Preparation method of camptothecin derivatives

Abstract

The present invention discloses a preparation method of camptothecin derivatives. The present invention provides a preparation method of a compound of formula 7, which comprises 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. The preparation method of the present invention uses a small amount of solvent during post-treatment, is easy to filter, the obtained product is off-white, the product purity and yield are higher, and it is suitable for industrial production. The recrystallization mother liquor obtained from the deprotection reaction is easier to recover, greatly reducing the raw material cost.

Description

Technical Field

[0001] The present invention relates to a method for preparing camptothecin derivatives. Background Art

[0002] Exatecan is a novel camptothecin derivative. Due to the introduction of an amino group, it has good water solubility and antitumor effects. The structural formula of exatecan is as follows:

[0003]

[0004] Currently, exatecan mainly adopts the classical synthesis route using acetyl as the amino protecting group. The synthesis process is disclosed in Patent CN111470998B. The specific synthesis route is as follows:

[0005]

[0006] The present invention repeated the synthesis process reported in Patent CN111470998B. However, experiments found that a large amount of black substances were generated in the reaction solution, the amount of solvent used for crystallization was large, and the final yield was only 22.2% (after conversion to content), the purity was only 95.4%, and the isomer content was 3.1%. Summary of the Invention

[0007] The technical problem to be solved by the present invention is that in the existing preparation method, the product decomposes during the reaction process, and the amount of crystallization solvent used in the post-treatment process is large, resulting in a long filtration time, low yield and purity. Therefore, a method for preparing camptothecin derivatives is provided. The preparation method of the present invention uses a small amount of solvent during post-treatment and is easy to filter. The obtained product is off-white, with higher product purity and yield, and is suitable for industrial production. The recrystallization mother liquor obtained from the deprotection reaction is easier to recycle, greatly reducing the raw material cost.

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

[0009]

[0010] In a certain embodiment of the preparation method, the definitions of some technical features are as described below, and the definitions of other technical features are as described in any of the following embodiments (hereinafter referred to as "in a certain embodiment").

[0011] In a certain embodiment, the preparation method of the compound of formula 7 may include the following specific steps: mixing the compound of formula 6 with the organic solvent, and then mixing with the methanesulfonic acid to carry out a deprotection reaction to obtain the compound of formula 7.

[0012] In one embodiment, the temperature of the mixture can be 15 - 25 °C.

[0013] In one embodiment, the molar ratio of the compound of formula 6 to the methanesulfonic acid can be 1:(3 - 15), preferably 1:(3 - 10), such as 1:8.8.

[0014] In one embodiment, the volume - mass ratio of the compound of formula 6 to the organic solvent can be 1:(3 - 10) mL / g, preferably 1:(3 - 5) mL / g, such as 1:4.4 mL / g.

[0015] In one embodiment, the organic solvent can be a haloacetic acid, acetic acid or a chlorinated hydrocarbon solvent. The haloacetic acid is preferably trifluoroacetic acid, and the chlorinated hydrocarbon solvent is preferably dichloromethane or chloroform. The organic solvent is, for example, trifluoroacetic acid.

[0016] In one embodiment, the temperature of the deprotection reaction can be 5 - 40 °C, such as 15 - 25 °C.

[0017] In one embodiment, the deprotection reaction system does not contain water.

[0018] In one embodiment, the deprotection reaction may further include a post - treatment step, and the post - treatment step includes one or more of crystallization, recrystallization, slurrying, filtration and drying.

[0019] In one embodiment, the solvent for crystallization can 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, such as ethanol and tetrahydrofuran.

[0020] In one embodiment, when the solvent for crystallization is an alcohol solvent and an ether solvent, the volume ratio of the alcohol solvent to the ether solvent can be 1:(1 - 2), such as 1:1.5.

[0021] In one embodiment, the mass - volume ratio of the compound of formula 6 to the solvent for crystallization can be 65.6 g / L.

[0022] In one embodiment, the solvent for recrystallization can be 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.

[0023] In one embodiment, the volume ratio of the sulfoxide solvent to the nitrile solvent can be 1:3.

[0024] In one embodiment, the solvent for slurrying can be a nitrile solvent, such as acetonitrile.

[0025] The preparation method of the compound of formula 7 may further include the preparation method of the compound of formula 6, which may include the following steps: In a solvent, in the presence of a catalyst, the compound of formula 4 and the compound of formula 5 are subjected to a condensation reaction to obtain the compound of formula 6,

[0026]

[0027] In one embodiment, the preparation method of the compound of formula 6 may include the following specific steps:

[0028] (a) Mix the compound of formula 4, the compound of formula 5, a part of the catalyst and the solvent, and carry out a condensation reaction to obtain reaction solution 1;

[0029] (b) Mix the remaining catalyst with reaction solution 1 and carry out a condensation reaction to obtain the compound of formula 6.

[0030] In one embodiment, the solvent may be an aromatic solvent, such as toluene.

[0031] In one embodiment, the catalyst may be p-toluenesulfonic acid or pyridinium p-toluenesulfonate, such as p-toluenesulfonic acid.

[0032] 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), such as 1:1.05.

[0033] In one embodiment, the molar ratio of the compound of formula 4 to the catalyst may be 1:(0.1 - 0.3), such as 1:0.2.

[0034] 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.

[0035] In one embodiment, the mass-volume ratio of the compound of formula 4 to the solvent is a conventional mass-volume ratio in the art, preferably 20 g / L - 30 g / L, such as 20 g / L.

[0036] In one embodiment, the condensation reaction may be carried out at the reflux temperature of the solvent.

[0037] In one embodiment, the condensation reaction may further include a post-treatment step, and the post-treatment step includes one or more of crystallization, slurrying, filtration and drying.

[0038] 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.

[0039] The preparation method of the compound of formula 7 may further include the preparation method of the compound of formula 4, which may include the following steps: In a solvent, in the presence of a catalyst, the compound of formula 3 reacts with carbobenzoxy chloride by a substitution reaction to obtain the compound of formula 4,

[0040]

[0041] In one embodiment, the preparation method of the compound of formula 4 may include the following specific steps:

[0042] (a) Mix the compound of formula 3, the catalyst and the solvent to obtain a mixture 1;

[0043] (b) Mix the carbobenzoxy chloride with the mixture 1 and carry out a substitution reaction to obtain the compound of formula 4.

[0044] In one embodiment, the mixing in step (b) may be adding the carbobenzoxy chloride to the mixture 1.

[0045] In one embodiment, the solvent may be an ether solvent, preferably tetrahydrofuran.

[0046] In one embodiment, the catalyst may be N,N-diisopropylethylamine.

[0047] In one embodiment, the molar ratio of the compound of formula 3 to the catalyst may be 1:(3 - 4), for example, 1:3.

[0048] In one embodiment, the molar ratio of the compound of formula 3 to the carbobenzoxy chloride may be 1:(1 - 1.5), for example, 1:1.15.

[0049] In one embodiment, the mass-volume ratio of the compound of formula 3 to the solvent is a conventional mass-volume ratio in the art, preferably 5 g / L - 6 g / L, for example, 5.9 g / L.

[0050] In one embodiment, the temperature of the substitution reaction may be 10 - 20 °C, for example, 20 °C.

[0051] In one embodiment, the substitution reaction may further include a post-treatment step, and the post-treatment step includes one or more of extraction, washing, filtration, concentration, pulping and drying.

[0052] The preparation method of the compound of formula 7 may further include the preparation method of the compound of formula 3, which may include the following steps: In a solvent, in the presence of a catalyst and an acid, the compound of formula 2 undergoes a catalytic hydrogenation reaction with H2 to obtain the compound of formula 3,

[0053]

[0054] In one embodiment, the method for preparing the compound of formula 3 may include the following specific steps: The compound of formula 2, the catalyst, the acid and the solvent are mixed, and a catalytic hydrogenation reaction is carried out under a H2 atmosphere to obtain the compound of formula 3.

[0055] In one embodiment, the solvent may be an alcohol solvent, such as methanol.

[0056] In one embodiment, the catalyst may be palladium on carbon (Pd / C), such as 10% Pd / C.

[0057] In one embodiment, the acid may be an organic acid, such as trifluoroacetic acid.

[0058] In one embodiment, the mass ratio of the compound of formula 2 to the catalyst may be 1:(0.002 - 0.003), such as 1:0.0025.

[0059] In one embodiment, the molar ratio of the compound of formula 2 to the acid may be 1:(2 - 4), such as 1:2.7.

[0060] In one embodiment, the mass-to-volume ratio of the compound of formula 2 to the solvent is a conventional mass-to-volume ratio in the art, preferably 90 g / L - 110 g / L, such as 100 g / L.

[0061] In one embodiment, the temperature of the catalytic hydrogenation reaction may be 20 - 40 °C, such as 25 °C.

[0062] In one embodiment, the catalytic hydrogenation reaction may further include a post-treatment step, and the post-treatment step includes one or more of dissolution, washing, filtration, concentration and drying.

[0063] The method for preparing the compound of formula 7 may further include the method for preparing the compound of formula 2, which may include the following steps: In a solvent, in the presence of a base, the compound of formula 1 reacts with an oximating agent to carry out an oximation reaction to obtain the compound of formula 2.

[0064]

[0065] In one embodiment, the method for preparing the compound of formula 2 may include the following specific steps:

[0066] (a) The base and the solvent are mixed to obtain a mixed solution 2;

[0067] (b) The mixed solution 2 and the compound of formula 1 are mixed to obtain a mixed solution 3;

[0068] (c) The oximating agent and the mixed solution 3 are mixed to carry out an oximation reaction to obtain the compound of formula 2;

[0069] Preferably, the temperature of the mixing in step (a) is preferably 20-25°C; the temperature of the mixing in step (b) is preferably 0-5°C; the temperature of the mixing in step (c) is preferably 5°C.

[0070] In one embodiment, the solvent can 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.

[0071] In one embodiment, the base can be an organic base, such as potassium tert-butoxide.

[0072] In one embodiment, the oximating agent can be one or more of amyl nitrite, isoamyl nitrite, n-butyl nitrite, and tert-butyl nitrite, such as isoamyl nitrite.

[0073] In one embodiment, the molar ratio of the compound of formula 1 to the base can be 1:(2.1-2.3), such as 1:2.2.

[0074] In one embodiment, the molar ratio of the compound of formula 1 to the oximating agent can be 1:(1.2-1.4), such as 1:1.3.

[0075] In one embodiment, the mass-volume ratio of the compound of formula 1 to the solvent is a conventional mass-volume ratio in the art, preferably 90 g / L - 100 g / L, such as 95.2 g / L.

[0076] In one embodiment, the temperature of the oximation reaction can be 0-5°C, such as 5°C.

[0077] In one embodiment, the oximation reaction can further include a post-treatment step, and the post-treatment step includes one or more of quenching, filtration, washing, and drying.

[0078] The preparation method of the compound of formula 7 can further include the preparation method of the compound of formula 6, which can include the following steps: in a solvent, in the presence of an acid, the compound of formula 6-2 undergoes a racemization reaction to obtain the compound of formula 6;

[0079]

[0080] In one embodiment, the solvent can be a halogenated hydrocarbon solvent, such as dichloromethane.

[0081] In one embodiment, the acid can be an organic acid, such as trifluoroacetic acid.

[0082] In one embodiment, the molar ratio of the compound of formula 6-2 to the acid can be 1:(3-7), such as 1:3.8.

[0083] In one embodiment, the mass-volume ratio of the compound of Formula 6-2 to the solvent can be 50 g / L - 200 g / L, such as 117.4 g / L.

[0084] In one embodiment, the temperature of the racemization reaction can be 35 - 45 °C, such as 40 °C.

[0085] The method for preparing the compound of Formula 7 may further include the method for preparing the compound of Formula 6-2, which may include the following steps: In a solvent, in the presence of a base, the compound of Formula 7-1 reacts with benzyloxycarbonyl chloride to carry out a protection reaction to obtain the compound of Formula 6-2.

[0086]

[0087] In one embodiment, the compound of Formula 7-1 can be the recrystallization mother liquor in the deprotection reaction in the method for preparing the compound of Formula 7 as described above.

[0088] In one embodiment, the solvent can be a sulfoxide solvent and / or a nitrile solvent. The sulfoxide solvent is preferably dimethyl sulfoxide; the nitrile solvent is preferably acetonitrile; the solvent is preferably dimethyl sulfoxide and / or acetonitrile, such as dimethyl sulfoxide.

[0089] In one embodiment, the base can be an organic base, such as N,N-diisopropylethylamine.

[0090] In one embodiment, the molar ratio of the compound of Formula 7-1 to the base can be 1:(3 - 8), such as 1:4.

[0091] In one embodiment, the molar ratio of the compound of Formula 7-1 to the benzyloxycarbonyl chloride can be 1:(1.2 - 2), such as 1:1.7.

[0092] In one embodiment, the mass-volume ratio of the compound of Formula 7-1 to the solvent can be 25 - 33 g / L.

[0093] In one embodiment, the temperature of the protection reaction can be -5 - 5 °C.

[0094] In one embodiment, the protection reaction may further include a post-treatment step, and the post-treatment step includes one or more of crystallization, filtration, washing, and drying.

[0095] On the basis of not violating the common knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention.

[0096] The reagents and raw materials used in the present invention are all commercially available.

[0097] The positive and progressive effects of the present invention are as follows: The preparation method of the present invention uses a small amount of solvent during post-treatment, is easy to filter, the obtained product is off-white, and the product purity and yield are higher, which is suitable for industrial production. The recrystallization mother liquor obtained from the deprotection reaction is easier to recycle, greatly reducing the raw material cost. Detailed implementation mode

[0098] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0099] Example 1 Preparation of Compound of Formula 2

[0100]

[0101] 18.9 g of potassium tert-butoxide was added to 170 mL of tetrahydrofuran and 40 mL of tert-butanol at 20 - 25 °C. It was cooled to 0 °C, 20 g of Compound 1 was added at 0 - 5 °C, and the reaction was stirred at 0 - 5 °C for 30 minutes. 11.7 g of isoamyl nitrite was added dropwise at 5 °C, and the reaction was continued to stir for 30 min. 240 mL of ice water was added to the reaction solution, and it was quenched with 120 mL of 2N dilute hydrochloric acid at 0 - 10 °C. Stir at 10 °C for 30 minutes, the product precipitated, filtered, and washed with 40 mL of methyl tert-butyl ether. 19.55 g of Compound 2 was obtained by drying, with a purity of 93.4% and a yield of 80%.

[0102] The retention time of Compound 2 is 6.333, and the detection conditions are as follows:

[0103]

[0104]

[0105] Compound 2: 1 H 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).

[0106] Example 2 Preparation of Compound of Formula 3

[0107]

[0108] Add 10 g of Compound 2 and 0.025 g of Pd / C to 7.5 mL of trifluoroacetic acid and 100 mL of methanol. Replace the gas with nitrogen and hydrogen three times respectively, react at 25 °C under a hydrogen pressure of 50 psi for 16 hours, add 100 mL of methanol to dissolve the system, filter (using diatomaceous earth), wash with 50 mL of methanol, and concentrate the filtrate to dryness. Add 100 mL of ethanol and concentrate to dryness at 55 °C. Add 75 mL of ethanol and 15 mL of 6N hydrochloric acid, stir at 65 °C for 16 hours. Concentrate under reduced pressure to 1V at 50 - 70 °C, add 100 mL of ethanol, and concentrate under reduced pressure to 1V. Add 100 mL of THF solution and stir. Cool to 20 °C and filter. Dry to obtain 7.9 g of Compound 3 with a purity of 98.0% and a yield of 78%.

[0109] The retention time of Compound 3: 4.918 minutes. The detection conditions are the same as those in Example 1.

[0110] 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).

[0111] Preparation of Compound 4 of Formula 4 in Example 3

[0112]

[0113] Add 5.7 g of Compound 3 and 10.6 g of N,N - diisopropylethylamine to 970 mL of tetrahydrofuran. Add 5.4 g of benzyloxycarbonyl chloride at -10 - 0 °C, then warm up to 20 °C and react for 1 hour. Add the reaction solution to 80 mL of ice water, separate the layers, and extract the aqueous phase with 28.5 mL of ethyl acetate twice. Combine the organic phases, wash with 12 mL of brine, dry over sodium sulfate, filter and concentrate to dryness. Pulverize the crude product 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%.

[0114] 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).

[0115] The retention time of Compound 4: 8.381 minutes. The detection conditions are as follows in the table:

[0116]

[0117]

[0118] Preparation of Compound of Formula 5 in Example 4

[0119]

[0120] 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, another 0.754 g of p-toluenesulfonic acid was added, and the temperature was further raised to 110 °C and reacted for 20 hours. The temperature was cooled to 15 - 25 °C, stirred for 4 hours and then filtered, and washed with 45 mL of toluene. The wet product was slurried with 300 mL of methanol / dichloromethane (equal volume ratio) for 0.5 hour. After the reaction, a small amount of material adhered to the wall. After slurrying with methanol / dichloromethane again, basically no material adhered to the wall. Filtered, washed 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 a purity of 97.2% and a yield of 82.2%.

[0121] Retention times of Compound 6 (a mixture of Compound 6-1 and Compound 6-2): 8.937 min and 9.080 min. The detection method is as follows in the table:

[0122]

[0123]

[0124] 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).

[0125] Preparation of Compound of Formula 7 in Example 5

[0126]

[0127] 18.7 g of Compound 6 was added to 126 g of trifluoroacetic acid, and the mixture was stirred and dissolved at 15 - 25 °C. Then 27.7 g of methanesulfonic acid was added. The reaction was stirred at 15 - 25 °C for 1 hour, and 114 mL of ethanol and 171 mL of tetrahydrofuran were slowly added dropwise respectively. After stirring for another 2 hours, the mixture was filtered, and the wet product was washed 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 temperature was slowly decreased to 15 - 25 °C, and stirring was continued for 10 hours. The mixture was filtered and washed with 90 mL of acetonitrile. The crude product was dissolved again 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 temperature was slowly decreased to 15 - 25 °C, and stirring was continued for 10 hours. The mixture was filtered and washed with 70 mL of acetonitrile. The wet product was slurried with 200 mL of acetonitrile to remove the residual dimethyl sulfoxide, and then filtered and dried to obtain 7.47 g (net content) of off - white Compound 7, with a purity of 99.9%, 0.1% of isomer (i.e., Compound 7 - 1), a chiral purity of 99.9%, and a yield of 42.8%.

[0128] Retention time of Compound 7: 9.617 min, retention time of isomer (i.e., Compound 7 - 1): 11.497 min. The detection method is as follows in the table:

[0129]

[0130]

[0131] Compound 7: 1 1H 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).

[0132] Reference substance:

[0133] Manufacturer: Changzhou Hequan Pharmaceutical Co., Ltd.; Batch number: PC13554 - 19 - SM26 - P.

[0134] Retention time of Compound 7: 32.76 min, the retention time is consistent with that of the reference substance. The detection method is as follows in the table:

[0135]

[0136]

[0137] Preparation of Compound of Formula 6-2 in Example 6

[0138]

[0139] In Example 5, the dimethyl sulfoxide / acetonitrile mother liquor (total net content of product and isomers: 8.36 g) during the crystallization and purification process was concentrated until no obvious distillate remained (about 300 mL). The temperature was lowered to -5 - 5°C, and 8.2 g of N,N-diisopropylethylamine was added. At a temperature below 5°C, 4.6 g of benzyloxycarbonyl chloride was added. The reaction was carried out at -5 - 5°C for 1 hour. At a temperature below 5°C, 300 mL of water was slowly added dropwise, and stirring was continued for 1 hour. Filtration was carried out, and the residue was washed with 25 mL of ethanol and then dried to obtain 11.85 g of crude product (a mixture of Compound 6-1 and Compound 6-2), with a purity of 97.5% (6-1 / 6-2 = 8.3% / 89.2%).

[0140] The detection method was the same as that in Example 4.

[0141] Preparation of Compound of Formula 6 in Example 7

[0142]

[0143] 11.85 g of the crude product (a mixture of Compound 6-1 and Compound 6-2) obtained in Example 6 was added to 90 mL of dichloromethane, and 9 g of trifluoroacetic acid was added. The temperature was raised to 40°C and stirred for 15 hours. The dichloromethane in the reaction solution was concentrated and removed. The temperature was adjusted to 20°C, and 45 mL of trifluoroacetic acid and 9 mL of methanesulfonic acid were added. The reaction was stirred at 20°C for 3 hours. 56 mL of ethanol and 84 mL of tetrahydrofuran were slowly added respectively, and stirring was continued for 2 hours. Filtration was carried out, and the residue was washed with 20 mL of tetrahydrofuran and then 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 temperature was slowly lowered to 15 - 25°C, and stirring was continued for 10 hours. Filtration was carried out, and the residue was washed with 30 mL of acetonitrile. The crude product was dissolved again 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 temperature was slowly lowered to 15 - 25°C, and stirring was continued for 10 hours. Filtration was carried out, and the residue was washed with 30 mL of acetonitrile. The wet product was slurried with 300 mL of acetonitrile to remove most of the residual dimethyl sulfoxide, and then filtered and dried to obtain 3.4 g of Compound 7, with a purity of 99.9%, 0.07% of isomer (i.e., Compound 7-1), a yield of 37.5% (yield after converting to content), and a total recovery yield of 18%.

[0144] The detection method was the same as that in Example 5.

[0145] Preparation of Compound of Formula 7 in Comparative Example 1

[0146]

[0147] 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 and under a hydrogen pressure of 15 - 25 psi for 3 - 5 h, then the reaction solution was filtered and washed 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 with 320 g of silica gel, eluted with methanol / dichloromethane (1:20, v / v). The column-passed solution was concentrated to 40V, and 10.8 g of methanesulfonic acid was added to form a salt. 2560 mL of methyl tert-butyl ether was added for crystallization, filtered, and washed 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. It was slowly cooled to 15 - 25 °C and stirred for 10 h. Filtered, and washed with 130 mL of acetonitrile. The crude product was dissolved again in 330 mL of dimethyl sulfoxide at 70 - 80 °C, cooled to 50 - 60 °C, and 990 mL of acetonitrile was slowly added dropwise. It was slowly cooled to 15 - 25 °C and stirred for 10 h. Filtered, and washed with 110 mL of acetonitrile. The wet product was slurried with 500 mL of acetonitrile to remove the residual dimethyl sulfoxide, filtered and dried to obtain 9.89 g of Compound 7, with a purity of 99.7% and a yield of 32.5% (yield after converting to the content).

[0148] The detection method was the same as that in Example 5.

[0149] Preparation of Compound 7 in Comparative Example 2

[0150]

[0151] Step h in Example 3 of CN111470998B was repeated. The specific experimental steps were as follows:

[0152] 8.16 g of Compound 8 was added to 163 mL of water, then 82 mL of methanesulfonic acid was added (with heat release), and the temperature was raised to 110 °C for reaction for 7 h. After cooling to 15 - 25 °C, the black insoluble matter in the reaction solution was filtered off (6.3 g after drying), and washed with 25 mL of water. The filtrate was added to a reaction kettle, and 1088 mL of ethanol was slowly added. After stirring for 0.5 h, it was filtered, and washed 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 for reflux stirring for 2 h, cooled to 15 - 25 °C and then filtered, and washed with 32 mL of ethanol. After drying, 2.22 g of Compound 7 was obtained, with a purity of 95.4%, 3.1% of isomer (i.e., Compound 7-1), and a yield of 22.2% (after converting to the content).

Claims

1. A method for preparing a compound of formula 7, characterized in that, It includes the following steps: In an organic solvent, the compound of formula 6 undergoes a deprotection reaction with methanesulfonic acid to obtain the compound of formula 7. The temperature of the deprotection reaction is 5 - 40 °C; the organic solvent is trifluoroacetic acid; the molar ratio of the compound of formula 6 to methanesulfonic acid is 1:(3 - 15); the deprotection reaction further includes a post-treatment step, and the post-treatment step includes crystallization, recrystallization, slurrying, filtration, and drying; the solvent for crystallization is an alcohol solvent and an ether solvent, the volume ratio of the alcohol solvent to the ether solvent is 1:(1 - 2), the alcohol solvent is ethanol, and the ether solvent is tetrahydrofuran; the solvent for recrystallization is a sulfoxide solvent and a nitrile solvent, the sulfoxide solvent is dimethyl sulfoxide, and the nitrile solvent is acetonitrile; 2. The preparation method of the compound of formula 7 according to claim 1, characterized in that, The preparation method of the compound of formula 7 satisfies one or more of the following conditions: (1) The preparation method of the compound of formula 7 includes the following specific steps: Mix the compound of formula 6 with the organic solvent, and then mix with methanesulfonic acid to carry out a deprotection reaction to obtain the compound of formula 7; (2) The volume-mass ratio of the compound of formula 6 to the organic solvent is 1:(3 - 10) mL / g; (3) The temperature of the deprotection reaction is 15 - 25 °C; (4) The deprotection reaction system does not contain water; and (5) the solvent for slurrying is a nitrile solvent.

3. The preparation method of the compound of formula 7 according to claim 2, characterized in that, The preparation method of the compound of formula 7 satisfies one or more of the following conditions: (1) The preparation method of the compound of formula 7 includes the following specific steps: Mix the compound of formula 6 with the organic solvent, and then mix with methanesulfonic acid to carry out a deprotection reaction to obtain the compound of formula 7; the temperature of the mixing is 15 - 25 °C; (2) The molar ratio of the compound of formula 6 to methanesulfonic acid is 1:(3 - 10); (3) The volume-mass ratio of the compound of formula 6 to the organic solvent is 1:(3 - 5) mL / g; (4) The mass-volume ratio of the compound of formula 6 to the solvent for crystallization is 65.6 g / L; (5) The solvent for slurrying is a nitrile solvent.

4. The preparation method of the compound of formula 7 according to claim 3, characterized in that, The preparation method of the compound of formula 7 satisfies one or more of the following conditions: (1) The molar ratio of the compound of formula 6 to methanesulfonic acid is 1:8.8; (2) The volume-mass ratio of the compound of formula 6 to the organic solvent is 1:4.4 mL / g; (3) The solvent for slurrying is acetonitrile.

5. The method for preparing the compound of formula 7 according to claim 4, characterized in that, The volume ratio of the sulfoxide solvent to the nitrile solvent is 1:

3.

6. The preparation method of the compound of formula 7 according to claim 1, characterized in that, The volume ratio of the alcohol solvent to the ether solvent is 1:1.

5.

7. The preparation method of the compound of formula 7 according to any one of claims 1-6, characterized in that, The preparation method of the compound of formula 7 further includes the preparation method of the compound of formula 6, which includes the following steps: In a solvent, in the presence of a catalyst, the compound of formula 4 and the compound of formula 5 undergo a condensation reaction to obtain the compound of formula 6, 8. The method for preparing the compound of formula 7 according to claim 7, characterized in that, The preparation method of the compound of formula 6 satisfies one or more of the following conditions: (1) The preparation method of the compound of formula 6 includes the following specific steps: (a) Mix the compound of formula 4, the compound of formula 5, a part of the catalyst with the solvent, and carry out a condensation reaction to obtain reaction solution 1; (b) Mix the remaining catalyst with the reaction solution 1 and carry out a condensation reaction to obtain the compound of Formula 6; (2) The solvent is an aromatic solvent; (3) The catalyst is p-toluenesulfonic acid or pyridinium p-toluenesulfonate; (4) The molar ratio of the compound of Formula 4 to the compound of Formula 5 is 1:(0.9 - 1.2); (5) The molar ratio of the compound of Formula 4 to the catalyst is 1:(0.1 - 0.3); (6) The mass ratio of the addition amount of the catalyst in step (a) to the addition amount of the catalyst in step (b) is 1:1; (7) The mass-volume ratio of the compound of Formula 4 to the solvent is 20 g / L - 30 g / L; (8) The condensation reaction is carried out at the reflux temperature of the solvent; (9) The condensation reaction further includes a post-treatment step, and the post-treatment step includes one or more of crystallization, slurrying, filtration, and drying.

9. The method for preparing the compound of formula 7 as claimed in claim 8, characterized in that, The preparation method of the compound of Formula 6 satisfies one or more of the following conditions: (1) The solvent is toluene; (2) The catalyst is p-toluenesulfonic acid; (3) The molar ratio of the compound of Formula 4 to the compound of Formula 5 is 1:1.05; (4) The molar ratio of the compound of Formula 4 to the catalyst is 1:0.2; (5) The mass-volume ratio of the compound of Formula 4 to the solvent is 20 g / L; (6) The solvent for slurrying is an alcohol solvent and / or a halogenated hydrocarbon solvent.

10. The method for preparing the compound of formula 7 according to claim 9, characterized in that, The alcohol solvent is methanol; the halogenated hydrocarbon solvent is dichloromethane.

11. The method for preparing the compound of formula 7 according to claim 7, characterized in that, The preparation method of the compound of Formula 7 further includes the preparation method of the compound of Formula 4, which includes the following steps: In a solvent, in the presence of a catalyst, the compound of Formula 3 reacts with benzyloxycarbonyl chloride by a substitution reaction to obtain the compound of Formula 4, 12. The method for preparing the compound of formula 7 according to claim 11, characterized in that, The preparation method of the compound of Formula 4 satisfies one or more of the following conditions: (1) The preparation method of the compound of Formula 4 includes the following specific steps: (a) Mix the compound of Formula 3, the catalyst, and the solvent to obtain a mixed solution 1; (b) Mix the benzyloxycarbonyl chloride with the mixed solution 1 and carry out a substitution reaction to obtain the compound of Formula 4; (2) The solvent is an ether solvent; (3) The catalyst is N,N-diisopropylethylamine; (4) The molar ratio of the compound of Formula 3 to the catalyst is 1:(3 - 4); (5) The molar ratio of the compound of Formula 3 to the benzyloxycarbonyl chloride is 1:(1 - 1.5); (6) The mass-volume ratio of the compound of Formula 3 to the solvent is 5 g / L - 6 g / L; (7) The temperature of the substitution reaction is 10 - 20 °C; and (8) The substitution reaction further includes a post-treatment step, and the post-treatment step includes one or more of extraction, washing, filtration, concentration, slurrying, and drying.

13. The method for preparing the compound of formula 7 according to claim 12, characterized in that, The preparation method of the compound of Formula 4 satisfies one or more of the following conditions: (1) In step (b), the mixing is to add the benzyloxycarbonyl chloride to the mixed solution 1; (2) The solvent is tetrahydrofuran; (3) The molar ratio of the compound of Formula 3 to the catalyst is 1:3; (4) The molar ratio of the compound of Formula 3 to the benzyloxycarbonyl chloride is 1:1.15; (5) The mass-volume ratio of the compound of formula 3 to the solvent is 5.9 g / L; (6) The temperature of the substitution reaction is 20 °C.

14. The method for preparing the compound of formula 7 according to claim 13, characterized in that, The preparation method of the compound of formula 7 further includes the preparation method of the compound of formula 3, which comprises the following steps: in a solvent, in the presence of a catalyst and an acid, the compound of formula 2 undergoes a catalytic hydrogenation reaction with H2 to obtain the compound of formula 3.

15. The method for preparing the compound of formula 7 according to claim 14, characterized in that, The preparation method of the compound of formula 3 satisfies one or more of the following conditions: (1) The preparation method of the compound of formula 3 includes the following specific steps: the compound of formula 2, the catalyst, the acid and the solvent are mixed, and a catalytic hydrogenation reaction is carried out under a H2 atmosphere to obtain the compound of formula 3; (2) The solvent is an alcohol solvent; (3) The catalyst is palladium on carbon (Pd / C); (4) The acid is an organic acid; (5) The mass ratio of the compound of formula 2 to the catalyst is 1:(0.002 - 0.003); (6) The molar ratio of the compound of formula 2 to the acid is 1:(2 - 4); (7) The mass-volume ratio of the compound of formula 2 to the solvent is 90 g / L - 110 g / L; (8) The temperature of the catalytic hydrogenation reaction is 20 - 40 °C; and (9) The catalytic hydrogenation reaction further includes a post-treatment step, and the post-treatment step includes one or more of dissolution, washing, filtration, concentration and drying.

16. The method for preparing the compound of formula 7 according to claim 15, characterized in that, The preparation method of the compound of formula 3 satisfies one or more of the following conditions: (1) The solvent is methanol; (2) The catalyst is 10% Pd / C; (3) The acid is trifluoroacetic acid; (4) The mass ratio of the compound of formula 2 to the catalyst is 1:0.0025; (5) The molar ratio of the compound of formula 2 to the acid is 1:2.7; (6) The mass-volume ratio of the compound of formula 2 to the solvent is 100 g / L; (7) The temperature of the catalytic hydrogenation reaction is 25 °C.

17. The method for preparing the compound of formula 7 according to claim 14, characterized in that, The preparation method of the compound of formula 7 further includes the preparation method of the compound of formula 2, which comprises the following steps: in a solvent, in the presence of a base, the compound of formula 1 undergoes an oximation reaction with an oximating agent to obtain the compound of formula 2.

18. The method for preparing the compound of formula 7 according to claim 17, characterized in that, The preparation method of the compound of formula 2 satisfies one or more of the following conditions: (1) The preparation method of the compound of formula 2 includes the following specific steps: (a) The base and the solvent are mixed to obtain a mixed solution 2; (b) The mixed solution 2 is mixed with the compound of formula 1 to obtain a mixed solution 3; (c) The oximating agent is mixed with the mixed solution 3 to carry out an oximation reaction to obtain the compound of formula 2; (2) The solvent is an ether solvent and / or an alcohol reagent; (3) The base is an organic base; (4) The oximating agent is one or more of amyl nitrite, isoamyl nitrite, n-butyl nitrite and tert-butyl nitrite; (5) The molar ratio of the compound of formula 1 to the base is 1:(2.1 - 2.3); (6) The molar ratio of the compound of formula 1 to the oximating agent is 1:(1.2 - 1.4); (7) The mass-volume ratio of the compound of formula 1 to the solvent is 90 g / L - 100 g / L; (8) The temperature of the oximation reaction is 0 - 5 °C; and (9) The oximation reaction further includes a post-treatment step, and the post-treatment step includes one or more of quenching, filtration, washing, and drying.

19. The method for preparing the compound of formula 7 according to claim 18, characterized in that, The preparation method of the compound of formula 2 satisfies one or more of the following conditions: (1) The temperature of the mixing in step (a) is 20 - 25 °C; the temperature of the mixing in step (b) is 0 - 5 °C; the temperature of the mixing in step (c) is 5 °C; (2) The solvent is an ether solvent and an alcohol reagent; (3) The base is potassium tert-butoxide; (4) The oximating agent is isoamyl nitrite; (5) The molar ratio of the compound of formula 1 to the base is 1:2.2; (6) The molar ratio of the compound of formula 1 to the oximating agent is 1:1.3; (7) The mass-volume ratio of the compound of formula 1 to the solvent is 95.2 g / L; (8) The temperature of the oximation reaction is 5 °C.

20. The method for preparing the compound of formula 7 according to claim 19, characterized in that The ether reagent is tetrahydrofuran, and the alcohol reagent is tert-butanol.

21. The method for preparing the compound of formula 7 according to claim 1, characterized in that, The preparation method of the compound of formula 7 further includes the preparation method of the compound of formula 6, which includes the following steps: In a solvent, in the presence of an acid, the compound of formula 6-2 undergoes a racemization reaction to obtain the compound of formula 6; 22. The method for preparing the compound of formula 7 according to claim 21, characterized in that, The preparation method of the compound of formula 6 satisfies one or more of the following conditions: (1) The solvent is a halogenated hydrocarbon solvent; (2) The acid is an organic acid; (3) The molar ratio of the compound of formula 6-2 to the acid is 1:(3 - 7); (4) The mass-volume ratio of the compound of formula 6-2 to the solvent is 50 g / L - 200 g / L; and (5) The temperature of the racemization reaction is 35 - 45 °C.

23. The method for preparing the compound of formula 7 according to claim 22, characterized in that, The preparation method of the compound of formula 6 satisfies one or more of the following conditions: (1) The solvent is dichloromethane; (2) The acid is trifluoroacetic acid; (3) The molar ratio of the compound of formula 6-2 to the acid is 1:3.8; (4) The mass-volume ratio of the compound of formula 6-2 to the solvent is 117.4 g / L; and (5) The temperature of the racemization reaction is 40 °C.

24. The method for preparing the compound of formula 7 according to any one of claims 21-23, characterized in that, The preparation method of the compound of formula 7 further includes the preparation method of the compound of formula 6-2, which includes the following steps: In a solvent, in the presence of a base, the compound of formula 7-1 reacts with benzyl chloroformate to carry out a protection reaction to obtain the compound of formula 6-2, 25. The method for preparing the compound of formula 7 according to claim 24, characterized in that, The preparation method of the compound of formula 6-2 satisfies one or more of the following conditions: (1) The compound of formula 7-1 is the recrystallization mother liquor in the preparation method of the compound of formula 7 as described in any one of claims 1 - 7, in the deprotection reaction; (2) The solvent is a sulfoxide solvent and / or a nitrile solvent; (3) The base is an organic base; (4) The molar ratio of the compound of formula 7-1 to the base is 1:(3 - 8); (5) The molar ratio of the compound of formula 7-1 to benzyl chloroformate is 1:(1.2 - 2); (6) The mass-volume ratio of the compound of formula 7-1 to the solvent is 25 - 33 g / L; (7) The temperature of the protection reaction is -5 - 5 °C; The upper protection reaction described in (8) further includes a post-treatment step, and the post-treatment step includes one or more of crystallization, filtration, washing, and drying.

26. The method for preparing the compound of formula 7 according to claim 25, characterized in that, The preparation method of the compound of formula 6-2 satisfies one or more of the following conditions: (1) The sulfoxide solvent is dimethyl sulfoxide; the nitrile solvent is acetonitrile; (2) The base is N,N-diisopropylethylamine; (3) The molar ratio of the compound of formula 7-1 to the base is 1:4; (4) The molar ratio of the compound of formula 7-1 to the benzyloxycarbonyl chloride is 1:1.

7.

27. The method for preparing the compound of formula 7 as claimed in claim 25, characterized in that, The solvent is dimethyl sulfoxide and / or acetonitrile.

28. The method for preparing the compound of formula 7 according to claim 27, characterized in that, The solvent is dimethyl sulfoxide.

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