Monepantel key intermediate and resolution method thereof

Abstract

The invention belongs to the technical field of organic synthesis and drug intermediate preparation, and relates to a resolution preparation method of a monepantel key intermediate. In the first aspect, the invention provides a preparation method of a compound shown as a formula 3, which comprises the following steps: # imgabs0 #, in which R1 is selected from TMS, TES, TBDMS, TIPS, TBDPS or # imgabs1 #, the reaction is as follows: # imgabs2 # comprises the following steps: step 2, reacting a compound shown as a formula 2 with an ammonia source and a cyaniding reagent to obtain the compound shown as the formula 3; according to the method 2, the reaction is as follows: # imgabs3 # comprises the following steps: step 5, a compound shown in a formula 7 is subjected to the action of ammonia gas to obtain a compound shown in a formula 3; on the second aspect, the invention provides a preparation method of a compound shown as a formula 5, and the reaction is as follows: # imgabs4, in which R1 is as described in the first aspect; the method comprises the following steps: step 3, obtaining a compound shown as a formula 5 from a compound shown as a formula 3 under the action of a resolving agent. The method disclosed by the invention is higher in yield, simpler in post-treatment and simple and convenient to operate, and has a good industrial production prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and preparation of pharmaceutical intermediates, and particularly relates to a splitting and preparation method of a veterinary drug monepantel intermediate. Background Art

[0002] As a new type of anti-insect drug, monepantel has been recognized in veterinary clinics for its good anti-insect effect, especially for nematodes that have developed drug resistance. Since the drug is not easy to develop drug resistance and has low toxicity, monepantel will play an important role in the prevention and treatment of parasitic diseases in animals in the future.

[0003] The key intermediate of monepantel is formula 3, and the structural formula is as follows:

[0004]

[0005] Wherein, R1 is selected from trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS) or

[0006] The prior art reports the preparation method of aminonitrile compounds as follows:

[0007] 1) The route disclosed in WO2006067430A1 is as follows:

[0008]

[0009] 1-(tert-butyldimethylsilyloxy)-2-acetone is used as a raw material to react with potassium cyanide and dimethylamine hydrochloride. The yield of the product is only 45%, which is too low to be conducive to industrial production.

[0010] 2) The routes disclosed in CN101600687B and WO2008096231A8 are as follows:

[0011]

[0012] 1-Hydroxyacetone reacts with sodium cyanide, ammonium chloride, and ammonia / methanol at room temperature for 23 hours, with a yield of 41%; the yield is low, and there are many by-products, which are difficult to purify and are not suitable for industrial production;.

[0013] The prior art reports on the separation and freeing methods of aminonitrile compounds are as follows:

[0014] The route disclosed in CN1665760A is as follows:

[0015]

[0016] The racemate was resolved by tartaric acid to obtain the target configuration, but the yield was only 36.7%, which is not conducive to commercial production for a reaction with relatively expensive raw materials.

[0017] CN101056849B discloses the following structure split and then racemized in the inferior configuration:

[0018]

[0019] It uses NaCN and dioxane to react at 101°C for 8 to 9 hours. This process route uses sodium cyanide again, which is a highly toxic substance and increases the process risk. At the same time, it does not involve the yield and racemization effect under this condition.

[0020] In view of the problems of low yield, long reaction time, complicated operation, difficult purification, etc. in the prior art, the present invention provides a key intermediate of monepantel which is economical, environmentally friendly, efficient, has short reaction steps, mild conditions, simple post-treatment, high yield, low price and recyclable, and a preparation method thereof, which has significant effects and is suitable for industrial production. Summary of the invention

[0021] In view of the above technical background, the present invention provides a monepantel key intermediate and a separation method thereof.

[0022] The first aspect of the present invention provides a method for preparing a compound of formula 3, comprising the following steps:

[0023]

[0024] Wherein, R1 is selected from TMS, TES, TBDMS, TIPS, TBDPS or

[0025] Method 1:

[0026] The reaction is as follows:

[0027]

[0028] The steps include:

[0029] Step 2: reacting the compound of formula 2 with an ammonia source and a cyaniding agent to obtain a compound of formula 3;

[0030] Method 2:

[0031] The reaction is as follows:

[0032]

[0033] The following steps are included:

[0034] Step 5: The compound of formula 7 is reacted with ammonia to obtain the compound of formula 3.

[0035] Preferably, the ammonia source in step 2 is selected from one or more of ammonium acetate, ammonium formate, ammonia gas, ammonia gas solution, ammonia water, ammonium chloride, ammonium sulfate, and ammonium carbonate, preferably ammonium chloride and ammonia gas solution or ammonia water;

[0036] The above-mentioned "ammonia solution" refers to an ammonia solution in an organic solvent, wherein the organic solvent is an alcohol solvent, an ether solvent, etc., such as methanol, ethanol, isopropanol, dioxane, and tetrahydrofuran.

[0037] Preferably, the cyaniding agent in step 2 is selected from potassium cyanide and sodium cyanide.

[0038] Preferably, the solvent used in step 2 is selected from one or more of acetone, benzene, toluene, xylene, tetrahydrofuran, n-heptane, N,N-dimethylformamide, dimethyl sulfoxide, ether, dioxane, dichloromethane, dichloroethane, chloroform, ethyl acetate, methanol, ethanol, isopropanol, propanol, butanol, tert-butanol, isobutanol, acetonitrile, and water; preferably one or more of tetrahydrofuran, dichloromethane, dichloroethane, chloroform, ethyl acetate, methanol, ethanol, isopropanol, propanol, N,N-dimethylformamide, dimethyl sulfoxide, and water; more preferably methanol, ethanol, isopropanol and water.

[0039] Preferably, the molar ratio of the compound of formula 2 to the ammonia source is 1:(1-15), preferably 1:(2-13).

[0040] The reaction temperature of step 2 is 10°C to 35°C, preferably 20°C to 30°C; the reaction time is 15 to 30 hours, preferably 18 to 24 hours.

[0041] The system pH of the racemization reaction in step 5 is 11-12.

[0042] The reaction temperature of step 5 is 10°C to 35°C, preferably 30°C to 35°C; the reaction time is 10 to 35 hours, preferably 15 to 30 hours.

[0043] The second aspect of the present invention provides a method for preparing a compound of formula 5, the reaction is as follows:

[0044]

[0045] Wherein, R1 is the same as described in the first aspect above;

[0046] The following steps are included:

[0047] Step 3: Compound 3 is treated with a resolving agent to obtain compound 5;

[0048] The resolving agent in step 3 is selected from D-(+) di-p-toluoyl tartaric acid (D-(+)-DTTA), D-(+)-dibenzoyl tartaric acid (D-(+)-DBTA), and (-)-diacetyl-L-tartaric acid.

[0049] Preferably, step 3 comprises dissolving the compound of formula 3 in an organic solvent and stirring at temperature A, then adding the resolving agent in batches, continuing to stir at temperature A, then gradually cooling, and keeping warm and stirring at the corresponding temperature for 0.5 to 2 hours, and finally stirring at 5 to 15° C. for 2 to 5 hours, filtering and drying to obtain the compound of formula 5.

[0050] Preferably, the temperature A in step 3 is 50° C. to 70° C.; the reaction time in step 3 is 12 to 30 hours, preferably 15 to 30 hours.

[0051] The gradient cooling in step 3 refers to naturally cooling the temperature by 8 to 15°C each time;

[0052] In some embodiments, when the temperature A is 50°C, stirring is performed at 35°C and 25°C for 1 hour each, and finally the temperature is lowered to 15°C and stirred for 2 hours;

[0053] In some embodiments, when the temperature A is 50°C, stirring is performed at 40°C and 30°C for 1 hour each, and finally the temperature is lowered to 15°C and stirred for 5 hours;

[0054] In certain embodiments, when temperature A is 60° C., stirring is performed at 50° C., 40° C., and 30° C. for 1 hour each, and finally the temperature is lowered to 10° C. and stirred for 3 hours.

[0055] Preferably, the solvent used in step 3 is selected from one or more of acetone, methanol, ethanol, n-propanol, isopropanol, methyl tert-butyl ether, n-heptane, cyclohexane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, dichloromethane, methyl tert-butyl ether, and ether, preferably one or more of acetonitrile, isopropanol, isopropyl acetate, and ethyl acetate;

[0056] Preferably, the molar ratio of the compound of formula 3 in step 3 to the resolving agent is 1:(0.5-2), preferably 1:(0.7-1.5).

[0057] The third aspect of the present invention provides a method for preparing a monepantel key intermediate formula 6, the reaction is as follows:

[0058]

[0059] Wherein, R1 is the same as described in the first aspect above;

[0060] The following steps are included:

[0061] Step 1: The compound of formula 1 and R1X are reacted with a base to obtain a compound of formula 2;

[0062] Wherein, R1 is the same as described in the first aspect above; X is Br or Cl;

[0063] Step 2: reacting the compound of formula 2 with an ammonia source and a cyaniding agent to obtain a compound of formula 3;

[0064] Step 3: Compound 3 is treated with a resolving agent to obtain compound 5;

[0065] Step 4: The compound of formula 5 is treated with a base to obtain the compound of formula 6.

[0066] Preferably, the base in step 1 is selected from one or more organic bases or inorganic bases, the organic base is preferably triethylamine, diethylamine, N,N-diisopropylethylamine (diisopropylethylamine), pyridine, imidazole, the inorganic base is selected from sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or cesium carbonate; imidazole is preferred;

[0067] In step 1, the molar ratio of the compound of formula 1, R1X and the base is 1:(1-2):(1-3), preferably 1:(1-1.5):(1.5-3);

[0068] The solvent used in step 1 is selected from one or more of dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride, tetrahydrofuran, acetone, N,N-dimethylformamide (DMF), THF, acetonitrile, dioxane, and toluene, preferably dichloromethane, tetrahydrofuran, and ethylene dichloride;

[0069] The reaction temperature of step 1 is 0°C to 30°C;

[0070] The reaction time of step 1 is 1h to 5h;

[0071] The preferred technical solution of the present invention, step 2 fully refers to the entire technical solution of the preparation method of the key intermediate formula 3 of monepantel in the first aspect of the specification of the present invention.

[0072] In the preferred technical solution of the present invention, step 3 fully refers to the entire technical solution of the method for preparing a compound of formula 5 in the second aspect of the present invention.

[0073] Preferably, the base in step 4 is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, sodium hydrogen phosphate, and potassium hydrogen phosphate, preferably dipotassium hydrogen phosphate and disodium hydrogen phosphate;

[0074] The pH of the free reaction system in step 4 is 7 to 7.8;

[0075] The reaction temperature of step 4 is 10°C to 45°C, preferably 20°C to 35°C; the reaction time is 1 to 5 hours, preferably 1 to 3 hours.

[0076] The fourth aspect of the present invention also provides a monepantel key intermediate, the structural formula of which is shown in Formula 3:

[0077]

[0078] Or its single configuration compound structure is as follows:

[0079]

[0080] Wherein, R1 is the same as described in the first aspect above.

[0081] The fifth aspect of the present invention provides a process for synthesizing monepantel, which includes the preparation method of the monepantel key intermediate formula 3 provided in the first aspect above, or the preparation method of the compound of formula 5 provided in the second aspect above, or the preparation method of the monepantel key intermediate formula 6 provided in the third aspect of the present invention above, or the use of the monepantel intermediate of formula 3 or the use of the monepantel intermediate of formula 5 as described above.

[0082] Beneficial effects of the present invention:

[0083] 1. The present invention provides a method for synthesizing a monepantel intermediate with higher yield, simpler post-treatment and better suitability for industrial production; the present invention first protects the hydroxyl group of 1-hydroxyacetone, and then obtains aminocyanide, i.e., compound of formula 3, by reacting an ammonia source with a cyaniding agent, and the yield is increased by 51% to 56% compared with the patent CN101600687B; the yield is increased by 47% to 52% compared with the reaction in which the same hydroxyl protecting group is a silane group in the patent WO2006067430A.

[0084] 2. The inventors of the present application screened the hydroxyl protecting group through multiple experiments. In particular, when the protecting group is a carboxylic acid ester, such as acetyl or benzoyl, the protecting group is easy to fall off during the addition step of preparing monepantel, resulting in failure to obtain the target product.

[0085] When the hydroxyl protecting group is a silane protecting group, no shedding of the protecting group is detected, which is significantly better than other types of protecting groups. Therefore, the present invention provides a method for improving the yield of monepantel, simplifying the purification method, and shortening the steps, thereby providing a higher possibility for industrial production.

[0086] 3. At the same time, the inventors of the present application screened the resolving agents for many times and found that when the resolving agents were (+)-dibenzoyl-D-tartaric acid, (-)-diacetyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, they were significantly better than other resolving agents and did not require secondary purification during post-treatment. The inventors also conducted multiple tests on the reaction temperature and time during the resolving of the compound of formula 3 to obtain the corresponding conditions of the present invention. The present invention only requires filtration to obtain the compound of formula 4, which greatly simplifies post-treatment, reduces costs, is more suitable for industrial production, and provides more possibilities for the synthesis of monepantel, which has good market value and far-reaching practical significance.

[0087] 4. The inventors also screened the pH of the reaction solution in step 4 and found that the best effect was achieved when the pH of the solution was 7-7.8, and when the pH was greater than 7.8, the dominant configuration was easily converted to a racemate, the target product was reduced, and the yield decreased.

[0088] 5. The inventors further screened the base used to prepare the compound of formula 3 from the compound of formula 7 and found that the ammonia used in the present invention is significantly better than the base used in patent CN101056849B. The present invention repeatedly used the conditions for the racemization of sodium cyanide and found that the R configuration was not converted into a racemic body. BRIEF DESCRIPTION OF THE DRAWINGS

[0089] Figure 1 This is the HPLC spectrum of compound 3A prepared in Example 2 of the present invention;

[0090] Figure 2 This is the HPLC spectrum of compound 3B prepared in Example 6 of the present invention;

[0091] Figure 3 This is the HPLC spectrum of compound 3C prepared in Example 9 of the present invention;

[0092] Figure 4 This is the HPLC spectrum of compound 3C prepared in Example 12 of the present invention;

[0093] Figure 5 This is the HPLC spectrum of compound 3C prepared in Example 13 of the present invention;

[0094] Figure 6 This is the HPLC spectrum of compound 3C prepared in Example 16 of the present invention;

[0095] Figure 7 HPLC spectrum of Formula 7C in Comparative Example 1 of the present invention;

[0096] Figure 8 This is the HPLC spectrum of comparative example 1 of the present invention after 24 hours of reaction. DETAILED DESCRIPTION

[0097] The technical solution of the present invention and the technical effects produced by it will be further described below in conjunction with embodiments, but the present invention is not limited to the described scope.

[0098] Embodiment 1:

[0099]

[0100] Under nitrogen protection, 1-hydroxypropyl-2-ketone (100 g, 1.0 eq) was added to 500 mL of dichloromethane, and imidazole (229.8 g, 2.5 eq) was added to the reaction solution, and the internal temperature was controlled at 0-5°C and stirred for 30 min. The reaction solution was clear and transparent, and TBDMSCl (244.2 g, 1.2 eq) was then added in batches, and the internal temperature of the reaction solution was controlled at 0-5°C. After the addition was completed, the temperature was raised to 25-35°C and stirred for 3 h. Thin layer chromatography (TLC) was used. The reaction was followed and the reaction was completed after 3 hours. The dichloromethane was removed by concentration under reduced pressure to obtain a colorless oily liquid. Methyl tert-butyl ether (500 mL) and water (200 mL) were then added to the oily liquid, and the mixture was stirred at 25°C for 30 minutes. The mixture was allowed to stand for separation and the organic phase was retained. The organic phase was then washed once with water (100 mL), allowed to stand for separation, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 40°C to obtain the compound of formula 2A (250 g, yield 98.3%) as a colorless oily liquid.

[0101] 1 HNMR (400MHz, CDCl3) δ4.15(s,2H,CH2),2.17(s,3H,CH3),0.93(s,9H,CH3),0.09(s,6H,CH3).

[0102] Embodiment 2:

[0103]

[0104] The compound of formula 2A (200 g, 1.0 eq) was added to 500 mL of methanol, and ammonium chloride (170.6 g, 3.0 eq) and 7 M ammonia / methanol solution (1.52 L, 10 eq) were added to the reaction system. The temperature was raised to 25° C. and stirred for 30 min. Then, sodium cyanide (78.25 g, 1.5 eq) was added to the reaction system in batches. After the addition was completed, the reaction solution was clarified, and then stirred at 25° C. for 20 h. The reaction was tracked by thin layer chromatography (TLC). After 20 h, the reaction was completed. The mixture was filtered, and the filter cake was washed with methanol (50 mL). It was concentrated under reduced pressure at 45° C. to obtain a brown viscous oil. Then, ethyl acetate (1 L) was added to the brown oil, and the mixture was stirred at 25°C for 1 h, filtered, and the filter cake was washed with ethyl acetate (200 mL). The organic phases were combined and concentrated under reduced pressure at 45°C to obtain the compound of formula 3A (220 g, yield 96.6%, R:S=50.9:49.1, HPLC spectrum as shown in FIG. Figure 1 ) is a yellow oil.

[0105] 1 HNMR (400MHz, DMSO-d6) δ3.59–3.39(m,2H,CH2),2.48(s,2H,NH2),1.30(s,3H,CH3),0.92–0.88(m,9H,CH3),0.08(s,6H,CH3).

[0106] Embodiment 3:

[0107]

[0108] Under nitrogen protection, the racemic compound of formula 3A (100 g, 1.0 eq) solid was added to 1000 mL of acetonitrile, the temperature was raised to 50°C, stirred and dissolved, and kept warm for 30 min. The resolving agent D-(+)-di-p-methylbenzoyltartaric acid (144.1 g, 0.8 eq) was added to the reaction system in batches, and the feeding rate was controlled. After the added resolving agent was dissolved, the next batch was added. After the addition was completed, the reaction solution was clear and transparent. The internal temperature was controlled at 50°C and stirred for 40 min. A white solid gradually precipitated. The mixture was kept warm and stirred at 50°C for 18 h, then gradually cooled, kept warm and stirred at 35°C and 25°C for 1 h, and finally cooled to 15°C for 2 h. The mixture was filtered, and the filter cake was washed with acetonitrile to obtain 160 g of a white solid. After drying at 45°C, the compound of formula 5A (138 g, yield 49.3%) was obtained as a white solid.

[0109] Embodiment 4:

[0110]

[0111] Disodium hydrogen phosphate (122.9 g, 4 eq) was added to 1300 mL of water, and the mixture was stirred at 25°C to dissolve. Subsequently, the compound of formula 5A (130 g, 1 eq) and ethyl acetate (1300 mL) were added to the reaction system, and the mixture was stirred at 25°C for 1.5 h. The mixture was allowed to stand for separation, and the upper organic phase was retained. Water (130 mL) was added to the organic phase for washing once. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 45°C to obtain the compound of formula 6A (45.65 g, yield 98.4%, HPLC: 98.6%, ee value 97%) as a colorless oily liquid.

[0112] 1 H NMR (400MHz, DMSO-d6) δ3.59–3.39(m,2H,CH2),2.48(s,2H,NH2),1.30(s,3H,CH3),0.92–0.88(m,9H,CH3),0.08(s,6H,CH3).

[0113] Embodiment 5:

[0114]

[0115] Under nitrogen protection, 1-hydroxypropyl-2-ketone (200 g, 1.0 eq) was added to 1 L of dichloromethane, and imidazole (459.4 g, 2.5 eq) was added to the reaction solution, and the internal temperature was controlled at 0-5 ° C. and stirred until the reaction solution was clear and transparent. TBDPSCl (890.48 g, 1.2 eq) was then added in batches, and the internal temperature of the reaction solution was controlled at 0-5 ° C. After the addition was completed, the temperature was raised to 35 ° C. and stirred for 2.5 h. The reaction was tracked by thin layer chromatography (TLC). After 2.5 h, the reaction was completed. The reaction solution was then cooled to 25 ° C. Water (600 mL) was added to the reaction system, and stirred at 25 ° C. for 60 min. The organic phase was retained after standing and separation, and then the organic phase was washed with water (400 mL) again. The organic phase was allowed to stand and separate, and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40 ° C to obtain the compound of formula 2B (818 g, yield 97%) as a light yellow oil.

[0116] 1 H NMR (400MHz, CDCl3) δ7.65 (dd, 4H), 7.44-7.38 (m, 6H), 4.16 (s, 2H, CH2), 2.20 (s, 3H, CH3), 1.10 (s, 9H, CH3).

[0117] Embodiment 6:

[0118]

[0119] The compound of formula 2B (400 g, 1.0 eq) was added to 1 L of methanol, and ammonium chloride (205.4 g, 3.0 eq) and 7 M ammonia / methanol solution (1.82 L, 10 eq) were added to the reaction system, and the temperature was raised to 25°C, and the mixture was stirred for 40 min. Then, sodium cyanide (94.1 g, 1.5 eq) was added to the reaction system in batches. After the addition, the reaction solution was colorless and transparent. The mixture was stirred at 25°C for 24 h, and the reaction was tracked by thin layer chromatography (TLC). After 24 h, The reaction was completed, and the mixture was concentrated under reduced pressure at 45°C to obtain a light yellow solid. Ethyl acetate (1 L) and water (400 mL) were then added thereto, and the mixture was stirred at 25°C for 30 min. The mixture was allowed to stand for separation, and the organic phase was washed with water again. The mixture was allowed to stand for separation, and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 421 g of a white solid. The compound 3B (398.7 g, yield 92%, R:S=53.6:46.9, HPLC spectrum as shown in FIG. Figure 2 ) is a white solid.

[0120] 1 H NMR (400MHz, CDCl3) δ8.01-7.34(m,10H),4.22-3.77(m,2H,CH2),1.53(s,3H,CH3),1.1(s,9H,CH3).

[0121] Embodiment 7:

[0122]

[0123] Under nitrogen protection, the compound of formula 3B (200 g, 1.0 eq) was added to an isopropyl acetate (2 L) solution, the temperature was raised to 60 ° C., stirred and dissolved, and kept warm for 40 min. The resolving agent D-(+)-di-p-methylbenzoyltartaric acid (217.6 g, 0.95 eq) was added to the reaction system in batches, and the feeding rate was controlled. After the added resolving agent was dissolved, the next batch was added. After the addition was completed, the reaction solution was clear and transparent. The internal temperature was controlled at 60 ° C. and stirred for 1.5 h. A white solid gradually precipitated. The mixture was kept warm and stirred at 60 ° C. for 24 h, and then the temperature was gradually reduced, and the mixture was kept warm and stirred at 50 ° C., 40 ° C. and 30 ° C. for 1 h, and finally the temperature was reduced to 10 ° C. and kept warm and stirred for 3 h. The mixture was filtered, and the filter cake was washed with isopropyl acetate (25 mL) to obtain 239 g of a white solid. After drying at 45 ° C., the compound of formula 5B (205.44 g, yield 48.0%) was obtained as a white solid.

[0124] Embodiment 8:

[0125]

[0126] Disodium hydrogen phosphate (156.6 g, 4 eq) was added to water (2 L), stirred at 25 ° C until dissolved, then the compound of formula 4B (200 g, 1 eq) and ethyl acetate (2 L) were added to the reaction system, and the mixture was stirred at 25 ° C for 2 h (the tartrate was completely dissolved), and the mixture was allowed to stand for separation, and the upper organic phase was retained. Water (300 mL) was added to the organic phase and washed once. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 45 ° C to obtain 110 g of a white solid. The compound of formula 5B (88.73 g, yield 95%, HPLC: 98.8%, ee value 98%) was dried under reduced pressure and vacuum to obtain a white solid.

[0127] 1 H NMR (400MHz, CDCl3) δ8.01-7.34(m,10H),4.22-3.77(m,2H,CH2),1.53(s,3H,CH3),1.1(s,9H,CH3).

[0128] Embodiment 9:

[0129]

[0130] 3-(2-Oxopropoxy)-4-(trifluoromethyl)benzonitrile (11 g, 1.0 eq) solid was added to ethanol (27.5 mL) and water (22 mL), and then 25% ammonia water (13.8 mL, 2.0 eq) was added, the temperature was raised to 20-25°C, and the mixture was stirred for 30 min. Then sodium cyanide (3.34 g, 1.5 eq) was added in batches, and the reaction solution gradually became clear. After the addition was completed, the mixture was kept warm and stirred at 25°C for 24 h. The reaction was tracked by thin layer chromatography (TLC). After 24 h, the reaction was completed. The temperature of the reaction solution was reduced to 15°C, and the mixture was filtered. The filter cake was washed with water (22 mL) to obtain a white solid. After drying, 11.5 g of a yellow solid was obtained, with a yield of 94.4%, R:S=56.3:43.7, and the HPLC spectrum was as shown in FIG. Figure 3 shown).

[0131] 1 H NMR (400MHz, DMSO) δ7.92(d,J=8.4Hz,2H),7.69(d,J=7.9Hz,1H),4.25(dd,J=27.7,9.4Hz,2H),2.77(s,2H),1.53(s,3H).

[0132] Embodiment 10:

[0133]

[0134] The compound of formula 3C (10 g, 1.0 eq) was added to isopropanol (180 mL). Under nitrogen protection, the temperature was raised to 50 ° C. and stirred to dissolve. The temperature was kept for 30 min. The resolving agent D-(+)-di-p-methylbenzoyltartaric acid (16 g, 1.1 eq) was added to the reaction system in batches. After the addition was completed, the reaction solution was clear and transparent. The internal temperature was controlled at 50 ° C. and stirred for 1 h. A white solid gradually precipitated. The temperature was kept at 50 ° C. and stirred for 15 h. Then, the mixture was heated to room temperature. The mixture was gradually cooled down at a low temperature, kept at 40°C and 30°C with stirring for 1 h, and finally cooled to 15°C with stirring for 5 h, filtered, and the filter cake was washed with isopropanol (10 mL) to obtain 12.22 g of a white solid, which was dried at 45°C to obtain 11.55 g of the compound of formula 5C with a yield of 47.4% and an ee value of 99.96%. The filtrate was concentrated under reduced pressure at 45°C to obtain 16.14 g of a yellow-white solid, which was dried to obtain 15.08 g of the compound of formula 4C.

[0135] Embodiment 11:

[0136]

[0137] Disodium hydrogen phosphate (13.66 g, 4 eq) was added to water (150 mL), and the mixture was stirred at 25° C. to dissolve. Subsequently, the compound of formula 4C (15.10 g, 1 eq) and ethyl acetate (150 mL) were added to the reaction system, and the mixture was stirred at 25° C. for 40 min. The mixture was allowed to stand for separation, and the organic phase was retained. Water (15 mL) was added to the organic phase and washed once. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 45° C. to obtain 6.2 g of a white solid. After vacuum drying at 45° C., 5.8 g of a white solid was obtained, with a yield of 93.5% and a purity of 99.99%.

[0138] 1 H NMR (400MHz, DMSO) δ7.92(d,J=8.4Hz,2H),7.69(d,J=7.9Hz,1H),4.25(dd,J=27.7,9.4Hz,2H),2.77(s,2H),1.53(s,3H).

[0139] Embodiment 12:

[0140]

[0141] The compound of formula 7C (5 g, 1.0 eq, purity 99.99%) was added to ethanol (12.5 mL) and water (10 mL), and the internal temperature was controlled at 35°C and stirred for 30 min. The temperature could not be higher than 35°C and the mixture was stirred vigorously. Ammonia (1 kg) was then inserted below the liquid surface through a catheter and slowly bubbled. The internal temperature was controlled at 30-35°C and the bubbling time was controlled for 18 h. The pH of the solution was 11-12. The reaction was tracked by NP-HPLC. After 18 h, the reaction was converted into the compound of formula 3C. The reaction solution was then cooled to 15°C and stirred for 1 h. A large amount of white solid precipitated. The mixture was filtered and the filter cake was washed with water (5 mL) to obtain a white solid. After drying at 45°C, 4.75 g of a white solid was obtained with a yield of 95.0%. R:S=49.9:49.3. The HPLC spectrum is shown in FIG. Figure 4 shown.

[0142] 1 H NMR (400MHz, DMSO) δ7.92(d,J=8.4Hz,2H),7.69(d,J=7.9Hz,1H),4.25(dd,J=27.7,9.4Hz,2H),2.77(s,2H),1.53(s,3H).

[0143] Embodiment 13:

[0144]

[0145] 3-(2-Oxopropoxy)-4-(trifluoromethyl)benzonitrile (110 g, 1.0 eq) solid was added to ethanol (275 mL) and water (220 mL), and then 25% ammonia water (138 mL, 2.0 eq) was added, the temperature was raised to 20-25°C, and the mixture was stirred for 30 min. Then sodium cyanide (33.4 g, 1.5 eq) was added in batches, and the reaction solution gradually became clear. After the addition was completed, the mixture was kept warm and stirred at 25°C for 24 h. The reaction was tracked by thin layer chromatography (TLC). After 24 h, the reaction was completed. The temperature of the reaction solution was reduced to 15°C, and the mixture was filtered. The filter cake was washed with water (22 mL) to obtain a white solid. After drying, 116 g of a yellow solid was obtained, with a yield of 95.3%, R:S=55.8:44.2, and the HPLC spectrum was as shown in FIG. Figure 5 shown.

[0146] Embodiment 14:

[0147]

[0148] The compound of formula 3C (100 g, 1.0 eq) was added to isopropanol (1.8 L), and the temperature was raised to 50° C. under nitrogen protection, stirred and dissolved, and kept warm for 30 min. The resolving agent D-(+)-di-p-methylbenzoyltartaric acid (159.7 g, 1.2 eq) was added to the reaction system in batches. After the addition, the reaction solution was clear and transparent. The internal temperature was controlled at 50° C. and stirred for 1 h. A white solid gradually precipitated. The mixture was kept warm and stirred at 50° C. for 15 h. The temperature was then gradually lowered at room temperature, and kept warm and stirred at 40° C. and 30° C. for 1 h, respectively. Finally, the temperature was lowered to 15° C. and kept warm and stirred for 5 h. The mixture was filtered, and the filter cake was washed with isopropanol (100 mL) to obtain 123 g of a white solid. After drying at 45° C., 116 g of the compound of formula 5C was obtained with a yield of 47.64%. The filtrate was concentrated under reduced pressure at 45° C. to obtain 163 g of a yellow-white solid, which was dried to obtain 155 g of the compound of formula 4C.

[0149] Embodiment 15:

[0150]

[0151] Disodium hydrogen phosphate (136.6 g, 4 eq) was added to water (1.5 L), and the mixture was stirred at 25°C until dissolved. Subsequently, the compound of formula 4C (151 g, 1 eq) and ethyl acetate (1.5 L) were added to the reaction system, and the mixture was stirred at 25°C for 40 min. The mixture was allowed to stand for separation, and the organic phase was retained. Water (15 mL) was added to the organic phase for washing once. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 45°C to obtain 64 g of a white solid. After vacuum drying at 45°C, 60 g of the compound of formula 7C was obtained with a yield of 96.8% and a purity of 99.99%.

[0152] Embodiment 16:

[0153]

[0154] The compound of formula 7C (50 g, 1.0 eq, purity of 99.99%) was added to ethanol (125 mL) and water (100 mL), and the internal temperature was controlled at 35°C and stirred for 30 min. The temperature could not be higher than 35°C and the mixture was stirred vigorously. Ammonia (10 kg) was then inserted below the liquid surface through a catheter and slowly bubbled. While the internal temperature was controlled at 30-35°C, the bubbling time was controlled for 26 h. The pH of the solution was 11-12. The reaction was tracked by NP-HPLC. After 26 h, it was shown that the compound 3C (racemate) was converted. The reaction solution was then cooled to 15°C and stirred for 1 h. A large amount of white solid precipitated. The mixture was filtered and the filter cake was washed with water (5 mL) to obtain a white solid. After drying at 45°C, 48.3 g of a white solid was obtained with a yield of 96.6%. R:S=49.6:49.5. The HPLC spectrum is shown in FIG. Figure 6 shown.

[0155] Comparative Example 1:

[0156]

[0157] The compound of formula 7C (25 g, 1.0 eq, purity 99.99%, HPLC Figure 7 The mixture was added with ethanol (75 mL) and water (75 mL), the internal temperature was controlled at 65°C to 75°C, and stirred for 10 min. Sodium cyanide (13.65 g, 3.0 eq) was added, and the reaction was followed by NP-HPLC. The reaction was monitored every 2 h. After 48 h, the main 7C was still in R configuration, and no conversion trend was observed. The purity of R configuration was 99.95%. HPLC showed Figure 8 shown.

Claims

1. A method for preparing a compound of formula 3, comprising the following steps: Wherein, R1 is selected from TMS, TES, TBDMS, TIPS, TBDPS or Method 1: The reaction is as follows: The steps include: Step 2: reacting the compound of formula 2 with an ammonia source and a cyaniding agent to obtain a compound of formula 3; Method 2: The reaction is as follows: The following steps are included: Step 5: The compound of formula 7 is reacted with ammonia to obtain the compound of formula 3.

2. A method for preparing a compound of formula 5, comprising the following steps: in, R1 is selected from TMS, TES, TBDMS, TIPS, TBDPS or The following steps are included: Step 3: obtaining a compound of formula 5 from the compound of formula 3 according to claim 1 under the action of a resolving agent; The resolving agent in step 3 is selected from D-(+) di-p-methylbenzoyltartaric acid, D-(+)-dibenzoyltartaric acid, and (-)-diacetyl-L-tartaric acid.

3. A preparation method of monepantel key intermediate formula 6, the reaction is as follows: The following steps are included: Step 1: Compound 1 is reacted with R1X and a base to obtain compound 2; Step 2: reacting the compound of formula 2 with an ammonia source and a cyaniding agent to obtain a compound of formula 3; Step 3: Compounds of formula 3 are treated with a resolving agent to obtain compounds of formula 4 and formula 5; Step 4: Compound 5 is reacted with a base to obtain compound 6; in, R1 is selected from TMS, TES, TBDMS, TIPS, TBDPS or X is Br or Cl; The resolving agent in step 3 is selected from D-(+) di-p-methylbenzoyltartaric acid, D-(+)-dibenzoyltartaric acid, and (-)-diacetyl-L-tartaric acid.

4. The preparation method according to claim 3, characterized in that: The preparation method in step 1 satisfies one or more of the following conditions: 1) The base in step 1 is selected from one or more organic bases or inorganic bases, the organic bases are preferably triethylamine, diethylamine, N,N-diisopropylethylamine (diisopropylethylamine), pyridine, imidazole, the inorganic base is selected from sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or cesium carbonate; imidazole is more preferred; 2) The molar ratio of the compound of formula 1, R1X and base in step 1 is 1:(1-2):(1-3), preferably 1:(1-1.5): (1.5～3)； 3) The solvent used in step 1 is selected from one or more of dichloromethane, chloroform, carbon tetrachloride, dichloroethane, tetrahydrofuran, acetone, N,N-dimethylformamide (DMF), THF, acetonitrile, dioxane, and toluene, preferably dichloromethane, tetrahydrofuran, and dichloroethane; 4) The reaction temperature of step 1 is 0°C to 30°C; 5) The reaction time of step 1 is 1 h to 5 h.

5. The preparation method according to claim 1 or 3, characterized in that: The preparation method in step 2 satisfies one or more of the following conditions: 1) The ammonia source in step 2 is selected from one or more of ammonium acetate, ammonium formate, ammonia gas, ammonia gas solution, ammonia water, ammonium chloride, ammonium sulfate, and ammonium carbonate, preferably ammonium chloride and ammonia gas solution or ammonia water; 2) The cyaniding agent in step 2 is selected from potassium cyanide and sodium cyanide; 3) The solvent used in step 2 is selected from one or more of acetone, benzene, toluene, xylene, tetrahydrofuran, n-heptane, N,N-dimethylformamide, dimethyl sulfoxide, ether, dioxane, dichloromethane, dichloroethane, chloroform, ethyl acetate, methanol, ethanol, isopropanol, propanol, butanol, tert-butanol, isobutanol, acetonitrile, and water; preferably one or more of tetrahydrofuran, dichloromethane, dichloroethane, chloroform, ethyl acetate, methanol, ethanol, isopropanol, propanol, N,N-dimethylformamide, dimethyl sulfoxide, and water, more preferably methanol, ethanol, isopropanol, and water; 5) In step 2, the molar ratio of the compound of formula 2 to the ammonia source is 1:(1-15), preferably 1:(2-13); 6) The reaction temperature of step 2 is 10°C to 35°C, preferably 20°C to 30°C; 7) The reaction time of step 2 is 15 to 30 hours, preferably 18 to 24 hours.

6. The preparation method according to claim 2 or 3, characterized in that: The preparation method in step 3 satisfies one or more of the following conditions: 1) Step 3 comprises dissolving the compound of formula 3 in an organic solvent and stirring at temperature A, then adding a resolving agent in batches, continuing to stir at temperature A, then gradually cooling, and keeping warm and stirring at the corresponding temperature for 0.5 to 2 hours, and finally stirring at 5 to 15° C. for 2 to 3 hours, filtering and drying to obtain a compound of formula 5; The gradient cooling refers to a natural cooling of 8 to 15°C each time; The temperature A is 50°C to 70°C; the reaction time of step 3 is 12 to 30 hours, preferably 18 to 30 hours; 2) The solvent used in step 3 is selected from one or more of acetone, methanol, ethanol, isopropanol, n-propanol, methyl tert-butyl ether, n-heptane, cyclohexane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, dichloromethane, methyl tert-butyl ether, and ether, preferably one or more of acetonitrile, isopropanol, isopropyl acetate, and ethyl acetate; 3) In step 3, the molar ratio of the compound of formula 3 to the resolving agent is 1:(0.5-2), preferably 1:(0.7-1.5).

7. The preparation method according to claim 3, characterized in that: The preparation method in step 4 satisfies one or more of the following conditions: 1) The base in step 4 is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, sodium hydrogen phosphate, and potassium hydrogen phosphate, preferably dipotassium hydrogen phosphate and disodium hydrogen phosphate; 2) The pH of the free reaction system in step 4 is 7 to 8; 3) The reaction temperature of step 4 is 10°C to 45°C, preferably 20°C to 35°C; 4) The reaction time of step 4 is 1 to 5 hours, preferably 1 to 3 hours.

8. The preparation method according to claim 1, characterized in that: The system pH of the racemization reaction in step 5 of method 2 is 11-12; The reaction temperature of step 5 is 10°C to 35°C, preferably 30°C to 35°C; the reaction time is 10 to 35h, preferably 15 to 30h.

9. A monepantel intermediate, the structural formula of which is shown in Formula 3: Or its single configuration compound structure is as follows: Wherein R1 is selected from TMS, TBDMS, TIPS, TES.

10. A process for synthesizing monepantel, comprising the preparation method of compound 3 described in claim 1, the preparation method of compound of formula 5 described in claim 2, or the preparation method of compound of formula 6 described in claim 3, or using the monepantel intermediate of formula 3 or formula 6 described in claim 9.

Images