Preparation method for isoindoline compound, intermediate thereof, and preparation method for intermediate

Abstract

Disclosed in the present invention are a preparation method for an isoindoline compound, an intermediate thereof, and a preparation method for the intermediate. The preparation method for the intermediate of the present invention comprises the following step: in the presence of a compound 1a and a compound 2, subjecting a compound 1 and a deuterated reagent to a deuteration reaction in a solvent to obtain a compound 5, the compound 2 being a compound 2a and / or compound 2b. The method of synthesis for the intermediate provided by the present invention can obtain the intermediate in high yield, improve the overall yield of the isoindoline compound, and has good industrial application prospects.

Description

Preparation method of isoindoline compound, intermediate thereof and preparation method of intermediate TECHNICAL FIELD

[0001] The present application relates to a preparation method of isoindoline compound, an intermediate thereof and a preparation method of the intermediate. BACKGROUND

[0002] The isoindoline derivative disclosed in patent CN105566290A is a latest generation of oral small molecule thalidomide drugs, which belongs to CRL4-CRBN (Cullin-RING E3 ubiquitin ligase complex) regulator.

[0003] However, the synthetic route of the isoindoline derivative disclosed in patent CN105566290A is long, the yield and deuterium substitution rate are general, and the cost is high, especially (1) the key intermediate The yield is low, only about 30% of the yield; (2) the chiral resolution by the preparation column is not conducive to scale-up production; (3) the deuterium substitution rate decreases significantly in the last few steps to the final product. It can be seen that it is of great significance to design a process route with easy-to-obtain raw materials, short route, excellent yield and deuterium substitution rate, stable process, and significantly reduced production cost, so as to better complete the synthesis of isoindoline derivative and intermediate thereof.

[0004] In view of this, the present application is proposed. SUMMARY

[0005] The present application provides a preparation method of isoindoline compound, an intermediate thereof and a preparation method of the intermediate, in order to overcome the defects of long synthetic route, low yield, high cost and not conducive to scale-up production of isoindoline derivative in the prior art. The present application designs and prepares a specific intermediate with high yield, thereby improving the yield and deuterium substitution rate of isoindoline compound, and effectively reducing the production cost.

[0006] The present application solves the above technical problems through the following technical solutions.

[0007] The present application provides a preparation method of compound 5, which is method I or method II:

[0008] Method I comprises the following steps: carrying out deuterium substitution reaction of compound 1 with deuterium substitution reagent in a solvent in the presence of compound 1a and compound 2, to obtain the compound 5;

[0009] The compound 2 is compound 2a and / or compound 2b;

[0010] Ra and R c independently H, halogen, C 1-6 alkyl or C 1-6 alkoxy; R b and R d independently H, halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0011] Method II comprises the step of reacting compound 4 in a solvent in the presence of an acid or a metal catalyst to provide said compound 5.

[0012] R 1 and R 2 independently H or D.

[0013] In Method I, the conditions and procedures for said deuterium exchange reaction are those conventional for such reactions, and the present application particularly prefers conditions and procedures as follows:

[0014] In Method I, R a , R b , R c and R d , said halogen can be F, Cl or Br.

[0015] In Method I, R a , R b , R c and R d , said C 1-6 alkyl can be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl.

[0016] In Method I, R a , R b , R c and R d , said C 1-6 alkoxy can be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy or t-butoxy.

[0017] In Method I, in compound 1a, R a and R c are independently halogen, R b and R d are H.

[0018] In Method I, said compound 1a is compound 1a-1.

[0019] In Method I, the molar ratio of the compound 1a to the compound 1 can be (0.02-0.10):1, preferably (0.02-0.04):1.

[0020] In Method I, the molar ratio of the compound 2 to the compound 1 can be (0.03-0.06):1, for example (0.03-0.05):1.

[0021] In Method I, the compound 2 is preferably compound 2a.

[0022] In Method I, the compound 2a can be 1, 2 or 3 of compound (S,S)-2a, compound (R,R)-2a and compound (R,S)-2a, for example a racemate of compound (S,S)-2a and compound (R,R)-2a;

[0023] In Method I, the compound 1 can be a free base or an acid salt of compound 1, for example a hydrochloride of compound 1.

[0024] In Method I, the compound 1 is compound (S)-1 and / or compound (R)-1, for example a racemate of compound (S)-1 and compound (R)-1.

[0025] In Method I, the deuterated reagent can be heavy water.

[0026] In Method I, the volume mass ratio of the deuterated reagent to the compound 1 can be ≥5 mL / g, preferably (5-22) mL / g, for example (5-10) mL / g.

[0027] In Method I, the solvent can be 1, 2, 3 or 4 of halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents and acetate solvents, preferably ether solvents and / or acetate solvents.

[0028] In Method I, the halogenated hydrocarbon solvent can be dichloromethane and / or trichloromethane.

[0029] In Method I, the ether solvent can be 1, 2 or 3 of methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (2-MeTHF) and cyclopentyl methyl ether (CPME), preferably methyl tert-butyl ether.

[0030] In Method I, the aromatic hydrocarbon solvent can be toluene.

[0031] In Method I, the acetate solvent can be isopropyl acetate (iPrOAc).

[0032] In some embodiments, the solvent is preferably 1, 2, 3, 4 or 5 of chloroform, methyl tert-butyl ether, 2-methyltetrahydrofuran, toluene and isopropyl acetate, more preferably methyl tert-butyl ether or isopropyl acetate.

[0033] In Method I, the volume mass ratio of the solvent to the compound 1 can be (2-22) mL / g, preferably (2-5) mL / g.

[0034] In Method I, the temperature of the deuterating reaction can be 20-40 °C, preferably 25-40 °C.

[0035] In Method I, the deuterating reaction can also be carried out in the presence or absence of an additive, when the deuterating reaction is carried out in the presence of an additive, the additive can be molecular sieves molecular sieves) and / or a phase transfer catalyst.

[0036] The phase transfer catalyst is preferably tetrabutylammonium bromide (TBAB).

[0037] In Method I, the deuterating reaction can also be carried out in the presence or absence of a base. When the deuterating reaction is carried out in the presence of a base, the base can be an organic base or an inorganic base.

[0038] The organic base is preferably 1, 2, 3, 4, 5, 6 or 7 of triethylamine (TEA), N,N-diisopropylethylamine (DIEA), N-methylmorpholine (NMM), 4-dimethylaminopyridine (DMAP), dicycloamidine (DBU), triethanolamine (TNPA) and potassium tert-butoxide.

[0039] The inorganic base is preferably 1, 2 or 3 of alkali metal carbonate, alkali metal bicarbonate and alkali metal phosphate, further preferably 1, 2 or 3 of Na2CO3, NaHCO3 and Na3PO4.

[0040] In a preferred embodiment of the present application, the deuterating reagent is deuterium water; the solvent is isopropyl acetate and / or methyl tert-butyl ether; and the temperature of the deuterating reaction is 25-40 °C.

[0041] In Method I, the progress of the deuterating reaction is monitored by conventional monitoring methods in the art (e.g. HNMR, LC-MS) with the disappearance of the starting material or no longer reaction or no longer increase of the product as the end of the reaction. The deuterating reaction time is not less than 4 hours, preferably 4-90 hours, for example 18 hours, 45 hours, 60 hours or 76 hours.

[0042] In Method I, after the deuterating reaction is completed, the reaction solution can be directly subjected to the next step after the steps of washing and concentrating.

[0043] In Method II, when the reaction is carried out in the presence of an acid, the acid is an acid commonly used in the art, and the acid according to the present application is preferably DCI, for example, deuterium water solution of mass concentration of 10-40% DCI. The molar ratio of the acid to compound 4 can be (1-3): 1, preferably (2-2.5): 1.

[0044] When the reaction is carried out in the presence of an acid, the temperature of the reaction is preferably -20 to -5°C, for example, -15 to -5°C.

[0045] When the reaction is carried out in the presence of an acid, the progress of the reaction is monitored by a monitoring method commonly used in the art (for example, TLC), with the disappearance of the raw material or no longer reaction or no longer increase of the product as the end of the reaction. The time of the reaction is preferably 0.5-5 hours, for example, 2 hours.

[0046] In some embodiments, when the reaction is carried out in the presence of an acid, the acid is DCI; the molar ratio of the acid to compound 4 is (2-2.5): 1; and the temperature of the reaction is -20 to -5°C.

[0047] In Method II, when the reaction is carried out in the presence of a metal catalyst, the metal catalyst is a kind and amount of metal catalyst commonly used in the art. The metal catalyst according to the present application is preferably a palladium catalyst, for example, PdCl2 and / or Pd / C. The weight ratio of the metal catalyst to the compound is preferably (0.1%-20%): 1.

[0048] When the reaction is carried out in the presence of a metal catalyst, the metal catalyst can be added in 1-2 times, for example, preferably PdCl2 (added in a weight ratio of 0.5%: 1) is added to the reaction system, and after the reaction is carried out to the disappearance of compound 4, Pd / C (added in a weight ratio of 10%: 1) is added to carry out the reaction.

[0049] When the reaction is carried out in the presence of a metal catalyst, the reaction is preferably carried out under 1-12 atm (for example, 8-12 atm) of hydrogen.

[0050] When the reaction is carried out in the presence of a metal catalyst, the temperature of the reaction is preferably 10-40°C, for example, 20-30°C.

[0051] When the reaction is carried out in the presence of a metal catalyst, the progress of the reaction is monitored by a monitoring method commonly used in the art (for example, HPLC), with the amount of the product no longer increasing as the end of the reaction. The time of the reaction is not less than 24 hours, preferably 40-48 hours.

[0052] In Method II, the compound 4 can be compound 4-1 or compound 4-2.

[0053] The compound 4-1 can be compound (S)-4-1 and / or compound (R)-4-1, for example a racemate of compound (S)-4-1 and compound (R)-4-1.

[0054] The compound 4-2 can be compound (S)-4-2 and / or compound (R)-4-2, for example a racemate of compound (S)-4-2 and compound (R)-4-2.

[0055] In Method II, the solvent can be one, two or three of an alcohol solvent (for example methanol or CH3OD), an ether solvent (for example MTBE) and an ester solvent (t-BuOAc), preferably a mixed solvent of an alcohol solvent and an ether solvent, or a mixed solvent of "an alcohol solvent, an ether solvent and an ester solvent".

[0056] The solvent can be one or more of methanol, CH3OD, MTBE and t-BuOAc, preferably a mixed solvent of CH3OD and MTBE (volume ratio 1:1), a mixed solvent of CH3OH and t-BuOAc (volume ratio 1:1) or a mixed solvent of CH3OH, t-BuOAc and MTBE (volume ratio 1:1:1), further preferably a mixed solvent of CH3OH and MTBE or a mixed solvent of "CH3OH, MTBE and t-BuOAc".

[0057] In Method I and Method II, after the reaction, the method for resolving compound 5 further comprises the following steps:

[0058] The compound 5 and L-(+)-tartaric acid (L-(+)-Tartaric acid can be used to represent L-(+)-tartaric acid) are subjected to a salt formation reaction in a solvent to obtain L-(+)-tartaric acid salt of compound I (L-(+)-tartaric acid salt of compound 5 in S configuration) and L-(+)-tartaric acid salt of compound I' (L-(+)-tartaric acid salt of compound 5 in R configuration) respectively.

[0059] In the present application, by the above-mentioned resolving method, the resolution of compound 5 can be realized to obtain L-(+)-tartaric acid salt of compound 5 in a single configuration, which means that all of the L-(+)-tartaric acid salt of compound 5 is in a single configuration or mainly exists in a certain configuration.

[0060] The molar ratio of L-(+)-tartaric acid to compound I in the L-(+)-tartaric acid salt of compound I is preferably (0.5-1.3):1, for example 0.5:1 or 1:1.

[0061] In the resolution method, the solvent is a conventional solvent for salt formation reaction of such compounds in the art, for example, the solubility difference of the chiral compound after salt formation is large, which is beneficial to separation; the solvent in the present application is preferably a mixed solvent of water and an alcohol solvent, more preferably a mixed solvent of water and ethanol, for example, 85% ethanol aqueous solution.

[0062] In the resolution method, the molar ratio of L-(+)-tartaric acid to compound 5 can refer to the conventional amount of salt formation reaction in the art, for example (0.5-1.3):1, for example (0.5-1):1, preferably (0.5-0.6):1 in the present application.

[0063] The temperature of the salt formation reaction is the conventional temperature of such salt formation reaction in the art, for example, heating to reflux of the solvent. In the present application, it is preferably 50-60°C; at the same time, according to the common sense in the art, the temperature should not exceed the reflux temperature.

[0064] In the resolution method, the volume / mass ratio of the solvent to compound 5 is preferably (8-20) mL / g, further preferably (8-15) mL / g.

[0065] The I' can also be converted into compound 5 by conventional methods in the art for recycling to the resolution of compound 5.

[0066] After the salt formation reaction, further post-treatment operations such as crystallization can be included. The crystallization refers to conventional operation methods in the art, for example, slow cooling method for crystallization (for example, the slow cooling rate is (8-9) ℃ / h, and the crystallization temperature is preferably 8-12 ℃; the mother liquor of crystallization can be recycled to the resolution of compound 5).

[0067] In method II, the preparation method of compound 5 can further include the preparation method of compound 4, which includes the following steps: deuterium substitution reaction of compound 3 with deuterium substitution reagent in the presence of a base to obtain compound 4.

[0068] In the present application, the conditions and operations of the deuterium substitution reaction are conventional conditions and operations of such reactions, and the present application particularly preferably has the following conditions and operations:

[0069] In the preparation method of compound 4, the molar ratio of the base to compound 3 can be (0.5-4):1, preferably (0.5-2):1, for example 0.5:1, 1.1:1 or 2:1.

[0070] In the preparation method of compound 4, the base can be 1, 2 or 3 of tertiary amine organic base, alkali metal carbonate and triethylene diamine (DABCO), preferably alkali metal carbonate.

[0071] Preferably, the tertiary amine organic base is 1, 2 or 3 of triethylamine (TEA), N,N-diisopropylethylamine (DIPEA) or triphenylamine (TPA), more preferably triethylamine.

[0072] Preferably, the alkali metal carbonate is sodium carbonate and / or potassium carbonate, more preferably sodium carbonate.

[0073] In a preferred embodiment, the base is 1, 2 or 3 of triethylamine, N,N-diisopropylethylamine, triphenylamine (TPA) or sodium carbonate, preferably sodium carbonate.

[0074] In the preparation method of compound 4, the deuterium reagent can be CH3OD and / or EtOD, preferably CH3OD. The deuterium reagent can be added in batches, preferably 1-4 times. The amount of each batch can be the same or different. When the deuterium reagent is added in batches, the reaction solution is preferably concentrated first.

[0075] In the preparation method of compound 4, the volume / mass ratio of the deuterium reagent to compound 3 can be ≥3 mL / g, preferably (3-12) mL / g, for example (8-11) mL / g.

[0076] In the preparation method of compound 4, the temperature of the deuterium reaction is preferably 10-35℃.

[0077] In the preparation method of compound 4, compound 3 can be compound (S)-3 and / or compound (R)-3, for example the racemate of compound (S)-3 and compound (R)-3;

[0078] In the present application, the progress of the deuterium reaction is monitored by conventional monitoring methods in the art (for example HNMR), and the reaction endpoint is that the raw material no longer reacts. The deuterium reaction time is preferably not less than 18 hours, for example 140 hours, 150 hours or 240 hours.

[0079] After the deuterium substitution reaction is completed, the reaction solution of the deuterium substitution reaction can be directly used for the next step reaction after concentration and washing (for example, washing with MTBE).

[0080] In Method II, the preparation method of compound 4 can further comprise a preparation method of compound 3, which comprises the following steps: subjecting compound 1 to an amination reaction with benzaldehyde in the presence of a base in a solvent to obtain compound 3.

[0081] In the present application, the conditions and operations of the amination reaction are conventional conditions and operations for such reactions, and the present application particularly preferably comprises the following conditions and operations:

[0082] In the preparation method of compound 3, the base can be one, two or three of tertiary amine organic bases, alkali metal carbonates and alkali metal bicarbonates, and preferably a tertiary amine organic base.

[0083] Preferably, the tertiary amine organic base is triethylamine (TEA).

[0084] Preferably, the alkali metal carbonate is potassium carbonate and / or sodium carbonate.

[0085] Preferably, the alkali metal bicarbonate is potassium bicarbonate.

[0086] In the preparation method of compound 3, the molar ratio of the base to compound 1 can be (0.9-1.1):1.

[0087] In the preparation method of compound 3, compound 1 can be the free base of compound 1 or a hydrochloride salt thereof.

[0088] In the preparation method of compound 3, the molar ratio of benzaldehyde to compound 1 can be (0.9-1.2):1.

[0089] In the preparation method of compound 3, the solvent can be one, two or three of halogenated hydrocarbon solvents, alcohol solvents and ether solvents, and preferably a halogenated hydrocarbon solvent.

[0090] Preferably, the halogenated hydrocarbon solvent is dichloromethane.

[0091] Preferably, the alcohol solvent is methanol and / or tert-butanol.

[0092] Preferably, the ether solvent is methyl tert-butyl ether (MTBE).

[0093] In the preparation method of the compound 3, the compound 1 is compound (S)-1 and / or compound (R)-1, for example, a racemate of compound (S)-1 and compound (R)-1;

[0094] In the present application, the progress of the amination reaction is monitored by a method conventional in the art (for example, HPLC), and the end of the reaction is determined by the fact that the starting material no longer reacts. The amination reaction time is preferably 3-48 hours, for example, 20 hours.

[0095] After the amination reaction is completed, the reaction solution of the amination reaction can be directly used in the next step after being washed with water and concentrated.

[0096] The second aspect of the present application also provides a preparation method of compound VI, which comprises the following steps:

[0097] Step one: compound III and compound K are reacted in the presence of a base to obtain compound IV;

[0098] Step two: compound IV is subjected to a deprotection reaction and a free reaction under acidic conditions to obtain compound V;

[0099] Step three: compound V is subjected to a ring closure reaction to obtain compound VI;

[0100] The conditions and operations of the reactions in steps one to three all adopt the conditions and operations conventional in the art for such reactions, and the present application is particularly preferred as follows:

[0101] In step one, the molar ratio of compound K to compound III can be (1-1.5):1, for example, (1.1-1.3):1.

[0102] In step one, compound K can be a free base or an acid salt of compound K, for example, a hydrochloride of compound K.

[0103] In step one, the base is preferably an alkali metal carbonate, and is further preferably K2CO3. The molar ratio of the base to compound III can be (2-5):1, for example, (2.5-3.5):1.

[0104] In step one, the solvent is preferably an amide solvent, and is further preferably N,N-dimethylformamide. The volume / mass ratio of the solvent to compound III can be (2-8) mL / g, and can also be (4-6) mL / g.

[0105] In step one, the reaction temperature can be 20-40°C, and can also be 25-35°C.

[0106] In Step 1, the progress of the reaction is monitored by a conventional monitoring method in the art (e.g., TLC) to the end point of the reaction where the starting material no longer reacts. The reaction time is preferably at least 8 hours or more.

[0107] In Step 1, the work-up procedure after the reaction is preferably carried out as follows: cooling the reaction solution, precipitating the solid (adding the reaction solution to water and methyl tert-butyl ether (volume ratio is preferably 10:1)), filtering, slurrying (in methyl tert-butyl ether), filtering, and drying.

[0108] In Step 2, the acid is preferably trifluoroacetic acid (TFA). The molar ratio of the acid to the compound M can be ≥ 8:1, preferably (8-15):1, for example (11-13):1.

[0109] In Step 2, the solvent used in the deprotection reaction is preferably a halogenated hydrocarbon solvent. The halogenated hydrocarbon solvent is preferably dichloromethane. The volume / mass ratio of the solvent to the compound IV can be (1-4) mL / g, for example (2-3) mL / g.

[0110] In Step 2, the temperature of the deprotection reaction can be 10-40°C, and can also be 15-25°C.

[0111] In Step 2, the progress of the deprotection reaction is monitored by a conventional monitoring method in the art (e.g., HPLC) to the end point of the reaction where the content of the starting material is ≤ 2.0%. The reaction time is preferably at least 8 hours or more.

[0112] In Step 2, the free reaction is preferably a free reaction carried out at a pH of 6.0-7.5, preferably 6.0-7.5. The pH adjusting agent used in the free reaction is an alkali metal bicarbonate or an alkali metal carbonate, preferably an alkali metal bicarbonate, and further preferably NaHCO3.

[0113] In Step 2, the solvent used in the free reaction is preferably water. The volume / mass ratio of the solvent to the compound IV can be (3-25) mL / g, for example (10-20) mL / g.

[0114] In Step 2, the temperature of the free reaction can be 0-40°C, and can also be 0-10°C.

[0115] In Step 2, the progress of the free reaction is monitored by a conventional monitoring method in the art (e.g., pH meter). The time of the free reaction is preferably at least 3 hours or more.

[0116] In Step two, the free reaction preferably includes the following steps: concentration of the reaction mixture (which can be concentrated multiple times with the addition of isopropyl acetate followed by concentration), solidification (by adding the concentrated mixture to methyl tert-butyl ether), filtration and collection of the solid.

[0117] The free reaction preferably also includes the following steps after the reaction is complete: filtration, trituration (e.g., in water), filtration, washing and drying.

[0118] In Step three, the ring closure reaction is preferably carried out in the presence of thionyl chloride and a base. The molar ratio of thionyl chloride to compound V can be (1-5): 1, for example (2-4): 1. The base can be triethylamine or pyridine, preferably pyridine. The molar ratio of base to compound V can be (2-5): 1, for example (3-4): 1.

[0119] In Step three, the solvent used in the ring closure reaction is preferably an amide solvent (e.g., N,N-dimethylformamide). The volume to mass ratio of solvent to compound V can be (3-20) mL / g, for example (4-6) mL / g.

[0120] In Step three, the temperature of the ring closure reaction can be -50 to 0 °C, and can also be -45 to -35 °C.

[0121] In Step three, the progress of the ring closure reaction is monitored by conventional monitoring methods (e.g., TLC) in the art, with the end of the reaction being indicated by the absence of starting material. The time for the ring closure reaction is not less than 4 hours, and is preferably 8-10 hours.

[0122] In Step three, the work-up procedure for the ring closure reaction preferably includes the following steps: adjustment of the pH (e.g., using 7.5% sodium bicarbonate to adjust the pH of the system to 6.0-8.0), filtration, trituration (e.g., in water), filtration, crystallization purification and drying.

[0123] The method for preparing compound VI can also include a method for preparing compound III, which includes the following step: deprotection of compound II in the presence of a deprotection reagent to obtain compound III.

[0124] R 3 is a hydroxyl protecting group (e.g., -TBDMS, -MOM, etc.).

[0125] The conditions and procedures for the above deprotection reaction are conventional for such reactions in the art, and the present application particularly prefers the following conditions and procedures:

[0126] The compound II is preferably compound II-TBDMS;

[0127] The deprotection reagent is preferably tetrabutylammonium fluoride (TBAF), for example 1 M tetrabutylammonium fluoride (tetrahydrofuran solution).

[0128] The temperature of the deprotection reaction can be 10-40 °C, and can also be 20-30 °C.

[0129] The progress of the deprotection reaction is monitored by a method conventional in the art (e.g. HPLC) with the end of the reaction being taken as the point at which the starting material no longer reacts. The reaction time is preferably at least 3 hours or more.

[0130] The work-up steps after the deprotection reaction is preferably extraction, washing, crystallization, filtration and drying.

[0131] The process for preparing compound VI can further comprise a process for preparing compound II, which comprises the step of reacting compound I and compound C in the presence of a base in a solvent to obtain compound II.

[0132] The conditions and procedures for the above reaction are conventional in the art for such reactions, and the present application is particularly preferred as follows:

[0133] The base can be a tertiary amine organic base, and is further preferably triethylamine (TEA) and / or N,N-diisopropylethylamine (DIPEA), and is preferably N,N-diisopropylethylamine.

[0134] The molar ratio of the base to compound I is preferably (1-5): 1, for example (2-4): 1.

[0135] The compound C can be compound C-TBDMS:

[0136] The molar ratio of compound C to compound I is preferably (1-3): 1, for example (1-2): 1.

[0137] The compound I is preferably a free base or an acid salt thereof.

[0138] The acid salt of compound I is preferably an L-(+)-tartaric acid salt of compound I.

[0139] The molar ratio of L-(+)-tartaric acid to Compound I in the L-(+)-tartaric acid salt of Compound I can be (0.5-1.3):1, for example 0.5:1 or 1:1.

[0140] The solvent is preferably a cyclic ether solvent. The cyclic ether solvent is preferably tetrahydrofuran. The amount of the solvent can not be specifically limited, as long as it does not affect the progress of the reaction. The volume / mass ratio of the solvent to Compound I in the present application is preferably (10-30) mL / g, for example 20 mL / g.

[0141] The temperature of the reaction can be 40-80°C, and can also be 60-70°C.

[0142] The progress of the reaction is monitored by a conventional monitoring method in the art (for example, HPLC), and the end of the reaction is determined when the starting material is no longer reacted. The reaction time is preferably at least 18 hours or more.

[0143] The reaction can be directly used for the reaction of removing the hydroxyl protecting group of Compound II without a post-treatment step after the reaction is completed.

[0144] The present application also provides a preparation method of Compound VI, which comprises the following steps:

[0145] The preparation method of Compound 5 described above; and, the preparation method of Compound VI further prepared from Compound 5;

[0146] The preparation method of Compound 5 is Method I or Method II:

[0147] Method I comprises the following step: deuterating Compound 1 with a deuterating reagent in a solvent in the presence of Compound 1 and Compound 2, to obtain Compound 5;

[0148] Compound 2 is Compound 2a and / or Compound 2b.

[0149] Method II comprises the following step: reacting Compound 4 in a solvent in the presence of an acid or a metal catalyst, to obtain Compound 5;

[0150] R 1 and R 2 are independently H or D.

[0151] The conditions and operations in Methods I and II described above can be the same as described above.

[0152] The preparation method of Compound VI preferably comprises one or more of the following steps:

[0153] The definitions of the groups and the reaction conditions and operations of the steps are as described above.

[0154] The preparation of compound VI is preferably carried out by the following synthesis route:

[0155] or,

[0156] The conditions and operations of the conditions and operations in the above synthesis route are as described above.

[0157] The fourth aspect of the present application also provides a compound of formula I or its L-(+)-tartaric acid salt:

[0158] The compound I is preferably a free base or an acid salt thereof.

[0159] The acid salt of compound I is preferably an L-(+)-tartaric acid salt of compound I.

[0160] The molar ratio of L-(+)-tartaric acid to compound I in the L-(+)-tartaric acid salt of compound I can be (0.5-1.3):1, for example 0.5:1 or 1:1.

[0161] The fifth aspect of the present application provides a resolution method of compound 5, which comprises the following steps:

[0162] Compound 5 and L-(+)-tartaric acid are subjected to a salt formation reaction in a solvent to obtain an L-(+)-tartaric acid salt of compound I and an L-(+)-tartaric acid salt of compound I', respectively;

[0163] The conditions and operations of the resolution method of compound 5 are as described above.

[0164] The sixth aspect of the present application provides the use of compound I or its acid salt as an intermediate in the preparation of compound VI:

[0165] In the use, compound VI is preferably prepared from compound IV;

[0166] The synthesis route of compound IV is as follows:

[0167] More preferably, compound VI is prepared by the following synthesis route:

[0168] In the synthesis route, the definitions of the groups and the conditions and operations of the steps are as described above in the corresponding reactions.

[0169] The seventh aspect of the present application provides a compound 3 or a compound 4 (which can be used to prepare a compound 5, I or VI):

[0170] R 1 and R 2 independently H or D.

[0171] The compound 3 can be a compound (S)-3 and / or a compound (R)-3, for example a racemate of a compound (S)-3 and a compound (R)-3;

[0172] The compound 4 can be a compound 4-1 or a compound 4-2;

[0173] Without departing from the common general knowledge, the above preferred conditions can be combined in any manner, thereby obtaining preferred embodiments of the present application.

[0174] The reagents and raw materials used in the present application are commercially available.

[0175] The positive progress effect of the present application is that the preparation method of the isoindoline compound and the intermediate thereof provided by the present application has one or more of the following advantages:

[0176] (1) The present application realizes the synthesis of isoindoline derivatives with high yield and good deuterium substitution rate by designing specific intermediates;

[0177] (2) The present application realizes simple and efficient synthesis by designing specific intermediates to avoid the high-cost operation of chiral separation by high performance liquid chromatography in the prior art;

[0178] (3) The synthesis method of the key intermediate of the present application has high yield and good deuterium substitution rate, which improves the yield and deuterium substitution rate of indoline derivatives;

[0179] (4) The process route of the present application has good deuterium substitution rate stability, still has good deuterium substitution rate in kilogram production, and has stable process route, which is suitable for industrial production. DETAILED DESCRIPTION

[0180] The present application will be further described by way of examples, but the present application is not limited to the examples. The experimental methods in the following examples are not specified, and are selected according to conventional methods and conditions, or according to the instructions of the goods.

[0181] The compounds involved in the following examples have the following structural formula:

[0182] Synthesis route 1:

[0183] Synthesis route 2:

[0184] Synthesis route 3:

[0185] Analytical method for L-(+)-tartaric acid salt of compound I

[0186] (1) Purity analysis method

[0187] Column: Xbridge C18, 4.6 x 150 mm, 3.5 μm; mobile phase A: 0.05% trifluoroacetic acid in water; mobile phase B: 0.05% trifluoroacetic acid in water; column temperature: 30 °C; detection wavelength: 220 nm; flow rate: 1 mL / min;

[0188] Elution gradient:

[0189] (2) Chiral purity analysis method

[0190] Derivatization of compound I into a benzyloxy carbonyl derivative to detect the chiral purity of compound I;

[0191] Column: CHIRALPAK AS-RH, 4.6 x 150 mm, 5 μm; mobile phase A: IPA; mobile phase B: acetonitrile; column temperature: 30 °C; detection wavelength: 210 nm; flow rate: 0.7 mL / min;

[0192] Elution gradient:

[0193] Analytical method for compound VI

[0194] (1) Purity analysis method:

[0195] Column: XBridge C18 4.6*50 mm, 3.5 μm; mobile phase A: 0.05% trifluoroacetic acid in water; mobile phase B: acetonitrile; column temperature: 40 °C; detection wavelength: 214 nm; flow rate: 1.5 mL / min;

[0196] Elution gradient:

[0197] (2) Chiral purity analysis method

[0198] Column: CHIRALPAK, 4.6 x 250 mm, 5 μm; mobile phase: ACN:IPA = 70:30; column temperature: 30 °C; detection wavelength: 220 nm; flow rate: 1 mL / min; run time: 25 min.

[0199] Deuterium substitution rate:

[0200] Deuterium substitution rate (D%) refers to the proportion of hydrogen atoms in the compound of the present application which are replaced by deuterium at the positions indicated by the boxes in the following fragment: For example, the present application employs 1 The deuterium substitution rate of the compound is detected by HNMR or LC-MS.

[0201] In the following test, "V" refers to volume ratio or volume mass ratio, wherein the unit of volume mass ratio is mL / g.

[0202] Preparation and resolution of compound 5 of Example 1

[0203] Step 1: Synthesis of compound 5

[0204] D2O (1000 mL, 5V), K2CO3 (0.5 eq), MTBE (800 mL, 4V) and compound (S)-1 (hydrochloride, 200 g, 1.0 eq.) were added to a reaction flask, and then compound 1a-1 (0.04 eq) and 2a (0.04 eq) were added to the reaction solution. The reaction solution was heated to 30 °C, and stirred at 30±5 °C for at least 48 hours. After the reaction was stopped, the water phase was separated after standing and concentrating to about 2V. Anhydrous ethanol (1 L, 5V) was added and concentrated to about 1V, and then anhydrous ethanol (1.2 L, 6V) was added. The reaction solution was stirred at 5 °C for 1 h, filtered, and the filtrate was concentrated under reduced pressure to about 1V to obtain a light yellow liquid (water content (KF) was 13.8%; the weight of compound 5 was 141 g, and the yield of compound 5 was 82.9%).

[0205] Step 2: Resolution of compound 5

[0206] The light yellow liquid obtained in step 1 and 85% ethanol (5V) were added to a three-necked flask, and the temperature was raised to 55±5 °C and stirred until clear. Then a solution of L-tartaric acid (0.6 eq) in ethanol (85% ethanol, 5V) was added dropwise to the reaction flask. Subsequently, the reaction was stirred for 0.5 h, and then the temperature was lowered to 10±5 °C, and stirred at 10±5 °C for 15 h. The reaction solution was filtered, the filter cake was washed with EtOH (2V), and the solid was collected and dried to obtain white solid compound I-1 (109.5 g, total yield of two steps: 39.5%, water content (KF) was 2.5%, purity: 100%, deuterium substitution rate: 97.25% D, ee: 98.8%).

[0207] 1 HNMR (D2O, 400 MHz, maleic acid as internal standard): δ 1.24 (s, 9H), 1.95 (t, J = 8.0 Hz, 2H), 2.28 (t, J = 8.0 Hz, 2H), 3.86 (t, J = 8 Hz, 0.0275H), 4.48 (s, 1H).

[0208] Preparation of compound 5 in Example 2

[0209] The starting materials and conditions in Example 1 step 1 were replaced by those in Table 1, and other operations and conditions were the same as in Example 1 to prepare compound 5, and the yield was basically the same as in Example 1.

[0210] Table 1

[0211] Using the method of the present application, the hydrochloride salt of compound (S)-1 as the starting material, under different base, catalyst and solvent conditions, compound 5 can be obtained in one step with high yield and high conversion rate, and the conversion rate can even reach more than 95%.

[0212] Preparation of compound 5 in Example 3

[0213] The free base of compound (S)-1 (0.2 g, 1.0 eq.), D2O (4.4 ml, 22V) and CHCl3(0.44 ml, 4.4V) were added to the reaction bottle, then compound 1a-1 (0.02 eq) and compound (R,R)-2a (0.04 eq) were added to the reaction solution, heated to 60°C, and stirred at 60°C for at least 20 hours to stop the reaction. After the reaction was completed, the same post-treatment as in Example 1 was used to obtain compound 5, and the yield was basically the same as in Example 1, and the deuterium substitution rate was 82.8%.

[0214] 1 H NMR (D2O, 400 MHz): δ 1.34-1.43 (m, 6.4H), 1.80-1.93 (m, 2H), 2.29-2.36 (m, 2H), 3.45-3.65 (m, 0.172H).

[0215] Preparation of compound 5 in Example 4

[0216] The starting materials and conditions in Example 3 were replaced by those in Table 2, and other operations and conditions were the same as in Example 3 to prepare compound 5, and the yield was basically the same as in Example 1.

[0217] Table 2

[0218] Using the method of the present invention, with the free base of compound (S)-1 as the starting material, the conversion rate can even reach more than 95% under different solvents, and compound 5 with high deuteration rate can be obtained in one step.

[0219] Example 5 Preparation of compound (S)-3

[0220] Under N2 protection, compound (S)-1 (270.0 g, 1.0 equiv.) and DCM (2.70 L, 10.0 V) were added to a three-necked flask; then benzaldehyde (132.0 g, 1.25 mol, 1.1 equiv.) was added to the three-necked flask; after the addition was complete, triethylamine (114.5 g, 1.14 mol, 1.0 equiv.) was added dropwise to the three-necked flask over 10 minutes; the reaction was then carried out at 25–30 °C with stirring for 24 hours. After the reaction was completed, the reaction solution was washed with water (5.0 V*2), the aqueous phase was extracted with DCM (5.0 V) and dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid compound (S)-3 (296.0 g, yield 90.1%, purity 99.87%).

[0221] 1 HNMR(DMSO-d6,400MHz): δ1.36(s,9H),1.86-2.19(m,4H),3.75-3.78(m,1H),7.17(d ,J=26.4Hz,2H),7.44-7.50(m,3H),7.83(dd,J1=8.0Hz,J2=2.4Hz,2H),8.32(s,1H).

[0222] Example 6 Preparation of compound (S)-3

[0223] Replace the conditions in Example 5 with the conditions in Table 3, and keep all other operations and conditions the same as those in Compound (S)-3 in Example 5 to prepare Compound (S)-3.

[0224] Table 3

[0225] Under different solvent and base conditions, the preparation method of the present invention can obtain compound (S)-3 in a yield of more than 83%, especially under DCM and TEA conditions, the yield can reach 90.6%.

[0226] Example 7 Preparation of compounds 4-1 and 5

[0227] Step 1: Preparation of compound 4-1

[0228] Compound (S)-3 (15.0 g, 1.0 equiv) was added into a 250 mL three-necked flask under nitrogen protection, then triethylamine (4.0 eq) and MeOD (3V) were added into the three-necked flask, after addition, the reaction was heated to 30-35 °C and stirred overnight;

[0229] The reaction solution was concentrated to about 1V, then MeOD (1V) and triethylamine (2.7 eq) were added into the concentrated solution, the reaction was continued to stir at 30-35 °C for 2 hours. This operation was repeated for 3 times, then MTBE (3V) was added into the reaction solution at 0 °C and stirred for 1 hour, then the filter cake was filtered and washed with MTBE (2V), and the filtrate was combined to obtain a solution of compound 4-1 (deuterium enrichment rate was 98.68%). Compound 4-1 can be directly used in the next step without isolation.

[0230] 1 HNMR (DMSO-d6, 400 MHz): δ 1.37 (s, 9H), 1.91-2.21 (m, 4H), 3.74-3.81 (m, 0.0132H), 7.47-7.49 (m, 3H), 7.83 (d, J = 7.6 Hz, 2H), 8.34 (s, 1H).

[0231] Step 2: Preparation of compound 5

[0232] DCl (35% DCl in D2O solution, w / w, 12.2 g, 2.2 equiv.) was added into the filtrate collected in the previous step at -10 °C, and the reaction was continued to react at -10 °C for 3 hours, and TLC detection showed that the reaction was completed; the reaction solution was added into MTBE (20V) pre-cooled at -10 °C, and stirred at -10 °C for 1 h. The solid was filtered and collected, and the obtained crude product was slurried with MTBE and i-PrOH, then filtered and the solid was collected to obtain the HCl salt of compound 5 (10 g, total yield of two steps was 81.0%, D% was 98.52% (LCMS detection)).

[0233] 1 HNMR (DMSO-d6, 400 MHz): δ 1.40 (s, 9H), 1.94-2.00 (m, 2H), 2.31-2.38 (m, 2H), 7.56 (s, 1H), 8.04 (s, 1H), 8.31-8.36 (m, 3H).

[0234] Preparation of compound 4-1 of Example 8

[0235] The conditions in step 1 in Example 7 were replaced with the conditions in Table 4, and other operations and conditions were the same as those in step 1 in Example 7 to prepare compound 4-1.

[0236] Table 4

[0237] The preparation method of the present application can have good conversion rate under different solvent and deuterium reagent conditions, especially under the condition of using MeOD as the deuterium reagent and TEA and / or Na2CO3 as the base, the conversion rate of compound (S)-3 can reach more than 95%.

[0238] Preparation of compound 5 of Example 9

[0239] Step 1: Preparation of compound 4-1

[0240] The feeding amount of compound (S)-3 in Example 7 Step 1 was replaced with the feeding amount in Table 5, and other operations and conditions were the same as those in Example 7 Step 1, to prepare compound 4-1, which was directly used in Step 2.

[0241] Step 2: Preparation of compound 5

[0242] The conditions in Example 7 Step 2 were replaced with the conditions in Table 5, and other operations and conditions were the same as those in Example 7, to prepare the hydrochloride salt of compound 5.

[0243] Table 5

[0244] Under different solvent conditions, the preparation method of the present application can obtain compound 5 from compound (S)-3 as raw material with good yield and deuterium substitution rate, especially when MeOD is used as the solvent and the mixture of MTBE, t-BuOAc and MeOH is used as the solvent, the yield can reach more than 80%, and the deuterium substitution rate is basically the same as that of compound 5 in Example 7.

[0245] Preparation of compound 4-2 of Example 10

[0246] Under N2 protection, compound (S)-3 (50.0 g, 1.0 eq.), Na2CO3 (0.5 eq.) and MeOD (4V) were added to the reaction bottle; after stirring at 10-20°C for 36 hours, the reaction solution was concentrated to about 1V solution, and MeOD (3V) was added to the reaction solution again; after stirring at 10-20°C for 24 hours, the reaction solution was concentrated to about 1V solution, and the operation of adding MeOD to concentrating to about 1V solution was repeated twice. Then MTBE (4V) was added to the reaction solution and stirred at 10-20°C for 0.5 hours, filtered, and the filter cake was washed with MTBE (2V), the filtrate was collected and concentrated to dryness, and directly used in the next reaction. The deuterium substitution rate of compound 4-2 was 99.2%.

[0247] 1HNMR (D2O, 400 MHz): δ 1.41 (s, 9H), 2.09-2.31 (m, 4H), 3.85-3.88 (m, 0.008H), 7.44-7.48 (m, 3H), 7.77-7.79 (m, 2H), 8.24 (s, 1H).

[0248] Preparation of compound 5 of example 11

[0249] A solution of compound 4-2 (50.0 g, 1.0 eq.) prepared in example 10, MeOD (4V) and MTBE (5V) and PdCl2 (0.5% w / w) were sequentially added to an autoclave; after the exclusion of air from the autoclave, the reaction was stirred under hydrogen (10 atm) at 25°C for 24 hours. After the disappearance of compound 4-2 was detected by HPLC, 10% Pd / C (15% w / w) was added to the reaction; after the exclusion of air from the autoclave, the reaction was stirred under hydrogen atmosphere (10 atm) at 20°C for 18 hours, and the disappearance of intermediate compound 4-2' was detected by HPLC. The reaction was completed, the catalyst was removed by filtration, the filtrate was collected and concentrated, MTBE (3V) was added to the residue, it was stirred at 0°C for 1 hour, it was filtered and the filter cake was washed with MTBE (1V), and it was dried to obtain 24.8 g of a white solid (yield: 74.3%, deuterium incorporation 98.49%).

[0250] 1 HNMR (CDC13, 400 MHz): δ 1.44 (s, 9H), 1.78-1.85 (m, 1H), 2.04-2.12 (m, 1H), 2.31-2.43 (m, 2H), 3.38-3.42 (m, 0.0151H).

[0251] Preparation of compound III of example 12

[0252] To a reactor was added tetrahydrofuran (60 L, 20V), and to the reactor was added compound I (3 kg (calculated as free state), 1.0 eq, purity 99.7%, D%: 98.4%, 99% ee) and DIEA (3.822 kg, 2.0 eq) at room temperature; after the addition was completed, it was stirred for 30 minutes, and then it was warmed to 65±5°C, and then compound C-TBDMS tetrahydrofuran solution (1.5 eq, 5V of THF) was added, and it was stirred at 65±5°C for 18 hours or more; the reaction was completed by HPLC detection.

[0253] After the reaction system was cooled to 25±5°C, TBFA / THF (0.675V, 1M) was added to the reaction kettle; the reaction was stirred at 25±5°C for 5 hours or more; after the reaction was completed by HPLC detection, it was concentrated, ethyl acetate (15V) and 10% NH4Cl aqueous solution (10V) were added, stirred and separated, the organic phase was washed with 10% NH4Cl aqueous solution (10V) and 5% NaCl aqueous solution (2.5V*2), respectively, the organic phase was collected and concentrated and crystallized, the solid was collected by filtration, the solid was washed and dried to obtain white powder solid compound III (3.575kg, total yield of two steps: 72.2%, purity: 99.5%, deuterium substitution rate: 98.0% (LCMS detection)).

[0254] 1 HNMR (DMSO-d6, 400MHz): δ 1.38 (s, 9H), 2.03-2.05 (m, 1H), 2.10-2.23 (m, 3H), 4.33 (d, J = 17.6 Hz, 1H), 4.50 (d, J = 17.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 7.15-7.19 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 10.03 (s, 1H).

[0255] Preparation of compound IV of Example 13

[0256] DMF (250mL, 5.0V) was added to the reaction bottle and cooled to 15±5°C; then compound III (50g, 1.0eq., D%: 98.0%), compound K (1.2eq., free state) and K2CO3 (3.0eq.) were added to the reaction bottle; after addition, the temperature was raised to 30±5°C and the reaction was stirred at this temperature for about 48 hours; after the reaction was completed by HPLC detection, the reaction system was cooled to 20±5°C, filtered, the filtrate was collected, the filtrate was added dropwise to a mixture of water (15V) and methyl tert-butyl ether (1.5V) and stirred for at least 5 hours, filtered, the filter cake was slurried in water (5V) for 15-30 minutes, filtered, the filter cake was again slurried in methyl tert-butyl ether (5V) for at least 3 hours, filtered, the filter cake was washed and dried to obtain a white solid (73g, yield: 90.1%, purity: 99.2%, deuterium substitution rate: 97.87% D% (LCMS detection)).

[0257] Preparation of compound V of Example 14

[0258] To the reaction flask was added dichloromethane (40 mL, 2.0 V) and temperature was adjusted to 20 ± 5 °C, then to the reaction flask was added compound IV (20 g, 1.0 eq, D%: 97.87%) and after completion of addition, to the reaction mixture was added trifluoroacetic acid (12 eq.) drop wise at a temperature of 20 ± 5 °C and the reaction was stirred for at least 20 h. After completion of reaction, the reaction mixture was concentrated to < 2 V and then to the concentrated mixture was added isopropyl acetate (254 mL, 5.0 V) and the mixture was concentrated to < 3 V. Then, the concentrated mixture was added drop wise to methyl tert-butyl ether (12 V) at a temperature of 20 ± 5 °C and stirred for at least 12 h, filtered and the filter cake was washed with methyl tert-butyl ether to obtain solid compound.

[0259] The above solid and water (15 V) were added to the reaction flask at room temperature, the pH of the system was adjusted to 6.0-7.0 with 5% sodium bicarbonate solution and stirred for at least 3 h; filtered and the filter cake was collected; then the filter cake was slurried in water (5.0 V) for 30 min; filtered, washed and dried to obtain white solid V (14.5 g, yield: 81%, purity: 99.4%, D%: 97.86% (LCMS detection)).

[0260] Preparation of compound VI of example 15

[0261] DMF (5.0 V) and compound V (20 g, 1.0 eq., purity: 99.4%, D%: 97.86%) were added to the reaction flask successively. To the reaction mixture was added thionyl chloride (3.0 eq.) drop wise at a temperature of -40 ± 5 °C and the reaction was stirred for 1 h; then to the reaction mixture was added pyridine (3.5 eq.) drop wise at a temperature of -40 ± 5 °C and stirred for at least 8 h; after completion of reaction, to the reaction mixture was added water (2.5 V) to quench the reaction; then to the reaction mixture was added 7.5% sodium bicarbonate solution at a temperature of 0 ± 5 °C to adjust the pH of the system to 7.0-8.0 and then stirred for about 3 h; filtered, the filter cake was slurried in water (10 V) for 30 min; filtered, the filter cake was collected and recrystallized with isopropyl alcohol to obtain solid VI (14.5 g, yield: 74.5%, purity: 99.75%, retention time: 11.112 min, chiral purity: 99.75% ee, D%: 97.66% (LCMS detection)).

[0262] 1HNMR (DMSO-d6, 400 MHz): δ 1.90-1.95 (m, 1H), 2.31-2.47 (m, 5H), 2.54-2.56 (m, 1H), 2.82-2.89 (m, 1H), 3.45 (s, 2H), 3.52-3.55 (m, 4H), 4.18 (d, J = 16.0 Hz, 1H), 4.33 (d, J = 16.0 Hz, 1H), 5.22 (s, 2H), 7.13-7.17 (m, 2H), 7.30-7.36 (m, 2H), 7.45-7.53 (m, 2H), 10.91 (s, 1H).

[0263] Comparative Example 1:

[0264] Preparation of compound 5 in patent CN105566290A1:

[0265] Synthesis of compound I-2:

[0266] Under nitrogen protection, tert-butyl glutamate (40 g) was added into a reaction kettle, followed by addition of deuterated acetic acid (120 ml) and benzaldehyde (1.7 g), and the temperature was raised to 55-65 °C, and reacted for at least 24 h. The reaction solution was concentrated, and the residual acetic acid was removed with toluene (100 mL) for four times. Deuterated acetic acid (120 ml) and benzaldehyde (1.7 g) were added, and the temperature was raised to 55-65 °C, and reacted for at least 24 h, and the reaction solution was concentrated. The residual acetic acid was removed with toluene (100 mL) for four times. The operation of adding deuterated acetic acid and benzaldehyde and removing the residual acetic acid with toluene was repeated for at least three times. The residue was slurried with methyl tert-butyl ether at 25-30 °C for 20 h, filtered, and the filter cake was rinsed with methyl tert-butyl ether. Then vacuum dried to obtain compound I-2 (22.1 g, solid yield 55%).

[0267] Synthesis of compound I-4:

[0268] Sodium bicarbonate (23.3 g) was dissolved in purified water (400 ml), and compound I-2 (22 g) and acetone (210 ml) were added under temperature control at 0 °C, and stirred for 30 min; then benzhydryl succinimidyl carbonate (30.5 g) was added under temperature control, and the reaction was allowed to proceed at room temperature for 16 h. The acetone was removed by concentration under reduced pressure, and the organic impurities were removed by extraction with ethyl acetate (200 ml x 2); the aqueous phase was adjusted to pH = 1-2 with 2N HCl solution, and then extracted with ethyl acetate (200 ml x 2); the organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. To the above solution, N-methylmorpholine (13.9 g) was added at 0 °C, and then methyl chloroformate (13.0 g) was slowly added dropwise, and the reaction was allowed to proceed at room temperature for 1 h; then ammonia water (51.1 g) was slowly added dropwise; after the addition was completed, the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, purified water (220 ml) was added to the reaction solution, and the phases were separated; the aqueous phase was extracted with ethyl acetate (200 ml) once; the organic phases were combined, and washed with saturated sodium bicarbonate aqueous solution (190 ml) and purified water (180 ml) once each. The organic phase was concentrated to about 1 / 4 of the volume, and then n-heptane (300 ml) was added under stirring, and the crystals were allowed to precipitate at 0 °C for 2 h. Filtration and vacuum drying gave compound I-4 (23.8 g, two-step yield 64.3%).

[0269] Synthesis of compound 5:

[0270] Compound I-4 (10 g) was dissolved in anhydrous methanol (80 ml) under nitrogen protection, and 10% palladium on carbon (0.5 g) was added, and hydrogenation was carried out under pressure control at 0.10 ± 0.05 MPa and stirring at 25 ± 5 °C for 3-5 h. After the reaction was completed, the reaction solution was filtered through diatomite. The filtrate was distilled under reduced pressure until no distillate was obtained, and a colorless liquid (8.9 g, NMR content: 62.7%, calculated content yield 92.6%) was obtained.

[0271] Preparation of compound IV in Comparative Example 2

[0272] Compound IV was synthesized according to the synthesis procedure of Example 69 of patent CN105566290A1, and the total yield of compound IV synthesized from A379A2 was 23%.

[0273] Preparation of compound VI in Comparative Example 3

[0274] Compound V (5.15 g of crude product, D%: 96.2%) was prepared according to the conditions and operations in step C in Example 67 of patent CN105566290A1, using starting material compound IV (5.5 g, D%: 96.3%).

[0275] Following the conditions and procedure in Step C of Example 67 of patent CN105566290A1, take the compound V (5 g crude, D%: 96.2%) in the previous step, to prepare compound VI (1.70 g, yield: 43.5% for two steps; purity: 99.2%, D%: 94.7%).

[0276] The deuterium enrichment is reduced by 1.5% from compound V to compound VI.

Claims

1. A process for the preparation of compound 5, characterized in that, The preparation method of the compound 5 is method I or method II: Method I comprises the following steps: deuterating compound 1 with a deuterating agent in a solvent in the presence of compound 1a and compound 2 to obtain the compound 5; The compound 2 is compound 2a and / or compound 2b; R a and R c are independently halogen, C 1-6 alkyl or C 1-6 alkoxy; R b and R d are independently H, halogen, C 1-6 alkyl or C 1-6 alkoxy; Method II comprises the following step: reacting compound 4 in a solvent in the presence of an acid or metal catalyst to provide said compound 5; R 1 and R 2 are independently H or D.

2. The process of claim 1, wherein the compound 5 is prepared by the process comprising: reacting compound 4 with compound 5a in the presence of a base to form compound 5b; and reducing compound 5b to form compound 5. It meets one or more of the following conditions: (1) In Method I, in compound 1a, R a and R c are independently halogen, R b and R d is H; The compound 1a is preferably compound 1a-1; (2) In method I, the molar ratio of the compound 1a to the compound 1 is (0.02-0.10):1, preferably (0.02-0.04):1; (2) In method I, the molar ratio of the compound 2 to the compound 1 is (0.03-0.06):1, for example (0.03-0.05):1; (3) In Method I, the compound 2a is 1, 2, or 3 of compound (S,S)-2a, compound (R,R)-2a, and compound (R,S)-2a, for example, the racemate of compound (S,S)-2a and compound (R,R)-2a, (4) In method I, the compound 1 is a free base or an acid salt of compound 1, for example a hydrochloride salt of compound 1; (5) In Method I, the compound 1 is compound (S)-1 and / or compound (R)-1, for example the racemate of compound (S)-1 and compound (R)-1 ; (6) In method I, the deuterating agent is heavy water; (7) In method I, the volume-to-mass ratio of the deuterating agent to the compound 1 is ≥5 mL / g, preferably (5-22) mL / g, for example (5-10) mL / g; (8) In method I, the solvent is one, two, three or four of halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents and acetate solvents, preferably ether solvents and / or acetate solvents, and further preferably methyl tert-butyl ether or isopropyl acetate; (9) In method I, the volume-to-mass ratio of the solvent to the compound 1 is (2-22) mL / g, preferably (2-5) mL / g; (10) In method I, the temperature of the deuterating reaction is 20-40°C, preferably 25-40°C; (11) In method I, the deuterating reaction is further carried out in the presence or absence of an additive, and when the deuterating reaction is carried out in the presence of an additive, the additive is a molecular sieve and / or a phase transfer catalyst; (12) In method I, the deuterating reaction is further carried out in the presence or absence of a base, and when the deuterating reaction is carried out in the presence of a base, the base is an organic base or an inorganic base; (13) In method I, after the deuterating reaction is completed, the reaction solution is directly subjected to the next reaction after the steps of washing and concentrating; (14) In method II, when the reaction is carried out in the presence of an acid, the acid is DCl, for example a deuterium water solution with a mass concentration of 10-40% DCl; (15) In method II, when the reaction is carried out in the presence of an acid, the molar ratio of the acid to the compound 4 is (1-3):1, preferably (2-2.5):1; (16) In method II, when the reaction is carried out in the presence of an acid, the temperature of the reaction is -20 to -5°C, for example -15 to -5°C; (17) In method II, when the reaction is carried out in the presence of a metal catalyst, the metal catalyst is a palladium catalyst, which can be PdCl2 and / or Pd / C; (18) In method II, when the reaction is carried out in the presence of a metal catalyst, the weight ratio of the metal catalyst to the compound is (0.1%-20%):

1. (19) In the method II, when the reaction is carried out in the presence of a metal catalyst, the reaction is carried out under a hydrogen atmosphere of 1-12 atm, for example, 8-12 atm; (20) In the method II, when the reaction is carried out in the presence of a metal catalyst, the temperature of the reaction is 10-40°C, which can be 20-30°C; (21) In Method II, the compound 4 is compound 4-1 or compound 4-2; The compound 4-1 can be compound (S)-4-1 and / or compound (R)-4-1, for example, racemate of compound (S)-4-1 and compound (R)-4-1; The compound 4-2 can be compound (S)-4-2 and / or compound (R)-4-2, for example a racemate of compound (S)-4-2 and compound (R)-4-2; and (22) In the method II, the solvent is 1, 2 or 3 kinds of alcoholic solvents, ether solvents and ester solvents, preferably a mixed solvent of alcoholic solvents and ether solvents, or a mixed solvent of "alcoholic solvents, ether solvents and ester solvents", further preferably a mixed solvent of CH3OH and MTBE or a mixed solvent of "CH3OH, MTBE and t-BuOAc".

3. The method for preparing compound 5 as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) In the method I, the deuterated reagent is heavy water; the solvent is isopropyl acetate and / or methyl tert-butyl ether; the temperature of the deuterium exchange reaction is 25-40°C; (2) In the method II, when the reaction is carried out in the presence of an acid, the acid is DCl; the molar ratio of the acid to the compound 4 is (2-2.5):1; the temperature of the reaction is -20 to -5°C; and (3) In the method II, when the reaction is carried out in the presence of a metal catalyst, the metal catalyst is added in two steps, PdCl2 is first added to the reaction system, and after the reaction proceeds to the disappearance of compound 4, Pd / C is added for reaction.

4. The process for the preparation of compound 5 according to any one of claims 1 to 3, characterized in that, In the method I and the method II, after the reaction is completed, the method for resolving compound 5 is further included, which comprises the following steps: The salt formation of compound 5 and L-(+)-tartaric acid in a solvent gives L-(+)-tartaric acid salt of compound I and L-(+)-tartaric acid salt of compound I', respectively; 5. The method for preparing compound 5 as described in claim 4, characterized in that, It meets one or more of the following conditions: (1) The molar ratio of L-(+)-tartaric acid to compound I in the L-(+)-tartaric acid salt of compound I is (0.5-1.3):1, for example, 0.5:1 or 1:1; (2) In the resolution method, the solvent is a mixed solvent of water and ethanol, for example, 85% ethanol aqueous solution; (3) In the resolution method, the molar ratio of L-(+)-tartaric acid to compound 5 is (0.5-1.3):1, which can also be (0.5-1):1, for example, (0.5-0.6):1; (4) In the resolution method, the temperature of the salt formation reaction is 50-60°C; and (5) In the resolution method, the volume / mass ratio of the solvent to compound 5 is (8-20) mL / g, preferably (8-15) mL / g.

6. The process for the preparation of compound 5 according to any one of claims 1 to 3, wherein, In Method II, the preparation method of the compound 5 further comprises the preparation method of the compound 4, wherein the preparation method of the compound 4 comprises the following step: deuterating the compound 3 with a deuterating reagent in the presence of a base to obtain the compound 4; 7. The method for preparing compound 5 as described in claim 6, characterized in that, It meets one or more of the following conditions: (1) In the method for preparing compound 4, the molar ratio of the base to compound 3 is (0.5-4):1, preferably (0.5-2.5):1; (2) In the preparation method of the compound 4, the base is 1, 2 or 3 of tertiary amine organic base, alkali metal carbonate and triethylene diamine, preferably alkali metal carbonate, and further preferably sodium carbonate; (3) In the preparation method of the compound 4, the deuterium reagent is CH3OD and / or EtOD, preferably CH3OD; (4) In the preparation method of the compound 4, the volume mass ratio of the deuterium reagent to the compound 3 is ≥3 mL / g, preferably (3-12) mL / g, for example (8-11) mL / g; (5) In the preparation method of the compound 4, the temperature of the deuterium reaction is 10-35℃; In the production process of the compound 4 described in (6), the compound 3 is the compound (S)-3 and / or the compound (R)-3, for example, a racemate of the compound (S)-3 and the compound (R)-3; 8. The method for preparing compound 5 as described in claim 6, characterized in that, In Method II, the preparation method of compound 4 further comprises a preparation method of compound 3, wherein the preparation method of compound 3 comprises the following steps: subjecting compound 1 to amination reaction with benzaldehyde in a solvent in the presence of a base to obtain the compound 3; 9. The process for the preparation of compound 5 as claimed in claim 8, wherein, It meets one or more of the following conditions: (1) In the preparation method of the compound 3, the base is 1, 2 or 3 of tertiary amine organic base, alkali metal carbonate and alkali metal bicarbonate, preferably tertiary amine organic base, and further preferably triethylamine; (2) In the preparation method of the compound 3, the molar ratio of the base to the compound 1 is (0.9-1.1):1; (3) In the preparation method of the compound 3, the compound 1 is the free base of the compound 1 or its hydrochloride; (4) In the preparation method of the compound 3, the molar ratio of the benzaldehyde to the compound 1 is (0.9-1.2):1; (5) In the preparation method of the compound 3, the solvent is 1, 2 or 3 of halogenated hydrocarbon solvent, alcohol solvent and ether solvent, preferably halogenated hydrocarbon solvent, and further preferably dichloromethane; (6) In the production method of the compound 3, the compound 1 is the compound (S)-1 and / or the compound (R)-1, for example, a racemate of the compound (S)-1 and the compound (R)-1; (7) After the completion of the amination reaction, the reaction solution of the amination reaction is directly used for the next step reaction after washing with water and concentration.

10. A process for the preparation of a compound VI, characterized in that, It is scheme 1 and / or 2: Scheme 1: The preparation method of the compound VI comprises the following steps: Step one: in the presence of a base, compound III and compound K are reacted to obtain compound IV; Step two: compound IV is subjected to deprotection reaction and free reaction under acidic conditions to obtain compound V; Step three: subjecting compound V to a ring closure reaction to obtain compound VI; Scheme 2: The preparation method of the compound VI comprises the following steps: The preparation method of the compound 5 as claimed in any one of claims 1-9; and, the compound 5 is further prepared into the preparation method of the compound VI.

11. The process for the preparation of compound VI according to claim 10, characterized in that, It meets one or more of the following conditions: (1) In scheme 1 step one, the molar ratio of the compound K to the compound III is (1-1.5):1, for example (1.1-1.3):1; (2) In scheme 1 step one, the base is alkali metal carbonate, and further preferably K2CO3; (4) In scheme 1 step one, the molar ratio of the base to the compound III is (2-5):1, for example (2.5-3.5):1; (5) In scheme 1 step one, the solvent is ether solvent and / or amide solvent, and further preferably N,N-dimethylformamide; ​ (6) In step one of Scheme 1, the volume / mass ratio of the solvent to the compound III is (2-8) mL / g, preferably (4-6) mL / g; (7) In step one of Scheme 1, the temperature of the reaction is 20-40 °C, preferably 25-35 °C; (8) In step one of Scheme 1, the post-treatment procedure after the reaction is completed includes the following steps: cooling the reaction solution, precipitating the solid, filtering, beating, filtering and drying; Preferably, in the step of precipitating the solid, the reaction solution is added to a mixed solvent of water and methyl tert-butyl ether, and then the solid is precipitated by stirring; (9) In step two of Scheme 1, the acid is trifluoroacetic acid; (10) In step two of Scheme 1, the molar ratio of the acid to the compound M is ≥8:1, preferably (8-15):1, for example (11-13):1; (11) In step two of Scheme 1, the solvent used in the deprotection reaction is a halogenated hydrocarbon solvent, further preferably dichloromethane; (12) In step two of Scheme 1, the temperature of the deprotection reaction is 10-40 °C, and can also be 15-25 °C; (13) In step two of Scheme 1, the free reaction is carried out at a pH of 6.0-7.5, preferably a pH of 6.0-7.0; (14) In step two of Scheme 1, the base used in the free reaction is an alkali metal bicarbonate or an alkali metal carbonate, preferably an alkali metal bicarbonate, further preferably NaHCO3; (15) In step two of Scheme 1, the solvent used in the free reaction is water; (16) In step two of Scheme 1, the volume / mass ratio of the solvent to the compound IV is (3-25) mL / g, for example (10-20) mL / g; (17) In step two of Scheme 1, the temperature of the free reaction is 0-40 °C, and can be 0-10 °C; (18) In step two of Scheme 1, before the free reaction, the following steps are included: concentrating the reaction solution, precipitating the solid, filtering and collecting the solid; (19) In step three of Scheme 1, the ring-closing reaction is carried out in the presence of thionyl chloride and a base; The molar ratio of the thionyl chloride to the compound V can be (1-5):1, for example (2-4):1; The base can be triethylamine or pyridine, preferably pyridine; The molar ratio of the base to the compound V can be (2-5):1, for example (3-4):1; (20) In step three of Scheme 1, the solvent used in the ring-closing reaction is an amide solvent, further preferably N,N-dimethylformamide; (21) In step three of Scheme 1, the volume / mass ratio of the solvent to the compound V is (3-20) mL / g, for example (4-6) mL / g; and (22) In step three of Scheme 1, the temperature of the ring-closing reaction is -50 to 0 °C, and can be -45 to -35 °C.

12. The process for the preparation of compound VI according to claim 10, characterized in that, In Scheme 1 and Scheme 2, the method for preparing the compound VI further comprises a method for preparing the compound III, wherein the method for preparing the compound III comprises the following step: subjecting the compound II to a deprotection reaction in the presence of a deprotection reagent to obtain the compound III; R 3 is a hydroxyl protecting group.

13. The process for the preparation of compound VI according to claim 12, characterized in that It meets one or more of the following conditions: (1) the compound II is compound II-TBDMS; (2) The deprotection reagent is tetrabutylammonium fluoride, for example 1M tetrabutylammonium fluoride in tetrahydrofuran; and (3) the temperature of the deprotection reaction is 10-40℃, and can also be 20-30℃.

14. The process for the preparation of compound VI according to claim 12, characterized in that, In Scheme 1 and Scheme 2, the method for preparing the compound VI further comprises a method for preparing the compound II, wherein the method for preparing the compound II comprises the following steps: reacting the compound I and the compound C in a solvent in the presence of a base to obtain the compound II.

15. The process for the preparation of compound VI according to claim 14, characterized in that, which satisfies one or more of the following conditions: (1) the base is a tertiary amine organic base, and is further preferably triethylamine and / or N,N-diisopropylethylamine, and is more preferably N,N-diisopropylethylamine; (2) the molar ratio of the base to the compound I is (1-5):1, for example (2-4):1; (3) the compound I is a free base or an acid salt thereof; the acid salt of the compound I is preferably an L-(+)-tartaric acid salt of the compound I; the molar ratio of L-(+)-tartaric acid to the compound I in the L-(+)-tartaric acid salt of the compound I is (0.5-1.3):1, for example 0.5:1 or 1:1; (4) the molar ratio of the compound C to the compound I is (1-3):1, for example (1-2):1; (5) the solvent is an ether solvent, and is further preferably tetrahydrofuran; (6) the temperature of the reaction is 40-80℃, and can be 60-70℃; (7) the compound C is compound C-TBDMS: and (8) the preparation method of the compound VI further comprises a preparation method of the L-(+)-tartaric acid salt of the compound I, and the conditions and operations in the preparation method of the L-(+)-tartaric acid salt are the same as those in the resolution method of the compound 5 in claim 4 or 5.

16. A compound I or L-(+)-tartaric acid salt thereof, Compound 3 or Compound 4: R 1 and R 2 are independently H or D.

17. Compound I, or the L-(+)-tartaric acid salt thereof, Compound 3, or Compound 4 according to claim 16, wherein, the acid salt of the compound I is an L-(+)-tartaric acid salt of the compound I; the molar ratio of L-(+)-tartaric acid to the compound I in the L-(+)-tartaric acid salt of the compound I is (0.5-1.3):1, for example 0.5:1 or 1:1; The compound 3 is compound (S)-3 and / or compound (R)-3, for example the racemate of compound (S)-3 and compound (R)-3; The compound 4 is compound 4-1 or compound 4-2; 18. A method of resolving compound 5, characterized by, which comprises the following steps: The salt formation of compound 5 and L-(+)-tartaric acid in a solvent gives L-(+)-tartaric acid salt of compound I and L-(+)-tartaric acid salt of compound I', respectively; the conditions and operations in the resolution method of the compound 5 are the same as those in the resolution method of the compound 5 in claim 4 or 5.

19. Use of a compound I or an acid salt thereof as an intermediate in the preparation of a compound VI: ###0009### I VI 20. Use of the compound I or the acid salt thereof in claim 19 as an intermediate for preparing the compound VI, characterized in that, In the use described, compound VI is prepared from compound IV, the synthesis route of which is as follows: Preferably, the compounds VI are prepared by the following synthesis route: the conditions and operations in the preparation method of the compound IV and the preparation method of the compound VI are the same as those in any one of claims 10-14.

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