CN114605410A - Preparation method of non-neferitone bulk drug - Google Patents

Preparation method of non-neferitone bulk drug Download PDF

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CN114605410A
CN114605410A CN202210359260.2A CN202210359260A CN114605410A CN 114605410 A CN114605410 A CN 114605410A CN 202210359260 A CN202210359260 A CN 202210359260A CN 114605410 A CN114605410 A CN 114605410A
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杨勇
沈超
刘沐为
王栋
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Zhejiang Chemtrue Biomedical Co ltd
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Abstract

The invention relates to a preparation method of a non-neferide ketone raw material medicine, which comprises the following steps: 4-formyl-3-methoxybenzonitrile and an acetoacetate compound are coupled to obtain a compound 1; dehydrating and cyclizing the compound 1 and 4-amino-5-methylpyridine-2-alcohol to obtain a compound 2; ethylating the compound 2 with ethyl orthoformate to obtain a compound 3; hydrolyzing the compound 3 under alkaline conditions to obtain a compound 4; performing CDI activation and ammonolysis on the compound 4 to obtain a compound 5; and carrying out reflux reaction on the compound 5 under the action of a catalyst, and finally carrying out tartaric acid resolution to obtain the non-neferide ketone raw material medicine. According to the invention, the acetoacetic ester is used for replacing 3-oxobutyric acid 2-cyanoethyl ester, so that the raw materials are cheap and easily available, and the synthesis cost and difficulty are greatly reduced; the invention can also avoid high-pressure reaction, greatly improve the safety of the reaction and the production efficiency; after the final step of splitting, the configuration proportion is improved by using a catalyst, and the raw material medicine is obtained with high yield.

Description

Preparation method of non-neferitone bulk drug
Technical Field
The invention belongs to the technical field of organic synthesis and preparation of raw material medicines, and particularly relates to a preparation method of a non-neferitone raw material medicine.
Background
Non-neferitone (BAY 94-8862) is a non-steroidal selective mineralocorticoid receptor antagonist that has been shown in preclinical studies to block the deleterious effects of mineralocorticoid receptor over-activation. In diabetic patients, mineralocorticoid receptor overactivation is thought to lead to chronic kidney disease progression and cardiovascular impairment, which may be driven by metabolic, hemodynamic or inflammatory and fibrotic factors.
Month 7 2021, based on positive results of the FIDELIO-DKD phase III clinical study in adult patients with chronic kidney disease with type 2 diabetes, FDA approved non-nellione (finerenone,
Figure BDA0003583161420000012
) On the market, the non-neferide ketone is submitted to market application in China and other countries around the world and is under examination.
In 12 months 2021, European Medicines Administration (EMA) recommended a marketed application for approval of the nsaid, non-neyrone, by the human medical products Committee (CHMP), and for the treatment of adult patients with chronic kidney disease (stages 3 and 4 with albuminuria) with type 2 diabetes, non-neyrone (10mg or 20mg) which, once approved, would be the first nsaid antagonist to improve the renal prognosis in adult patients with chronic kidney disease with type 2 diabetes.
The chemical structure of the non-nekinone is shown as follows:
Figure BDA0003583161420000011
at present, the patent US2018244668a1 discloses a preparation method of non-nerolidone (Finerenone), which uses 3-oxobutanoic acid 2-cyanoethyl ester as a raw material, and the synthetic route is as follows:
Figure BDA0003583161420000021
the prior art mainly has the following problems: 1) the 3-oxobutyric acid 2-cyanoethyl ester is not common, and the source of raw materials is few, so that the preparation has certain limitation; 2) the second step adopts high-pressure reaction, so that the danger coefficient is high, and the amplification production is not facilitated; 3) the loss of the final splitting step is large, and the like.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a preparation method of a non-neferitone bulk drug.
The technical scheme adopted by the invention is as follows:
a preparation method of a non-neferitone bulk drug comprises the following steps:
(1) 4-formyl-3-methoxybenzonitrile and acetoacetate ester compounds are coupled to obtain a compound 1 with a structural formula shown in (I);
Figure BDA0003583161420000022
(2) dehydrating and cyclizing the compound 1 and 4-amino-5-methylpyridine-2-alcohol to obtain a compound 2 with a structural formula shown in (II);
Figure BDA0003583161420000023
(3) the compound 2 is ethylated by ethyl orthoformate to obtain a compound 3 with a structural formula shown as (III);
Figure BDA0003583161420000031
(4) hydrolyzing the compound 3 under alkaline conditions to obtain a compound 4 with a structural formula shown as (IV);
Figure BDA0003583161420000032
(5) performing CDI activation and ammonolysis on the compound 4 to obtain a compound 5 with a structural formula shown as (V);
Figure BDA0003583161420000033
(6) and carrying out reflux reaction on the compound 5 under the action of a catalyst, and finally carrying out tartaric acid resolution to obtain the non-neferide ketone raw material medicine.
The synthetic route is as follows:
Figure BDA0003583161420000034
preferably, the catalyst in step (6) is S2O8 2-/ZrO2/γ-Al2O3. Experiments prove that the catalyst adopted by the invention can improve the configuration proportion of the bulk drugs.
Preferably, the catalyst is prepared by the following method: weighing 50g of zirconium oxychloride octahydrate, adding 450g of deionized water to prepare a solution with the mass fraction of 10%, slowly dropwise adding ammonia water under the condition of uniform stirring until the pH value reaches 10, and stopping adding the ammonia water to generate a white precipitate Zr (OH)4(ii) a Standing and aging the precipitate for 24 hours; vacuum filtering, and washing with deionized water until no Cl is formed-Drying in infrared ray fast drier; grinding, adding 20g of gamma-Al2O3Uniformly mixing, grinding and sieving with a 100-mesh sieve to obtain mixture powder; after the mixture powder was immersed in 300g of a 10% ammonium persulfate solution; vacuum filtering, infrared drying, and calcining at 650 deg.C for 3 hr in muffle furnace to obtain solid acid catalyst S2O8 2-/ZrO2/γ-Al2O3。
Preferably, the reaction solvent adopted in the step (1) is one or any combination of more than two of xylene, toluene, butanol and isopropanol; the reaction solvent adopted in the step (2) is one or any combination of more than two of dimethylbenzene, methylbenzene, ethanol and isopropanol; the reaction solvent adopted in the step (3) is one or any combination of more than two of DMAC, NMP, DMF and DME; the reaction solvent adopted in the step (4) is one or any combination of more than two of methanol, ethanol, DMF and THF; the reaction solvent adopted in the step (5) is one or any combination of more than two of toluene, acetonitrile, DMF and THF; the reaction solvent adopted in the step (6) is one or any combination of more than two of toluene, xylene, chlorobenzene and NMP.
Preferably, the step (1) is specifically: sequentially adding isopropanol, 4-formyl-3-methoxybenzonitrile, piperidine and acetic acid into a reactor, starting to add acetoacetic ester in batches when the temperature of a reaction liquid is 30 ℃, maintaining the temperature of 30 ℃ to a reflux temperature, and stirring for 1h at the same temperature after dropwise addition is finished; after the reaction is finished, cooling to 0-30 ℃, stirring for 0.5 hour, fully separating the materials, filtering, drying by pressure, washing twice by using ice isopropanol to obtain a product, and drying the product at 55 ℃ to obtain the product; the acetoacetic ester is selected from one of benzyl acetoacetate, methyl acetoacetate, ethyl acetoacetate and tert-butyl acetoacetate; the mol ratio of 4-formyl-3-methoxybenzonitrile, acetoacetic ester, piperidine and acetic acid is 1: 1.1: 0.1: 0.1.
preferably, the step (2) is specifically: adding toluene into a reaction bottle, adding a compound 1 and 4-amino-5-methylpyridine-2-ol, adding p-toluenesulfonic acid, reacting at 60 ℃ to a reflux temperature for 10-24 hours, cooling to 5 ℃ after the reaction is finished, stirring for 0.5 hour, performing suction filtration, rinsing a filter cake with glacial isopropanol to obtain a yellow solid, and drying to obtain a product; wherein the mol ratio of the 4-amino-5-methylpyridine-2-alcohol to the compound 1 to the p-toluenesulfonic acid is 1: 1.05: 0.21.
preferably, the step (3) is specifically: adding a compound 2 into a reaction bottle, adding a solvent DMF (dimethyl formamide), adding triethyl orthoformate, adding sulfuric acid, heating to 60-150 ℃, reacting for 2-6 hours, cooling to room temperature after the reaction is finished, dripping water for precipitation, adding methanol, stirring for 0.5 hour, precipitating a yellow solid product, and drying to obtain a product; wherein the molar ratio of the compound 2 to the triethyl orthoformate to the sulfuric acid is 1: 1.5: 0.1.
preferably, the step (4) is specifically: adding a compound 3 into a reaction bottle, adding a solvent anhydrous THF (tetrahydrofuran), adding potassium trimethylsilanolate, reacting at room temperature-60 ℃ for 1-12 h, after the reaction is finished, adding ethyl acetate for separating liquid, adjusting the pH of a water phase to 5-6 by using concentrated hydrochloric acid, separating out a solid, recrystallizing by using methanol to obtain an off-white solid, and drying to obtain an off-white product; wherein the molar ratio of the compound 3 to the potassium trimethylsilanolate is 1: 2.
preferably, the step (5) is specifically: adding THF (tetrahydrofuran) into a reaction bottle, adding a compound 4, adding CDI (dehydrochlorination) into the reaction bottle, carrying out reflux reaction for 1-12 h at room temperature, adding ammonia water after TLC is finished, carrying out reflux reaction for 1-20 h, adding water to dilute reaction liquid after the reaction is finished, adding ethyl acetate to extract the reaction liquid, washing the reaction liquid with saline water, drying, and carrying out rotary evaporation to dryness to obtain a white solid; wherein the mol ratio of the compound 4 to the CDI to the ammonia water is 1: 1.1: 2 to 10.
Preferably, the step (6) is specifically: adding a solvent xylene into a reaction bottle, adding a compound 5, adding a catalyst, stirring at room temperature to reflux for 1-12 h, and measuring the target configuration by HPLC: non-target configuration 84:16, finishing the rotation structure; filtering, carrying out spin drying on the mother liquor to obtain a crude product, adding ethanol (methanol, isopropanol or propanol can also be selected), adding water, stirring for dissolving, adding D-dibenzoyltartaric acid, heating for refluxing for 1-5 h, cooling to 30 ℃, stirring for 1h, filtering to obtain a crude product, adding the crude product into water, adding a 10% sodium phosphate solution to adjust the pH value to 7.5, stirring for 0.5h, precipitating, filtering to obtain a crude product, and recrystallizing with ethanol to obtain a non-neferide bulk drug; wherein the mol ratio of the compound 5 to the catalyst is 1: 0.2.
in the first step of the invention, common lipids such as methyl acetoacetate, ethyl acetoacetate, tert-butyl acetoacetate and the like are adopted to replace 3-oxobutanoic acid 2-cyanoethyl ester, so that the raw materials are cheap and easy to obtain, and the synthesis cost and difficulty are greatly reduced; in the second step, toluene is used as a solvent, p-toluenesulfonic acid is used for catalysis, and a product can be obtained through a reflux reaction, so that a high-pressure reaction is avoided, and the safety and the production efficiency of the reaction are greatly improved; after the last step of resolution, the other configuration adopts xylene as solvent and adds catalyst S2O8 2-/ZrO2/γ-Al2O3High-temperature reflux can convert the configuration into a required configuration, thereby greatly improving the yieldAnd (4) the ratio.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention avoids high-pressure reaction, and improves the reaction efficiency and safety;
2. the catalyst has the advantages of high activity, good stability, high dispersion degree of active components, long service life, repeated use and the like, and has short preparation flow, simple operation, easy control of reaction and simple equipment requirement;
3. the configuration proportion is improved by using a catalyst, and the raw material medicine is obtained with high yield;
4. by adopting the common C1-C7 lipids such as benzyl acetoacetate, methyl acetoacetate, ethyl acetoacetate, tert-butyl acetoacetate and the like to replace 3-oxobutanoic acid 2-cyanoethyl ester, the raw materials are easy to obtain, the cost is reduced, and the non-neyrone is synthesized efficiently.
Drawings
FIG. 1 is a nuclear magnetic spectrum of prepared non-neferone.
Detailed Description
The invention is further illustrated with reference to specific examples, without however being limited thereto. Those skilled in the art can and should understand that any simple changes or substitutions based on the spirit of the present invention should fall within the protection scope of the present invention.
The raw materials mentioned herein are all available on the market unless otherwise specified, and the percentages mentioned herein are percentages by mass unless otherwise specified.
Catalyst S2O8 2-/ZrO2/γ-Al2O3The preparation of (1):
weighing 50g of zirconium oxychloride octahydrate, adding 450g of deionized water to prepare a solution with the mass fraction of 10%, slowly dropwise adding ammonia water under the condition of uniform stirring until the pH value reaches 10, and stopping adding the ammonia water to generate a white precipitate Zr (OH)4(ii) a Standing and aging the precipitate for 24 hours; vacuum filtering, and washing with deionized water until no Cl is formed-Drying in infrared ray fast drier; grinding, adding 20g of gamma-Al2O3Mixing, grindingSieving with 100 mesh sieve to obtain mixture powder; after the mixture powder was immersed in 300g of a 10% ammonium persulfate solution; vacuum filtering, infrared drying, and calcining at 650 deg.C for 3 hr in muffle furnace to obtain solid acid catalyst S2O8 2-/ZrO2/γ-Al2O3。
Example 1
(1) Synthesis of Compound 1:
Figure BDA0003583161420000061
150g of isopropanol, 33.8g (0.21mol) of 4-formyl-3-methoxybenzonitrile, 1.86g (0.021mol) of piperidine and 1.26g (0.021mol) of acetic acid are sequentially added into a reactor, the temperature of the reaction solution is kept at 30 ℃, the acetoacetic ester is added in batches, the temperature is kept at 35-40 ℃, and after the dropwise addition is finished, the mixture is stirred for 1h at the same temperature. HPLC detection, starting cooling, cooling to T ═ 0-3 ℃, stirring for 0.5 hour, fully separating out materials, filtering, drying under pressure, washing twice with ice isopropanol to obtain a product, drying the product T ═ 55 ℃ to obtain the product, wherein the yield of various acetoacetic acid esters is shown in Table 1:
TABLE 1
Figure BDA0003583161420000071
(2) Synthesis of Compound 2:
Figure BDA0003583161420000072
80g of toluene was charged into a reaction flask, and 14.07g (0.042mol) of Compound 1 and 5g (0.04mol) of 4-amino-5-methylpyridin-2-ol were added to the flask, and 1.44g (0.0084mol) of p-toluenesulfonic acid was added to the flask, and the mixture was heated to reflux reaction for 16 hours. The reaction was complete by TLC and a large amount of yellow solid appeared, stopping the reaction. Cooling to 5 deg.c, stirring for 0.5 hr, suction filtering, rinsing the filter cake with small amount of glacial isopropanol to obtain yellow solid, and stoving to obtain yellow solid 16.3g in 92% yield.
(3) Synthesis of Compound 3:
Figure BDA0003583161420000081
15.4g (0.035mol) of Compound 2 was charged into a reaction flask, 80g of DMF as a solvent was added, 7.8g (0.053mol) of triethyl orthoformate was added, 0.35g (0.0035mol) of sulfuric acid was added, and the mixture was heated to 120 ℃ to react for 4 hours. After the reaction is finished, cooling to room temperature, slowly dropping water for precipitation, adding 10g of methanol, stirring for 0.5h, precipitating a yellow solid product, and drying to obtain a 14.7 product with the yield of 90%.
(4) Synthesis of Compound 4:
Figure BDA0003583161420000082
14.4g (0.0308mol) of compound 3 was charged into a reaction flask, solvent anhydrous THF 80g was added, 7.88g (0.0616mol) potassium trimethylsilanolate was added, reaction was carried out at 30 ℃ for 8 hours, after passing HPLC detection, 80g ethyl acetate was added after completion of the reaction for liquid separation, the aqueous phase was adjusted to pH 5-6 with concentrated hydrochloric acid to precipitate a solid, recrystallization was carried out with 20g methanol to obtain an off-white solid, and drying was carried out to obtain 10.5g of an off-white product with a yield of 90%.
(5) Synthesis of Compound 5:
Figure BDA0003583161420000091
adding 60g of THF (tetrahydrofuran) into a reaction flask, adding 9g (0.0237mol) of compound 4, adding 4.23g (0.0261mol) of CDI, heating to 60 ℃ for reacting for 8h, adding 6.45g of 25% ammonia water after TLC (thin layer chromatography) is finished, carrying out reflux reaction for 12h, adding water to dilute the reaction solution after TLC detection reaction is finished, adding ethyl acetate to extract the reaction solution, washing the reaction solution with saline, drying, and carrying out rotary evaporation to dryness to obtain 7.88g of white solid with the yield of 88%.
(6) Synthesis of Compound 6:
Figure BDA0003583161420000092
the solvent xylene was added to a reaction flask, 7g (0.0185mol) of Compound 5 was added, and 1.4g of catalyst S was added2O8 2-/ZrO2/γ-Al2O3And stirring under reflux for 8 h. HPLC determination of target configuration: the off-target configuration 84:16, end-turn configuration. Filtering, carrying out spin drying on the mother liquor to obtain a crude product, adding 15g of ethanol, adding 5g of water, stirring for dissolving, adding 5.84g (0.0155mol) of D-dibenzoyltartaric acid, heating and refluxing for 3h, cooling to 30 ℃, stirring for 1h, filtering to obtain a crude product, adding the crude product into water, adding a 10% sodium phosphate solution to adjust the pH to 7.5, stirring for 0.5h, precipitating, filtering to obtain a crude product, and recrystallizing with 20g of ethanol to obtain 5.6g of the non-neyrone raw material medicine with the yield of 80%. The nuclear magnetic spectrum of the prepared non-neferide ketone is shown in figure 1.
Example 2
(1) Synthesis of Compound 1:
150g of isopropanol, 33.8g (0.21mol) of 4-formyl-3-methoxybenzonitrile, 1.86g (0.021mol) of piperidine and 1.26g (0.021mol) of acetic acid are sequentially added into a reactor, the temperature T of the reaction solution is 30 ℃, 44.3g (0.231mol) of benzyl acetoacetate are added in portions, the temperature is maintained at 35-40 ℃, and after the dropwise addition, the mixture is stirred at the same temperature for 1 h. And (5) carrying out HPLC detection, and starting cooling. Cooling to 0-3 deg.c, stirring for 0.5 hr, filtering, press drying and washing twice with ice isopropanol to obtain product, and drying at 55 deg.c to obtain 64g of product in 91% yield.
(2) Synthesis of Compound 2:
80g of toluene was charged into a reaction flask, and 14.07g (0.042mol) of Compound 1 and 5g (0.04mol) of 4-amino-5-methylpyridin-2-ol were added thereto, and 1.44g (0.0084mol) of p-toluenesulfonic acid was added thereto, and the mixture was heated to 80 ℃ to react for 26 hours. The reaction was complete by TLC and a large amount of yellow solid appeared, stopping the reaction. Cooling to 5 deg.c, stirring for 0.5 hr, suction filtering, rinsing the filter cake with small amount of ice isopropanol to obtain yellow solid, and stoving to obtain yellow solid 13.6g in yield of 77%.
(3) Synthesis of Compound 3:
15.4g (0.035mol) of Compound 2 was charged into a reaction flask, solvent 80g DMF was added, 6.1g (0.042mol) triethyl orthoformate was added, 0.35g (0.0035mol) sulfuric acid was added, and the temperature was raised to 110 ℃ for reaction for 4 hours. After the reaction is finished, cooling to room temperature, slowly dropping water for precipitation, adding 10g of methanol, stirring for 0.5h, precipitating a yellow solid product, and drying to obtain a 12.6 product with a yield of 76.8%.
(4) Synthesis of Compound 4:
14.4g (0.0308mol) of compound 3 was charged into a reaction flask, solvent anhydrous THF 80g was added, 5.91g (0.0462mol) potassium trimethylsilanolate was added, reaction was carried out at 40 ℃ for 8 hours, after passing HPLC detection, 80g ethyl acetate was added after completion of the reaction for separation, the aqueous phase was adjusted to pH 5-6 with concentrated hydrochloric acid to precipitate a solid, the solid was recrystallized from 20g methanol to give an off-white solid, which was dried to give 8.6g of an off-white product with a yield of 73.7%. EI-MS M/z 380.4[ M + H ]]+。
(5) Synthesis of Compound 5:
adding 60g of THF (tetrahydrofuran) into a reaction flask, adding 9g (0.0237mol) of compound 4, adding 4.23g (0.0261mol) of CDI, heating to 60 ℃ for reacting for 8h, adding 12.8g of 25% ammonia water after TLC (thin layer chromatography) is finished, carrying out reflux reaction for 12h, adding water to dilute the reaction solution after TLC detection reaction is finished, adding ethyl acetate to extract the reaction solution, washing the reaction solution with saline, drying, and carrying out rotary evaporation to dryness to obtain 6.9g of white solid with the yield of 77%.
(6) Synthesis of Compound 6:
the solvent xylene was added to the reaction flask, 7g (0.0185mol) of compound 5 was added, 2.8g of catalyst was added, and the mixture was stirred under reflux for 8 hours. HPLC determination of target configuration: the off-target configuration is 84:16, and the end-turn configuration. Filtering, adding 15g of ethanol, adding 5g of water, stirring to dissolve, adding 5.84g (0.0155mol) of D-dibenzoyltartaric acid, heating and refluxing for 3h, cooling to 30 ℃, stirring for 1h, filtering to obtain a crude product, adding the crude product into water, adding a 10% sodium phosphate solution to adjust the pH to 7.5, stirring for 0.5h, precipitating, filtering to obtain the crude product, and recrystallizing with 20g of ethanol to obtain 5.6g of the non-neferide bulk drug, wherein the yield is 80%.
Example 3
(1) Synthesis of Compound 1:
1500g of isopropanol were added to the reactor successively, 338g (2.1mol) of 4-formyl-3-methoxybenzonitrile, 37.2g (0.42mol) of piperidine and 25.2g (0.42mol) of acetic acid were added, 443g (2.31mol) of benzyl acetoacetate were initially added in portions at a temperature T of 30 ℃ and the temperature was maintained at 35-40 ℃ and after the addition was complete, the mixture was stirred at the same temperature for 1 hour. And (5) carrying out HPLC detection, and starting cooling. The mixture was cooled to 0-3 ℃ and stirred for 0.5h to precipitate thoroughly, filtered, press dried and washed twice with ice isopropanol to give the product, which was dried at 55 ℃ to give 647.22g with 92% yield. EI-MS M/z 336.3[ M + H ]]+。
(2) Synthesis of Compound 2:
500g of toluene was charged in a reaction flask, 201g (0.6mol) of Compound 1 and 50g (0.4mol) of 4-amino-5-methylpyridin-2-ol were added, 14.4g (0.084mol) of p-toluenesulfonic acid was added, and the mixture was heated to reflux reaction for 16 hours. The reaction was complete by TLC and a large amount of yellow solid appeared, stopping the reaction. Cooling to 5 deg.c and stirring for 0.5 hr, suction filtering, rinsing the filter cake with small amount of glacial isopropanol to obtain yellow solid, and stoving to obtain yellow solid 161.46g in 90.8% yield. EI-MS M/z 442.2[ M + H ]]+。
(3) Synthesis of Compound 3:
to a reaction flask was added 154.3g (0.35mol) of compound 2, solvent 1000g of DMF, 78g (0.53mol) of triethyl orthoformate, 3.5g (0.035mol) of sulfuric acid, and the mixture was heated to 130 ℃ for 4 hours. After the reaction is finished, cooling to room temperature, slowly dripping water for precipitation, adding 50g of methanol, stirring for 0.5h, precipitating a yellow solid product, and drying to obtain 147.7 product with the yield of 90%. EI-MS M/z 470.4[ M + H ]]+。
(4) Synthesis of Compound 4:
144.4g (0.308mol) of compound 3 was charged into a reaction flask, 800g of anhydrous THF was added as a solvent, 51.2g (0.4mol) of potassium trimethylsilanolate was added, the reaction was carried out at 30 ℃ for 8 hours, after passing HPLC detection, 800g of ethyl acetate was added after completion of the reaction to separate the solution, the pH of the aqueous phase was adjusted to 5 to 6 with concentrated hydrochloric acid to precipitate a solid, the solid was recrystallized from 300g of methanol to obtain an off-white solid, and the off-white solid was dried to obtain 95g of an off-white product with a yield of 81.4%. EI-MS M/z 380.3[ M + H ]]+。
(5) Synthesis of Compound 5:
adding 600g of THF (tetrahydrofuran) into a reaction bottle, adding 90g (0.237mol) of compound 4, adding 57.5g (0.355mol) of CDI, heating to 60 ℃ for reaction for 8h, adding 160g of 25% ammonia water after TLC is finished, carrying out reflux reaction for 12h, adding water to dilute the reaction solution after TLC detection reaction is finished, adding ethyl acetate to extract the reaction solution, washing the reaction solution with saline, drying, and carrying out rotary evaporation to dryness to obtain 78g of white solid with the yield of 87%. EI-MS M/z 379.4[ M + H ]]+。
(6) Synthesis of Compound 6:
the solvent xylene was added to the reaction flask, 70g (0.185mol) of Compound 5 was added, 30g of catalyst was added, and the mixture was stirred under reflux for 8 hours. HPLC determination of target configuration: the off-target configuration 84:16, end-turn configuration. Filtering, adding 150g of ethanol, adding 50g of water, stirring to dissolve, adding 58.4g (0.155mol) of D-dibenzoyltartaric acid, heating and refluxing for 3h, cooling to 30 ℃, stirring for 1h, filtering to obtain a crude product, adding the crude product into water, adding a 10% sodium phosphate solution to adjust the pH to 7.5, stirring for 0.5h, precipitating, filtering to obtain the crude product, and recrystallizing with 200g of ethanol to obtain 56g of the non-neferide ketone bulk drug with the yield of 80%. EI-MS M/z 379.4[ M + H ]]+。
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.

Claims (10)

1. A preparation method of a non-naltrexone raw material medicine is characterized by comprising the following steps:
(1) 4-formyl-3-methoxybenzonitrile and acetoacetate ester compounds are coupled to obtain a compound 1 with a structural formula shown in (I);
Figure FDA0003583161410000011
(2) dehydrating and cyclizing the compound 1 and 4-amino-5-methylpyridine-2-alcohol to obtain a compound 2 with a structural formula shown in (II);
Figure FDA0003583161410000012
(3) the compound 2 is ethylated by ethyl orthoformate to obtain a compound 3 with a structural formula shown as (III);
Figure FDA0003583161410000013
(4) hydrolyzing the compound 3 under alkaline conditions to obtain a compound 4 with a structural formula shown as (IV);
Figure FDA0003583161410000014
(5) performing CDI activation and ammonolysis on the compound 4 to obtain a compound 5 with a structural formula shown as (V);
Figure FDA0003583161410000021
(6) and carrying out reflux reaction on the compound 5 under the action of a catalyst, and finally carrying out tartaric acid resolution to obtain the non-neferide ketone raw material medicine.
2. The method of claim 1 for preparing a non-neferitone drug substance, wherein: in the step (6), the catalyst is S2O8 2-/ZrO2/γ-Al2O3。
3. The method of claim 2 for preparing a non-neupon drug substance, wherein: the catalyst is prepared by the following method: 50g of eight are weighedAdding 450g of deionized water into zirconium oxychloride hydrate to prepare a solution with the mass fraction of 10%, slowly dripping ammonia water under the condition of uniform stirring until the pH value reaches 10, and stopping adding the ammonia water to generate a white precipitate Zr (OH)4(ii) a Standing and aging the precipitate for 24 hours; vacuum filtering, and washing with deionized water until no Cl is formed-Drying in infrared ray fast drier; grinding, adding 20g of gamma-Al2O3Uniformly mixing, grinding and sieving with a 100-mesh sieve to obtain mixture powder; after the mixture powder was immersed in 300g of a 10% ammonium persulfate solution; vacuum filtering, infrared drying, and calcining at 650 deg.C for 3 hr in muffle furnace to obtain solid acid catalyst S2O8 2-/ZrO2/γ-Al2O3。
4. The method of claim 2 for preparing a non-neupon drug substance, wherein: the reaction solvent adopted in the step (1) is one or any combination of more than two of dimethylbenzene, methylbenzene, butanol and isopropanol; the reaction solvent adopted in the step (2) is one or any combination of more than two of dimethylbenzene, methylbenzene, ethanol and isopropanol; the reaction solvent adopted in the step (3) is one or any combination of more than two of DMAC, NMP, DMF and DME; the reaction solvent adopted in the step (4) is one or any combination of more than two of methanol, ethanol, DMF and THF; the reaction solvent adopted in the step (5) is one or any combination of more than two of toluene, acetonitrile, DMF and THF; the reaction solvent adopted in the step (6) is one or any combination of more than two of toluene, xylene, chlorobenzene and NMP.
5. The method for preparing a non-neferitone drug substance as claimed in claim 3, wherein the step (1) is specifically as follows: sequentially adding isopropanol, 4-formyl-3-methoxybenzonitrile, piperidine and acetic acid into a reactor, keeping the temperature of the reaction liquid at 30 ℃, adding acetoacetic ester in batches, keeping the temperature at 30 ℃ to the reflux temperature, and stirring for 1h at the same temperature after dropwise addition; after the reaction is finished, cooling to 0-30 ℃, stirring for 0.5 hour, fully separating the materials, filtering, drying by pressure, washing twice by using ice isopropanol to obtain a product, and drying the product at 55 ℃ to obtain the product; the acetoacetic ester is selected from one of benzyl acetoacetate, methyl acetoacetate, ethyl acetoacetate and tert-butyl acetoacetate; the mol ratio of 4-formyl-3-methoxybenzonitrile, acetoacetic ester, piperidine and acetic acid is 1: 1.1: 0.1: 0.1.
6. the method for preparing a non-neferone drug substance according to claim 3, wherein the step (2) is specifically: adding toluene into a reaction bottle, adding a compound 1 and 4-amino-5-methylpyridine-2-ol, adding p-toluenesulfonic acid, reacting at 60 ℃ to a reflux temperature for 10-24 hours, cooling to 5 ℃ after the reaction is finished, stirring for 0.5 hour, performing suction filtration, rinsing a filter cake with glacial isopropanol to obtain a yellow solid, and drying to obtain a product; wherein the mol ratio of the 4-amino-5-methylpyridine-2-alcohol to the compound 1 to the p-toluenesulfonic acid is 1: 1.05: 0.21.
7. the method for preparing a non-neferitone drug substance as claimed in claim 3, wherein the step (3) is specifically as follows: adding a compound 2 into a reaction bottle, adding a solvent DMF, adding triethyl orthoformate, adding sulfuric acid, heating to 60-150 ℃ for reaction for 2-6 hours, cooling to room temperature after the reaction is finished, dropwise adding water for precipitation, adding methanol, stirring for 0.5 hour, precipitating a yellow solid product, and drying to obtain a product; wherein the mol ratio of the compound 2 to the triethyl orthoformate to the sulfuric acid is 1: 1.5: 0.1.
8. the method for preparing a non-neferitone drug substance as claimed in claim 3, wherein the step (4) is specifically as follows: adding a compound 3 into a reaction bottle, adding a solvent anhydrous THF (tetrahydrofuran), adding potassium trimethylsilanolate, reacting at room temperature-60 ℃ for 1-12 h, after the reaction is finished, adding ethyl acetate for separating liquid, adjusting the pH of a water phase to 5-6 by using concentrated hydrochloric acid, separating out a solid, recrystallizing by using methanol to obtain an off-white solid, and drying to obtain an off-white product; wherein the molar ratio of the compound 3 to the potassium trimethylsilanolate is 1: 2.
9. the method for preparing a non-neferitone drug substance as claimed in claim 3, wherein the step (5) is specifically: adding THF (tetrahydrofuran) into a reaction bottle, adding a compound 4, adding CDI (dehydrochlorination) into the reaction bottle, carrying out reflux reaction for 1-12 h at room temperature, adding ammonia water after TLC is finished, carrying out reflux reaction for 1-20 h, adding water to dilute reaction liquid after the reaction is finished, adding ethyl acetate to extract the reaction liquid, washing the reaction liquid with saline water, drying, and carrying out rotary evaporation to dryness to obtain a white solid; wherein the mol ratio of the compound 4 to the CDI to the ammonia water is 1: 1.1: 2 to 10.
10. The method for preparing a non-neferitone drug substance as claimed in claim 3, wherein the step (6) is specifically as follows: adding a solvent xylene into a reaction bottle, adding a compound 5, adding a catalyst, stirring at room temperature to reflux for 1-12 h, and measuring the target configuration by HPLC: non-target configuration 84:16, finishing the rotation structure; filtering, carrying out spin drying on the mother liquor to obtain a crude product, adding ethanol, adding water, stirring for dissolving, adding D-dibenzoyltartaric acid, heating and refluxing for 1-5 h, cooling to 30 ℃, stirring for 1h, filtering to obtain a crude product, adding the crude product into water, adding a 10% sodium phosphate solution, adjusting the pH value to 7.5, stirring for 0.5h, precipitating, filtering to obtain a crude product, and recrystallizing with ethanol to obtain a non-neferitone bulk drug; wherein the mol ratio of the compound 5 to the catalyst is 1: 0.2.
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