Synthesis method of hydroximic acid analogue intermediate

Abstract

The invention discloses a synthesis method of a hydroximic acid analogue intermediate, and belongs to the field of medicine synthesis. The preparation method comprises the following steps: by taking 3-(2-acetamido-2-oxoethyl)-1, 2, 4-thiadiazole-5-yl amino ethyl formate (III) as a starting material, carrying out five-step reaction of alcoholysis, oxidation, oximation, protective group connection and hydrolysis, so as to obtain (Z)-2-(5-amino-1, 2, 4-thiadiazole-3-yl)-2-triphenylmethoxy imino acetic acid (II). The method provided by the invention has the characteristics of cheap and easily available raw materials, mild and safe reaction conditions, simple and convenient post-treatment and the like, thereby having great production value and social and economic benefits.

Description

Technical Field

[0001] This invention relates to a method for synthesizing an oxime acid analog intermediate, belonging to the field of pharmaceutical synthesis technology. Background Technology

[0002] (Z)-2-(5-amino-1,2,4-thiadiazole-3-yl)-2-alkoxyiminoacetic acid, as a "key structural fragment" in cephalosporin drug I, is linked to the C-7 amino group of the cephalosporin nucleus via an amide bond. Through the synergistic effect of the two key structural fragments, the "5-amino-1,2,4-thiadiazole ring" and the "(Z)-alkoxyimino group," stability against β-lactamases is significantly enhanced (against drug-resistant bacteria), while simultaneously broadening the antibacterial spectrum against Gram-negative bacteria, optimizing oral absorption and half-life, ultimately achieving the clinical requirements of "high efficacy, broad spectrum, resistance to drug resistance, and ease of use."

[0003]

[0004] However, the key structural fragment, thiadiazolium oxime acid (II), has many heteroatoms, high polarity, and poor stability, making its preparation quite difficult. For example, the presence of an acid-sensitive triphenylmethyl (Trt) protecting group makes product purification challenging. Currently, there are two main synthetic processes for this thiadiazolium oxime acid (II):

[0005] Route A: According to US6723716, a patent of Essential Therapeutics, thiadiazole oxime acid (II) is synthesized from 2-(5-ethoxyformamido-1,2,4-thiadiazole-3-yl)-acetaldehyde (A1) as the starting material through a series of 7 steps including oxidation, methylation, α-bromination, secondary oxidation, oximeization, introduction of protecting groups, and hydrolysis.

[0006]

[0007] Process advantages: 1) The key intermediate A5 (α-keto ester) exhibits significant cis-trans isomer selectivity when undergoing oxime reaction with hydroxylamine; 2) The intermediates in each step have stable physicochemical properties and are easy to separate and purify.

[0008] Main drawbacks: 1) The route is lengthy and has low safety, involving high-risk reagents such as peracetic acid (strong oxidizing agent) and liquid bromine (highly toxic and volatile), requiring strict safety protection measures; 2) The raw material cost is high; 3) The starting material A1 has poor stability, limited market supply, and high cost, resulting in high overall production cost and an uneconomical route.

[0009] Route B: The literature [Organic Process Research & Development, 2011, 15, 698-703] reports a relatively economical preparation route: malononitrile, the starting material, undergoes six steps of reaction including cyclization, acylation, rearrangement, oximeization, attachment of a protecting group, and hydrolysis to obtain thiadiazolium oxime acid (II).

[0010]

[0011] This route employs isopropyl nitrite oxidation and TrtCl protection, with a two-step yield of only 50-70% (Z / E of 1-2 / 1). The main drawback lies in the unusual stability of the benzamide group at the C-5 position of the thiadiazole. Even under strong alkaline, high-temperature, and prolonged reaction conditions, this amide group is extremely difficult to hydrolyze to release the free amine group. Furthermore, the harsh reaction conditions lead to the degradation of the heterocyclic portion of the thiadiazole, triggering serious side reactions. Summary of the Invention:

[0012] To overcome the aforementioned technical deficiencies, this invention aims to provide a novel method for synthesizing the oxime acid analog intermediate (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-triphenylmethoxyiminoacetic acid (II). The synthetic method employed in this invention utilizes readily available raw materials, operates under mild conditions, is convenient, and is economical and efficient.

[0013] The method for synthesizing the oxime acid analog intermediate (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-triphenylmethoxyiminoacetic acid (II) of the present invention includes the following steps:

[0014]

[0015] A. Alcohololysis: Compound III is reacted with methanol under acid catalysis to obtain intermediate IV;

[0016] B. Oxidation: Intermediate IV reacts in the presence of an oxidizing agent to give intermediate V;

[0017] C. Oximeification: Intermediate V reacts with hydroxylamine hydrochloride in the presence of a base to give intermediate VI;

[0018] D. Protection: Intermediate VI reacts with triphenylmethyl chloride in the presence of a base, and is separated by silica gel column chromatography to obtain intermediate VII;

[0019] E. Hydrolysis: Intermediate VII undergoes hydrolysis in the presence of a base to give (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)triphenylmethoxyiminoacetic acid (II).

[0020] Furthermore, in the alcoholysis step of the above technical solution, the acid is selected from hydrochloric acid, sulfuric acid, or p-toluenesulfonic acid, with sulfuric acid being preferred.

[0021] Furthermore, in the alcoholysis step of the above technical solution, the molar ratio of compound III to acid is 1:1-2, preferably 1:1.5-2.

[0022] Furthermore, in the alcoholysis step of the above technical solution, the reaction temperature is 40-66℃, preferably 60-66℃.

[0023] Furthermore, in the oxidation step of the above technical solution, the oxidant is selenium dioxide.

[0024] Furthermore, in the oxidation step of the above technical solution, the molar ratio of intermediate IV to oxidant is 1:1.5-2.5, preferably 1:1.5.

[0025] Furthermore, in the oxidation step of the above technical solution, the reaction solvent is selected from 1,4-dioxane, acetonitrile, or acetic acid, with 1,4-dioxane being the preferred reaction solvent.

[0026] Furthermore, in the oxidation step of the above technical solution, the reaction temperature is 80-120℃, preferably 100-110℃.

[0027] Furthermore, in the oxime step of the above technical solution, the base is selected from potassium carbonate, triethylamine, pyridine, or N-methylmorpholine, preferably pyridine.

[0028] Furthermore, in the oxime step of the above technical solution, the molar ratio of intermediate V, hydroxylamine hydrochloride and base is 1:1-2:1-2, preferably 1:1.1-1.5:1.1-1.5, and more preferably 1:1.2:1.2.

[0029] Furthermore, in the protection steps of the above technical solution, the alkali is selected from triethylamine, diisopropylethylamine, or N-methylmorpholine, preferably triethylamine.

[0030] Furthermore, in the protection steps of the above technical solution, the molar ratio of intermediate VI, triphenylmethyl chloride and alkali is 1:1-2.5:1-2.5, preferably 1:1.5-2.2:1.5-2.5, and more preferably 1:2.0:2.5.

[0031] Furthermore, in the protection step of the above technical solution, the column chromatography elution solvent is petroleum ether / dichloromethane = 1 / 0.8-1.2, more preferably 1:1.

[0032] Furthermore, in the hydrolysis step of the above technical solution, the alkali is selected from sodium hydroxide, potassium hydroxide, or lithium hydroxide, with sodium hydroxide being preferred.

[0033] Furthermore, in the hydrolysis step of the above technical solution, the molar ratio of intermediate VII to alkali is 1:6-12, preferably 1:8-11, and more preferably 1:10.

[0034] Furthermore, in the hydrolysis step of the above technical solution, the reaction temperature is 80-105℃, preferably 84-90℃.

[0035] Compared with the prior art, the present invention has the following advantages:

[0036] 1. The starting material, ethyl 3-(2-acetamido-2-oxoethyl)-1,2,4-thiadiazole-5-ylaminocarbamate (III), is inexpensive and readily available. The imide group in the C-3 side chain can be directly converted into a methyl carboxylate through a reflux reaction with methanol / sulfuric acid, yielding the key intermediate (IV). Compared to the method of first hydrolyzing into a carboxylic acid with alkali and then methylating, this method is simpler, more time-saving, and more efficient.

[0037] 2. Intermediate IV is oxidized by selenium dioxide to α-keto ester V in high yield. Compared with route A, this method eliminates the need for hazardous reagents such as liquid bromine, reduces the number of reaction steps, and simplifies post-processing. Compared with route B, it avoids the use of hazardous and explosive isopropyl nitrite oxidant, and also improves oxidation yield and ease of operation.

[0038] 3. Intermediate VI was protected with a triphenylmethyl (Trt) group to obtain a mixture of Z / E type triphenylmethoxyimino acetate (VII). Column chromatography using a 1 / 1 PE / DCM mixed solvent for elution effectively separated the Z-type and E-type triphenylmethoxyimino acetate (VII). The intermediate VII prepared by this method achieved a Z / E selectivity of 5 / 1, a significant improvement over the reported 2 / 1 selectivity. Attached Figure Description

[0039] Figure 1 The HNMR spectrum of the Z-isomer of intermediate (VII) obtained in Example 8;

[0040] Figure 2 The image shows the HNMR spectrum of the E-type isomer of intermediate (Ⅶ) obtained in Example 8. Detailed implementation method:

[0041] Example 1: Methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetate (IV)

[0042] At room temperature, concentrated sulfuric acid (0.30 mol, 29.2 g) was added dropwise to a suspension of ethyl 3-(2-acetamido-2-oxoethyl)-1,2,4-thiadiazol-5-ylaminocarbamate III (0.15 mol, 40.8 g) and methanol (800 mL). After the addition was complete, the mixture was heated to reflux and maintained for 6 h. The reaction mixture was monitored by TLC (PE / EA = 1 / 1) to detect the disappearance of the starting material. The reaction solution was cooled to below 10 °C, and potassium carbonate powder was added in batches to adjust the pH to 7-8. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give 32.8 g of compound (Ⅳ), with a yield of 89.3%. 1 H NMR (400MHz, CDCl3): δ11.81(s,1H),4.34(q,J=7.1Hz,2H),3.96(s,2H),3.66(s,3H),1.33(t,J=7.1Hz,3H).LC-MS(ES + ):m / z 246.5[M+H] + .

[0043] Example 2: Methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetate (IV)

[0044] p-Toluenesulfonic acid (0.03 mol, 5.1 g) was added to a suspension of ethyl 3-(2-acetamido-2-oxoethyl)-1,2,4-thiadiazol-5-ylaminocarbamate (III, 0.02 mol, 5.4 g) and methanol (100 ml). The mixture was heated to reflux for 16 h. The starting material was monitored by TLC (PE / EA = 1 / 1). The reaction solution was cooled to below 10 °C, and sodium carbonate powder was added in batches to adjust the pH to 7-8. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Compound (IV) was purified to 4.1 g, yield 82.6%.

[0045] Example 3: Methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)oxoacetate (V)

[0046] Intermediate IV (0.13 mol, 32.0 g) and selenium dioxide (0.20 mol, 22.2 g) were added to 1,4-dioxane (250 mL). The mixture was heated to reflux, and the solid gradually dissolved. The reaction was maintained at this temperature for 6 h. The disappearance of the starting material was monitored by TLC (PE / EA = 1 / 1). The reaction solution was cooled to room temperature, post-processed, and concentrated to dryness under reduced pressure to give 31.5 g of compound (V), with a yield of 93.6%. 1 HNMR (400MHz, CD3OD): δ4.34(q,J=7.1Hz,2H),3.75(s,3H),1.35(t,J=7.1Hz,2H).LC-MS(ES + ):m / z 260.4[M+H] +.

[0047] Example 4: Methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)oxoacetate (V)

[0048] Intermediate IV (0.02 mol, 4.9 g) and selenium dioxide (0.06 mol, 6.6 g) were added to 1,4-dioxane (40 mL). The mixture was heated to reflux and maintained at this temperature for 2 h. The disappearance of the starting material was monitored by TLC (PE / EA = 1 / 1). The reaction solution was cooled to room temperature and post-processed to give 4.7 g of the title compound (V), with a yield of 90.7%.

[0049] Example 5: Methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)oxoacetate (V)

[0050] Intermediate IV (0.02 mol, 4.9 g) and selenium dioxide (0.03 mol, 3.3 g) were refluxed in acetonitrile (40 mL) for 15 h. The reaction solution was cooled to room temperature, and the crude product was purified by column chromatography to give compound (V) 3.9 g, with a yield of 75.7%.

[0051] Example 6: Methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)oxime acetate (VI)

[0052] Hydroxylamine hydrochloride (0.14 mol, 9.7 g) and intermediate V (0.11 mol, 28.5 g) were added to an ethanol solution (400 mL) at room temperature. Pyridine (0.16 mol, 12.6 g) was added dropwise, and the mixture was stirred at room temperature for 15 h. The starting material was detected by HPLC. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (400 mL). The solution was washed successively with water (200 mL), 2M hydrochloric acid (200 mL), and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to give compound (VI), 25.7 g of an off-white solid, yield 85.3%. LC-MS (ES) was performed. + ):m / z 275.4[M+H] + .

[0053] Example 7: Methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)oxime acetate (VI)

[0054] Hydroxylamine hydrochloride (0.030 mol, 2.09 g) and intermediate V (0.020 mol, 5.20 g) were added to an ethanol solution (400 mL) at room temperature. Potassium carbonate powder (0.020 mol, 2.76 g) was added in portions, and the mixture was stirred at room temperature for 15 h. The starting material was detected by HPLC and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (80 mL). The residue was washed successively with water (40 mL), 2M hydrochloric acid (40 mL), and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to give compound (VI), 4.17 g of an off-white solid, yield 76.1%.

[0055] Example 8 (Z)-2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)triphenylmethoxyiminoacetic acid methyl ester (VII)

[0056] At 0°C, triphenylmethyl chloride (0.16 mol, 44.6 g) was added to intermediate VI (0.08 mol, 22.0 g) dissolved in DCM (220 mL). Triethylamine (0.20 mol, 20.2 g) was then added dropwise. The solution was heated to room temperature and stirred for 3 h. The disappearance of the starting material was monitored by TLC (PE / EA = 1 / 1 as the developing solvent). The reaction solution was washed with water (2 × 150 mL) and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to approximately 100 mL. The solution was loaded onto a wet plate, purified by column chromatography, and the target fraction was collected to obtain 28.9 g of the Z-isomer of methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)triphenylmethoxyiminoacetate. f =0.25 (developing solvent PE / EA = 1:1), 1 H NMR (400MHz, DMSO-d6): δ12.88(s,1H),7.20-7.40(m,15H),4.26(q,J=7.1Hz,2H),3.98(s,3H),1.24(t,J=7.1Hz,3H).LC-MS(ES + ):m / z 539.6[M+Na] + ; 5.7 g of the E isomer of methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)triphenylmethoxyiminoacetate was obtained. f =0.35 (developing solvent PE / EA = 1 / 1), 1 H NMR (400MHz, DMSO-d6): δ12.89(s,1H),7.17-7.37(m,15H),4.33(q,J=7.1Hz,2H),3.71(s,3H),1.31(t,J=7.1Hz,3H).LC-MS(ES + ):m / z539.6[M+Na]+ .

[0057] Example 9 (Z)-2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)triphenylmethoxyiminoacetic acid methyl ester (VII)

[0058] At 0°C, triphenylmethyl chloride (0.03 mol, 8.4 g) was added to intermediate VI (0.02 mol, 5.5 g) dissolved in DCM (60 mL). Pyridine (0.04 mol, 3.2 g) was then added dropwise. The solution was heated to room temperature and stirred for 5 h. The disappearance of the starting material was monitored by TLC (PE / EA = 1 / 1). The reaction mixture was washed with water (2 × 150 mL) and separated. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to approximately 20 mL. Column chromatography yielded 5.8 g of the Z-isomer of methyl 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)triphenylmethoxyiminoacetate.

[0059] Example 10 (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)triphenylmethoxyiminoacetic acid (II)

[0060] Intermediate VII (0.04 mol, 20.7 g) and sodium hydroxide (0.40 mol, 16.0 g) were added to water (200 mL) and ethanol (200 mL). The mixture was then heated to 40-50 °C and reacted for 1 h. TLC (PE / EA = 1 / 1 eluent) showed that the starting material was converted to an intermediate state. The reaction mixture was heated to reflux and maintained at this temperature for 24 h. TLC (DCM / MeOH = 5 / 1 eluent) and HPLC showed that the intermediate state had essentially disappeared. The reaction mixture was cooled to below 5 °C and filtered. The filter cake was mixed with water (120 mL) pre-cooled to 5 °C, and while stirring, 2 M citric acid aqueous solution was added dropwise to adjust the pH to 3-4. The mixture was filtered, and the filter cake was washed with ice water (2 × 20 mL). The filter cake was dried under vacuum at 40 °C for 15 h to give compound (II), 12.1 g of white solid, yield 70.3%. 1 H NMR (400MHz, DMSO-d6): δ7.92(s,2H),7.17-7.37(m,15H).LC-MS(ES + ):m / z453.6[M+Na] + .

[0061] Example 11 (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)triphenylmethoxyiminoacetic acid (II)

[0062] Intermediate VII (0.01 mol, 5.2 g) and sodium hydroxide (0.08 mol, 3.2 g) were reacted in water (50 mL) and ethanol (50 mL), and the mixture was heated to reflux for 36 h. The reaction mixture was cooled to below 5 °C and filtered. The filter cake was added to water (30 mL) pre-cooled to 5 °C and mixed. While stirring, 2 M citric acid aqueous solution was added dropwise to adjust the pH to 3-4. The mixture was filtered, and the filter cake was washed with ice water (2 × 5 mL). The filter cake was dried under vacuum at 40 °C for 15 h to give compound (II), 2.4 g of white solid, yield 55.8%.

[0063] Example 12 (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)triphenylmethoxyiminoacetic acid (II)

[0064] Intermediate VII (0.01 mol, 5.2 g) and potassium hydroxide (0.12 mol, 6.7 g) were added to water (100 mL), and the mixture was heated to reflux for 48 h. The reaction mixture was cooled to below 5 °C and filtered. The filter cake was added to water (30 mL) pre-cooled to 5 °C and mixed. While stirring, 2 M citric acid aqueous solution was added dropwise to adjust the pH to 3-4. The mixture was filtered, and the filter cake was washed with ice water (2 × 5 mL). The filter cake was dried under vacuum at 40 °C for 15 h to give compound (II), 2.9 g of white solid, yield 67.4%.

[0065] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. For those skilled in the art, various improvements and modifications can be made without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for synthesizing an oxime acid analog intermediate, characterized in that, Includes the following steps: A. Alcohololysis: Compound III is reacted with methanol under acid catalysis to obtain intermediate IV; B. Oxidation: Intermediate IV reacts in the presence of an oxidizing agent to give intermediate V; C. Oximeification: Intermediate V reacts with hydroxylamine hydrochloride in the presence of a base to give intermediate VI; D. Protection: Intermediate VI reacts with triphenylmethyl chloride in the presence of a base, and is separated by silica gel column chromatography to obtain intermediate VII; E. Hydrolysis: Intermediate VII undergoes hydrolysis in the presence of a base to give (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)triphenylmethoxyiminoacetic acid (II).

2. The method for synthesizing the oxime acid analog intermediate according to claim 1, characterized in that: In the alcoholysis step, the acid is selected from hydrochloric acid, sulfuric acid, or p-toluenesulfonic acid; the molar ratio of compound III to acid is 1:1-2.

3. The method for synthesizing the oxime acid analog intermediate according to claim 1, characterized in that: In the alcoholysis step, the reaction temperature is 40-66℃.

4. The method for synthesizing the oxime acid analog intermediate according to claim 1, characterized in that: In the oxidation step, the oxidant is selenium dioxide; the molar ratio of intermediate IV to the oxidant is 1:1.5-2.5; and the reaction solvent is selected from 1,4-dioxane, acetonitrile, or acetic acid.

5. The method for synthesizing the oxime acid analog intermediate according to claim 1, characterized in that: In the oxidation step, the reaction temperature is 80-120℃.

6. The method for synthesizing the oxime acid analog intermediate according to claim 1, characterized in that: In the oxime step, the base is selected from potassium carbonate, sodium carbonate, triethylamine, pyridine, or N-methylmorpholine; the molar ratio of intermediate V, hydroxylamine hydrochloride, and base is 1:1-2:1-2.

7. The method for synthesizing the oxime acid analog intermediate according to claim 1, characterized in that: In the protection step, the base is selected from triethylamine, diisopropylethylamine, or N-methylmorpholine; The molar ratio of intermediate VI, triphenylmethyl chloride, and alkali is 1:1-2.5:1-2.

5.

8. The method for synthesizing the oxime acid analog intermediate according to claim 1, characterized in that: In the protection step, the column chromatography elution solvent is petroleum ether / dichloromethane = 1 / 0.8-1.

2.

9. The method for synthesizing the oxime acid analog intermediate according to claim 1, characterized in that: In the hydrolysis step, the alkali is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide; the molar ratio of intermediate VII to alkali is 1:6-12.

10. The method for synthesizing the oxime acid analog intermediate according to claim 1, characterized in that: During the hydrolysis step, the reaction temperature is 80-105℃.

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