Monetrel key intermediates and methods for their resolution

Abstract

The present application belongs to the technical field of organic synthesis and preparation of pharmaceutical intermediates, and relates to a preparation method of a key intermediate of monopertin. The present application provides a preparation method of a compound of formula 3, which comprises the following steps: wherein R1 is selected from TMS, TES, TBDMS, TIPS, TBDPS or Method 1: the reaction is as follows: comprising the following steps: Step 2: the compound of formula 2 is reacted with an ammonia source and a cyanation reagent to obtain the compound of formula 3; Method 2: the reaction is as follows: comprising the following steps: Step 5: the compound of formula 7 is reacted under the action of ammonia to obtain the compound of formula 3. The present application provides a preparation method of a compound of formula 5, the reaction is as follows: wherein R1 is the same as described in the first aspect; comprising the following steps: Step 3: the compound of formula 3 is reacted under the action of a resolving agent to obtain the compound of formula 5. The method of the present application has the advantages of higher yield, simpler post-treatment, simple operation and good industrial production prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis and preparation of pharmaceutical intermediates, and particularly relates to a method for preparing a veterinary drug monametal intermediate by resolution. BACKGROUND

[0002] Monametal, as a new type of anti-parasitic drug, has been affirmed in veterinary clinics due to its good anti-parasitic effect, especially on nematodes that have developed drug resistance. Due to the low drug resistance and low toxicity, monametal will play an important role in the prevention and treatment of animal parasitic diseases in the future.

[0003] A key intermediate of monametal is shown in the following structural formula:

[0004]

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

[0006] The prior art reports the following preparation methods of aminonitrile compounds:

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

[0008]

[0009] 1-(tert-butyldimethylsilyloxy)-2-propanone 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 suitable for industrial production.

[0010] 2) The route disclosed in CN101600687B and WO2008096231A8 is as follows:

[0011]

[0012] 1-hydroxypropanone 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 not easy to purify and are not suitable for industrial production.

[0013] The prior art reports the following resolution and isolation methods of aminonitrile compounds:

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

[0015]

[0016] The target configuration is obtained by resolving the racemate by tartaric acid, and the yield is only 36.7%, which is not conducive to commercial production for relatively expensive raw materials;

[0017] CN101056849B discloses the following structure after resolution of the inferior configuration:

[0018]

[0019] It uses NaCN and dioxane to react at 101℃ for 8 to 9 hours, and the process route uses sodium cyanide again, which is a toxic product, increasing the process risk, and the yield and racemization effect under the condition are not involved.

[0020] In view of the problems of low yield, long reaction time, complicated operation, difficult purification and the like in the prior art, the present application provides a kind of economic, environmental protection, high efficiency, short reaction step, mild condition, simple post-treatment, high yield, low price and recyclable monnetil key intermediate and its preparation method, which has remarkable effect and is suitable for industrial production. SUMMARY

[0021] In view of the above technical background, the present application provides a kind of monnetil key intermediate and its resolution method.

[0022] The first aspect of the present application provides a preparation method of 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] comprising the following steps:

[0029] Step 2: the compound of formula 2 is reacted with an ammonia source and a cyanation reagent to obtain a compound of formula 3;

[0030] Method 2:

[0031] The reaction is as follows:

[0032]

[0033] comprising the following steps:

[0034] Step 5: the compound of formula 7 is reacted under the action of ammonia to obtain a 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, aqueous ammonia, ammonium chloride, ammonium sulfate, ammonium carbonate, preferably ammonium chloride and ammonia gas solution or aqueous ammonia;

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

[0037] Preferably, the cyanation reagent in step 2 is selected from potassium cyanide, 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, diethyl ether, dioxane, dichloromethane, dichloroethane, chloroform, ethyl acetate, methanol, ethanol, isopropanol, propanol, butanol, tert-butanol, isobutanol, acetonitrile, water; preferably one or more of tetrahydrofuran, dichloromethane, dichloroethane, chloroform, ethyl acetate, methanol, ethanol, isopropanol, propanol, N,N-dimethylformamide, dimethyl sulfoxide, 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 10-35°C, preferably 20-30°C; the reaction time is 15-30h, preferably 18-24h.

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

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

[0043] The second aspect of the present application provides a preparation method of a compound of formula 5, the reaction being as follows:

[0044]

[0045] wherein R1 is as described above in the first aspect;

[0046] comprising the following steps:

[0047] Step 3: the compound of formula 3 is subjected to a resolution agent to obtain a compound of formula 5;

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

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

[0050] Preferably, the temperature A of step 3 is 50℃ to 70℃; and the reaction time of step 3 is 12 to 30 hours, preferably 15 to 30 hours.

[0051] The gradiently reducing temperature of step 3 refers to reducing the temperature by 8 to 15℃ each time;

[0052] In some embodiments, when the temperature A is 50℃, the temperature is reduced to 35℃, 25℃ respectively for 1 hour each time, and finally reduced to 15℃ for 2 hours;

[0053] In some embodiments, when the temperature A is 50℃, the temperature is reduced to 40℃, 30℃ respectively for 1 hour each time, and finally reduced to 15℃ for 5 hours;

[0054] In some embodiments, when the temperature A is 60℃, the temperature is reduced to 50℃, 40℃, 30℃ respectively for 1 hour each time, and finally reduced to 10℃ 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, diethyl ether, preferably one or more of acetonitrile, isopropanol, isopropyl acetate, ethyl acetate;

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

[0057] The third aspect of the present application provides a preparation method of a key intermediate of monoprolil, formula 6, as follows:

[0058]

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

[0060] Comprising the following steps:

[0061] Step 1: the compound of formula 1 reacts with R1X under the action of a base to obtain the compound of formula 2;

[0062] wherein R1is as described above in the first aspect; X is Br or Cl;

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

[0064] Step 3: reacting the compound of formula 3 with a resolving agent to obtain a compound of formula 5;

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

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

[0067] The molar ratio of the compound of formula 1, R1X and the base in step 1 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, dichloroethane, tetrahydrofuran, acetone, N,N-dimethylformamide (DMF), THF, acetonitrile, dioxane, toluene, preferably dichloromethane, tetrahydrofuran, dichloroethane;

[0069] The reaction temperature in step 1 is 0-30°C;

[0070] The reaction time in step 1 is 1-5h;

[0071] In the preferred technical solution of the present application, step 2 refers to all the technical solutions of the preparation method of the key intermediate of monnetil of formula 3 in the first aspect of the present application.

[0072] In the preferred technical solution of the present application, step 3 refers to all the technical solutions of the preparation method of a compound of formula 5 in the second aspect of the present application.

[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, potassium hydrogen phosphate, preferably dipotassium hydrogen phosphate and disodium hydrogen phosphate;

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

[0075] The reaction temperature in step 4 is 10-45°C, preferably 20-35°C; and the reaction time is 1-5h, preferably 1-3h.

[0076] The fourth aspect of the present application also provides a monoprolil key intermediate, the structural formula of which is shown as formula 3:

[0077]

[0078] or the structural formula of a single configuration compound thereof is as follows:

[0079]

[0080] wherein R1 is as described above in the first aspect.

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

[0082] The beneficial effects of the present application are:

[0083] 1. The present application provides a synthesis method of a monoprolil intermediate with higher yield, simpler post-treatment and more suitable for industrial production. The present application first protects the hydroxyl group of 1-hydroxypropanone, and then reacts with an ammonia source and a cyanating agent to obtain an amino cyanide, i.e. a compound of formula 3. 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 hydroxyl protecting group is also a silane group in the patent WO2006067430A.

[0084] 2. The present application inventors screened the hydroxyl protecting group through multiple experiments. In particular, when the protecting group is a carboxylic acid ester such as acetyl and benzoyl, the protecting group is easy to fall off in the addition step of preparing monoprolil, resulting in that the target product cannot be obtained.

[0085] When the hydroxyl protecting group is a silane group, no falling off of the protecting group is monitored, which is obviously superior to other types of protecting groups. Therefore, the present application provides a method for increasing the yield of monoprolil, simplifying the purification method, shortening the steps, and providing higher possibility for industrial production.

[0086] 3.The inventors of the present application have found that the resolution reagent (+)-dibenzoyl-D-tartaric acid, (-)-diacetyl-L-tartaric acid and (+)-di-p-toluoyl-D-tartaric acid are obviously superior to other resolution reagents, and do not need secondary purification in post-processing, and the inventors have also carried out multiple tests on the reaction temperature and time of the resolution of the compound of formula 3, and thus obtained the corresponding conditions of the present application, the compound of formula 4 can be obtained by filtration, the post-processing is greatly simplified, the cost is reduced, and the present application is more suitable for industrial production, provides more possibilities for the synthesis of Monetrel, has good market value and far-reaching practical significance.

[0087] 4.The inventors of the present application have also screened the pH of the reaction solution of step 4, and found that when the pH of the solution is 7-7.8, the effect is best, and when the pH is greater than 7.8, the advantageous configuration is easily converted into a racemate, the target product is reduced, and the yield is reduced.

[0088] 5.The inventors of the present application have further screened the base used for preparing the compound of formula 3 from the compound of formula 7, and found that the ammonia gas used in the present application is obviously superior to the base used in patent CN101056849B, and the inventors have found that the racemate is not converted from the R configuration under the condition of repeated use of sodium cyanide. BRIEF DESCRIPTION OF DRAWINGS

[0089] Figure 1 The HPLC spectrum of the compound 3A prepared in Example 2 of the present application is shown in the figure;

[0090] Figure 2 The HPLC spectrum of the compound 3B prepared in Example 6 of the present application is shown in the figure;

[0091] Figure 3 The HPLC spectrum of the compound 3C prepared in Example 9 of the present application is shown in the figure;

[0092] Figure 4 The HPLC spectrum of the compound 3C prepared in Example 12 of the present application is shown in the figure;

[0093] Figure 5 The HPLC spectrum of the compound 3C prepared in Example 13 of the present application is shown in the figure;

[0094] Figure 6 The HPLC spectrum of the compound 3C prepared in Example 16 of the present application is shown in the figure;

[0095] Figure 7 The HPLC spectrum of the compound 7C in Comparative Example 1 of the present application is shown in the figure;

[0096] Figure 8 The HPLC spectrum of the reaction of Comparative Example 1 for 24 hours is shown in the figure. DETAILED DESCRIPTION

[0097] The technical solutions of the present application and the technical effects thereof will be further described in combination with the examples below, but the present application will not be limited in the scope expressed by the description.

[0098] Example 1:

[0099]

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

[0101] 1 HNMR (400 MHz, CDCl3) δ 4.15 (s, 2H, CH2), 2.17 (s, 3H, CH3), 0.93 (s, 9H, CH3), 0.09 (s, 6H, CH3).

[0102] Example 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 continuously added to the reaction system, and the temperature was raised to 25 °C, and the reaction was stirred for 30 min, and then sodium cyanide (78.25 g, 1.5 eq) was added to the reaction system in batches, and after the addition was completed, the reaction solution was clear, and then it was stirred at 25 °C for 20 h, and the reaction was tracked by thin layer chromatography (TLC), and after 20 h, it was shown that the reaction was completed, and then it was filtered, and the filter cake was washed with methanol (50 mL), and 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 stirred at 25 °C for 1 h, and then filtered, and the filter cake was washed with ethyl acetate (200 mL), and 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 Figure 1

[0105] 1 HNMR (400 MHz, DMSO-d6) δ 3.59-3.39 (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] Example 3:

[0107]

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

[0109] Example 4:

[0110]

[0111] ​Disodium hydrogen phosphate (122.9 g, 4 eq) was added to 1300 mL of water and stirred at 25 °C until dissolved. Then, compound 5A (130 g, 1 eq) and ethyl acetate (1300 mL) were added to the reaction system. The mixture was stirred at 25 °C for 1.5 h, allowed to stand, and separated. The upper organic phase was retained and washed once with water (130 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 45 °C to obtain compound 6A (45.65 g, yield 98.4%, HPLC: 98.6%, ee value 97%), which was 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] Example 5:

[0114]

[0115] Under nitrogen protection, 200 g of 1-hydroxypropyl-2-one (1.0 eq) was added to 1 L of dichloromethane. Imidazole (459.4 g, 2.5 eq) was then added to the reaction solution. The mixture was stirred at 0–5 °C until the reaction solution became clear and transparent. Subsequently, 890.48 g of TBDPSCl (1.2 eq) was added in portions, and the reaction solution was stirred at 0–5 °C. After the addition was complete, the temperature was raised to 35 °C and stirred for 2.5 h. The reaction was monitored by thin-layer chromatography (TLC). After 2.5 h, the reaction was considered complete. The reaction solution was then cooled to 25 °C, and 600 mL of water was added to the reaction system. The mixture was stirred at 25 °C for 60 min. The mixture was allowed to stand and the organic phase was separated. The organic phase was then washed once with water (400 mL), allowed to stand, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40 °C to obtain compound 2B (818 g, 97% yield) as a pale 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] Example 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 continuously added to the reaction system, and the temperature was raised to 25 °C, and the stirring was continued for 40 min, and then sodium cyanide (94.1 g, 1.5 eq) was added to the reaction system in batches, and the reaction solution was colorless and transparent, and then the stirring was continued at 25 °C for 24 h, and the reaction was tracked by thin layer chromatography (TLC), and after 24 h, it was shown that the reaction was completed, and the yellowish solid was obtained by concentration under reduced pressure at 45 °C, and then ethyl acetate (1 L) and water (400 mL) were added thereto, and the stirring was continued at 25 °C for 30 min, and the liquid was separated, and the organic phase was washed with water once again, and the liquid was separated, and the organic phase was combined, and the organic phase was dried over anhydrous sodium sulfate, and the white solid 421 g was obtained by concentration under reduced pressure, and the compound of formula 3B (398.7 g, yield 92%, R:S = 53.6:46.9, HPLC spectrum as shown in Figure 2 was a white solid.

[0120] 1 H NMR (400 MHz, CDCl3) δ 8.01-7.34 (m, 10H), 4.22-3.77 (m, 2H, CH2), 1.53 (s, 3H, CH3), 1.1 (s, 9H, CH3).

[0121] Example 7:

[0122]

[0123] The compound of formula 3B (200 g, 1.0 eq) was added to a solution of isopropyl acetate (2 L) under nitrogen protection, and the stirring was continued to dissolve at 60 °C for 40 min, and then the resolution agent D-(+)-di-p-toluoyl tartaric acid (217.6 g, 0.95 eq) was continuously added to the reaction system in batches, and the speed of addition was controlled, and after the resolution agent was dissolved, the next batch was continuously added, and after the addition was completed, the reaction solution was clear and transparent, and the internal temperature was controlled at 60 °C, and the stirring was continued for 1.5 h, and then white solid was gradually precipitated, and the stirring was continued at 60 °C for 24 h, and then the temperature was gradually reduced, and the stirring was continued at 50 °C, 40 °C and 30 °C for 1 h respectively, and finally the internal temperature was reduced to 10 °C, and the stirring was continued for 3 h, and then the filtration was performed, and the filter cake was washed with isopropyl acetate (25 mL) to obtain white solid 239 g, and the compound of formula 5B (205.44 g, yield 48.0%) was obtained as a white solid after drying at 45 °C.

[0124] Example 8:

[0125]

[0126] Sodium hydrogen phosphate (156.6 g, 4 eq) was added to water (2 L), the solution was stirred at 25 °C, 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 (all tartarate was dissolved), and then the mixture was allowed to stand and separate, the upper organic phase was retained, the organic phase was washed once with water (300 mL), and then the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 45 °C to obtain 110 g of white solid, which was dried under reduced pressure and vacuum to obtain the compound of formula 5B (88.73 g, yield 95%, HPLC: 98.8%, ee value 98%) as a white solid.

[0127] 1 H NMR (400 MHz, CDCl3) δ 8.01-7.34 (m, 10H), 4.22-3.77 (m, 2H, CH2), 1.53 (s, 3H, CH3), 1.1 (s, 9H, CH3).

[0128] Example 9:

[0129]

[0130] The compound of formula 4B (200 g, 1 eq) was added to water (2 L), and the mixture was stirred at 25 °C, then sodium hydrogen phosphate (156.6 g, 4 eq) was added to the reaction system, and the mixture was stirred at 25 °C for 2 h (all tartarate was dissolved), and then the mixture was allowed to stand and separate, the upper organic phase was retained, the organic phase was washed once with water (300 mL), and then the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 45 °C to obtain 110 g of white solid, which was dried under reduced pressure and vacuum to obtain the compound of formula 5B (88.73 g, yield 95%, HPLC: 98.8%, ee value 98%) as a white solid. Figure 3

[0131] 1 H NMR (400 MHz, DMSO) δ 7.92 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 7.9 Hz, 1H), 4.25 (dd, J = 27.7, 9.4 Hz, 2H), 2.77 (s, 2H), 1.53 (s, 3H).

[0132] Example 10:

[0133]

[0134] ​The compound of formula 3C (10 g, 1.0 eq) was added to isopropyl alcohol (180 mL), stirred and dissolved under nitrogen protection, and warmed to 50°C, and 30 min was maintained, and the resolution agent D-(+)-di-p-toluoyl tartaric acid (16 g, 1.1 eq) was added to the reaction system in batches, after addition, the reaction solution was clear and transparent, the internal temperature was controlled at 50°C, and stirring was continued for 1 h, and white solid gradually precipitated, and the temperature was maintained at 50°C for 15 h, and then the temperature was gradually lowered to 40°C and 30°C for 1 h, and finally the temperature was lowered to 15°C for 5 h, and filtration was performed, and the filter cake was washed with isopropyl alcohol (10 mL) to obtain 12.22 g of white solid, and after drying at 45°C, 11.55 g of the compound of formula 5C was obtained, the yield was 47.4%, and the ee value was 99.96%; the filtrate was concentrated under reduced pressure at 45°C to obtain 16.14 g of yellow-white solid, and after drying, 15.08 g of the compound of formula 4C was obtained.

[0135] Example 11:

[0136]

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

[0138] 1 H NMR (400 MHz, DMSO) δ 7.92 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 7.9 Hz, 1H), 4.25 (dd, J = 27.7, 9.4 Hz, 2H), 2.77 (s, 2H), 1.53 (s, 3H).

[0139] Example 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 stirred at 35 °C for 30 min, the temperature should not be higher than 35 °C, and then ammonia gas (1 kg) was inserted into the liquid surface through a pipe, and bubbled slowly, the internal temperature was controlled at 30-35 °C, and the bubbling time was controlled for 18 h, the solution pH was 11-12, and the reaction was tracked by NP-HPLC, which showed that the conversion to the compound of formula 3C was 18 h, then the reaction solution was cooled to 15 °C, and stirred for 1 h, a large amount of white solid was precipitated, filtered, and the filter cake was washed with water (5 mL) to obtain a white solid, which was dried at 45 °C to obtain a white solid 4.75 g, the yield was 95.0%, R:S = 49.9:49.3, and the HPLC spectrum was as shown in Figure 4 .

[0142] 1 H NMR (400 MHz, DMSO) δ 7.92 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 7.9 Hz, 1H), 4.25 (dd, J = 27.7, 9.4 Hz, 2H), 2.77 (s, 2H), 1.53 (s, 3H).

[0143] Example 13:

[0144]

[0145] 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 stirred at 35 °C for 30 min, the temperature should not be higher than 35 °C, and then ammonia gas (1 kg) was inserted into the liquid surface through a pipe, and bubbled slowly, the internal temperature was controlled at 30-35 °C, and the bubbling time was controlled for 18 h, the solution pH was 11-12, and the reaction was tracked by NP-HPLC, which showed that the conversion to the compound of formula 3C was 18 h, then the reaction solution was cooled to 15 °C, and stirred for 1 h, a large amount of white solid was precipitated, filtered, and the filter cake was washed with water (5 mL) to obtain a white solid, which was dried at 45 °C to obtain a white solid 4.75 g, the yield was 95.0%, R:S = 49.9:49.3, and the HPLC spectrum was as shown in Figure 5 .

[0146] Example 14:

[0147]

[0148] The compound of formula 3C (100 g, 1.0 eq) was added to isopropyl alcohol (1.8 L), stirred and dissolved under nitrogen protection, and warmed to 50°C, and incubated for 30 min. The resolution agent D-(+)-di-p-toluoyl tartaric acid (159.7 g, 1.2 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 stirring was continued for 1 h. White solids gradually precipitated. The incubation was continued at 50°C for 15 h. Then the temperature was gradually reduced to 40°C and 30°C, and incubated and stirred for 1 h at each temperature. Finally, the temperature was reduced to 15°C and incubated and stirred for 5 h. Filtration was performed, and the filter cake was washed with isopropyl alcohol (100 mL) to obtain 123 g of white solids. 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 yellow-white solids. After drying, 155 g of the compound of formula 4C was obtained.

[0149] Example 15:

[0150]

[0151] Sodium hydrogen phosphate (136.6 g, 4 eq) was added to water (1.5 L), and stirred to dissolve at 25°C. Then the compound of formula 4C (151 g, 1 eq) and ethyl acetate (1.5 L) were added to the reaction system. Incubation and stirring were performed at 25°C for 40 min. The solution was allowed to stand and separate. The organic phase was retained and washed once with water (15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 45°C to obtain 64 g of white solids. After drying under vacuum 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] Example 16:

[0153]

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

[0155] Comparative Example 1:

[0156]

[0157] Compound of formula 7C (25 g, 1.0 eq, purity 99.99%) was analyzed by HPLC as follows: Figure 7 As shown, ethanol (75 mL) and water (75 mL) were added, and the internal temperature was controlled at 65℃ to 75℃. The mixture was stirred for 10 min, and sodium cyanide (13.65 g, 3.0 eq) was added. The reaction was monitored using NP-HPLC, with monitoring every 2 h. After 48 h, the R configuration 7C was still predominant, with no transformation trend observed. The purity of the R configuration was 99.95%. HPLC results are as follows: Figure 8 As shown.

Claims

1. A method for preparing a compound of formula 3, comprising the following steps: R1 is selected from trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and triisopropylsilyl. Method 1: The reaction is as follows: Includes the following steps: Step 2: The compound of formula 2 reacts with an ammonia source and a cyaniding reagent to obtain the compound of formula 3; In step 2, the ammonia source is selected from one or more of ammonium acetate, ammonium formate, ammonia gas, ammonia solution, ammonia water, ammonium chloride, ammonium sulfate, and ammonium carbonate, and the ammonia solution is an organic ammonia solution. The cyaniding reagent in step 2 is selected from potassium cyanide and sodium cyanide; Method 2: The reaction is as follows: It includes the following steps: Step 5: Compound 7 is reacted with ammonia to yield compound 3; The pH of the racemic reaction system in step 5 is 11-12.

2. A method for preparing a compound of formula 3, comprising the following reaction: R1 is selected from trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, or... ; It includes the following steps: Step 5: Compound 7 is reacted with ammonia to yield compound 3; The pH of the racemic reaction system in step 5 is 11-12.

3. A method for preparing a compound of formula 5, comprising the following reaction: in, R1 is selected from trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and triisopropylsilyl; It includes the following steps: Step 3: Obtain compound 5 from compound 3 as described in claim 1 under the action of a resolving agent; The resolving agent in step 3 is selected from D-(+)-di-p-methylbenzoyl tartaric acid, D-(+)-dibenzoyl tartaric acid, and (-)-diacetyl-L-tartaric acid.

4. A method for preparing the Monetate key intermediate of formula 6, comprising the following reaction: It includes the following steps: Step 1: Compound 1 is reacted with R1X and a base to yield compound 2; Step 2: The compound of formula 2 reacts with an ammonia source and a cyaniding reagent to obtain the compound of formula 3; Step 3: Compound 3 is reacted with a resolving agent to yield compounds 4 and 5; Step 4: Compound 5 is reacted with a base to yield compound 6; in, R1 is selected from trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and triisopropylsilyl; X is Br or Cl; The resolving agent in step 3 is selected from D-(+)-di-p-methylbenzoyl tartaric acid, D-(+)-dibenzoyl tartaric acid, and (-)-diacetyl-L-tartaric acid.

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

6. The preparation method according to claim 5, characterized in that, The preparation method in step 1 satisfies one or more of the following conditions: 1) The base mentioned in step 1 is selected from one or more organic or inorganic bases, wherein the organic base is imidazole; 2) The molar ratio of the compound of formula 1, R1X, and base described in step 1 is 1:(1~1.5):(1.5~3). 3) The solvent used in step 1 is selected from one or more of dichloromethane, tetrahydrofuran, and dichloroethane.

7. The preparation method according to claim 1 or 4, 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 chloride and ammonia gas solution or ammonia water, and the ammonia gas solution is an organic ammonia gas solution; 2) The solvent used in step 2 is selected from one or more of the following: acetone, benzene, toluene, xylene, tetrahydrofuran, n-heptane, N,N-dimethylformamide, dimethyl sulfoxide, diethyl ether, dioxane, dichloromethane, dichloroethane, chloroform, ethyl acetate, methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol, isobutanol, acetonitrile, and water; 3) In step 2, the molar ratio of compound 2 and ammonia source is 1:(1~15); 4) The reaction temperature in step 2 is 10 ℃~35 ℃; 5) The reaction time in step 2 is 15 to 30 hours.

8. The preparation method according to claim 7, characterized in that, The preparation method in step 2 satisfies one or more of the following conditions: 1) The solvent used in step 2 is selected from one or more of tetrahydrofuran, dichloromethane, dichloroethane, chloroform, ethyl acetate, methanol, ethanol, isopropanol, n-propanol, N,N-dimethylformamide, dimethyl sulfoxide, and water; 2) In step 2, the molar ratio of compound 2 and ammonia source is 1:(2~13); 3) The reaction temperature in step 2 is 20 ℃~30 ℃; 4) The reaction time in step 2 is 18 to 24 hours.

9. The preparation method according to claim 3 or 4, characterized in that, The preparation method in step 3 satisfies one or more of the following conditions: 1) Step 3 includes 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 down 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 evaporating to obtain the compound of formula 5. The gradient cooling refers to a natural temperature drop of 8 to 15°C each time. The temperature A is 50 ℃~70 ℃; the reaction time of step 3 is 12 to 30 h; 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 diethyl ether; 3) The molar ratio of the compound of formula 3 described in step 3 to the resolving agent is 1:(0.5~2).

10. The preparation method according to claim 9, characterized in that, The preparation method in step 3 satisfies one or more of the following conditions: 1) The reaction time in step 3 is 18 to 30 hours; 2) The solvent used in step 3 is selected from one or more of acetonitrile, isopropanol, isopropyl acetate, and ethyl acetate; 3) The molar ratio of the compound of formula 3 described in step 3 to the resolving agent is 1:(0.7~1.5).

11. The preparation method according to claim 4, characterized in that, The preparation method in step 4 satisfies one or more of the following conditions: 1) The alkali mentioned 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; 2) The pH of the free reaction system in step 4 is 7-8; 3) The reaction temperature in step 4 is 10 ℃~45 ℃; 4) The reaction time in step 4 is 1 to 5 hours.

12. The preparation method according to claim 11, characterized in that, The preparation method in step 4 satisfies one or more of the following conditions: 1) The alkali mentioned in step 4 is selected from dipotassium hydrogen phosphate and disodium hydrogen phosphate; 2) The reaction temperature in step 4 is 20 ℃~35 ℃; 3) The reaction time in step 4 is 1 to 3 hours.

13. The preparation method according to claim 1 or 2, characterized in that, The reaction temperature in step 5 is 10℃ to 35℃, and the reaction time is 10 to 35 h.

14. The preparation method according to claim 13, characterized in that, The reaction temperature in step 5 is 30℃ to 35℃, and the reaction time is 15 to 30 h.

15. A monotere intermediate, with the structural formula shown in Formula 3: Or the structural formula of its single configuration compound is as follows: R1 is selected from trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and triisopropylsilyl.

16. A process for synthesizing monotereil, comprising the preparation method of compound 3 as described in claim 1 or 2, or the preparation method of compound 5 as described in claim 3, or the preparation method of compound 6 as described in claim 4, or the preparation of monotereil using the monotereil intermediate of formula 3 or formula 6 as described in claim 15.

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