Method for producing camptothecin derivatives

Abstract

A method for producing camptothecin derivatives is provided. Specifically, a method for producing the compound of formula 7 is provided, comprising the following steps: a deprotection reaction is carried out with the compound of formula 6 and methanesulfonic acid in an organic solvent to obtain the compound of formula 7. The resulting production method involves a small amount of solvent during post-treatment and is easy to filter. The produced product is white, and the purity and yield of the product are relatively high, making this method suitable for industrial production. The mother liquor obtained from the deprotection reaction is easier to recover, significantly reducing the cost of raw materials. JPEG2026530668000033.jpg39149

Description

[[Technical Field]]

[0001] The present application claims priority to the Chinese patent application 2023111664626 filed on September 11, 2023. This Chinese patent application is incorporated herein by reference in its entirety.

[0002] The present invention relates to a method for producing a camptothecin derivative. [[Background Art]]

[0003] Exatecan is a novel camptothecin derivative that exhibits good water solubility and antitumor effect via introduction of an amino group. The structural formula of exatecan is as follows: [[Chemical Formula]]

[0004] Exatecan is currently mainly synthesized using the classical route that uses acetyl as an amino protecting group, and this synthetic process is disclosed in patent CN111470998B. The specific synthetic route is as follows.

[0005] [[Chemical Formula]]

[0006] The synthetic process reported in patent CN111470998B was reproduced in the present invention. However, experimental results showed that a large amount of black solid was generated in the reaction solution, a large amount of solvent was required for crystallization, the final yield was only 22.2% based on corrected content, the purity was only 95.4%, and the isomer content was 3.1%. [[Summary of the Invention]]

[0007] The technical problem solved by the present invention is that existing manufacturing methods result in product decomposition during the reaction and require a large amount of crystallization solvent during post-treatment, leading to long filtration times and reduced yield and purity. Therefore, the present invention provides a method for producing camptothecin derivatives. The manufacturing method of the present invention uses a small amount of solvent in post-treatment, is easy to filter, and the produced product is grayish-white, with higher purity and yield, making it suitable for industrial production. The recrystallized mother liquor obtained from the deprotection reaction is easier to recover, significantly reducing raw material costs.

[0008] The present invention involves the following steps: subjecting the compound of formula 6 to a deprotection reaction with methanesulfonic acid in an organic solvent to obtain the compound of formula 7. [ka] The present invention provides a method for producing the compound of formula 7, which includes [the compound].

[0009] In one embodiment of the manufacturing method, certain technical features are defined as follows, and other technical features are defined as described in any of the following embodiments (hereinafter referred to as "in one embodiment").

[0010] In one embodiment, the method for producing the compound of formula 7 may include the following specific steps: mixing the compound of formula 6 with an organic solvent, then mixing the mixture with methanesulfonic acid to carry out a deprotection reaction to obtain the compound of formula 7.

[0011] In one embodiment, the mixing can be carried out at a temperature of 15-25°C.

[0012] In one embodiment, the molar ratio of the compound of formula 6 to methanesulfonic acid may be 1:(3-15), preferably 1:(3-10), for example, 1:8.8.

[0013] In one embodiment, the volume-to-mass ratio of the compound of formula 6 to the organic solvent may be 1:(3-10) mL / g, preferably 1:(3-5) mL / g, for example, 1:4.4 mL / g.

[0014] In one embodiment, the organic solvent may be a haloacetic acid, acetic acid, or a chlorinated hydrocarbon solvent, wherein the haloacetic acid is preferably trifluoroacetic acid, the chlorinated hydrocarbon solvent is preferably dichloromethane or chloroform, and the organic solvent is, for example, trifluoroacetic acid.

[0015] In one embodiment, the deprotection reaction can be carried out at a temperature of 5 to 40°C, for example, 15 to 25°C.

[0016] In one embodiment, the deprotection reaction system does not contain water.

[0017] In one embodiment, the deprotection reaction may further comprise a post-treatment step comprising one or more of crystallization, recrystallization, slurrying, filtration, and drying.

[0018] In one embodiment, the solvent for crystallization may be an alcohol solvent and / or an ether solvent; the alcohol solvent is preferably ethanol; the ether solvent is preferably tetrahydrofuran; the solvent for crystallization is preferably an alcohol solvent and an ether solvent, for example, ethanol and tetrahydrofuran.

[0019] In one embodiment, when the solvents for crystallization are an alcohol solvent and an ether solvent, the volume ratio of the alcohol solvent to the ether solvent may be 1:(1-2), for example, 1:1.5.

[0020] In one embodiment, the mass-to-volume ratio of the compound of formula 6 to the solvent for crystallization may be 65.6 g / L.

[0021] In one embodiment, the solvent for recrystallization may be a sulfoxide solvent and / or a nitrile solvent, preferably a sulfoxide solvent and a nitrile solvent. The sulfoxide solvent is preferably dimethyl sulfoxide, and the nitrile solvent is preferably acetonitrile.

[0022] In one embodiment, the volume ratio of the sulfoxide solvent to the nitrile solvent may be 1:3.

[0023] In one embodiment, the solvent for slurrying may be a nitrile solvent, for example, acetonitrile.

[0024] The method for producing the compound of formula 7 may further comprise a method for producing the compound of formula 6, which may comprise the following step: performing a condensation reaction of the compound of formula 4 and the compound of formula 5 in a solvent and in the presence of a catalyst to obtain the compound of formula 6

Chemical formula

[0025] In one embodiment, the method for producing the compound of formula 6 comprises the following specific steps: (a) mixing the compound of formula 4, the compound of formula 5, a part of the catalyst, and a solvent, and performing the condensation reaction to obtain a reaction solution 1; (b) mixing the remaining catalyst with the reaction solution 1, and performing the condensation reaction to obtain the compound of formula 6.

[0026] In one embodiment, the solvent may be an aromatic solvent, for example, toluene.

[0027] In one embodiment, the catalyst may be p-toluenesulfonic acid or pyridinium p-toluenesulfonate, for example, p-toluenesulfonic acid.

[0028] In one embodiment, the molar ratio of the compound of formula 4 to the compound of formula 5 may be 1:(0.9-1.2), for example, 1:1.05.

[0029] In one embodiment, the molar ratio of the compound of formula 4 to the catalyst may be 1:(0.1-0.3), for example, 1:0.2.

[0030] In one embodiment, the mass ratio of the amount of the catalyst added in step (a) to the amount of the catalyst added in step (b) may be 1:1.

[0031] In one embodiment, the mass-to-volume ratio of the compound of formula 4 to the solvent is the conventional mass-to-volume ratio in the art, preferably 20 g / L to 30 g / L, for example, 20 g / L.

[0032] In one embodiment, the condensation reaction may be carried out at the reflux temperature of the solvent.

[0033] In one embodiment, the condensation reaction may further include a post-treatment step comprising one or more of the following: crystallization, slurring, filtration, and drying.

[0034] In one embodiment, the solvent for slurrying may be an alcohol solvent and / or a halogenated hydrocarbon solvent, preferably an alcohol solvent and a halogenated hydrocarbon solvent. The alcohol solvent is preferably methanol; the halogenated hydrocarbon solvent is preferably dichloromethane.

[0035] A method for producing the compound of formula 7 may further include the following step: a method for producing the compound of formula 4, in which the compound of formula 3 is subjected to a substitution reaction with benzyl chloroformate in a solvent and in the presence of a catalyst to obtain the compound of formula 4. [ka]

[0036] In one embodiment, the method for producing the compound of formula 4 involves the following specific steps: (a) A step of mixing the compound of formula 3, the catalyst, and the solvent to obtain a mixed solution 1; (b) The process may include the step of mixing benzyl chloroformate with mixed solution 1 to carry out a substitution reaction to obtain the compound of formula 4.

[0037] In one embodiment, the mixing in step (b) may involve adding benzyl chloroformate to the mixed solution 1.

[0038] In one embodiment, the solvent may be an ether solvent, preferably a tetrahydrofuran.

[0039] In one embodiment, the catalyst may be N,N-diisopropylethylamine.

[0040] In one embodiment, the molar ratio of the compound of formula 3 to the catalyst may be 1:(3-4), for example, 1:3.

[0041] In one embodiment, the molar ratio of the compound of formula 3 to benzyl chloroformate may be 1:(1-1.5), for example, 1:1.15.

[0042] In one embodiment, the mass-to-volume ratio of the compound of formula 3 to the solvent is the conventional mass-to-volume ratio in the art, preferably 5 g / L to 6 g / L, for example, 5.9 g / L.

[0043] In one embodiment, the substitution reaction can be carried out at a temperature of 10-20°C, for example, 20°C.

[0044] In one embodiment, the substitution reaction may further include a post-treatment step comprising one or more of the following: extraction, washing, filtration, concentration, slurring, and drying.

[0045] A method for producing the compound of formula 7 may further include the following steps: a catalytic hydrogenation reaction of the compound of formula 2 using H2 in a solvent and in the presence of a catalyst and an acid to obtain the compound of formula 3. [ka]

[0046] In one embodiment, a method for producing the compound of formula 3 may include the following specific steps: mixing the compound of formula 2, a catalyst, an acid, and a solvent, and carrying out a catalytic hydrogenation reaction under an H2 atmosphere to obtain the compound of formula 3.

[0047] In one embodiment, the solvent may be an alcoholic solvent, such as methanol.

[0048] In one embodiment, the catalyst may be palladium-carbon (Pd / C), for example, 10% Pd / C.

[0049] In one embodiment, the acid may be an organic acid, such as trifluoroacetic acid.

[0050] In one embodiment, the mass ratio of the compound of formula 2 to the catalyst may be 1:(0.002-0.003), for example, 1:0.0025.

[0051] In one embodiment, the molar ratio of the compound of formula 2 to the acid may be 1:(2-4), for example, 1:2.7.

[0052] In one embodiment, the mass-to-volume ratio of the compound of formula 2 to the solvent is the conventional mass-to-volume ratio in the art, preferably 90 g / L to 110 g / L, for example, 100 g / L.

[0053] In one embodiment, the catalytic hydrogenation reaction can be carried out at a temperature of 20-40°C, for example, 25°C.

[0054] In one embodiment, the catalytic hydrogenation reaction may further include a post-treatment step comprising one or more of the following: dissolution, washing, filtration, concentration, and drying.

[0055] A method for producing the compound of formula 7 may further include the following step: a method for producing the compound of formula 2, in which the compound of formula 1 is subjected to an oximing reaction using an oximing agent in a solvent and in the presence of a base to obtain the compound of formula 2. [ka]

[0056] In one embodiment, the method for producing the compound of formula 2 involves the following specific steps: (a) A step of mixing the base and the solvent to obtain mixed solution 2; (b) Mixing mixed solution 2 with the compound of formula 1 to obtain mixed solution 3; (c) The step may include mixing the oximizing agent with the mixed solution 3 to carry out an oximation reaction and obtain the compound of formula 2; Preferably, the mixing in step (a) is carried out at a temperature of 20 to 25°C; the mixing in step (b) is carried out at a temperature of 0 to 5°C; and the mixing in step (c) is carried out at a temperature of 5°C.

[0057] In one embodiment, the solvent may be an ether solvent and / or an alcohol reagent, preferably an ether solvent and an alcohol reagent. The ether reagent is preferably tetrahydrofuran, and the alcohol reagent is preferably tert-butanol.

[0058] In one embodiment, the base may be an organic base, such as potassium tert-butoxide.

[0059] In one embodiment, the oximing agent may be one or more of amyl nitrite, isoamyl nitrite, n-butyl nitrite, and tert-butyl nitrite, for example, isoamyl nitrite.

[0060] In one embodiment, the molar ratio of the compound of formula 1 to the base may be 1:(2.1-2.3), for example, 1:2.2.

[0061] In one embodiment, the molar ratio of the compound of formula 1 to the oximating agent may be 1:(1.2-1.4), for example, 1:1.3.

[0062] In one embodiment, the mass-to-volume ratio of the compound of formula 1 to the solvent is the conventional mass-to-volume ratio in the art, preferably 90 g / L to 100 g / L, for example, 95.2 g / L.

[0063] In one embodiment, the oxime reaction can be carried out at a temperature of 0 to 5°C, for example, 5°C.

[0064] In one embodiment, the oxime reaction may further include a post-treatment step comprising one or more of quenching, filtration, washing, and drying.

[0065] A method for producing the compound of formula 7 may further include the following step: subjecting the compound of formula 6-2 to a racemization reaction in a solvent and in the presence of an acid to obtain the compound of formula 6. [ka]

[0066] In one embodiment, the solvent may be a halogenated hydrocarbon solvent, such as dichloromethane.

[0067] In one embodiment, the acid may be an organic acid, such as trifluoroacetic acid.

[0068] In one embodiment, the molar ratio of the compound of formula 6-2 to the acid may be 1:(3-7), for example, 1:3.8.

[0069] In one embodiment, the mass-to-volume ratio of the compound of formula 6-2 to the solvent may be 50 g / L to 200 g / L, for example, 117.4 g / L.

[0070] In one embodiment, the racemization reaction can be carried out at a temperature of 35-45°C, for example, 40°C.

[0071] A method for producing the compound of formula 7 may further include the following step: subjecting the compound of formula 7-1 to a protection reaction with benzyl chloroformate in a solvent and in the presence of a base to obtain the compound of formula 6-2. [ka]

[0072] In one embodiment, the compound of formula 7-1 may be the mother liquor from the recrystallization reaction in the method for producing the compound of formula 7 as described above.

[0073] In one embodiment, the solvent may be a sulfoxide solvent and / or a nitrile solvent, the sulfoxide solvent preferably being dimethyl sulfoxide, and the nitrile solvent preferably being acetonitrile, and the solvent preferably being dimethyl sulfoxide and / or acetonitrile, for example, dimethyl sulfoxide.

[0074] In one embodiment, the base may be N,N-diisopropylethylamine.

[0075] In one embodiment, the molar ratio of the compound of formula 7-1 to the base may be 1:(3-8), for example, 1:4.

[0076] In one embodiment, the molar ratio of the compound of formula 7-1 to benzyl chloroformate may be 1:(1.2-2), for example, 1:1.7.

[0077] In one embodiment, the mass-to-volume ratio of the compound of formula 7-1 to the solvent may be 25 to 33 g / L.

[0078] In one embodiment, the protective reaction can be carried out at a temperature of -5 to 5°C.

[0079] In one embodiment, the protective reaction may further include a post-treatment step comprising one or more of the following: crystallization, filtration, washing, and drying.

[0080] Without departing from the general knowledge in the art, the above preferred conditions can be arbitrarily combined, thereby yielding various preferred embodiments of the present invention.

[0081] All reagents and raw materials used in this invention are commercially available.

[0082] The remarkable and progressive effects of the present invention are that, in the production method of the present invention, a small amount of solvent is used in the post-treatment, filtration is easy, the produced product is grayish-white, has higher purity and yield, and is suitable for industrial production. The recrystallized mother liquor obtained from the deprotection reaction is easier to recover, and the cost of raw materials is significantly reduced. [Modes for carrying out the invention]

[0083] The present invention will be further illustrated below by examples, but the present invention is not limited to the examples described herein. In the following examples, conventional methods and conditions are used or selected in accordance with the product instructions, except for certain conditions shown in the experimental methods.

[0084] Example 1. Preparation of the compound of formula 2 [ka] 18.9 g of potassium tert-butoxide was added to 170 mL of tetrahydrofuran and 40 mL of tert-butanol at 20-25°C. The mixture was cooled to 0°C, and 20 g of compound 1 was added at 0-5°C. The mixture was reacted for 30 minutes with stirring at 0-5°C. 11.7 g of isoamyl nitrite was added dropwise at 5°C, and the reaction was continued with stirring for 30 minutes. 240 mL of ice water was added to the reaction solution, and the mixture was quenched with 120 mL of 2N diluted hydrochloric acid at 0-10°C. After stirring the mixture at 10°C for 30 minutes, the product was precipitated, followed by filtration and rinsing with 40 mL of methyl tert-butyl ether. After drying, 19.55 g of compound 2 was obtained with a purity of 93.4% and a yield of 80%.

[0085] The retention time for compound 2 was 6.333, and the detection conditions are shown in the table below. [Table 1]

[0086] Compound 2: 1H NMR (CDCl3) δ: 11.84 (s, 1H), 8.24 (m, 1H), 2.87 (m, 2H), 2.76 (m, 2H), 2.01 (s, 3H), 1.96 (s, 3H).

[0087] Example 2. Preparation of the compound of formula 3 [ka] 10 g of compound 2 and 0.025 g of Pd / C were added to 7.5 mL of trifluoroacetic acid and 100 mL of methanol. The mixture was purged three times each with nitrogen and hydrogen, and then reacted under hydrogen at a pressure of 50 psi at 25°C for 16 hours. 100 mL of methanol was added to dissolve the system, followed by filtration (through Celite), rinsing with 50 mL of methanol, and the resulting filtrate was concentrated to dryness. 100 mL of ethanol was added, and the mixture was concentrated to dryness at 55°C. 75 mL of ethanol and 15 mL of 6N hydrochloric acid were added, and the mixture was stirred at 65°C for 16 hours. The mixture was concentrated under reduced pressure to 1 V at 50-70°C, and then 100 mL of ethanol was added, and the mixture was concentrated under reduced pressure to 1 V. 100 mL of THF solution was added and the mixture was stirred. The mixture was cooled to 20°C and filtered. After drying, 7.9 g of compound 3 was obtained with a purity of 98.0% and a yield of 78%.

[0088] The retention time for compound 3 was 4.918 minutes, and the detection conditions were the same as in Example 1.

[0089] Compound 3: 1 H NMR(DMSO)δ:8.51(s,3H),6.49(m,1H),4.17(m,1H),2.98(m,2H),2.83(m,2H),2.39(m,1H),1.99(s,3H).

[0090] Example 3. Preparation of the compound of formula 4 [ka] 5.7 g of compound 3 and 10.6 g of N,N-diisopropylethylamine were added to 970 mL of tetrahydrofuran, and 5.4 g of benzyl chloroformate was added at -10 to 0°C. The mixture was heated to 20°C and reacted for 1 hour. The reaction solution was added to 80 mL of ice water, and the mixture was separated into layers. The aqueous phase was extracted twice with 28.5 mL of ethyl acetate. The organic phases were combined, washed with 12 mL of brine, dried over sodium sulfate, filtered, concentrated, and dried. The crude product was slurryed with 28.5 mL of methyl tert-butyl ether at 20°C for 2 hours to obtain 4.2 g of compound 4 with a purity of 96.3% and a yield of 69%.

[0091] Compound 4: 1 H NMR(DMSO)δ:7.39(m,7H),6.38(m,1H),5.07(s,1H),4.24(m,1H),2.92(m,1H),2.83(m,1H),2.13(m,1H),1.98(s,3H),1.91(m,1H).

[0092] The retention time for compound 4 was 8.381, and the detection conditions are shown in the table below. [Table 2]

[0093] Example 4. Preparation of the compound of formula 5 [ka] 15 g of compound 4, 12.11 g of compound 5, and 0.754 g of p-toluenesulfonic acid were added to 750 mL of toluene. The mixture was heated to 110°C and reacted for 10 hours. After cooling to 55°C, an additional 0.754 g of p-toluenesulfonic acid was added, and the mixture was heated to 110°C and reacted for a further 20 hours. After cooling to 15-25°C, the mixture was stirred for 4 hours, then filtered and rinsed with 45 mL of toluene. The wet product was slurried with 300 mL of methanol / dichloromethane (equal volume ratio) for 0.5 hours. After the reaction, a small amount of material adhered to the walls. After further slurriing with methanol / dichloromethane, almost no material adhered to the walls. The mixture was filtered, then rinsed with 45 mL of methanol / dichloromethane (equal volume ratio), and dried to obtain 21.38 g of product 6 (net content: 20.5 g) with purities of 97.2% and 82.2%.

[0094] The retention times for compound 6 (i.e., a mixture of compounds 6-1 and 6-2) were 8.937 minutes and 9.080 minutes. The detection method is shown in the table below. [Table 3]

[0095] Compound 6: 1 H NMR(DMSO)δ:8.09(m,1H),7.76(m,1H),7.32(m,6H),5.45(s,2H),5.24(m,3H),5.16( m,2H),3.21(m,1H),3.10(m,1H),2.34(s,3H),2.30(m,3H),1.88(m,2H),0.90(m,3H).

[0096] Example 5. Preparation of the compound of formula 7 [ka] 18.7 g of compound 6 was added to 126 g of trifluoroacetic acid, and the mixture was stirred at 15-25°C to dissolve it. Then 27.7 g of methanesulfonic acid was added. The mixture was stirred at 15-25°C for 1 hour, and 114 mL of ethanol and 171 mL of tetrahydrofuran were slowly added dropwise. After stirring for a further 2 hours, the mixture was filtered, and the wet product was rinsed with 93.5 mL of tetrahydrofuran. The crude product was dissolved in 250 mL of dimethyl sulfoxide at 60-70°C, cooled to 50-60°C, and 750 mL of acetonitrile was slowly added dropwise. The mixture was slowly cooled to 15-25°C, and stirring was continued for 10 hours. The mixture was filtered, and then rinsed with 90 mL of acetonitrile. The crude product was again dissolved in 200 mL of dimethyl sulfoxide at 70-80°C, cooled to 50-60°C, and 600 mL of acetonitrile was slowly added dropwise. The mixture was slowly cooled to 15-25°C and stirred for 10 hours. The mixture was filtered and then rinsed with 70 mL of acetonitrile. The wet product was slurryed with 200 mL of acetonitrile to remove residual dimethyl sulfoxide, followed by filtration and drying to obtain 7.47 g (net content) of a grayish-white compound 7. The purity was 99.9%, the isomer (i.e., compound 7-1) content was 0.1%, the chiral purity was 99.9%, and the yield was 42.8%.

[0097] The retention time for compound 7 was 9.617 minutes, and the retention time for the isomer (i.e., compound 7-1) was 11.497 minutes. The detection method is shown in the table below. [Table 4]

[0098] Compound 7: 1 H NMR(DMSO)δ:8.49(s,3H),7.92(m,1H),7.38(s,1H),6.60(s,1H),5.77(m,1H),5.49(m,3H),5.14(s,1H), 3.32(s,1H),3.15(m,1H),2.58(m,2H),2.46(s,3H),2.34(s,3H),2.25(m,1H),1.92(m,1H),0.92(m,1H).

[0099] [ka]

[0100] Manufacturer: Changzhou Syntheall Pharmaceuticals Co., Ltd; Lot number: PC13554-19-SM26-P.

[0101] The retention time for compound 7 was 32.76 minutes, which was consistent with the control. The detection method is shown in the table below. [Table 5]

[0102] Example 6. Preparation of the compound of formula 6-2 [ka] The dimethyl sulfoxide / acetonitrile mother liquor (net content of product and isomers: 8.36 g) from the crystallization and purification in Example 5 was concentrated to a volume (approximately 300 mL) in which no obvious distillates were present. After cooling to -5 to 5°C, 8.2 g of N,N-diisopropylethylamine was added. 4.6 g of benzyl chloroformate was added at a temperature below 5°C. The mixture was reacted at -5 to 5°C for 1 hour. 300 mL of water was slowly added dropwise at a temperature below 5°C, and stirring was continued for 1 hour. The mixture was filtered, then rinsed with 25 mL of ethanol, and dried to obtain 11.85 g of crude product (a mixture of compounds 6-1 and 6-2) with a purity of 97.5% (6-1 / 6-2 = 8.3% / 89.2%).

[0103] The detection method was the same as in Example 4.

[0104] Example 7. Preparation of the compound of formula 6 [ka] 11.85 g of the crude product (a mixture of compounds 6-1 and 6-2) obtained in Example 6 was added to 90 mL of dichloromethane, and 9 g of trifluoroacetic acid was added. The mixture was heated to 40°C and stirred for 15 hours. The dichloromethane in the reaction solution was removed by concentration, the temperature was adjusted to 20°C, and 45 mL of trifluoroacetic acid and 9 mL of methanesulfonic acid were added. The mixture was stirred at 20°C for 3 hours, and 56 mL of ethanol and 84 mL of tetrahydrofuran were slowly added, with stirring continued for 2 hours. The mixture was filtered, then rinsed with 20 mL of tetrahydrofuran, and dried to obtain 8.8 g of crude product. The crude product was dissolved in 120 mL of dimethyl sulfoxide at 60-70°C, cooled to 50-60°C, and 360 mL of acetonitrile was slowly added dropwise. The mixture was slowly cooled to 15-25°C, with stirring continued for 10 hours. The mixture was filtered and then rinsed with 30 mL of acetonitrile. The crude product was again dissolved in 90 mL of dimethyl sulfoxide at 70–80°C, cooled to 50–60°C, and 270 mL of acetonitrile was slowly added dropwise. The mixture was slowly cooled to 15–25°C and stirred for 10 hours. The mixture was filtered and then rinsed with 30 mL of acetonitrile. The wet product was slurried with 300 mL of acetonitrile to remove most of the residual dimethyl sulfoxide, followed by filtration and drying to obtain 3.4 g of compound 7. The purity was 99.9%, the isomer (i.e., compound 7-1) content was 0.07%, the yield (on a corrected content basis) was 37.5%, and the overall recovery yield was 18%.

[0105] The detection method was the same as in Example 5.

[0106] Comparative Example 1. Preparation of the compound in Equation 7 [ka] 32 g of compound 6 and 6.4 g of Pd / C were added to 1280 mL of N,N-dimethylformamide. The mixture was stirred at 20-30°C for 3-5 hours under a hydrogen pressure of 15-25 psi, the reaction solution was filtered, and then rinsed with 160 mL of N,N-dimethylformamide. The filtrate was diluted with 3840 mL of dichloromethane and 2560 mL of n-heptane. The diluted solution was passed through a flash column equipped with 320 g of silica gel and eluted with methanol / dichloromethane (1:20, v / v). The column-passed solution was concentrated to 40 V, and then 10.8 g of methanesulfonic acid was added to form a salt. Crystallization was induced by adding 2560 mL of methyl tert-butyl ether, followed by filtration and rinsing with 160 mL of methyl tert-butyl ether. The crude product was dissolved in 400 mL of dimethyl sulfoxide at 60–70°C, cooled to 50–60°C, and 1200 mL of acetonitrile was slowly added dropwise. The mixture was slowly cooled to 15–25°C, and stirring was continued for 10 hours. The mixture was filtered and then rinsed with 130 mL of acetonitrile. The crude product was again dissolved in 330 mL of dimethyl sulfoxide at 70–80°C, cooled to 50–60°C, and 990 mL of acetonitrile was slowly added dropwise. The mixture was slowly cooled to 15–25°C, and stirring was continued for 10 hours. The mixture was filtered and then rinsed with 110 mL of acetonitrile. The wet product was slurried with 500 mL of acetonitrile to remove residual dimethyl sulfoxide, followed by filtration and drying to obtain 9.89 g of compound 7. The purity was 99.7%, and the yield (based on corrected content) was 32.5%.

[0107] The detection method was the same as in Example 5.

[0108] Comparative Example 2. Preparation of the compound of formula 7 [ka] To reproduce step h of Example 3 of CN111470998B, the specific experimental steps were as follows:

[0109] 8.16 g of compound 8 was added to 163 mL of water, followed by 82 mL of methanesulfonic acid (exothermic reaction). The mixture was heated to 110 °C and reacted for 7 hours. After cooling to 15-25 °C, the black insoluble substance in the reaction solution was removed by filtration (6.3 g after drying), followed by rinsing with 25 mL of water. The filtrate was added to the reaction vessel, and 1088 mL of ethanol was slowly added. After stirring for 0.5 hours, the mixture was filtered and followed by rinsing with 40 mL of ethanol. The wet product was added to 275 mL of ethanol / water (4:1, v / v), heated to 70-80 °C, and stirred under reflux for 2 hours. After cooling to 15-25 °C, the mixture was filtered, followed by rinsing with 32 mL of ethanol, and dried to obtain 2.22 g of compound 7. The purity was 95.4%, the isomer (i.e., compound 7-1) content was 3.1%, and the yield (based on corrected content) was 22.2%.

Claims

1. The following steps: In an organic solvent, the compound of formula 6 is subjected to a deprotection reaction with methanesulfonic acid to obtain the compound of formula 7. 【Chemistry 1】 A method for producing the compound of formula 7, including [the compound].

2. The method for producing the compound of formula 7 is as follows: (1) A method for producing the compound of formula 7 includes the following specific steps: mixing the compound of formula 6 with the organic solvent, then mixing the mixture with methanesulfonic acid to carry out a deprotection reaction to obtain the compound of formula 7; preferably, the mixing is carried out at 15 to 25°C; (2) The molar ratio of the compound of formula 6 to methanesulfonic acid is 1:(3-15), preferably 1:(3-10), for example, 1:8.8; (3) The volume-to-mass ratio of the compound of formula 6 to the organic solvent is 1:(3-10) mL / g, preferably 1:(3-5) mL / g, for example, 1:4.4 mL / g; (4) The organic solvent is haloacetic acid, acetic acid, or a chlorinated hydrocarbon solvent, wherein the haloacetic acid is preferably trifluoroacetic acid, and the chlorinated hydrocarbon solvent is preferably dichloromethane or chloroform; preferably, the organic solvent is, for example, trifluoroacetic acid; (5) The deprotection reaction is carried out at a temperature of 5 to 40°C, for example, 15 to 25°C; (6) The deprotection reaction system does not contain water; (7) The deprotection reaction further includes a post-treatment step comprising one or more of the following: crystallization, recrystallization, slurrying, filtration, and drying; (8) The solvent for crystallization is an alcohol solvent and / or an ether solvent; the alcohol solvent is preferably ethanol; the ether solvent is preferably tetrahydrofuran; preferably the solvent for crystallization is an alcohol solvent and an ether solvent, for example ethanol and tetrahydrofuran; more preferably the volume ratio of the alcohol solvent to the ether solvent is 1:(1-2), for example 1:1.5; (9) The mass-to-volume ratio of the compound of formula 6 to the solvent for crystallization is 65.6 g / L; (10) The solvent for recrystallization is a sulfoxide solvent and / or a nitrile solvent, preferably a sulfoxide solvent and a nitrile solvent; the sulfoxide solvent is preferably dimethyl sulfoxide; the nitrile solvent is preferably acetonitrile; (11) The volume ratio of the sulfoxide solvent to the nitrile solvent is 1:3; (12) The solvent for slurry formation is a nitrile solvent, for example, acetonitrile. A method for producing the compound of formula 7 according to claim 1, satisfying one or more of the following conditions.

3. The method for producing the compound of formula 7 further includes the following steps: a condensation reaction between the compound of formula 4 and the compound of formula 5 in a solvent in the presence of a catalyst to obtain the compound of formula 6, 【Chemistry 2】 Preferably, the method for producing the compound of formula 6 is as follows: (1) The method for producing the compound of formula 6 is the following specific steps: (a) A step of mixing the compound of formula 4, the compound of formula 5, a part of the catalyst, and the solvent to carry out a condensation reaction to obtain a reaction solution 1; (b) The remaining catalyst is mixed with the reaction solution 1 to carry out a condensation reaction to obtain the compound of formula 6; (2) The solvent is an aromatic solvent, for example, toluene; (3) The catalyst is p-toluenesulfonic acid or pyridinium p-toluenesulfonic acid, for example, p-toluenesulfonic acid; (4) The molar ratio of the compound of formula 4 to the compound of formula 5 is 1:(0.9-1.2), for example, 1:1.05; (5) The molar ratio of the compound of formula 4 to the catalyst is 1:(0.1-0.3), for example, 1:0.2; (6) The mass ratio of the amount of catalyst added in step (a) to the amount of catalyst added in step (b) is 1:1; (7) The mass-to-volume ratio of the compound of formula 4 to the solvent is 20 g / L to 30 g / L, for example, 20 g / L; (8) The condensation reaction is carried out at the reflux temperature of the solvent; (9) The condensation reaction further includes a post-processing step comprising one or more of the following: crystallization, slurrying, filtration, and drying; (10) The solvent for slurrying is an alcohol solvent and / or a halogenated hydrocarbon solvent, preferably an alcohol solvent and a halogenated hydrocarbon solvent; the alcohol solvent is preferably methanol; and the halogenated hydrocarbon solvent is preferably dichloromethane. A method for producing the compound of formula 7 according to claim 1 or 2, which satisfies one or more of the following conditions.

4. The method for producing the compound of formula 7 further includes the following steps: a method for producing the compound of formula 4, which involves subjecting the compound of formula 3 to a substitution reaction using benzyl chloroformate in a solvent in the presence of a catalyst to obtain the compound of formula 4. 【Transformation 3】 Preferably, the method for producing the compound of formula 4 is as follows: (1) The method for producing the compound of formula 4 is the following specific steps: (a) A step of mixing the compound of formula 3, the catalyst, and the solvent to obtain a mixed solution 1; (b) The process includes the step of mixing the benzyl chloroformate and the mixed solution 1 to carry out the substitution reaction and obtain the compound of formula 4; Preferably, the mixing in step (b) involves adding the benzyl chloroformate to the mixed solution 1; (2) The solvent is an ether solvent, preferably tetrahydrofuran; (3) The catalyst is N,N-diisopropylethylamine; (4) The molar ratio of the compound of formula 3 to the catalyst is 1:(3-4), for example, 1:3; (5) The molar ratio of the compound of formula 3 to benzyl chloroformate is 1:(1-1.5), for example, 1:1.15; (6) The mass-to-volume ratio of the compound of formula 3 to the solvent is 5 g / L to 6 g / L, for example, 5.9 g / L; (7) The substitution reaction is carried out at a temperature of 10 to 20°C, for example, 20°C; (8) The substitution reaction further includes a post-treatment step comprising one or more of the following: extraction, washing, filtration, concentration, slurrying, and drying. A method for producing the compound of formula 7 according to claim 3, which satisfies one or more of the following conditions.

5. The method for producing the compound of formula 7 further involves the following steps: in a solvent and in the presence of a catalyst and an acid, H is added to the compound of formula 2. ２ The method for producing the compound of formula 3 includes a step of performing a catalytic hydrogenation reaction using to obtain the compound of formula 3, 【Chemistry 4】 Preferably, the method for producing the compound of formula 3 is as follows: (1) The method for producing the compound of formula 3 is the following specific steps: mixing the compound of formula 2, the catalyst, the acid, and the solvent, H ２ The process includes a step of carrying out a catalytic hydrogenation reaction under atmospheric conditions to obtain the compound of formula 3; (2) The solvent is an alcohol solvent, for example, methanol; (3) The catalyst is palladium carbon (Pd / C), for example, 10% Pd / C; (4) The acid is an organic acid, for example, trifluoroacetic acid; (5) The mass ratio of the compound of formula 2 to the catalyst is 1:(0.002-0.003), for example, 1:0.0025; (6) The molar ratio of the compound of formula 2 to the acid is 1:(2-4), for example, 1:2.7; (7) The mass-to-volume ratio of the compound of formula 2 to the solvent is 90 g / L to 110 g / L, for example, 100 g / L; (8) The catalytic hydrogenation reaction is carried out at a temperature of 20 to 40°C, for example, 25°C; (9) The catalytic hydrogenation reaction further includes a post-treatment step comprising one or more of the following: dissolution, washing, filtration, concentration, and drying. A method for producing the compound of formula 7 according to claim 4, which satisfies one or more of the following conditions.

6. The method for producing the compound of formula 7 further includes the following steps: a method for producing the compound of formula 2, which involves subjecting the compound of formula 1 to an oximing reaction using an oximing agent in a solvent and in the presence of a base to obtain the compound of formula 2. 【Transformation 5】 Preferably, the method for producing the compound of formula 2 is as follows: (1) The method for producing the compound of formula 2 is the following specific steps: (a) A step of mixing the base and the solvent to obtain a mixed solution 2; (b) A step of mixing the mixed solution 2 with the compound of formula 1 to obtain a mixed solution 3; (c) The step of mixing the oximizing agent with the mixed solution 3 to carry out an oximation reaction to obtain the compound of formula 2; Preferably, the mixing in step (a) is carried out at a temperature of 20 to 25°C; the mixing in step (b) is carried out at a temperature of 0 to 5°C; and the mixing in step (c) is carried out at a temperature of 5°C. (2) The solvent is an ether solvent and / or an alcohol reagent, preferably an ether solvent and an alcohol reagent; the ether reagent is preferably tetrahydrofuran, and the alcohol reagent is preferably tert-butanol; (3) The base is an organic base, for example, potassium tert-butoxide; (4) The oximing agent is one or more of amyl nitrite, isoamyl nitrite, n-butyl nitrite, and tert-butyl nitrite, for example, isoamyl nitrite; (5) The molar ratio of the compound of formula 1 to the base is 1:(2.1-2.3), for example, 1:2.2; (6) The molar ratio of the compound of formula 1 to the oximating agent is 1:(1.2-1.4), for example, 1:1.3; (7) The mass-to-volume ratio of the compound of formula 1 to the solvent is 90 g / L to 100 g / L, for example, 95.2 g / L; (8) The oxime reaction is carried out at a temperature of 0 to 5°C, for example, 5°C; (9) The oxime reaction further includes a post-treatment step comprising one or more of quenching, filtration, washing, and drying. A method for producing the compound of formula 7 according to claim 5, which satisfies one or more of the following conditions.

7. The method for producing the compound of formula 7 further includes the following steps: subjecting the compound of formula 6-2 to a racemization reaction in a solvent and in the presence of an acid to obtain the compound of formula 6; 【Transformation 6】 A method for producing the compound of formula 7 as described in claim 1.

8. The method for producing the compound of formula 6 is as follows: (1) The solvent is a halogenated hydrocarbon solvent, for example, dichloromethane; (2) The acid is an organic acid, for example, trifluoroacetic acid; (3) The molar ratio of the compound of formula 6-2 to the acid is 1:(3-7), for example, 1:3.8; (4) The mass-to-volume ratio of the compound of formula 6-2 to the solvent is 50 g / L to 200 g / L, for example, 117.4 g / L; (5) The racemization reaction is carried out at a temperature of 35 to 45°C, for example, 40°C. A method for producing the compound of formula 7 according to claim 7, which satisfies one or more of the following conditions.

9. The method for producing the compound of formula 7 further includes the following steps: a method for producing the compound of formula 6-2, which involves subjecting the compound of formula 7-1 to a protective reaction with benzyl chloroformate in a solvent and in the presence of a base to obtain the compound of formula 6-2. 【Transformation 7】 A method for producing the compound of formula 7 according to claim 7 or 8.

10. The method for producing the compound of formula 6-2 is as follows: (1) The compound of formula 7-1 is the mother liquor of the recrystallization from the deprotection reaction in the method for producing the compound of formula 7 according to any one of claims 1 to 9; (2) The solvent is a sulfoxide solvent and / or a nitrile solvent, the sulfoxide solvent is preferably dimethyl sulfoxide, and the nitrile solvent is preferably acetonitrile; preferably the solvent is dimethyl sulfoxide and / or acetonitrile, for example, dimethyl sulfoxide; (3) The base is an organic base, for example, N,N-diisopropylethylamine; (4) The molar ratio of the compound of formula 7-1 to the base is 1:(3-8), for example, 1:4; (5) The molar ratio of the compound of formula 7-1 to benzyl chloroformate is 1:(1.2-2), for example, 1:1.7; (6) The mass-to-volume ratio of the compound of formula 7-1 to the solvent is 25 to 33 g / L; (7) The protective reaction is carried out at a temperature of -5 to 5°C; (8) The protective reaction further includes a post-treatment step comprising one or more of the following: crystallization, filtration, washing, and drying. A method for producing the compound of formula 7 according to claim 9, which satisfies one or more of the following conditions.

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