Process for the preparation of high purity monopantyl of r / s configuration

Abstract

The application discloses a preparation method of high-purity R / S configuration monensin, and belongs to the technical field of veterinary drugs. The application is characterized in that: compound 3 is prepared by docking 3-hydroxy-4-(trifluoromethyl) benzyl cyanide with chloroacetone; compound 4 is prepared by reacting compound 3 with R / S-tert-butyl sulfoximine; compound 5 is prepared by reacting compound 4 with a cyano-containing compound; compound 6 is obtained by deprotection of compound 5 under the action of an acid; and finally, the target product R / S configuration monensin is obtained by amide docking of compound 6 and compound 7. Compared with the existing preparation method, the preparation process directly constructs a chiral center by a chemical synthesis method, avoids chiral chromatographic separation, is simple in process, easy in reaction, and is more suitable for industrial amplification and production, because the HPLC purity of the obtained monensin is greater than 99.00%, and the ee value is greater than 99.5%.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drug technology, specifically, it relates to a method for preparing high-purity R / S configuration monoterpenes. Background Technology

[0002] Monepantel, chemically named N-[(1S)-1-cyano-2-[5-cyano-2-(trifluoromethyl)phenoxy]-1-methylethyl]-4-[(trifluoromethyl)thio]benzamide, has a chiral center in its structure. The S configuration is the pharmaceutically effective configuration, while the R configuration is a chiral isomer impurity that needs to be controlled in the Monepantel active pharmaceutical ingredient. Monepantel is a novel aminoacetonitrile derivative anthelmintic developed by Novartis Animal Health. Monepantel oral solution (trade name ZOLVIX) ® It was first approved for marketing in Europe in September 2009 for the treatment and control of intestinal worm infection in sheep. Subsequently, the drug was marketed in countries such as Australia, New Zealand, and Brazil.

[0003] Currently, only the original manufacturer has reported the preparation method of mononitrate active pharmaceutical ingredient in the literature [Kaminsky R, Ducray P, et al. A new class of anthelmintics effective against drug-resistant nematodes[J]. Nature, 2008, 452(7184): 176-180]. The preparation method uses the highly toxic compound NaCN, which poses serious safety problems during the production process; and obtaining the S-configuration active pharmaceutical ingredient through chiral resolution is expensive and not conducive to industrial scale-up. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a method for preparing high-purity R / S configuration monotertyl. The method involves reacting compound 1 [3-hydroxy-4-(trifluoromethyl)benzylnitrile] with compound 2 (chloroacetone) to prepare compound 3. Compound 3 then reacts with R / S-tert-butylsulfonylimide to prepare compound 4. Compound 4 reacts with a cyano-containing compound to prepare compound 5. Compound 5 is deprotected under acid to obtain compound 6. Finally, compound 6 is amidated with compound 7 to obtain the target product, monotertyl. Compared with existing methods, this invention directly constructs the chiral center through chemical synthesis, avoiding chiral chromatographic separation. The process is simpler and the reaction is easier. The obtained monotertyl has an HPLC purity greater than 99.00% and an ee value greater than 99.5%, making it more suitable for industrial scale-up and production.

[0005] The objective of this invention can be achieved through the following technical solutions: A method for preparing high-purity R / S configuration monotyl, the synthetic route of which is shown below: In compound 7, L represents: carboxylic acid (-COOH); acyl chloride (-COCl); halogen (chlorine, bromine, iodine) atom; and carboxylic acid ester (-COOR). 1 ), R 1 For independent C 1-6 Alkyl, C 1-6 Halogenated alkane, alkoxy, phenyl or substituted phenyl.

[0006] The specific steps are as follows: (1) In a polar aprotic solvent, under the condition of the presence of an acid-binding agent, 3-hydroxy-4-(trifluoromethyl)benzyl nitrile reacts with chloroacetone to give compound 3; (2) Under the protection of an inert gas, compound 3 and R / S-tert-butylsulfonylimide were dissolved in a polar aprotic solvent, and tetraisopropyl titanate was added dropwise at a controlled temperature to react and obtain compound 4. (3) Under the protection of an inert gas, compound 4 was dissolved in a polar aprotic solvent, and cyanide solution was added dropwise at a controlled temperature to react and obtain compound 5; (4) Under the protection of an inert gas, compound 5 was dissolved in a polar aprotic solvent, and acid solution was added dropwise at a controlled temperature to deprotect the compound 6. (5) Dissolve compound 6 in a polar aprotic solvent, add compound 7, and react under certain conditions to form an amide bond structure to obtain monotereil.

[0007] Furthermore, in step (1), the molar ratio of 3-hydroxy-4-(trifluoromethyl)benzyl nitrile, chloroacetone, and acid-binding agent is 1:1~1.5:1~1.5; the acid-binding agent is one of alkali metal carbonate and alkali metal hydroxide; the polar aprotic solvent is one of DMF, DMSO, THF, acetonitrile, and acetone.

[0008] Furthermore, in step (2), the molar ratio of compound 3, R / S-tert-butylsulfonylimide, and tetraisopropyl titanate is 1:1~1.5:1.5~2.5; the polar aprotic solvent is one of DMF, DMSO, THF, acetonitrile, and acetone.

[0009] Furthermore, in step (3), the molar ratio of compound 4 to cyanide is 1:1 to 1.5; the cyanide is one of sodium cyanide, potassium cyanide, trimethylcyanosilane or acetone cyanohydrin; the polar aprotic solvent is one of DMF, DMSO, THF, acetonitrile or dichloromethane.

[0010] Furthermore, in step (4), the molar ratio of compound 5 to acid is 1:1 to 2.0; the acid is one of hydrochloric acid, sulfuric acid, and acetic acid; the polar aprotic solvent is one of DMF, DMSO, THF, ethyl acetate, and dioxane.

[0011] Furthermore, in step (5), when L in the structure of compound 7 is a carboxylic acid, a condensing agent is added to carry out the reaction, and the molar ratio of compound 6, compound 7 and condensing agent is 1:1~1.5:1:1.5; the condensing agent is one of EDCI / HOBt, CDI, PyBOP / iPr2NEt, and HATU. When L in the structure of compound 7 is an acyl chloride, an acid-binding agent is added to carry out the reaction. The molar ratio of compound 6, compound 7, and acid-binding agent is 1:1~1.5:1~2.0. The acid-binding agent is one of alkali metal carbonate, alkali metal hydroxide, or organic amine compound. When L in the structure of compound 7 is a carboxylic ester -COOR 1 At that time, the molar ratio of compound 6 to compound 7 was 1:1 to 1.5, and the reaction was carried out under heating conditions; When L is a halogen atom in the structure of compound 7, the reaction is carried out in a reactor under the conditions of a transition metal catalyst, an organic ligand, and a base, with CO introduced at a certain pressure. The molar ratio of compound 6, compound 7, and base is 1:1~1.5:1~2.0. The amount of metal catalyst is 2%~6% of the molar amount of compound 6, the amount of ligand is 2%~10% of the molar amount of compound 6, and the CO gas pressure is 1 atm~10 atm. The catalyst is a complex of palladium, platinum, and rhodium. The organic ligand is one of dppf (1,1'-bis(diphenylphosphine)ferrocene), Xantphos (4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene), and BrettPhos (2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tris-1-propyl-11'-biphenyl). The base is one of alkali metal carbonate and alkali metal hydroxide. The polar aprotic solvent is one of DMF, DMSO, methanol, ethanol, THF, ethyl acetate, dichloromethane, acetonitrile, toluene, and dioxane.

[0012] Furthermore, the inert gas in steps (2) to (4) is nitrogen or argon.

[0013] The beneficial effects of this invention are: 1. By utilizing the steric hindrance of R-tert-butylsulfonylimide as a basis for chiral localization, the target chiral compound can be obtained directly, avoiding the chiral resolution process, improving the utilization rate of raw materials, and controlling chiral impurities within the standard range (ee value greater than 99.5%).

[0014] 2. Using TMSCN or acetone cyanohydrin as the cyaniding reagent can avoid the use of highly toxic raw material NaCN and improve process safety.

[0015] 3. By utilizing the steric hindrance of S-tert-butylsulfonylimide as a basis for chiral localization, R-monetil can be obtained directly. The operation is simple, the product has high chiral purity, and it can be directly used for the analysis and research of isomer impurities in the monoteretil active pharmaceutical ingredient, ensuring the safety and reliability of the monoteretil active pharmaceutical ingredient quality. Attached Figure Description

[0016] The invention will now be further described with reference to the accompanying drawings.

[0017] Figure 1 The hydrogen nuclear magnetic resonance spectrum of Moneter prepared in Example 5.

[0018] Figure 2 The image shows the carbon NMR spectrum of Moneter prepared in Example 5.

[0019] Figure 3 The mass spectra of Monetair prepared in Example 5 are shown.

[0020] Figure 4 The liquid phase spectrum of Monetate prepared in Example 5 is shown.

[0021] Figure 5 The liquid chromatography spectrum of Monetair-racemic reference standard.

[0022] Figure 6 The liquid chromatography spectrum for determining the chiral purity of the Moneter-S configuration prepared in Example 5 is shown.

[0023] Figure 7 The results of optical rotation tests are for the Moneter-S configuration prepared in Example 5.

[0024] Figure 8 The liquid chromatography spectrum for determining the chiral purity of the Moneter-R configuration prepared in Example 6 is shown.

[0025] Figure 9 The results of optical rotation tests are for the Moneter-R configuration prepared in Example 6. Detailed Implementation

[0026] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0027] Example 1: Synthesis of Compound 3 Compound 1 [3-hydroxy-4-(trifluoromethyl)benzyl nitrile, 18.7 g, 0.1 mol], compound 2 (chloroacetone, 9.2 g, 0.1 mol), potassium carbonate (13.8 g, 0.1 mol) and DMF (200 ml) were added to a dry reactor. The air was replaced with nitrogen three times, the temperature was raised to 80-90 °C, and the reaction was stirred and kept at this temperature for 16 h.

[0028] After the reaction was completed, the DMF was concentrated under reduced pressure. Water (250 ml) and ethyl acetate (250 ml) were added to the residue, and the mixture was stirred and separated. The organic layer was washed once with water, dried, and the ethyl acetate was concentrated under reduced pressure to give compound 3 (22.79 g, 0.0937 ml), with a yield of 93.7%.

[0029] Example 2: Synthesis of Compound 4 Compound 3 (24.3 g, 0.1 mol), R-tert-butylsulfonylimide (13.3 g, 0.11 mol), and THF (100 ml) were added to a dry reactor and stirred. The air was replaced with nitrogen three times. After the replacement was completed, the temperature was controlled below 60 °C. Tetraisopropyl titanate (56.8 g, 0.2 mol) was added dropwise over 30 min. The reaction was maintained at 60-70 °C for 1 h.

[0030] After the reaction was completed, the THF was concentrated under reduced pressure, and ethyl acetate (200 ml) was added and stirred to dissolve. The mixture was washed once with saturated sodium bicarbonate solution and once with water. After the organic layer was dried, the ethyl acetate was concentrated under reduced pressure to obtain compound 4 (28.47 g, 0.0822 mol), with a yield of 82.2%.

[0031] Example 3: Synthesis of Compound 5 Compound 4 (34.6 g, 0.1 mol) and THF (200 ml) were added to a dry reactor and stirred. The air was replaced with nitrogen three times, and the temperature was controlled below 20 °C during the replacement. TMSCN (10.9 g, 0.11 mol) was added dropwise over 20 min. The reaction was maintained at 20-30 °C for 4 h.

[0032] After the reaction was completed, the THF was concentrated under reduced pressure, ethyl acetate (200 ml) was added and stirred to dissolve, water was added to wash once, the organic layer was dried and the ethyl acetate was concentrated under reduced pressure to give compound 5 (31.4 g, 0.0841 mol), with a yield of 84.1%.

[0033] Example 4: Synthesis of Compound 6 Add compound 5 (37.3 g, 0.1 mol) and THF (100 ml) to a dry reactor and stir to mix. Replace the air with nitrogen three times, keeping the temperature below 20°C during the replacement process. Add 1N HCl solution (100 ml, 0.1 mol) dropwise over 30 min and maintain the reaction temperature at 20-30°C for 2 h.

[0034] After the reaction was completed, the THF was concentrated under reduced pressure, and ethyl acetate (200 ml) was added and stirred to dissolve. The organic layer was separated, washed once with water, dried, and then concentrated under reduced pressure to obtain compound 6 (25.25 g, 0.0938 mol), with a yield of 93.8%.

[0035] Example 5: Synthesis of Monetate 5-1: Compound 6 (26.9 g, 0.1 mol), compound 7-1 (24.4 g, 0.11 mol), CDI (16.2 g, 0.1 mol), and DMF (250 ml) were added to a dry reactor and stirred. The air was replaced with nitrogen three times, and the reaction was maintained at 40-50 °C for 16 h.

[0036] After the reaction was complete, the DMF was concentrated under reduced pressure, and ethyl acetate (200 ml) was added and stirred to dissolve. The mixture was then washed once with saturated sodium bicarbonate solution and once with water. After drying the organic layer, half of the ethyl acetate was concentrated under reduced pressure. The mixture was cooled to 0°C, and a solid precipitated. After stirring and crystallizing for 1 hour, the crystals were filtered and dried to obtain monotyl (42.23 g, 0.0892 mol), with a yield of 89.3%. Figures 1-4 The image shows the characterization spectra of the prepared Monetaire; as shown. Figures 5-7 The image shows the chiral purity spectrum of Monetair, indicating that the target chiral compound obtained by this invention avoids the chiral separation process.

[0037] 5-2: Add compound 6 (26.9 g, 0.1 mol) and triethylamine (13.13 g, 0.13 mol) dissolved in 250 ml of dichloromethane to a dry reactor. Then, slowly add a solution of compound 7-2 (26.5 g, 0.11 mol) (dissolved in 50 ml) at a temperature of 0-10 °C. After the addition is complete, react at a temperature of 20-30 °C for 3-4 h.

[0038] After the reaction was completed, the reaction solution was washed successively with sodium chloride solution and sodium bicarbonate solution at a controlled temperature of 0~10℃. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. Then, it was recrystallized with ethyl acetate / n-heptane to obtain monotyl (43.13 g, 0.0912 mol) with a yield of 91.2%.

[0039] 5-3: Compound 6 (26.9 g, 0.1 mol) and compound 7-3 (25.98 g, 0.11 mol) were added to a dry reactor and dissolved in 300 mL of toluene. The system was then heated to reflux for 8-10 h.

[0040] After the reaction was completed, the reaction solution was concentrated to dryness and then recrystallized with ethyl acetate / n-heptane to obtain monotyl (39.39 g, 0.0832 mol) in 83.2% yield.

[0041] 5-4: Compound 6 (26.9 g, 0.1 mol), compound 7-4 (23.39 g, 0.11 mol), Cs₂CO₃ (52.93 g, 0.15 mol), Pd(OAc)₂ (0.45 g, 0.002 mol), Xantphos (1.14 g, 0.004 mol), and 300 mL of dioxane were added to a clean, high-pressure reactor. After three purgings with nitrogen gas at 0.1 MPa, the reactor was purged three times with CO gas. The reactor pressure was then controlled at 2–3 atm, and the temperature at 50–60 °C for 8–10 h. After the reaction was completed, the mixture was filtered, the organic phase was concentrated, and then purified by recrystallization from isopropanol / n-heptane and ethyl acetate / n-heptane to obtain monotyl (25.94 g, 0.0548 mol) in 54.8% yield.

[0042] Example 6 By replacing R-tert-butylsulfonylimide with S-tert-butylsulfonylimide in Example 2, and following the operating steps of Examples 2 to 5, the R-configuration of Monetate (i.e., the chiral isomer of Monetate) can be obtained, such as... Figures 8-9 The image shown is its chiral purity spectrum.

[0043] Synthesis of Compound 3 in Examples 7 to 9 Other conditions are the same as in Example 1, except that the molar ratio of compound 1, compound 2, and acid-binding agent, and the type of acid-binding agent are changed. The reaction conditions and yields of Examples 1 and 7 to 9 are detailed in Table 1.

[0044] Table 1. Different conditions and results for Examples 1, 7 to 9 one 1:1:1 Potassium carbonate 93.7 seven 1:1.2:1.2 Potassium carbonate 91.8 eight 1:1:1 Sodium carbonate 92.5 Nine 1:1:1 potassium hydroxide 90.3 Synthesis of Compound 4 in Examples 10 and 11 Other conditions are the same as in Example 2, except that the molar ratio of compound 3, R-tert-butylsulfonylimide, and tetraisopropyl titanate is changed. The reaction conditions and yields of Examples 2 and 10 to 11 are detailed in Table 2.

[0045] Table 2. Different conditions and results of Examples 2, 10, and 11 two 1:1.1:2 82.2 ten 1:1:1.5 78.2 eleven 1:1.5:2.5 75.6 Synthesis of Compound 5 in Examples Twelve and Thirteen Other conditions are the same as in Example 3, except that the molar ratio of compound 4 to TMSCN is changed. The reaction conditions and yields of Examples 3 and 12 to 13 are detailed in Table 3.

[0046] Table 3. Different conditions and results of Examples 3, 12 and 13 three 1:1.1 84.1 twelve 1:1 82.3 Thirteen 1:1.5 83.8 Synthesis of Compound 6 in Examples Fourteen to Sixteen Other conditions are the same as in Example 4, except that the molar ratio of compound 5 to acid and the type of acid binder are changed. The reaction conditions and yields of Examples 4 and 14 to 16 are detailed in Table 4.

[0047] Table 4. Results under different conditions in Examples 4, 14 to 16 Four 1:1 hydrochloric acid 93.8 fourteen 1:1.2 hydrochloric acid 92.8 fifteen 1:1 sulfuric acid 90.5 sixteen 1:1 acetic acid 91.2 Synthesis of Monetaire in Examples 17 to 19 Other conditions are the same as in Example 5, except that the molar ratio of compound 6 and compound 7, the type of condensing agent, and the reaction conditions and yields of Examples 5, 17 to 19 are detailed in Table 5.

[0048] Table 5. Results under different conditions in Examples 5, 17 to 19 five 1:1.1:1 CDI 89.3 Seventeen 1:1:1 CDI 87.9 eighteen 1:1.5:1.2 CDI 88.2 nineteen 1:1.1:1 EDCI / HOBt 87.1 The above detailed embodiments provide a specific description of the analytical methods involved in this invention. It should be noted that the above description is only intended to help those skilled in the art better understand the methods and ideas of this invention, and is not intended to limit the scope of the invention. Without departing from the principles of this invention, those skilled in the art can make appropriate adjustments or modifications to this invention, and such adjustments and modifications should also fall within the protection scope of this invention.

Claims

1. A method for preparing high-purity R / S configuration monotyl, characterized in that, The synthetic route is shown below: In compound 7, L represents a carboxylic acid, acyl chloride, halogen atom, or carboxylic acid ester -COOR. 1 Any one of them.

2. The method for preparing high-purity R / S configuration monotereyl according to claim 1, characterized in that, The specific steps are as follows: (1) In a polar aprotic solvent, under the condition of the presence of an acid-binding agent, 3-hydroxy-4-(trifluoromethyl)benzyl nitrile reacts with chloroacetone to give compound 3; (2) Under the protection of an inert gas, compound 3 and R / S-tert-butylsulfonylimide were dissolved in a polar aprotic solvent, and tetraisopropyl titanate was added dropwise at a controlled temperature to react and obtain compound 4. (3) Under the protection of an inert gas, compound 4 was dissolved in a polar aprotic solvent, and cyanide solution was added dropwise at a controlled temperature to react and obtain compound 5; (4) Under the protection of an inert gas, compound 5 was dissolved in a polar aprotic solvent, and acid solution was added dropwise at a controlled temperature to deprotect the compound 6. (5) Dissolve compound 6 in a polar aprotic solvent, add compound 7, and react under certain conditions to form an amide bond structure to obtain monotereil.

3. The method for preparing high-purity R / S configuration monotereyl according to claim 2, characterized in that, In step (1), the molar ratio of 3-hydroxy-4-(trifluoromethyl)benzyl nitrile, chloroacetone, and acid-binding agent is 1:1~1.5:1~1.5; the acid-binding agent is one of alkali metal carbonate and alkali metal hydroxide; the polar aprotic solvent is one of DMF, DMSO, THF, acetonitrile, and acetone.

4. The method for preparing high-purity R / S configuration monotyl according to claim 2, characterized in that, In step (2), the molar ratio of compound 3, R / S-tert-butylsulfonylimide, and tetraisopropyl titanate is 1:1~1.5:1.5~2.5; the polar aprotic solvent is one of DMF, DMSO, THF, acetonitrile, and acetone.

5. The method for preparing high-purity R / S configuration monotereyl according to claim 2, characterized in that, In step (3), the molar ratio of compound 4 to cyanide is 1:1 to 1.5; the cyanide is one of sodium cyanide, potassium cyanide, trimethylcyanosilane or acetone cyanohydrin; the polar aprotic solvent is one of DMF, DMSO, THF, acetonitrile or dichloromethane.

6. The method for preparing high-purity R / S configuration monotyl according to claim 2, characterized in that, In step (4), the molar ratio of compound 5 to acid is 1:1 to 2.0; the acid is one of hydrochloric acid, sulfuric acid, and acetic acid; the polar aprotic solvent is one of DMF, DMSO, THF, ethyl acetate, and dioxane.

7. The method for preparing high-purity R / S configuration monotyl according to claim 2, characterized in that, In step (5), when L in the structure of compound 7 is a carboxylic acid, a condensing agent is added to carry out the reaction. The molar ratio of compound 6, compound 7 and condensing agent is 1:1 to 1.5:1:1.

5. The condensing agent is one of EDCI / HOBt, CDI, PyBOP / iPr2NEt, and HATU. When L in the structure of compound 7 is an acyl chloride, an acid-binding agent is added to carry out the reaction. The molar ratio of compound 6, compound 7, and acid-binding agent is 1:1~1.5:1~2.

0. The acid-binding agent is one of alkali metal carbonate, alkali metal hydroxide, or organic amine compound. When L in the structure of compound 7 is a carboxylic ester -COOR 1 At that time, the molar ratio of compound 6 to compound 7 was 1:1 to 1.5, and the reaction was carried out under heating conditions; When L in the structure of compound 7 is a halogen atom, CO is introduced into the reactor at a certain pressure to carry out the reaction under the conditions of a transition metal catalyst, an organic ligand, and a base. The molar ratio of compound 6, compound 7, and base is 1:1~1.5:1~2.

0. The amount of metal catalyst is 2%~6% of the molar amount of compound 6, the amount of ligand is 2%~10% of the molar amount of compound 6, and the CO gas pressure is 1 atm~10 atm. The catalyst is a complex of palladium, platinum, and rhodium, the organic ligand is one of dppf, Xantphos, and BrettPhos, and the base is one of alkali metal carbonate and alkali metal hydroxide. The polar aprotic solvent is one of DMF, DMSO, methanol, ethanol, THF, ethyl acetate, dichloromethane, acetonitrile, toluene, and dioxane.

8. The method for preparing high-purity R / S configuration monotereyl according to claim 2, characterized in that, In steps (2) to (4), the inert gas is either nitrogen or argon.

9. A method for preparing high-purity R / S configuration monotereyl according to claim 1 or 7, characterized in that, The carboxylic acid ester - COOR 1 Chinese R 1 For independent C 1-6 Alkyl, C 1-6 Halogenated alkane, alkoxy, phenyl, or substituted phenyl; the halogen atom is one of chlorine, bromine, or iodine.

10. A method for preparing high-purity R / S configuration monotereyl according to claim 1 or 2, characterized in that, When the tert-butylsulfonyl imide used in step (2) is in the R configuration, the product obtained is the S configuration of monotel; when the tert-butylsulfonyl imide used is in the S configuration, the product obtained is the R configuration of monotel.

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