WO2018032555A1 - Method for preparing dihydroisoindole derivative and analogs thereof - Google Patents

Abstract

A method for preparing a dihydroisoindole derivative and analogs thereof, comprising: using a compound of formula (VII) as a raw material, and protecting an amino group or a hydroxyl group to prepare a compound of formula (VI); using the compound of formula (VI) as a raw material to react with a lithiating agent, and then adding a formylating reagent for reaction to prepare a compound of formula (V); reducing a formyl group of the compound of formula (V) to a hydroxyl group with a reducing agent to prepare a compound of formula (IV); and preparing a compound of formula (I) by using the compound of formula (IV) as a raw material. The method uses readily available raw materials and fewer steps, has a relatively high yield and product purity, and improves the safety of products serving as drugs due to no use of heavy metals.

Description

Method for preparing dihydroisoindole derivatives and analogs thereof Technical field

The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of dihydroisoindole derivatives and analogs thereof.

Background technique

Dihydroisoindole derivatives and their analogues are widely used in the fields of medicine, pesticides, etc., and can be used as key intermediates in many drugs. A key part of a polycyclic compound which is highly effective in inhibiting hepatitis C virus disclosed in the patent CN102140100 is a dihydroisoindole derivative; a 1,3-dihydroisoindole derivative disclosed in CN101790518 is an HSP90 inhibitor. And can be used for the preparation of a medicament for treating a disease in which inhibition, modulation or regulation of HSP90 plays a role; CN00818254 discloses a pharmaceutically active dihydroisoindole derivative which is used as a TNFa and phosphodiesterase inhibitor and can For the treatment of TNFa and phosphodiesterase mediated diseases; the isoindole derivatives disclosed in US 4,400, 520 can be used for the treatment of rheumatoid arthritis, osteoarthritis, spondylolisthesis and post-operative, fracture, skeletal muscle pain and the like.

At present, however, the literature and patents disclose that there are few methods for synthesizing dihydroisoindole derivatives, and these methods are also difficult to adapt to industrial mass production. E.g:

CN101790513 reports a process for preparing a derivative of isoindole-1,3-dione by reduction with a strong reducing agent to obtain a dihydroisoindole derivative, the specific route is as follows:

The isoindole-1,3-diketone derivative used in the method has no commercial product and needs to be synthesized in multiple steps and is expensive. Moreover, this method uses a highly hazardous reagent, borane, during the reduction process, and the yield of the final product is usually very low. For example, the yield of the 2,3-dihydro-5-hydroxy-1H-isoindole hydrochloride compound prepared by the method is only 20%, and the preparation of 5-bromo-2,3-dihydro-1H-isoindole is prepared. The rate is only 41.3%.

CN102140100 reports a method for derivatization and synthesis of other substituted dihydroisoindole derivatives in the case where the dihydroisoindole parent ring is completed, and the specific route is as follows:

The parent synthesis of dihydroisoindole in this method has not been reported in the literature and there is no commercial product supply on the market. The synthetic route from the starting material is not suitable for commercial production applications.

Another common method is reported in Inorganica Chimica Acta, 363 (2010), 3222-3228, which uses a sulfonate of an o-dibenzyl bromide and an amino group to deprotect the N atom to give a dihydroisoindole. Derivatives, the specific route is as follows:

When the method is deprotected in the last step, hydrobromic acid and phenol are used, the reaction conditions are extremely harsh, and the wastes treated thereafter have a very bad environmental impact, and when the method has active substituents on the benzene ring, The reaction yield is far below the reported yield of this document.

Therefore, there is a need for a process for the preparation of dihydroisoindole derivatives and analogs thereof which are relatively inexpensive and suitable for industrial mass production.

Summary of the invention

In order to solve the above problems, the present invention provides a process for producing a dihydroisoindole derivative represented by the formula (I) and an analogue thereof, which comprises the steps of:

among them,

A represents O or NH;

When A represents O, PG represents a hydroxy protecting group; when A represents NH, PG represents an amino protecting group;

R ₁ and R _{2 are} independently selected from C ₁ -C ₆ alkyl;

(1) using a compound of the formula (VII) as a starting material, protecting an amino group or a hydroxyl group to prepare a compound of the formula (VI);

(2) reacting a compound of the formula (VI) with a lithiation reagent, and then adding a formylating reagent to prepare a compound of the formula (V);

(3) reducing a formyl group of the compound of the formula (V) to a hydroxyl group with a reducing agent to prepare a compound of the formula (IV);

(4) A compound of the formula (I) is obtained by using a compound of the formula (IV) as a starting material.

Further, the hydroxy protecting group is an etheric hydroxy protecting group or an ester hydroxy protecting group, preferably a methoxymethyl group.

Further, the amino protecting group is an alkyl-based amino protecting group, an amide-based amino protecting group or an imine-based amino protecting group, preferably a pivaloyl group.

Further, the hydroxy protecting group is a methoxymethyl group. In step (1) of a specific embodiment, the compound of formula (VII) of the present invention is reacted with chloromethyl methyl ether.

Further, the amino protecting group is a pivaloyl group. In step (1) of a specific embodiment, the compound of formula (VII) of the present invention is reacted with pivaloyl chloride.

Further, R _{1 is} selected from a linear alkyl group of C ₁ , C ₂ or C ₃ , and includes -CH ₂ -, -CH ₂ CH ₂ - and -CH ₂ CH ₂ CH ₂ -.

Further, R _{2 is} selected from a methylene group.

Further, in the step (2), the lithiation reagent is n-butyllithium, cyclohexyllithium, sec-butyllithium or tert-butyllithium; preferably n-butyllithium.

Further, in the step (2), the formylating agent is N,N-dimethylformamide, ethyl formate or isopropyl formate.

Further, in the reaction in the step (2), the reaction temperature is -100 ° C to 50 ° C, preferably -80 ° C to 30 ° C, more preferably - 80 ° C to -30 ° C.

Further, in the step (3), the reducing agent is sodium borohydride, potassium borohydride or lithium aluminum hydride.

Further, in the reduction of the step (3), the reaction temperature is -20 ° C to 30 ° C, preferably -10 ° C to 15 ° C.

Further, when A represents O, the step (4) comprises the following steps:

Wherein X represents Cl, Br, I, MsO or TsO;

Pga represents an amino protecting group;

(4a-1) using the compound of the formula (IVa) as a starting material, the reaction is prepared to obtain the compound of the formula (IIIa);

(4a-2) using the compound of the formula (IIIa) as a starting material, in the presence of an organic base, reacting with Pga-NH ₂ to obtain a compound of the formula (IIa);

(4a-3) Deprotection of the amino group provides the compound of formula (I).

Further, X represents Cl or Br, and in the reaction of the step (4a-1), the halogenating reagent used is dichlorosulfoxide, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosphorus tribromide. Any one of phosphorus pentabromide.

Further, in the reaction of the step (4a-2), the reaction temperature is from 0 ° C to 50 ° C, preferably from 20 ° C to 50 ° C.

Further, in the step (4a-2), the organic base is selected from any one or more of triethylamine, N-methylmorpholine, and diisopropylethylamine.

Further, Pga is benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl or 4-methoxy Benzyl.

Further, when A represents NH, the step (4) comprises the following steps:

Wherein X represents Cl, Br, I, MsO or TsO;

(4b-1) using the compound of the formula (IVb) as a starting material, the reaction is prepared to obtain the compound of the formula (IIIb);

(4b-2) using the compound of the formula (IIIb) as a starting material, in the presence of an inorganic base, in the intramolecular reaction to prepare a compound of the formula (IIa);

(4b-3) Deprotection of the amino group provides the compound of formula (I).

Further, X represents Cl or Br, and in the reaction of the step (4b-1), the halogenating reagent used is dichlorosulfoxide, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, phosphorus tribromide. Any one of phosphorus pentabromide.

Further, in the reaction of the step (4b-1), the temperature of the reaction is from 0 ° C to 50 ° C, preferably from 15 ° C to 50 ° C. In a specific embodiment of the invention, PG is a pivaloyl group at this time.

Further, in the step (4b-2), the inorganic base is selected from the group consisting of sodium hydride, potassium hydride, potassium carbonate, cesium carbonate, and A Any one or more of sodium alkoxide, sodium ethoxide, sodium t-butoxide, and potassium t-butoxide.

Further, in the reaction of the step (4b-2), the reaction temperature is -5 ° C to 100 ° C, preferably 0 ° C to 30 ° C.

The present invention also provides a preparation intermediate of the compound of the formula (I), that is, the compound of the formula V, the compound of the formula (VI), and more specifically, the intermediate structure of the preparation is the compound 5 in the specific embodiment. , 5a, 5b, 6, 6a, 6b.

The C ₁ -C ₆ alkyl group means an alkyl group of C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , that is, a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl and the like.

For the aforementioned step (1), the reaction can be carried out in an alkaline environment, specifically in the presence of an organic base such as triethylamine, N-methylmorpholine and diisopropylethylamine. The reaction can be carried out in an organic solvent, which may be a halogenated hydrocarbon solvent, an ether solvent, an ester solvent, and/or an aromatic hydrocarbon solvent, including dichloromethane, 1,2-dichloroethane, chloroform, Any one of tetrahydrofuran, methyl tert-butyl ether, acetic acid, ethyl ester, butyl acetate, toluene, and isopropyl acetate or a mixed solvent thereof. The temperature of the reaction may range from -20 ° C to 80 ° C, with a preferred range of from -5 ° C to 50 ° C.

For the foregoing step (2), the reaction can be carried out in an organic solvent, and the organic solvent used may be an ether solvent including tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether. One of them or a mixed solvent thereof. The reaction temperature may range from -100 ° C to 50 ° C, preferably in the range of -80 ° C to 30 ° C, and further preferably -80 ° C to -30 ° C.

For the foregoing step (3), the reaction can be carried out in an organic solvent, and the organic solvent used may be water, an alcohol solvent and/or an ether solvent, including methanol, ethanol, propanol, butanol, isopropanol, tetrahydrofuran. Or one of 2-methyltetrahydrofuran and 1,4-dioxane or a mixed solvent thereof. The reducing agent used may be sodium borohydride, potassium borohydride or lithium aluminum hydride. The temperature of the reaction may range from -20 ° C to 30 ° C, with a preferred range of from -10 ° C to 30 ° C.

With respect to the aforementioned step (4a-1) or (4b-1), as a specific embodiment of the present invention, when X is chlorine, the compound of the formula (IVa) or the compound of the formula (IVb) may be dissolved in a solvent for reaction. The solvent of the compound of the formula (IVa) or the solvent of the formula (IVb) may be used in dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene or chlorobenzene without directly reacting with a halogenated hydrocarbon solvent. Any one or a mixed solvent thereof. When PG is pivaloyl, the temperature of the chlorination reaction ranges from 0 ° C to 50 ° C, and the preferred reaction range is from 20 ° C to 50 ° C.

For the aforementioned step (4a-2), the reaction may be carried out in an organic solvent, and the organic solvent used may be a halogenated hydrocarbon solvent, an ether solvent, an ester solvent, a nitrile solvent, and/or an aromatic hydrocarbon solvent, including One of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, toluene or a mixture thereof Soluble solvent.

For the foregoing step (4a-3), as a specific embodiment of the present invention, when Pga is a benzyl group or a substituted benzyl group, the catalyst for the reaction is a palladium carbon catalyst having a palladium content of 3% to 10%, for example, Palladium hydroxide. The solvent used for the reaction may be an alcohol solvent and/or an ether solvent, and one of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, butyl acetate or a mixed solvent thereof. The hydrogen source used may be hydrogen, amine formate, hydrazine hydrate, cyclohexadiene or formic acid, preferably hydrogen.

For the aforementioned step (4b-2), the reaction can be carried out in an organic solvent, and the organic solvent used may be an ether solvent and/or an amide solvent, including N,N-dimethylformamide, tetrahydrofuran, 2-methyl One of tetrahydrofuran, ethylene glycol dimethyl ether, N-methylpyrrolidone or a mixed solvent thereof.

With respect to the aforementioned step (4b-3), as a specific embodiment of the present invention, when PG is a pivaloyl group, the deprotecting agent used may be any one of concentrated hydrochloric acid, hydrobromic acid or trifluoroacetic acid. The solvent used may be water, an alcohol solvent, a halogenated hydrocarbon solvent and/or an ether solvent, including methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, 1,4-two. One of oxygen rings or a mixed solvent thereof. The temperature for deprotection ranges from 0 °C to 130 °C, with a preferred range of from 40 °C to 100 °C.

The test results show that the method of the present invention can produce dihydroisoindole derivatives and the like by a few simple reactions using inexpensive and readily available raw materials, and has high yield and purity. At the same time, in the method of the invention, the use of heavy metals is not involved, the problem of heavy metal residues existing in the preparation route is eliminated, and the safety of the final product as a medicine is improved.

In the present invention, the full Chinese name corresponding to the English abbreviation is as follows:

EA	Ethyl acetate
MTBE	Methyl tert-butyl ether
MsO	Mesylate
TsO	P-toluenesulfonate
TLC	TLC
MS	Mass spectrometry
HPLC	High performance liquid chromatography
H-NMR	Nuclear magnetic resonance spectrum
DMF	N,N-dimethylformamide
THF	Tetrahydrofuran
MTBE	Methyl tert-butyl ether
DIPEA	Diisopropylethylamine
MOMCl	Chloromethyl methyl ether
EA	Ethyl acetate

DCM	Dichloromethane
DMSO	Dimethyl sulfoxide
CDCl 3	Deuterated chloroform

It is apparent that various other modifications, substitutions and changes can be made in the form of the above-described embodiments of the present invention.

The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention.

detailed description

The materials used in the following examples were from commercial products and the purity involved was HPLC purity.

Example 1 Synthesis of 7,8-dihydro-6H-[1,3]dioxo[4,5-e]isoindole hydrochloride (1)

Add 400g of compound 7,400g of triethylamine and 2000g of dichloromethane to 3000mL three-necked flask, stir for 10min, cool down to 0 °C-5 °C in ice water bath; start slowly adding 380g of pivaloyl chloride slowly, control internal temperature less than 10 °C, drop After the addition is completed, the reaction is stirred at room temperature, controlled by TLC, and reacted for 2 h. After the reaction is completed, the pH is adjusted to 6-7 with 1 L of 0.5 N diluted hydrochloric acid, and the organic phase is washed twice with water (1000 mL), 150 g. powder sulfate, filtered, and concentrated under reduced pressure, slurried with petroleum ether, filtered off with suction, and dried in vacuo to give 576g of compound 6, yield: 92.6%, HPLC purity: 99.4%; mass spectrum ^{MS (MH +): m /} z 236.2,1H- _{NMR (400MHz, CDCl 3):} 6.75 (m, 3H), 5.94 (s, 2H), 5.81 (br1H), 4.33 (d, J = 8.0Hz, 2H), 1.21 (s, 9H).

Add 530 g of compound 6 and 5.2 L of THF to a 10 L three-necked flask, stir until clarified with nitrogen, cool to -75 ° C with liquid nitrogen, control the reaction temperature to less than -70 ° C, add 1.25 L of n-BuLi, and add dropwise , reaction 0.5h, start adding 250g DMF, control the reaction temperature is not higher than -70 ° C, after the completion of the addition, -80 ° C - 70 ° C reaction 0.5h, add water quenching, adjust the pH to 2 with concentrated hydrochloric acid 3, 1.0 L MTBE was extracted twice, and the solvent was recovered under reduced pressure to give 401 g of Compound 5, yield: 67.1%, purity: 99.9%; mass spectrum MS (MH ⁺ ): m/z 264.2, ¹ H-NMR (400 MHz, CDCl ₃ ): 10.33 (s, 1H), 6.92 (m, 2H), 6.12 (s, 2H), 4.45 (s, 2H), 1.13 (s, 9H).

Add 263g of compound 5 and 2.6L of methanol to the 3L three-necked flask, stir until clarified, cool the ice water bath to 0 °C-5 °C, control the temperature less than 10 °C, add 30g of sodium borohydride in batches, and add the reaction in ice water bath after adding After the reaction was completed, TLC was charged. After the reaction was completed, 1000 mL of water was added, stirred for 20 min, and extracted twice with 2 L of dichloromethane. The organic phase was combined and concentrated under reduced pressure to give 240 g of compound 4, yield: 90.5%, purity: 99.7%; (MH ⁺ ): m/z 264.1, ¹ H-NMR (400MHz, CDCl ₃ ): 6.79 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.47 (br, 1H) ), 5.98 (s, 2H), 4.74 (d, J = 4.0 Hz, 1H), 4.43 (d, J = 4.0 Hz, 1H), 3.13 (t, J = 4.0 Hz, 1H), 1.16 (s, 9H) ).

Add 2000 mL of dichloromethane and 205 g of Compound 4 to a 3 L three-necked flask, heat to an internal temperature of 25-30 ° C, completely dissolve the white solid of Compound 4, and control the internal temperature at 25-30 ° C to add 117 g of thionyl chloride, and react for 2 h. TLC control, after the disappearance of the raw materials, the temperature was lowered to room temperature, and an off-white solid precipitated, suction filtration and infrared drying to obtain 234 g of compound 3, yield: 100%, purity 93.8%, mass spectrum MS (MH ⁺ ): m/z _{284.1,1H-NMR (400HMz, CDCl 3} ): 6.74-6.78 (m, 2H), 6.01 (s, 3H), 4.65 (s, 2H), 4.43 (d, 2H), 1.18 (s, 9H).

Under nitrogen protection, add 200g of compound 3 and 1600mL of DMF to 2000mL three-necked bottle, stir until dissolved, control the temperature 0-10 °C, add 84.7g of sodium hydride in batches, react for 1~1.5h, control in TLC, after the reaction is finished, react The solution was slowly poured into a 5000 mL beaker containing 3000 mL of water, which was produced as a white solid, suction filtered, washed, and dried under an infrared lamp to obtain 177.5 g of compound 2 white solid, yield 92.6%, purity 81.3%; mass spectrometry MS ( MH ⁺ ): m/z 248.1, ¹ H-NMR (400MHz, CDCl ₃ ): 6.77 (m, 2H), 5.99 (s, 2H), 4.81-4.91 (br, 4H), 1.34 (s, 9H) .

Add 6.37g of crude compound 2 (90% content) to a 100mL three-necked flask, 90mL of 12N concentrated hydrochloric acid, heat to reflux, control reaction in TLC, complete reaction in 10 hours, drop to room temperature, produce off-white solid, suction filtration, get White-like 7,8-dihydro-6H-[1,3]dioxo[4,5-e]isoindole hydrochloride 1.63 g, yield 34%, purity: 98.2%; mass spectrum MS (MH ⁺ : m/z 163.8, ¹ H-NMR (400 MHz, d6-DMSO): 10.05 (br, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.08 (s, 2H), 4.45 (br, 2H), 4.40 (br, 2H).

Example 2 Synthesis of 7,8-dihydro-6H-[1,3]dioxo[4,5-e]isoindole hydrochloride (1)

To a 500 mL three-necked flask was added 25.0 g of compound 7a, 100 mL of dichloromethane, and 53.1 g of DIPEA. Control the temperature 10 ~ 20 ° C, add 26.5g MOMCl, add dropwise, keep 15-25 ° C, reaction for 16 hours, TLC control, after the reaction is completed, add 200mL of dichloromethane, washed with water, washed with saturated brine, decompressed organic phase concentrated and the resulting crude product by column (petroleum ether: ethyl acetate = 10: 1 elution) to give 11.1g compound 6a, appearance of pale yellow oil, yield 86%; purity: 99%; mass MS (MH ^+): m / z 197.1,1H-NMR (400HMz , CDCl 3): 6.75-6.85 (m, 3H), 5.93 (s, 2H), 4.67 (s, 2H), 4.48 (s, 2H), 3.39 (s, 3H ).

Add 8.0 g of compound 6a and 80 mL of THF to a 250 mL three-necked flask, stir until clarified under nitrogen atmosphere, cool the liquid nitrogen to -78 ° C, control the temperature to be less than -70 ° C, add 26.1 mL of n-BuLi, react 3-4 h, add dropwise 8.9 g DMF, low temperature reaction for 8-16 hours, quenched with aqueous ammonium chloride solution, and warmed to 10-20 °C. Separate, wash with water, wash with 1N HCl, wash with aqueous sodium hydrogencarbonate, and wash with brine, and then, then, then ⁺ ): m/z 225.1, ¹ H-NMR (400MHz, CDCl ₃ ): 10.33 (s, 1H), 6.93-6.97 (m, 2H), 6.11 (s, 2H), 4.84 (s, 2H), 4.71 (s, 2H), 3.39 (s, 3H).

Add 4.5g of compound 5a and 36mL of ethanol to 100mL three-necked flask, stir for 10min, cool to 0-10 °C in ice water bath, control temperature is less than 10 °C, add 0.3g potassium borohydride in batches, react for 30min, control in TLC, raw material reaction Completely, 3N HCl was added dropwise to adjust pH=2, most of the ethanol was distilled off, 50 mL of water was added, the product was extracted with EA, and the organic phase was concentrated to dryness to give 4.2 g of a white oil, yield 93%, purity 95%.

Add 4.2g of compound 4a and 35mL of dichloromethane to 100mL three-necked flask, stir for 10min, cool to 0-10 °C in ice water bath, control temperature is less than 10 °C, add 14.3g phosphorus oxychloride to react for 16h, control in TLC, reaction After completion, the solvent was evaporated to dryness, and the crude material was purified to give 2.6 g of Compound 3a, yield: 63%, purity 99%; ¹ H-NMR (400 MHz, CDCl ₃ ): 6.87 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.05 (s, 2H), 4.76 (s, 2H), 4.70 (s, 2H).

To a 30 mL reaction vial was added 0.7 g of compound 3a and 0.7 g of benzylamine, 1.2 g of DIPEA, 14 mL of THF. The temperature was raised at 60-70 ° C, the reaction was carried out for 16 hours, controlled by TLC, water was added after the reaction was completed, and the product was extracted by MTBE. The organic phase was evaporated to dryness, the crude product was purified by column to give Compound 2a 0.4g; yield 50%, purity 99%; Mass Spectrum ^{MS (MH +): m /} z 254.1, 1 H-NMR (400MHz, CDCl 3): 6.87 (d , J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.05 (s, 2H), 4.76 (s, 2H), 4.70 (s, 2H).

Add 0.2g of compound 2a and 0.05g of 10% palladium carbon to 10mL reaction flask, 10mL of ethanol and 0.5mL of 3N HCl, replace N ₂ with N ₂ , charge hydrogen to 2-3kg pressure, react for 16-24 hours, control in TLC After the reaction, the mixture was filtered through celite, dried, and stirred with <RTI ID=0.0>>&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& 0.1 g, yield 60%, purity 99%, mass spectrum MS (M-H+): m/z 168.3, ¹ H-NMR (400 MHz, d ₆ -DMSO): 10.05 (br, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.08 (s, 2H), 4.45 (br, 2H), 4.40 (br, 2H).

Example 3 Synthesis of 3,7,8,9-tetrahydro-2H-[1,4]dioxo[2,3-e]isoindole hydrochloride (1b)

Add 42g of compound 7b, 400g of N-methylmorpholine and 250mL of DCM to a 500mL three-necked flask, stir for 10min, and cool to 10°C in an ice water bath; start slowly adding 38g of pivaloyl chloride slowly, and control the internal temperature to not exceed 20°C. After the addition is completed, the reaction is stirred at room temperature, controlled by TLC. After the reaction is finished, the pH is adjusted to 6-7 with 100 mL of 0.5 N diluted hydrochloric acid, and the organic phase is washed twice with 100 mL of water, and 15 g of the powder is dried and filtered. Concentrated under reduced pressure, petroleum ether was beaten, suction filtered, and dried under vacuum to give 55 g of compound 6b, purity: 99.1%, yield 86%.

Add 50g of compound 6b and 300mL of THF to 500mL three-necked flask, stir to clarify under nitrogen atmosphere, cool to -75 °C with liquid nitrogen, control the reaction temperature to be less than -70 °C, add 120mL of cyclohexyllithium dropwise, after the addition is completed, the reaction 0.5h, start adding 30g DMF, control the reaction temperature is not higher than -70 ° C, after the completion of the addition, -80 ° C - 70 ° C reaction for 2h, add water to quench, adjust the pH to 2-3, 150mL MTBE with concentrated hydrochloric acid The mixture was extracted twice, and the solvent was evaporated under reduced pressure to give 38 g of Compound 5b, purity: 97.6%, yield 68%.

Add 30g of compound 5b and 300mL of methanol to a 500mL three-necked flask, stir until clarified, cool the ice water bath to 10 ° C, control the temperature to less than 20 ° C, add 2.5g of sodium borohydride in batches, and then react in ice water bath for 1 hour, TLC In the middle of the reaction, after completion of the reaction, 100 mL of water was added, stirred for 20 min, extracted twice with 200 mL of DCM, and the organic phases were combined and concentrated under reduced pressure to give 28 g of compound 4b, purity: 99.5%. The yield was 92%.

250 mL of 1,2-dichloroethane and 22 g of compound 4b were added to a 500 mL three-necked flask, and the temperature was raised to 50 ° C. The internal temperature was controlled at 45-55 ° C to add 13 g of thionyl chloride, and the reaction was carried out for 2 h. At room temperature, an off-white solid precipitated, suction filtration, and infrared drying to obtain 24 g of compound 3b, yield: 100%, purity 95.8%, yield 99%.

Under nitrogen protection, add 20g of compound 3b and 150mL of DMF to a 250mL three-necked flask, stir until dissolved, control the temperature 0-10 °C to add 15g of potassium t-butoxide in batches, react for 1 ~ 1.5h, control in TLC, after the reaction is over, The reaction solution was slowly poured into a 2000 mL beaker containing 500 mL of water, and a white solid was produced, suction filtered, washed, and dried under an infrared lamp to obtain 16 g of a compound 2b white solid having a purity of 85.7% and a yield of 91%. .

To a 250 mL three-necked flask, 10 g of the compound 2b obtained in the above step, 100 mL of ethanol, and 20 mL of concentrated hydrochloric acid 50 mL, 2 g of activated carbon were added, and the mixture was heated to reflux overnight, and the reaction was completely cooled to room temperature by TLC, suction filtered, and concentrated to dryness under reduced pressure. Add 20 mL of absolute ethanol, freeze crystallize, and suction filter to obtain a pale yellow solid. Dry it under infrared to obtain 3,7,8,9-tetrahydro-2H-[1,4]diox[2,3- e] isoindole hydrochloride (1b) 5.7 g, HPLC purity: 99.1%, yield 70%; mass spectrum MS (MH ⁺ ): m/z 177.9; ¹ H-NMR (400 MHz, d ₆ -DMSO) :10.1 (br, 2H), 6.90 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 4.42 (br, 2H), 4.36 (br, 2H), 4.30 (m, 4H).

Example 4 Synthesis of 2,3,4,8,9,10-hexahydro-[1,4]dioxo[2,3-e]isoindole hydrochloride (1c)

To a 500 mL three-necked flask was added 30.0 g of compound 7c, 200 mL of dichloromethane, 60 g of DIPEA. Control the temperature below 20 ° C, add 35g MOMCl, add dropwise, keep 15-25 ° C, reaction for 16 hours, TLC control, after the reaction is completed, add 100mL of dichloromethane, washed with water, saturated brine, organic phase concentrated under reduced pressure The obtained crude product was subjected to column ( petroleum ether: ethyl acetate = 10:1 elution) to give 17 g of compound 6c, purity: 98%, yield 46%.

Add 10.0g of compound 6c and 100mL of THF to a 250mL three-necked flask, stir until clarified under nitrogen atmosphere, liquid nitrogen is cooled to -78 °C, control temperature is less than -70 °C, add 35mL of n-BuLi, react for 1h, add 15mL of formic acid The ester was reacted at low temperature for 0.5 hour, quenched with aqueous ammonium chloride solution, and warmed to room temperature. The liquid was separated, washed with water, washed with 1N HCl, washed with aqueous sodium hydrogencarbonate, and brine, and then evaporated, and then evaporated and evaporated to give the crude product, and the crude product was subjected to column to obtain 7 g of 5c product with a purity of 99% and a yield of 63%.

Add 5g of compound 5c and 50mL of methanol to 100mL three-necked flask, stir for 10min, cool down to 0-10 °C in ice water bath, control temperature is less than 20 °C, add 2.5g lithium aluminum hydride in batches, react for 30min, control in TLC, the reaction is finished. 3N HCl was added dropwise to adjust pH=2, most of the methanol was distilled off, 30 mL of water was added, and the product was extracted with EA. The organic phase was concentrated to give 5 g of milky white oil, purity 98%, yield 99%.

Add 5g of compound 4c and 50mL of dichloromethane to 100mL three-necked flask, stir for 10min, cool to 0-10 °C in ice water bath, control temperature is less than 10 °C, add 20g of phosphorus tribromide, react for 2h, control in TLC, complete reaction After that, the reaction solution was slowly added to 100 mL of water, and then 100 mL of dichloromethane was added thereto, and the layers were separated. The organic phase was washed with saturated sodium hydrogen carbonate solution and washed with saturated brine to give 4 g of 3c, purity 91%, yield 83%.

To a 100 mL three-necked flask, 8 g of compound 3c and 4 g of benzhydrylamine, 2 g of DIPEA, 50 mL of THF were added, and the temperature was raised at 60-70 ° C for 16 hours. TLC was controlled. After the reaction was completed, water was added and MTBE was extracted. The organic phase was evaporated to dryness.

Add 4.5g of compound 2c and 0.5g of 5% palladium carbon, 50mL of methanol, 2mL of 12N concentrated hydrochloric acid, N _{2 for} 3 times, charge hydrogen to 2-3kg pressure, react for 20-24 hours, and control in TLC. After the reaction is completed, the diatomaceous earth is filtered, spin-dried, and stirred with MTBE to obtain a white solid 2,3,4,8,9,10-hexahydro-[1,4]dioxy[2,3-e] Isoindole hydrochloride (1c) 2g, purity 99%, yield 56%, mass spectrum MS (M-H+): m/z 191.9, ¹ H-NMR (400 MHz, d ₆ -DMSO): 10.10 (br, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 4.40 (m, 4H), 4.20 (t, J = 6 Hz, 2H), 4.15 (t, J =6 Hz, 2H), 2.20 (m, 2H).

Performing 5 screening tests of process parameters of the present invention

1. Key step condition optimization

Conditional optimization is carried out using representative compounds as templates, and the optimum conditions are applicable to other substrates.

1.1 Condition optimization for the preparation of compound 5

Add 5.3 g of compound 6 and 52 mL of THF to a 100 mL three-necked flask, stir until clarified under nitrogen atmosphere, and cool to a certain temperature with liquid nitrogen, and add 1.25 equivalents of lithiation reagent. After the addition is completed, the reaction is started for 0.5 h. 3 equivalents of formylating reagent, control reaction for 0.5 h, quench with water, adjust the pH to 2-3 with concentrated hydrochloric acid, extract twice with 100 mL of MTBE, and recover the solvent under reduced pressure to obtain compound 5, the data is as shown in Table 1 below:

Table 1

1.2 Optimization of conditions for the preparation of compound 4

Add 26.3g of compound 5 and 260mL of methanol to a 300L three-necked flask, stir until clarified, control a certain temperature, add 1.5 equivalents of reducing agent in batches, and after the addition, keep the reaction for 1 hour, control in TLC, after the reaction is over, add 100 mL of water, stirred for 20 min, extracted twice with 200 mL of dichloromethane, combined organics and concentrated under reduced pressure to give compound 4, as shown in Table 2 below:

Table 2

Numbering	Reaction temperature (°C)	reducing agent	Yield	HPLC purity (%)
1	-10	Sodium borohydride	90%	98%
2	-10	Potassium borohydride	90%	98%
3	-10	Lithium aluminum hydride	85%	98%
4	-20	Sodium borohydride	88%	98%
5	20	Sodium borohydride	86%	98%

1.3 Optimization of conditions for the preparation of compound 3

Add 200mL of dichloromethane and 20.5g of compound 4 to a 300mL three-necked flask, stir and dissolve, control to add 1.2 equivalents of halogenating reagent in a certain temperature, react for 2h, control in TLC, disappear after the raw materials disappear, and have a white solid. Precipitation, suction filtration, infrared drying, get 3, the data is shown in Table 3 below:

table 3

1.4 Optimization of conditions for the preparation of compound 2

Under nitrogen protection, add 20g of compound 3 and 160mL of DMF to a 200mL three-necked bottle, stir until dissolved, control Add 2.5 equivalents of base in batches at a certain temperature, react for 1 to 1.5 hours, and control in TLC. After the reaction is finished, slowly pour the reaction solution into a 500 mL beaker containing 300 mL of water, which is produced as a white solid, suction filtered, and washed. Drying under infrared light gave compound 2 white solids. The data is shown in Table 4 below:

Table 4

Numbering	Alkali	Temperature (°C)	Yield (%)	HPLC purity (%)
1	Sodium hydride	5	81	97
2	Potassium hydride	5	78	98
3	Barium carbonate	5	56	98
4	Sodium methoxide	5	twenty three	80
5	Sodium ethoxide	5	34	85
6	Sodium tert-butoxide	5	60	89
7	Potassium tert-butoxide	5	67	92
8	Sodium hydride	30	75	97
9	Sodium hydride	-5	33	98

In summary, the method of the present invention uses a cheap and readily available raw material, and after several simple reactions, dihydroisoindole derivatives and the like can be obtained, and have high yield and purity. At the same time, in the method of the invention, the use of heavy metals is not involved, the problem of heavy metal residues existing in the preparation route is eliminated, and the safety of the final product as a medicine is improved.

Claims (10)

1. A method for preparing a compound of formula (I), characterized in that it comprises the following steps:

   

   among them,

   A represents O or NH;

   When A represents O, PG represents a hydroxy protecting group; when A represents NH, PG represents an amino protecting group;

   R ₁ and R _{2 are} independently selected from C ₁ -C ₆ alkyl;

   (1) using a compound of the formula (VII) as a starting material, protecting an amino group or a hydroxyl group to prepare a compound of the formula (VI);

   (2) reacting a compound of the formula (VI) with a lithiation reagent, and then adding a formylating reagent to prepare a compound of the formula (V);

   (3) reducing a formyl group of the compound of the formula (V) to a hydroxyl group with a reducing agent to prepare a compound of the formula (IV);

   (4) preparing a compound of the formula (I) from a compound of the formula (IV);

   The hydroxy protecting group is an ether hydroxy protecting group or an ester hydroxy protecting group, preferably a methoxymethyl group;

   The amino protecting group is an alkyl-based amino protecting group, an amide-based amino protecting group or an imine-based amino protecting group, preferably a pivaloyl group.
2. The method of claim 1 wherein R _{1 is} selected from a linear alkyl group of C ₁ , C ₂ or C ₃ .
3. The method according to claim 1 or 2, wherein R _{2 is} selected from the group consisting of methylene groups.
4. The method according to any one of claims 1 to 3, wherein in the step (2), the lithiation reagent is n-butyllithium, cyclohexyllithium, sec-butyllithium or t-butyllithium; n-Butyllithium;

   The formylating agent is N,N-dimethylformamide, ethyl formate or isopropyl formate;

   The reaction temperature is -100 ° C to 50 ° C, preferably -80 ° C to 30 ° C, more preferably -80 ° C to -30 ° C.
5. The method according to any one of claims 1 to 4, wherein in the step (3), the reducing agent is sodium borohydride, potassium borohydride or lithium aluminum hydride;

   The reaction temperature is -20 ° C to 30 ° C, preferably -10 ° C to 15 ° C.
6. The method according to any one of claims 1 to 5, wherein when A represents O, said step (4) comprises the steps of:

   

   Wherein X represents Cl, Br, I, MsO or TsO;

   PGa represents an amino protecting group;

   (4a-1) using the compound of the formula (IVa) as a starting material, the reaction is prepared to obtain the compound of the formula (IIIa);

   (4a-2) using the compound of the formula (IIIa) as a starting material, in the presence of an organic base, reacting with Pga-NH ₂ to obtain a compound of the formula (IIa);

   (4a-3) Deprotection of the amino group provides the compound of formula (I).
7. The method according to claim 6, wherein X represents Cl or Br, and in the reaction of the step (4a-1), the halogenating reagent used is dichlorosulfoxide, sulfuryl chloride, phosphorus trichloride, pentachlorobenzene. Any of phosphorus, oxalyl chloride, phosphorus tribromide, and phosphorus pentabromide;

   In the reaction of the step (4a-2), the reaction temperature is 0 ° C to 50 ° C, preferably 20 ° C to 50 ° C; the organic base is selected from the group consisting of triethylamine, N-methylmorpholine, diisopropyl Any one or more of ethylamine;

   Pga is benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl or 4-methoxybenzyl.
8. The method according to any one of claims 1 to 5, wherein when A represents NH, said step (4) comprises the steps of:

   

   Wherein X represents Cl, Br, I, MsO or TsO;

   (4b-1) using the compound of the formula (IVb) as a starting material, the reaction is prepared to obtain the compound of the formula (IIIb);

   (4b-2) using the compound of the formula (IIIb) as a starting material, in the presence of an inorganic base, in the intramolecular reaction to prepare a compound of the formula (IIa);

   (4b-3) Deprotection of the amino group provides the compound of formula (I).
9. The method according to claim 8, wherein X represents Cl or Br, and in the reaction of the step (4b-1), the halogenating reagent used is thionyl chloride, sulfuryl chloride, phosphorus trichloride, pentachlorobenzene. Phosphorus, oxalyl chloride, phosphorus tribromide, phosphorus pentabromide; the reaction temperature is 0 ° C ~ 50 ° C, preferably 15 ° C ~ 50 ° C;

   In the step (4b-2), the inorganic base is selected from any one or more selected from the group consisting of sodium hydride, potassium hydride, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium t-butoxide, and potassium t-butoxide; The reaction temperature is -5 ° C to 100 ° C, preferably 0 ° C to 30 ° C.
10. Preparation of the compound of the formula (I): a compound of the formula V as defined in claims 1 to 3, a compound of the formula (VI).