution was diluted with water (1 L) and neutralized with Na2CO3. The aqueous solution was then extracted three times with Et2O and the combined organic fractions were dried over MgSO4. After concentration, vacuum distillation (10 mmHg, b.p. 53 C.-61 C.) gave a mixture of starting material and 4-Methyl-oxazole-5-carboxylic acid ethyl ester as a colorless oil (21.7 grams). This mixture was dissolved in 100 mL of aqueous sodium hydroxide (2 N) and refluxed for 1 minute. The reaction was then poured onto ice and acidified with concentrated HCl and the known (Sen & Sengupta (1985) Ind. J. Chem. Section B: Org. Chem. Including Med. Chem. 24B(5):535-8) free acid precipitated as a white solid (6.04 grams, 20% overall yield) Mp: 241.4-242.6 C.
Preparation 2: 3-[(3-Chloropropyl)thio]-4-methyl-5-(4-methyl-1 ,3-oxazol-5-yl)-4H- 1.2.4-triazole; Ethyl 4-methyl-1,3-oxazole-5-carboxylate (7.0 g) was stirred at 25 C with a solution of sodium hydroxide (8.0 g) in water (70 ml) for 2 h. The resulting solution was cooled in an ice bath and conc. aqueous HCI was slowly added with vigorous stirring until pH 2 had been reached. Filtration, washing with a small volume of cold water and drying resulted in an off-white solid (3.5 g). This material (5.4 g) was allowed to react in DMF (60 ml) with 4-methyl-3- thiosemicarbazide (4.6 g), 1H-1,2,3-benzotriazo)-1-ol (1.1 g), N-[2-(dimethylamino)ethyl]- N-ethylcarbodiimide hydrochloride (8.6 g), and triethylamine (6.2 ml) for 14 h at 25 C. The solvent was evaporated under reduced pressure and the residue heated wit NaOH (8.5 g) in water (150 ml) at 70 C for 3.5 h. The resulting solution was cooled in an ice bath and conc. aqueous HCI (17.7 ml) was slowly added with vigorous stirring. Filtration, washing with a small volume of cold water and drying resulted in a yellow powder (5.3 g). To this material (4.8 g) in EtOH (60 ml) containing 1-bromo-3-chloropropane (3.7 ml) was carefully added with stirring sodium hydride (1.1 g, 60% in mineral oil). The mixture was heated at 60 C for 1.5 h. Acetic acid (0.15 ml) was added, volatiles evaporated under reduced pressure and the residue submitted to column chromatography (EtOAc - acetone gradient). The material thus obtained was triturated with cyclohexane to provide the title compound as a faint yellow solid (6.1 g). NMR (¹H, CDC13): 8 7.90 (s, 1 H), 3.70 (s, 5H), 3.40 (t, 2H), 2.52 (s, 3H), 2.30 (m, 2H).
4-Methyl-oxazole-5-carboxylic acid A solution of 40.0 grams (0.243 mol, 1.0 eq) of 2-Chloro-3-oxo-butyric acid ethyl ester in 240 mL formic acid (99%) was stirred at room temperature in a 500 mL round bottom flask equipped with a H2O condenser. To this solution was added 80.0 grams (1.27 mmol, 5.2 eq) of ammonium formate. The solution was then heated to reflux for five hours. After cooling to room temperature, the solution was diluted with water (1 L) and neutralized with Na2CO3. The aqueous solution was then extracted three times with Et2O and the combined organic fractions were dried over MgSO4. After concentration, vacuum distillation (~10 mmHg, b.p. 53 C.-61 C.) gave a mixture of starting material and 4-Methyl-oxazole-5-carboxylic acid ethyl ester as a colorless oil (21.7 grams). This mixture was dissolved in 100 mL of aqueous sodium hydroxide (2 N) and refluxed for 1 minute.
With formic acid; at 115℃; for 17h;Inert atmosphere;
Ethyl 2-chloro-3-oxobutanoate (Ethyl 2-chloroacetoacetate) (0.243 mol) was dissolved in formic acid (240 mL) and ammonium formate (1.26 mol) was added portionwise. The reaction mixture was stirred at 115 C external temperature under reflux and N2 atmosphere for 17 hours. The reaction mixture was concentrated until no more formic acid could be removed (60 C 50 mbar) . The resulting suspension was diluted with water (300 mL) and was neutralized with sodium carbonate (1.63 mol) or 30% aqueous NaOH in batches while cooling in ice/water. At pH 8, the two layers were separated and the aqueous layer was extracted with EtOAc (2 x 150 mL) . The combined organic layers were dried with sodium sulfate, filtered and concentrated to give a brown oil. The product was purified by manual silicagel chromatography (250 g, eluting with 40% EtOAc/heptanes) to give the product as an orange oil. NMR (300 MHz, CDCI3) : delta 1.42 (t, 3H) , 2.53 (s, 3H) , 4.42 (q, 2H) , 7.89 (s, 1H) ppm.
Preparation 2: 3-[(3-Chloropropyl)thio]-4-methyl-5-(4-methyl1- ,3-oxazol-5-yl)-4H-1 ,2,4-triazole; Ethyl 4-methyl-1,3-oxazole-5-carboxylate (7.0 g) was stirred at 25 C with a solution of sodium hydroxide (8.0 g) in water (70 ml) for 2 h. The resulting solution was cooled in an ice bath and cone, aqueous HCI was slowly added with vigorous stirring until pH 2 hadbeen reached. Filtration, washing with a small volume of cold water and drying resulted inan off-white solid (3.5 g).This material (5.4 g) was allowed to react in DMF (60 ml) with 4-methyl-3-thiosemicarbazide (4.6 g), 1/-/-1,2,3-benzotriazol-1-ol (1.1 g), A/-[2-(dimethylamino)ethyl]-/V-ethylcarbodiimide hydrochloride (8.6 g), and triethylamine (6.2 ml) for 14 h at 25 C. The solvent was evaporated in vacua and the residue heated wit NaOH (8.5 g) in water (150 ml) at 70 C for 3.5 h. The resulting solution was cooled in an ice bath and cone, aqueous HCI (17.7 ml) was slowly added with vigorous stirring. Filtration, washing with a small volume of cold water and drying resulted in a yellow powder (5.3 g). To this material (4.8 g) in EtOH (60 ml) containing 1-bromo-3-chloropropane (3.7 ml) was carefully added with stirring sodium hydride (1.1 g, 60% in mineral oil). The mixture was heated at 60 C for 1.5 h. Acetic acid (0.15 ml) was added, volatiles evaporated in vacua and the residue submitted to column chromatography (EtOAc - acetone gradient). The material thus obtained was triturated with cyclohexane to provide the title compound as afaint yellow solid (6.1 g)._NMR (1H, CDCI3): 8 7.90 (s, 1H), 3.70 (s, 5H), 3.40 (t, 2H), 2.52 (s, 3H), 2.30 (m, 2H).
a) Preparation of 4-methyl-5-oxazolecarboxylic acid ethyl ester To ethyl-2-chloroacetoacetate(5.6 g) was added formamide(4.6 g). The reaction mixture was stirred at 120 C. for 12 hours, cooled to 0 C. and aqueous potassium carbonate was added thereto. The mixture was extracted with benzene, dried with anhydrous magnesium sulfate, and concentrated in vacuo to obtain the target product(2.1 g). NMR(CDCl3) delta (ppm): 1.40(t,3H), 2.50(s,3H), 4.35(q,2H), 7.84(s,1H).
b) Preparation of 5-hydroxymethyl-4-methyloxazole After <strong>[20485-39-6]4-methyl-5-oxazolecarboxylic acid ethyl ester</strong>(3 g) was dissolved in ethyl alcohol(50 ml), sodiumborohydride(3 g) was added thereto and refluxed for 17 hours. The reaction mixture was concentrated under reduced pressure, water was added to the concentrated solution. After extraction with ethyl acetate dried with anhydrous magnesium sulfate, and then concentrated to obtain the target product(0.9 g). NMR(CDCl3) delta (ppm): 2.18(s,3H), 3.45(s,1H), 4.65(s,2H), 7.80(s,1H).
EXAMPLE 1 Preparation of Ethyl 4-Methyl-5-Oxazolecarboxylate This compound was prepared according to the procedure described in French Pat. No. 1,543,853. A mixture of 50.0 g (0.337 moles) of ethyl chloroacetoacetate and 42.0 g (0.933 moles) of formamide was stirred at 120-135 for 18 hr. Thereafter, the mixture was cooled using an ice bath to 10 C. 300 ml of 1 N K2 CO3 was added dropwise with gas evolution noted. After complete addition of K2 CO3 solution, the reaction mixture was stirred with 200 ml of benzene/ether (2:1) and saturated with NaCl. The insoluble material was filtered and the benzene/ether layer was separated and washed with water, dried (MgSO4) and concentrated under reduced pressure. The brown residue was distilled on a Kugelrohr to give 14.8 g of white solid, mp 31-33 C.; yield 31%; nmr (CDCl3) 8.0 (s,1H,C2 H), 44 (q, J=7 Hz, 2H,CH2), 2.5 (s,3H,CH3), 1.4 (t,3H,CH3).
2-formyloxy-3-oxobutanoic acid ethyl ester[ No CAS ]
[ 77287-34-4 ]
[ 20485-39-6 ]
Yield
Reaction Conditions
Operation in experiment
80%
Example 7: Preparation of 4-methyloxazole-5-formic acid ethyl ester (OXE) A 500 mL-stirred reaction vessel with a 30 mm chi 30 cm Kerapak column was charged with 1 50.2 g formamide (98%, 3.267 mole, 1 .60 eq. ) and 1 3.4 g sulphuric acid (98%, 0.1 35 mole, 0.07 eq. ). The mixture was heated at p = 65 mbar to an inner temperature = 120 C. Then 400.2 g FOXE crude (88.6%, 2.036 mole, 1 .00 eq. ) was added within 5 h.. A HCOOH/water mixture was distilled from the reaction mixture during the FOXE dosage time. After the end of the FOXE dosage HCOOH/water was further distilled of to complete the reaction. This was the case after additional 1 .5 h of reaction and distillation after the end of the FOXE addition. During the complete reaction an overall amount of 100.8 g HCOOH/water mixture (HCOOH 56.7%, water 37.7%) was distilled off. In the sump, 407.0 g OXE crude with precipitated ammonium sulphate was obtained. 400.5 g OXE crude with precipitated ammonium sulphate were filtered through a filter nutsch to get 6.0 g filter cake and 391 .5 g OXE crude (OXE 68.7%) as the filtrate. Yield in filtrate: 86.5% Washing of the reaction equipment with ethanol affords additional 5.4% yield. Overall yield: 91 .9 % Washing of the filter cake was done twice with 1 1 .0 g FOXE crude for each washing. After the washing 4.8 g filter cake which was free of OXE and 24.2 g filtrate (FOXE 76.9%, OXE 2.0 %) were obtained. The filtrate can be recycled. OXE yield saving: 0.6% Overall OXE yield from FOXE: 92.5% Overall OXE yield from EACA: 80.1% The FOXE remaining in the filter cake was washed from 4.4 g filter cake with 18.5 g toluene. After the washing, 3.9 g filter cake were obtained, which was free of FOXE. The 18.8 g filtrate (FOXE 8.6%) can be recycled. Example 8: Rectification to purified OXE To a thin film evaporator with a 50 cm chi 30 mm Kerapak column at a temperature of 1 10C and at p = 5 mbar, 380.5 OXE crude was fed continuously. At the head of the column which is run at a reflux ratio of 0.2, 246.1 g OXE (OXE 89.8%) was obtained as the distillate and as a sump 67.4 g high boiling impurities (OXE 0.6%) was obtained. Also 37.4 g hold-up was collected after the experiment. Loss of OXE in the sump: 0.2 % Overall yield of OXE purified from EACA: 80.0%
150.2 g formamide (98%, 3.267 mol, 1.60 eq.) and 13.4 g sulfuric acid (98%, 0.135 mol, 0.07 eq.) were added into a 500 mL stirred reactor equipped with a 30 mmx30 cm erapak column. The mixture was heated to 120C under the pressure of 65 mbar. Later 400.2 g FOXE crude product (88.6%, 2.036 mol, 1,00 eq.) was added in 5 hours. HOOCH/water was distilled out from the reaction mixture during the addition of FOXE. After the addition of FOXE finished, HOOCH/water was continued to be distilled out until the reaction was completed. During the whole reaction, 100.8 g HCOOH/mixture (HCOOH 56.7% and water 37.7%) was distilled out, and 407.0 g OXE crude product and deposited ammonium sulphate were obtained. 400.5 g OXE crude product and deposited ammonium sulphate were filtrated to give 6,0 g filter cake and 391.5 g OXE crude product filtrate (OXE 68.7%). The total yield was 91.9%, The filter cake was washed by 11.0 g FOXE crude product twice to give 4.8 g filter cake without OXE and 24.2 g filtrate (FOXE 76.9% and OXE 2.0%). The total yield of OXE was 92.5%.
With trimethylaluminum; ammonium chloride; In toluene; at 80℃;
[00203] Ammonium chloride was suspended in toluene and azeotroped on a rotary evaporator. The ammonium chloride (1 .59 g, 30.0 mmol) was weighed into a 3-neck round bottom flask under a nitrogen atmosphere. Toluene (15 mL) was added and the suspension was cooled to 0 C. The reaction mixture was treated dropwise with trimethylaluminium 2 M in toluene (15 mL, 30.0 mmol). The reaction mixture was left to warm to room temperature and stirred for 3 hours. 4-Methyl-oxazole-5-carboxylic acid ethyl ester (0.465 g, 3.00 mmol) was added and the reaction mixture was heated at 80 C overnight. The reaction was cooled and quenched by slow addition of methanol (30 ml_). A white solid precipitated which was then filtered off through celite, washing with more methanol. The methanol was then evaporated until approximately 5 mL was left. This was then treated with diethyl ether (20 mL) and filtered again. The filtrate was then evaporated to yield the title compound (0.34 g, 89%). 1 H NMR (400 MHz, DMSO-cfe) delta 9.52 (s, 2H), 9.35 (s, 2H), 8.78 (s, 1 H), 2.41 (s, 3H).
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