CN112457264A - Preparation method of hymexazol crude drug - Google Patents
Preparation method of hymexazol crude drug Download PDFInfo
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- CN112457264A CN112457264A CN202011449334.9A CN202011449334A CN112457264A CN 112457264 A CN112457264 A CN 112457264A CN 202011449334 A CN202011449334 A CN 202011449334A CN 112457264 A CN112457264 A CN 112457264A
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- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention provides a preparation method of a hymexazol crude drug, which comprises the steps of reacting acetaminophen and 2-fluoro-5-nitrotoluene as initial raw materials to obtain a compound II, and then performing diazotization coupling reaction to obtain a compound IV, wherein a conjugate adopted in the diazotization coupling reaction is the compound III. The invention provides a preparation method of a cimetidine raw material drug, which uses malonate monoester monoamido formate as a conjugate and acetaminophen and 2-fluoro-5-nitrotoluene as starting raw materials, can more efficiently and mildly realize the construction of triazine ring, and has higher yield and higher purity of the obtained target product cimetidine.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of a hymexazol crude drug.
Background
The cimetiril (Ethanamizruil) has the chemical name of N- [4- [4- (4, 5-dioxo-4, 5-dihydro-1, 2, 4-triazine ring- (3H) -yl-2-methylphenoxy) phenyl acetamide, is a triazine anticoccidial drug with a novel chemical structure independently developed by Shanghai veterinary research institute of Chinese academy of agricultural sciences, is mainly used for preventing and treating avian coccidia, and has good effect, no toxic or side effect and good safety. Compared with the existing anticoccidial drugs such as diclazuril and toltrazuril, the compound has no cross drug resistance, has more obvious anticoccidial effect, has no oocysts and pathological changes, and is a good substitute of diclazuril and toltrazuril. The cimetiril serving as a new veterinary drug in China successfully realizes industrial application and has profound significance for poultry breeding in China, particularly for prevention and treatment of coccidiosis in chickens.
At present, the main synthesis process route of cimetidine is shown in fig. 1, 2-chloro-5-nitrotoluene and acetaminophen are used as starting raw materials, condensation reaction is carried out under the catalysis of an acid binding agent to obtain a compound with a structure I, and the cimetidine is prepared through reduction, diazotization, coupling, cyclization, hydrolysis and decarboxylation in sequence, wherein the total yield is about 75%.
However, the cimetiril obtained by the synthesis process route has more impurities and is difficult to purify, and the application of the cimetiril in anti-coccidiosis veterinary drugs is not facilitated.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a preparation method of a hymexazol crude drug.
The invention adopts the following technical scheme:
the invention provides a preparation method of a hymexazol crude drug, which comprises the steps of reacting acetaminophen and 2-fluoro-5-nitrotoluene as initial raw materials to obtain a compound II, and then performing diazotization coupling reaction to obtain a compound IV, wherein a conjugate adopted in the diazotization coupling reaction is a compound III;
wherein R is1Is methyl or ethyl, R2Is methyl or ethyl.
The research of the invention finds that in the prior art, when 2-chloro-5-nitrotoluene is taken as a raw material to perform nucleophilic substitution reaction with sodium phenolate, the activity is poor, the reaction time is long, the excessive 2-chloro-5-nitrotoluene is inconvenient to remove, the impurities are more, and the purification is difficult; furthermore, almost equimolar amounts of hydrochloric acid are used to hydrolyze the "structure four", the acetyl group (CH) on aniline being more easily hydrolyzed under heating3CONHAr) rather than the intended imide group in-CONHCOOEt, the purity of the product "structure five" is significantly reduced. According to the invention, malonic acid monoester monoamido formate is used as a conjugate, acetaminophen and 2-fluoro-5-nitrotoluene are used as starting materials, the construction of a triazine ring can be realized more efficiently and mildly, and the obtained target product cimetidine has higher yield and higher purity.
Preferably, R1Is ethyl, R2Is ethyl.
Further, the specific steps of the diazotization coupling reaction comprise:
and dropwise adding a sodium nitrite aqueous solution into the solvent in which the compound II and the compound III are dissolved at 0-20 ℃ for reaction.
Wherein, the solvent is one or more of acetic acid, formic acid and water, preferably glacial acetic acid.
Preferably, the concentration of the sodium nitrite aqueous solution is 18-25%, and the molar ratio of the compound II, the compound III and the sodium nitrite is 1.0 (1.0-1.2) to 1.0-1.2.
Further, after the compound IV is obtained, cyclization, hydrolysis and decarboxylation are carried out on the compound IV to obtain the cimetidine bulk drug.
Wherein, the compound IV obtained by the diazotization coupling reaction does not need to be separated, sodium acetate is directly added for the cyclization reaction, the reaction temperature is 80-120 ℃, and the molar ratio of the sodium acetate to the compound II is (1.0-1.2): 1.0, preferably 1: 1. The reaction time is about 2-6 h, and the cyclization product compound V is obtained after post-treatment. In the prior art, cyclization reaction is generally carried out at 50-65 ℃, but researches of the invention find that the reaction system of the invention adopts the conditions to carry out reaction, and the result reaction is fast and the yield is high.
The hydrolysis is carried out under an alkaline condition, the reaction temperature is 25-80 ℃, the reaction time is 1-5 h, and after the hydrolysis is finished, the pH value is adjusted to be acidic by hydrochloric acid or dilute sulfuric acid, preferably 3-4.
Preferably, the hydrolysis comprises in particular: hydrolyzing by adopting a sodium hydroxide or potassium hydroxide aqueous solution at the reaction temperature of 30-50 ℃, wherein the molar ratio of the sodium hydroxide or potassium hydroxide to the cyclization product compound V is (2.0-4.0): 1.0;
the decarboxylation reaction comprises the steps of reacting a hydrolysate compound VI with a decarboxylation reagent at the temperature of 70-180 ℃ for 2-12 hours until the reaction is complete, and separating to obtain a target product, namely the climbazole;
wherein, the decarboxylation reagent can be thioglycolic acid, thiourea or ethanethiol. The decarboxylation reaction can be carried out by using the decarboxylation reagent as a solvent or additionally adding an organic solvent, such as alcohols like ethanol, propanol, isopropanol and n-butanol, or polar solvents like acetonitrile, DMF, DMAC, NMP and DMSO.
Preferably, in the decarboxylation reaction, the decarboxylation reagent is thioglycolic acid, the organic solvent is DMF, and the mass ratio of the decarboxylation reagent to the compound VI is (0.5-2.0): 1.0, and the reaction temperature is 100-150 ℃.
Further, the compound II is obtained by sequentially carrying out condensation and reduction reactions on the acetaminophen and the 2-fluoro-5-nitrotoluene, wherein hydrazine hydrate is used as a reduction reagent in the reduction reaction.
The condensation reaction specifically comprises: heating the mixture in the presence of an organic solvent and an acid-binding agent to cause the acetaminophen and the 2-fluoro-5-nitrotoluene to generate intermolecular substitution reaction, thus obtaining a condensation product compound I.
Wherein the organic solvent is one or more of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMAC), N-methylpyrrolidone (NMP) and dimethyl sulfoxide (DMSO). The acid-binding agent is one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium hydroxide and sodium hydroxide.
Preferably, in the condensation reaction, the organic solvent is DMF, the acid-binding agent is potassium carbonate, the reaction temperature is 100-150 ℃, and the molar ratio of the acetaminophen to the 2-fluoro-5-nitrotoluene (1.0-1.2): 1.0.
the reduction reaction specifically comprises: adding activated carbon, a catalyst ferric trichloride, an inorganic base and a condensation product compound I into methanol or ethanol, and dropwise adding hydrazine hydrate to perform a reduction reaction under a reflux condition, wherein the molar ratio of the hydrazine hydrate to the compound I is (2.0-4.0): 1.0;
preferably, in the reduction reaction, a solvent is methanol, and the dosage of a catalyst ferric trichloride is 0.5-1 wt% of the compound I; the inorganic alkali is sodium hydroxide or potassium hydroxide, and the using amount of the inorganic alkali is 0.25 to 0.5 weight percent of the compound I; the amount of the active carbon is 2.5-5 wt% of the compound I.
The invention has the beneficial effects that:
the invention provides a preparation method of a cimetidine bulk drug, which uses malonate monoester monoamidoformate as a conjugate and acetaminophen and 2-fluoro-5-nitrotoluene as starting raw materials, can realize the construction of a triazine ring more efficiently and mildly, has mild hydrolysis conditions, performs reactions under normal pressure, obtains a target product cimetidine with higher yield (up to 79.9%), has higher purity (98.0%) and has better industrial application value.
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In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on the drawings without creative efforts.
FIG. 1 is a schematic diagram of the main synthetic process route of the prior art Saimiqili;
FIG. 2 shows the synthesis route of the drug substance of Saimizuril in example 1 of the present invention.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention. The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products available from regular distributors, not indicated by the manufacturer.
Example 1
The present embodiment provides a method for preparing a cimetidine bulk drug, wherein a synthetic route of the method is shown in fig. 2, and the method specifically includes the following steps:
synthesis of Compound I:
adding solvents DMF (250mL), potassium carbonate (64g) and p-acetylaminophenol (61g, 0.40mol) into a 500mL round-bottom flask at room temperature, stirring for one hour, adding 2-fluoro-5-nitrotoluene (62g, 0.36mol), heating to 140 ℃ in an oil bath, stirring for reaction for 5 hours, removing the oil bath, stirring and cooling, adding water (500mL), precipitating a large amount of light yellow solid, stirring for ten minutes, performing suction filtration to obtain a solid product, washing with water, and drying at 80 ℃ to obtain a compound I, wherein the yield is 99.5% of light yellow powder 103 g.
Recrystallizing to obtain colorless needle crystal, wherein the melting point is as follows: 164.2-164.6 ℃.1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.20(d,J＝2.8Hz,1H),8.02(dd,J＝9.1,2.9Hz,1H),7.71-7.64(m,1H),7.12-7.05(m,1H),6.76(d,J＝9.0Hz,1H),2.37(s,1H),2.06(s,1H)
Synthesis of Compound II:
adding anhydrous methanol (500mL), ferric trichloride (0.5g), activated carbon (5g), sodium hydroxide (0.5g) and a compound I (100g and 0.35mol) into a 1000mL round-bottom flask, heating the flask in an oil bath to reflux, dropwise adding 85% hydrazine hydrate (41g and 0.70mol) while stirring, continuously stirring for reacting for 2 hours after dropwise adding is finished within 2 hours, filtering while hot, removing the catalyst and the activated carbon, cooling the filtrate to room temperature, precipitating a large amount of white needle-shaped solid after concentration, performing suction filtration and drying to obtain a compound II, wherein the amount of the off-white solid is 85g, and the yield is 95%.
Recrystallizing to obtain colorless needle crystal. Melting point: 175.9-178.8 ℃. ESI-MS (m/z): 257.1[ M + H]+；1H NMR(300MHz,DMSO-d6)δ9.81(s,1H),7.51-7.39(m,2H),6.76-6.67(m,2H),6.64(d,J＝8.5Hz,1H),6.47(d,J＝2.7Hz,1H),6.41(dd,J＝8.5,2.8Hz,1H),4.93(s,2H),2.00(s,3H),1.97(s,3H).
Synthesis of compound IV:
glacial acetic acid (400mL), Compound II (85g, 0.33mol) and Compound III (where R is R) were added to a 1000mL round bottom flask at room temperature1、R2All ethyl groups) (74g, 0.36mol), dropwise adding 20% sodium nitrite (23g, 0.33mol) aqueous solution at 10-18 ℃ under continuous stirring, stirring for reaction for 0.5 h after dropwise adding, naturally heating, stirring for reaction for 8h to obtain a compound IV, and directly carrying out the next operation without treatment.
Recrystallization to give a yellow solid, melting point: 193.2-195.2 ℃. ESI-MS (m/z): 471.0[ M + H]+；1H NMR(400MHz,DMSO-d6)δ12.69(s,1H),11.14(s,1H),9.90(d,J＝2.7Hz,1H),7.56-7.49(m,2H),7.38(dd,J＝8.3,2.7Hz,1H),7.27(ddd,J＝11.6,8.7,2.7Hz,1H),6.92-6.78(m,3H),4.24(q,J＝6.9Hz,2H),4.19-4.08(m,2H),2.17(s,3H),2.01(s,3H),1.29-1.20(m,6H).
Synthesis of compound V:
weighing sodium acetate (27g, 0.33mol), adding the sodium acetate into the system obtained in the previous step at one time, heating to reflux, stirring for reacting for 4 hours, reducing pressure to remove most of acetic acid, adding 500mL of water into the system, separating out a large amount of tawny solid, stirring for 10 minutes, carrying out suction filtration and water washing to obtain a tawny filter cake wet product, and directly using the tawny filter cake wet product in the next step without drying.
Recrystallization to give an off-white powder, melting point: 262.4-263.4 ℃. ESI-MS (m/z): 425.0[ M + H [ ]]+；1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),9.95(s,1H),7.71-7.49(m,2H),7.41(d,J＝2.6Hz,1H),7.28(dd,J＝8.7,2.7Hz,1H),7.02-6.90(m,2H),6.86(d,J＝8.7Hz,1H),4.28(q,J＝7.1Hz,2H),2.24(s,3H),2.02(s,3H),1.25(t,J＝7.1Hz,3H)；13C NMR(100MHz,DMSO-d6)δ168.35,160.77,155.23,154.56,152.11,148.18,135.48,135.07,129.21,129.15,125.54,121.07,118.87,118.19,61.99,24.17,16.18,14.30。
Synthesis of Compound VI:
adding the wet compound V into a 1000mL three-necked bottle at room temperature, adding water (500g), stirring into a slurry, dropwise adding a 30% sodium hydroxide aqueous solution (90g), heating to 35 ℃ in a water bath, stirring for reacting for 2h, removing the water bath, cooling to room temperature, dropwise adding concentrated hydrochloric acid to adjust the pH value to be 3-4, precipitating a solid, stirring for 10 min, carrying out suction filtration, washing with water, and drying to obtain 116g of yellow powder, wherein the yield is 89% calculated by using a compound II.
Melting point: 233.0 to 234.8 ℃; ESI-MS (m/z): 396.9[ M + H ]]+；1H NMR(400MHz,DMSO-d6)δ13.95(brs,1H),12.54(s,1H),9.95(s,1H),7.62–7.54(m,2H),7.42(d,J＝2.6Hz,1H),7.29(dd,J＝8.7,2.7Hz,1H),6.98–6.90(m,2H),6.87(d,J＝8.7Hz,1H),2.24(s,3H),2.02(s,3H)。
Synthesizing raw material medicine cimetiril:
adding a compound VI (50g), 50g of thioglycolic acid and 150mL of DMF into a 500mL round-bottom flask at room temperature under the atmosphere of nitrogen, heating to 130 ℃, stirring for reacting for 4 hours, distilling to remove the DMF, dropwise adding the residue into cold water, precipitating a large amount of solid, performing suction filtration, and washing with water to obtain cimetidine, 42.2g of light yellow powder, the yield of 95%, and the chromatographic purity of HPLC: 98.0 percent. ESI-MS (m/z): 353.1[ M + H]+；1H NMR(400MHz,DMSO-d6)δ12.34(s,1H),9.96(s,1H),7.64-7.55(m,3H),7.42(d,J＝2.7Hz,1H),7.29(dd,J＝8.7,2.7Hz,1H),7.01-6.90(m,2H),6.86(d, J ═ 8.7Hz,1H),2.25(s,3H),2.04(s, 3H). The total yield was 79.9%.
Example 2
The embodiment provides a preparation method of a hymexazol crude drug, which specifically comprises the following steps:
synthesis of Compound I:
adding DMAC (250mL), sodium carbonate (49g) and p-acetylaminophenol (59g, 0.39mol) serving as solvents into a 500mL round-bottom flask at room temperature, stirring for one hour, adding 2-fluoro-5-nitrotoluene (62g, 0.36mol), heating in an oil bath to 140 ℃, stirring for reaction for 5 hours, removing the oil bath, stirring for cooling, adding water (500mL), precipitating a large amount of light yellow solid, stirring for ten minutes, performing suction filtration to obtain a solid product, washing with water, and drying at 80 ℃ to obtain a compound I, wherein the yield of the compound I is 99.0% and the light yellow powder is 102 g.
Synthesis of Compound II:
adding anhydrous methanol (500mL), ferric trichloride (0.5g), activated carbon (5g), sodium hydroxide (0.5g) and a compound I (100g and 0.35mol) into a 1000mL round-bottom flask, heating the flask in an oil bath to reflux, dropwise adding 85% hydrazine hydrate (61.5g and 1.05mol) while stirring, continuing stirring for reaction for 1.5h after dropwise adding within 2h, filtering while hot, cooling the filtrate to room temperature, precipitating a large amount of white needle-shaped solid after concentration, performing suction filtration and drying to obtain 83g of an off-white solid compound II, wherein the yield is 93%.
Synthesis of compound IV:
glacial acetic acid (400mL), Compound II (80g, 0.31mol) and Compound III (wherein R is1、R2All ethyl) (70g, 0.34mol), dropwise adding 25% sodium nitrite (23.5g, 0.34mol) aqueous solution at 10-18 ℃ under continuous stirring, stirring and reacting for 0.5 h after dropwise adding, naturally heating, stirring and reacting for 8h to obtain a compound IV, and directly carrying out the next operation without treatment.
Synthesis of compound V:
weighing sodium acetate (30g, 0.37mol), adding the sodium acetate into the system obtained in the previous step at one time, heating to reflux, stirring for reaction for 3 hours, reducing pressure to remove most of acetic acid, adding 500mL of water into the system, separating out a large amount of tawny solid, stirring for 10 minutes, carrying out suction filtration and water washing to obtain a tawny filter cake wet product, and directly using the tawny filter cake wet product in the next step without drying.
Synthesis of Compound VI:
adding the wet compound V into a 1000mL three-necked bottle at room temperature, adding water (500g), stirring into a slurry, dropwise adding 30% potassium hydroxide (125g), heating to 35 ℃ in a water bath, stirring for reacting for 2h, removing the water bath, cooling to room temperature, dropwise adding concentrated hydrochloric acid to adjust the pH value to be 3-4, separating out a solid during the reaction, stirring for 10 min, performing suction filtration, washing with water, and drying to obtain 109g of yellow powder, wherein the yield is 88% calculated from the compound II.
Synthesizing raw material medicine cimetiril:
adding a compound VI (100g), thiourea (70g) and DMAC (dimethylacetamide) 300 mL into a 500mL round-bottom flask under the atmosphere of nitrogen at room temperature, heating to 140 ℃, stirring for reaction for 10h, distilling to remove part of DMAC, dropwise adding the residue into cold water, precipitating a large amount of solid, performing suction filtration, washing with water, and drying to obtain cimetidine, wherein the yield is 93%, and the cimetidine is a pale yellow powder and 83 g. HPLC chromatographic purity: 98.2 percent and the total yield is 75.4 percent.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. The preparation method of the cimetidine bulk drug is characterized by comprising the steps of reacting acetaminophen and 2-fluoro-5-nitrotoluene as initial raw materials to obtain a compound II, and then performing diazotization coupling reaction to obtain a compound IV, wherein a conjugate adopted in the diazotization coupling reaction is a compound III;
wherein R is1Is methyl or ethyl, R2Is methyl or ethyl.
2. The method of preparing a cimetiril drug substance as claimed in claim 1, wherein R is1Is ethyl, R2Is ethyl.
3. The method for preparing a cimetiril drug substance according to claim 1 or 2, wherein the diazotization coupling reaction comprises the following specific steps:
and (3) dropwise adding a sodium nitrite aqueous solution into a solvent in which the compound II and the compound III are dissolved at 0-20 ℃ for reaction.
4. The method for preparing a cimetiril raw material drug according to claim 3, wherein the concentration of the sodium nitrite aqueous solution is 18-25%, and the molar ratio of the compound II, the compound III and the sodium nitrite is 1.0 (1.0-1.2) to 1.0-1.2.
5. The method of preparing a cimetiril drug substance according to any one of claims 1 to 4, wherein the cimetiril drug substance is obtained by cyclizing, hydrolyzing and decarboxylating the compound IV after it is obtained.
6. The preparation method of the cimetiril bulk drug according to claim 5, characterized in that the compound IV obtained through the diazotization coupling reaction is directly added with sodium acetate for the cyclization reaction without separation, the reaction temperature is 80-120 ℃, and the molar ratio of the sodium acetate to the compound II is (1.0-1.2): 1.0.
7. The method for preparing a cimetiril drug substance according to claim 5 or 6, wherein the hydrolysis is performed under an alkaline condition, the reaction temperature is 25-80 ℃, and the pH is adjusted to be acidic after the hydrolysis is completed.
8. The method of preparing a cimetiril drug substance as claimed in claim 7, wherein the hydrolysis specifically comprises: hydrolyzing by adopting a sodium hydroxide or potassium hydroxide aqueous solution at the reaction temperature of 30-50 ℃, wherein the molar ratio of the sodium hydroxide or potassium hydroxide to the cyclization product compound V is (2.0-4.0): 1.0;
9. the preparation method of the cimetiril bulk drug according to any one of claims 1 to 8, wherein the compound II is obtained by sequentially carrying out condensation and reduction reactions on acetaminophen and 2-fluoro-5-nitrotoluene, and hydrazine hydrate is used as a reduction reagent in the reduction reaction.
10. The method for preparing a cimetiril drug substance as claimed in claim 9, wherein the reduction reaction specifically comprises: adding activated carbon, a catalyst ferric trichloride, an inorganic base and a condensation product compound I into methanol or ethanol, and dropwise adding hydrazine hydrate to perform a reduction reaction under a reflux condition, wherein the molar ratio of the hydrazine hydrate to the compound I is (2.0-4.0): 1.0;
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| CN113248453B (en) * | 2021-06-28 | 2021-11-16 | 山东国邦药业有限公司 | Preparation method of triazinone ring |
| CN116535362A (en) * | 2023-07-05 | 2023-08-04 | 山东国邦药业有限公司 | Crystal form A of cimetidine and preparation method thereof |
| CN116606259A (en) * | 2023-07-19 | 2023-08-18 | 山东国邦药业有限公司 | Preparation method of Sha Mizhu key intermediate of anti-insect veterinary drug |
| CN116606259B (en) * | 2023-07-19 | 2023-09-15 | 山东国邦药业有限公司 | Preparation method of Sha Mizhu key intermediate of anti-insect veterinary drug |
| CN117510426A (en) * | 2024-01-04 | 2024-02-06 | 山东国邦药业有限公司 | Synthesis method of anticoccidial veterinary drug triazine ring |
| CN117510426B (en) * | 2024-01-04 | 2024-04-19 | 山东国邦药业有限公司 | Synthesis method of anticoccidial veterinary drug triazine ring |
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