WO2024017150A1 - Method for synthesizing deucravacitinib - Google Patents

Abstract

Provided in the present application is a method for synthesizing deucravacitinib. The method comprises: subjecting the compound of formula (I) to chlorination and to electrophilic substitution with the compound of formula (VI) to synthesize the compound of formula (III); then carrying out an amine transesterification reaction on the compound of formula (III) and deuterated methylamine to synthesize the compound of formula (IV); and finally carrying out a coupling reaction on the compound of formula (VII) and the compound of formula (IV) to prepare compound (V). The method for synthesizing a heterocyclic drug intermediate has a simple process, convenient post-treatment, cheap and easily available starting materials, a stable isolated intermediate and easy industrial production.

Description

A kind of synthesis method of deuterated colexitinib Technical field

The present application relates to the field of drug synthesis, specifically, to a method for synthesizing heterocyclic drug active molecules.

Background technique

The specific causes of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are unknown. From medical practice, it is speculated that they are closely related to partial defects in the patient's immune function. Rheumatoid arthritis has a long course, and because most patients have immune dysfunction, patients often die from complications such as cardiovascular disease, infection, and impaired renal function.

Currently, JAK inhibitors are one of the effective treatments for such immune system diseases. Among them, TYK2 is a member of the JAK family and plays an important role in mediating the signaling of pro-inflammatory cytokines (including IL-12, IL-23 and type I interferon). Its important role in regulating many of the cytokines responsible for inflammatory diseases makes it a popular target for the treatment of inflammatory or autoimmune diseases.

Deucravacitinib (code BMS986165) is Bristol-Myers-Squibb’s experimental new drug for the treatment of moderate to severe plaque psoriasis. It uses the new target TYK2 in the treatment of diseases in related fields. It shows better curative effect. It is also being evaluated for the treatment of a wide range of immune-mediated diseases, including psoriasis, psoriatic arthritis, lupus and inflammatory bowel disease.

technical problem

Regarding its pharmaceutically active molecules, there are few reports on related synthesis patents at home and abroad. The main reported synthesis route is Bristol-Myers Squibb, of which the first-generation synthesis route is as follows (WO2014074661):

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The first-generation synthesis route uses A1 hydrolysis, chlorination, condensation of deuterated methylamine, and then electrophilic substitution and coupling to obtain the target compound BMS986165. The stability of compounds A3 and A4 in the first-generation route is poor. The chlorine atom at the alpha position of the acyl group of A3 and A4 is easily hydrolyzed; the more expensive reagent deuterated methylamine is used first; the overall yield is low. Many factors cause problems in stable production and material costs in this route.

Its improved commercialization process route is as follows (WO2018183649):

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The process patent WO2018183649 and related research documents Org. Process Res. Dev. 2022, 26, 1202−1222 report the research process of BMS986165. A stable intermediate compound A12 was developed, and the use of zinc acetate was optimized to promote the electrophilic substitution reaction of the A5 compound A12 compound. Intermediates A13 and A14 exist in the form of zinc salts with high yields. The final step uses the high-cost deuterated methylamine raw material to undergo a condensation reaction to obtain the final product BMS986165; placing the high-cost material in the last reaction is beneficial to reducing the overall cost of the final product. However, the disadvantage is that in the last step of the reaction from compound A14 to BMS986165, a large amount of condensing agents and other auxiliaries are used, which makes the purification of the final product more difficult. The yield after purification is only 70~79%. From compound A1, The total yield is 48~65%.

Regarding the main intermediate fragment A5 of its pharmaceutically active molecule, there are few reports on related synthesis patents at home and abroad. The main reported synthesis route is Bristol-Myers Squibb, of which the first-generation synthesis route is as follows (WO2014074661):

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The synthesis of compound A5 is through the methyl protecting group on compound B1 to obtain compound B2, and then through urethane exchange reaction to obtain compound B3, and then through cyclomethylation and hydrogenation reaction to obtain compound A5. Among them, after many studies were conducted on steps B4 to A6, the selectivity could only reach a ratio of 8:2:1 for the methylation of three nitrogen atoms, and the highest isolation yield could only reach 40%.

Its second-generation commercial process route is as follows (WO2018183649):

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The process patent WO2018183649 and related research documents Org. Process Res. Dev. 2022, 26, 1202−1222 report the research process of compound A5. The relevant design idea is to use chlorine atoms as space-occupying protective groups, and the ingenious idea of ring-closing the cyano fragment with formylmethylhydrazine to construct compound A5 through a three-step reaction. However, the commercial price of compound B7 is relatively high. It is also a trisubstituted aryl compound. The selling price of B7 is about 1.5 to 2 times that of compound B1. The overall synthesis route cost is relatively high.

In addition, the existing synthesis conditions for similar compounds also have many unfavorable factors such as harsh reaction conditions and low yields. It is also unknown whether the synthesis conditions of analogues are feasible for the synthesis of compound A5.

For example, the WO2009105500 patent of Schering Company reports that in the following synthetic route, the total yield of the three-step reaction is about 40%.

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For example, Bayer's WO2011045224 patent reports that in the following synthesis route, the total yield of the two-step reaction is about 50%, and it requires a high-temperature reaction above 140°C, which consumes energy and is not conducive to safe production.

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Therefore, exploring a low-cost and high-efficiency method for synthesizing related compounds has practical scientific significance and economic value.

Technical solutions

The purpose of this application is to provide a method for preparing compounds of formula V.

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Among them, the chlorinated reagent is phosphorus oxychloride; the deuterated methylamine is deuterated methylamine free base or deuterated methylamine salt; the coupling reaction condition is a coupling reaction in which transition metal participates in catalysis.

Compound I, which can be prepared through reference documents, is a starting material that undergoes chlorination and electrophilic substitution to obtain compound III. Compound V is then prepared through a total of four steps of chemical reactions such as amine transesterification and coupling reaction. The overall yield is about 55%.

According to conventional understanding, amine ester exchange needs to occur in an alkaline environment, and the boiling point of methylamine compounds is only -6°C. It is a gas at room temperature, and there is a risk of escaping in the reaction solution. It is generally understood that when methylamine and the corresponding aromatic ester are used to complete amine transesterification, the dosage of methylamine or methylamine hydrochloride is generally greatly excessive. For example, in the following synthesis process reported in Pfizer's process research literature ( Organic Process Research and Development , 2012 , vol. 16, # 11, p. 1805-181), the amount of methylamine used is 5 times the molar amount of another reaction substrate. .

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In this solution, since the price of deuterated reagents is relatively high, using a large excess of deuterated methylamine is not a cost-effective solution. Through the exploration of reaction conditions, this application optimized a series of conditions such as reaction solvent, reaction additives, reaction temperature, etc., and found that the usage amount of deuterated methylamine can be effectively reduced by adding organic bases.

On the other hand, the present application provides a method for obtaining compounds of formula VI by reducing compound X-a with cheap metals:

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Among them, R1 is the protective group of hydroxyl group, and R2 is the protective group of ester group. In the prior art, due to the presence of chlorine as a space-occupying atom at the para-position of the methoxy group, only noble metal catalysts (such as palladium/carbon, palladium hydroxide, platinum oxide, etc.) can be used to catalytically hydrogenate and reduce the nitro group while simultaneously reducing the chlorine atom. After this application has changed the synthesis idea, since there is no chlorine atom, the nitro reduction reaction can be completed with cheaper metals.

In yet another aspect, a method for preparing the compound of formula X is provided.

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Among them, R ¹ is a phenolic hydroxyl group or a methoxy group, and R ² is hydrogen, tert-butoxycarbonyl or a similar protective group that can be removed under acidic conditions.

In another aspect, the present application provides a preparation method for synthesizing the compound of formula VI .

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Compound XI, which can be prepared through the reference document, is the starting material and undergoes a total of five steps of chemical reactions including thio, methylation, condensation, cyclization, and reduction to prepare compound VI. The overall yield is about 65~70%.

beneficial effects

In summary, compared with the prior art, the method for synthesizing deuterated colexitinib compounds of the present application has the following benefits:

(1) The total yield of the overall route is close to the commercial route reported today, but the total material cost of the process is about 20% lower. Among them, the starting materials are lower in cost than the current commercial route, and no precious metal catalyst is used in the reduction step;

(2) Use amine ester exchange reaction to complete carboxylic acid amidation. Conventional amine ester exchange requires a large excess of amine source. However, after the conditions of this reaction are optimized, the amount of amine can be effectively controlled and the use of more expensive amide condensation reagents can be avoided. The input-output ratio of materials is higher;

(3) The operation is simple and the process is easy for industrial scale-up production. There is no high-temperature or high-pressure reaction, the separation intermediate is stable, the reagents used to prepare Compound V are cheap and easy to obtain, and the operation is continuous, which is conducive to improving production efficiency.

Embodiments of the invention

The embodiments of the present application are described below through examples. Those skilled in the art should realize that these specific examples only illustrate the implementation technical solutions selected to achieve the purpose of the present application, and do not limit the technical solutions. Based on the teachings of this application, it is obvious to improve the technical solution of this application in combination with the existing technology, and they all fall within the scope of protection of this application.

The implementation conditions used in the examples can be further adjusted according to specific requirements. Unspecified implementation conditions are usually the conditions in routine experiments.

Example 1

First add compound 1 (80 g, 1 eq) and DMF (800 mL) to the reaction flask, start stirring, add K ₂ CO ₃ (110g, 2.0 eq) and MeI (115g, 2.0 eq) respectively, and raise the temperature to 60 °C. , incubate the reaction for 1 h, take samples for control, add 20 vol ice water to the reaction solution to quench, stir for 10 min, filter, and wash the solid with water (4 x 5 vol); collect the filter cake and send it to a vacuum oven for drying at 50 °C to obtain The product of compound 2 was 71.5 g, and the yield was 83%.

The NMR data of compound 2 are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (dd, J = 7.8, 1.8 Hz, 1H), 7.91 (dd, J = 8.1, 1.8 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 4.01 (s, 3H), 3.97 (s, 3H).

Example 2

Prepare a clean and dry three-necked flask, add 7 N NH ₃ ·MeOH (600mL) and compound 2 (60 g, 1 eq) under an ice-water bath, stir to dissolve, then add NH ₃ ·H ₂ O (240mL), and heat to Stir at room temperature and react overnight. The reaction solution is concentrated until there is no obvious fraction. Water (900 mL) is added dropwise to dilute, filtered, and washed with water to obtain 44.0 g of compound 2 product, with a yield of 78.9%. The aqueous phase of the filtrate is extracted with EA (3* 300 mL), the combined organic phases were washed with 300 ml saturated brine, and concentrated to obtain 6.9 g of compound 2 product, with a yield of 12.4%, and a total yield of 91.3%.

The NMR data of compound 3 are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (dd, J = 7.8, 1.8 Hz, 1H), 7.97 (dd, J = 8.0, 1.8 Hz, 1H), 7.37 (t, J = 8.0 Hz, 2H), 4.03 (s, 3H).

Example 3

Compound 3 (10.0 g, 1.0eq) was added to THF (100mL), Lawson's reagent (12.37g, 0.6eq) was added in batches, refluxed at 70 °C for 1 h, concentrated to remove THF, and saturated NaHCO ₃ (100mL) solution was added , then extracted with EtOAc (2 x 100mL), concentrated to obtain a crude product, slurried with a mixed solvent of EtOH/H ₂ O = 50mL/17mL, and dried under vacuum to obtain 10.3g of compound 4 product, with a yield of 95.2%.

The NMR data of compound 4 are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42 (dd, J = 8.0, 1.8 Hz, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.88 (dd, J = 8.1, 1.8 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 3.99 (s, 3H).

Mass spectrum data of compound 4: [M+H] ⁺ =213.0.

Example 4

Compound 4 (0.5 g, 1.0 eq) was added to acetone (5 mL), Mel (0.86 g, 2.5 eq) was added dropwise, and stirred at room temperature. A mixture of compound 5 and compound 6 was generated. The HI salt of the product was concentrated to obtain a total of 0.90 g, the subsequent steps are calculated based on the 100% yield of this step. The presence of HI acid caused the removal of part of the anisole.

Mass spectrum data of compound 5: [M+H] ⁺ =213.0.

Mass spectrum data of compound 6: [M+H] ⁺ =227.0 .

Example 5

The HI salt (0.16g) of the mixture of compound 5 and compound 6 obtained above was added to pyridine (1 mL), followed by the addition of Boc-methylhydrazine compound 7 (0.13g, 2.0 eq), and stirring was continued at room temperature overnight. It showed that compound 8 and compound 9 were produced, and the crude product was concentrated and fed directly to the next step.

Mass spectrum data of compound 8: [M+H] ⁺ =269.0.

Mass spectrum data of compound 9: [M+H] ⁺ =311.1.

Example 6

The mixture of compound 8 and compound 9 obtained above was added to HCOOH (2.6 mL), and the reaction was continued at 100 °C for 2 h. A mixture of compound 10 and compound 11 was obtained. The mixture was concentrated to obtain a mixture of products, which was directly added to the next step.

Mass spectrum data of compound 10: [M+H] ⁺ =235.2.

Mass spectrum data of compound 11: [M+H] ⁺ =221.2.

Example 7

The mixture of compound 10 and compound 11 obtained above was added to DMF (3 mL); anhydrous K ₂ CO ₃ (0.32 g, 5 eq) was added, the pH was controlled to >8, MeI (0.16 g) was added dropwise, and the temperature was raised to 45 °C for 2 h, add water (20 mL), extract three times with MTBE (3 * 20 mL), combine the organic phases, wash once with water, and concentrate to obtain 0.09 g of compound 10 product, with a yield of 81%.

The NMR data of compound 10 are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (dd, J = 7.9, 1.8 Hz, 1H), 8.15 (s, 1H), 7.80 (dd, J = 8.0, 1.8 Hz, 1H ), 7.30 (d, J = 8.0 Hz, 1H), 4.03 (s, 3H), 3.94 (s, 3H).

Mass spectrum data of compound 10: [M+H] ⁺ =235.2.

Example 8

Prepare a clean and dry reaction flask; add compound 10 (1 g, 1 eq), EtOH (30 vol), Pd/C (0.25 g), replace with hydrogen three times; stir the reaction for 1.5 h at room temperature, filter, and use the filter cake Rinse with a small amount of EtOH and concentrate to obtain the crude product. Column chromatography (silica gel, EA/heptane=30-100%) obtains 0.74 g of light yellow solid compound 12 product, with a yield of 84.8%.

The NMR data of compound 12 are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.34 (dd, J = 7.8, 1.6 Hz, 1H), 6.99 (t, J = 7.8 Hz, 1H), 6.82 (dd, J = 7.8, 1.6 Hz, 1H), 3.98 (s, 3H), 3.77 (s, 3H).

Mass spectrum data of compound 12: [M+H] ⁺ =205.0.

Example 9

Prepare a clean and dry reaction bottle, add L914-124 (1.0 g, 1 eq), EtOH (30 vol), Raney Ni (0.25 g), replace with hydrogen three times, stir the reaction at room temperature overnight, filter to remove the catalyst, and filter the cake. Rinse with a small amount of EtOH, collect the filtrate, and concentrate to obtain 0.79g of compound 12 product, with a yield of 90.0%.

Example 10

Prepare a clean and dry reaction flask, add compound (0.5g g, 1 eq), add EtOH (5mL) and AcOH (5mL), add reduced iron powder (0.6g), heat to 70-80 °C, react for 3h, concentrate and remove For ethanol and acetic acid, add Na2CO3 aqueous solution to adjust the pH to >9, add EtOAc (10mL) for extraction, filter to remove insoluble matter, separate the liquids, extract the water phase twice with EtOAc (5mL*2), combine the organic phases, and concentrate to obtain 0.37g of the product. The yield is 85%.

Example 11

Compound 4 (8.0 g, 1.0 eq) was added to acetone (25 mL), Me ₂ SO ₄ (4.68 g, 3.5 eq) was added dropwise, the temperature was raised to 35 °C overnight, and concentrated to obtain compound 5 sulfate, using n-heptane After beating, 11.6 g of compound 5 sulfate solid product was obtained, with a yield of 95%.

The NMR data of compound 5 are as follows: ¹ H NMR (400 MHz, DMSO-d6) δ 8.24 (dd, J = 8.2, 1.7 Hz, 1H), 7.91 (dd, J = 7.8, 1.7 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.36 – 6.85 (m, 1H), 3.88 (s, 3H), 2.84 (s, 3H).

Example 12

The crude sulfate of compound 5 in the previous step (0.43g) was added to pyridine (3 mL), then Boc-methylhydrazine compound 7 (0.39g) was added, stirring at room temperature was continued overnight, concentrated to obtain the crude product, and added to HCOOH (6.0 mL ), raise the temperature to 100 °C and continue the reaction for 2 h, concentrate to obtain the crude product, and obtain 0.26g of compound 10 by column chromatography, with a yield of 84%.

The NMR data of compound 10 are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (dd, J = 7.9, 1.8 Hz, 1H), 8.15 (s, 1H), 7.80 (dd, J = 8.0, 1.8 Hz, 1H ), 7.30 (d, J = 8.0 Hz, 1H), 4.03 (s, 3H), 3.94 (s, 3H).

Mass spectrum data of compound 10: [M+H] ⁺ =235.2.

Comparative Example 13

Compound 4 (0.13g) and compound 13 (1.19g, 26eq) were added to the reaction bottle, and the temperature was raised to 110°C for reaction. HPLC showed that 55% of the raw materials remained and only about 7% of the product was produced.

Comparative Example 14

Add compound 3 (1.0eq, 20.0g), ethyl acetate (200 mL), and pyridine (33.2g) to a clean and dry three-necked flask. Control the temperature at 10~20°C, add TFAA (32.0g) dropwise, and complete the dropwise addition. After the reaction, the temperature is controlled at 10~20°C. After the reaction is complete, add 10% NaCl (80mL) and wash once. The aqueous phase is extracted with EtOAc (60mL*2). Combine the organic phases and add 0.1N hydrochloric acid (60mL) and NaCl (20mL). Wash once, concentrate and dry 17.2g of compound 14 product, yield 94.8%.

The NMR data of compound 14 are as follows: ¹ H NMR (400 MHz, DMSO-d6) δ 8.28 (ddd, J = 8.2, 1.6, 0.7 Hz, 1H), 8.18 (ddd, J = 7.8, 1.7, 0.8 Hz, 1H), 7.58 – 7.47 (m, 1H), 4.09 (d, J = 0.7 Hz, 3H).

Mass spectrum data of compound 14: [M+H] ⁺ =179.1.

Comparative Example 15

Add THF (6mL) and 2.4eq potassium tert-butoxide (0.76g, 2.4eq) into the reaction bottle, cool to 0~10°C, and add compound 14 (0.5g, 1.0 eq) and compound 13 (0.48g, 2.3 eq) THF (4mL) solution, after adding it, react at a controlled temperature of 0~10°C. HPLC shows that the reaction system is complex, the color of the reaction solution turns dark brown, and the reaction fails.

Comparative Example 16

Add absolute ethanol (10 mL) and 1.4-dioxane (5 mL) to the three-necked flask, add compound 14 (1.0 eq, 1.0 g), cool to 0~10°C, and pass dry HCl gas for 24 hours. HPLC still shows There is 30% of the raw materials remaining, and the extension time is no longer advanced. The product peak area is 53%. Concentrate and evaporate with EtOH to obtain 1.0g of the crude product of compound 15; continue to add pyridine (10ml) and compound 7 (0.88g), and stir at room temperature overnight. HPLC showed that there was 32% of the product peak area. Concentrate to obtain the crude product of compound 8, then add HCOOH (10 ml), raise the temperature to 100 °C and continue the reaction for 2 hours. HPLC showed that there was only 30% of the product peak area.

Comparative Example 17

Add DMF-DMA (121.5g) and compound 3 (20 g, 1 eq) to the reaction bottle, raise the temperature to 95°C, and react for 30 minutes; concentrate until there is no obvious fraction, add ethanol (100mL) to dissolve and set aside; another reaction bottle , add ethanol (400mL) and acetic acid (100mL) at a temperature of 0-10°C, add hydrazine hydrate (64.0g, 10 eq) dropwise, stir evenly until there is no white smoke, add the hydrazine solution dropwise to the ethanol solution prepared above in, raise the temperature to room temperature, stir the reaction for 4 hours, concentrate to remove ethanol, add water (200 mL), stir for 30 minutes, filter, and rinse the filter cake with a small amount of water to obtain the wet product of compound 16; control the temperature at 0-10°C. Add the wet compound 16 to DMF (400 mL), then add K ₂ CO ₃ (42.3g), stir evenly, add Mel (21.3g) dropwise, stir at room temperature overnight, control the temperature at 0-10°C, add water ( 400mL) to quench the reaction, extract with EtOAc (200mL*2), combine the organic phases, wash the organic phase with saturated brine, concentrate to obtain the crude product as a yellow oily liquid, add MTBE (100mL) to beat and refine to obtain the product compound 10, a total of 7.5g. The yield is 31.5%.

Example 18

Add Compound I (50 g, 1.0eq) and MeCN (250 ml) to a clean and dry 1 L three-necked flask, control the temperature at 0~10°C, add POCl3 (108.24 g, 2.6 eq) dropwise, and stir after the addition is complete. 30mins, continue to control the temperature at 0~15°C, slowly add TEA (49.46 g, 1.8 eq) dropwise; after the dripping is completed, raise the temperature to 60~65°C, keep the reaction warm, cool the reaction solution to 0~10°C, and slowly add it dropwise 100 ml water, then add 400 ml phosphate buffer solution and 600 ml methyl tert-butyl ether, stir at 0~10°C for 10~20 minutes; let stand, separate the liquids, and wash the organic phase twice with 400 ml phosphate buffer solution. Wash once with 200 ml of water, concentrate under reduced pressure until there is no flow to obtain 58.3g of product, and feed directly to the next step.

The NMR data of compound II are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (s, 1H), 4.54 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H).

Mass spectrum data of compound II: [M+H] ⁺ =221.0, 223.0, 225.0.

Example 19

Add compound VI (5.0 g, 1 eq) and DMF (30 ml) to a clean and dry reaction flask, then add TMP (5.19 g, 1.5 eq) and compound I (7.04 g, 1.3 eq), heat to 110°C and stir. The reaction was carried out overnight. After the reaction was complete, water (90 ml) was slowly added dropwise, the solid was precipitated, and filtered with suction. The filter cake was rinsed with 2 vol of water and dried with air to obtain 7.6 g of product, with a yield of 79.8%.

The NMR data of compound III are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.93 (s, 1H), 8.15 (s, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.33 – 7.23 (m, 1H), 7.07 (s, 1H), 4.57 (q, J = 7.1 Hz, 2H), 4.03 (s, 3H), 3.78 (s, 3H), 1.51 (t , J = 7.1 Hz, 3H).

Mass spectrum data of compound III: [M+H] ⁺ =389.2.

Example 20

Add EtOH (10 ml), 1.1 eq deuterated methylamine hydrochloride (0.20 g, 1.1eq) and DBU (0.48 g, 1.2eq) into a clean and dry sealed tube, stir for 10 minutes, then add compound III (1.00 g, 1.0eq), react at room temperature overnight; after the reaction is complete, the reaction solution is concentrated under reduced pressure until there is no flow. Add ethyl acetate (20mL) and n-heptane (30mL) to the concentrate, beat for 2h, suction filter, and use 15 ml of the solid Beat with water once, filter and dry to obtain 0.82g of product, with a yield of 84.8%.

The NMR data of compound IV are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.88 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.30 – 7.22 (m, 1H), 6.96 (s, 1H), 4.03 (s, 3H), 3.80 (s, 3H).

Mass spectrum data of compound IV: [M+H] ⁺ =377.1.

Example 21

In turn, compound IV (0.40g, 1.0eq), compound VII (0.23g, 2.5eq), XantPhos (0.115g, 0.18eq), dioxane (5ml) and Cs ₂ CO ₃ (0.85g, 2.5eq) Add it to the reaction bottle, replace it with nitrogen three times, add the catalyst Pd ₂ (dba) ₃ (0.12g, 0.1eq), continue to replace it with nitrogen three times, raise the temperature to 95~105°C, keep the reaction for 2.5 hours, the reaction is complete, and concentrate to obtain the crude product. Column chromatography obtained 0.36g of the product, with a yield of 80.1%.

The NMR data of compound V are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.99 (s, 1H), 8.63 (s, 1H), 8.18 (s, 1H), 8.10 (d, J = 0.4 Hz, 2H), 7.81 (dd, J = 6.3,1.4 Hz, 1H), 7.51(dd, J = 6.3,1.4 Hz, 1H), 7.33-7.20(m, 7H), 4.01(d, J = 0.3 Hz, 3H),3.82 (s, 3H), 1.73-1.60(m, 1H), 1.16-1.06(m, 2H), 0.97-0.84(m, 2H).

Mass spectrum data of compound V: [M+H] ⁺ =426.2.

This application includes but is not limited to the above embodiments. Any equivalent substitution or partial improvement made under the spirit of this application will be deemed to be within the protection scope of this application.

Claims (10)

1. A method for preparing a compound of formula V, which includes: (1) the compound of formula I is synthesized by chlorination and electrophilic substitution with a compound of formula VI to obtain a compound of formula III; (2) the compound of formula III and deuterated methylamine are synthesized in alkaline The compound of formula IV is synthesized by amine transesterification reaction under the condition of auxiliary agent; (3) the compound of formula VII and the compound of formula IV are subjected to coupling reaction conditions to prepare compound V;

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2. As claimed in claim 1, the chlorinated reagent is phosphorus oxychloride.
3. As claimed in claim 1, the compound of formula III and deuterated methylamine undergo an amine transesterification reaction under the condition of an alkaline auxiliary agent to synthesize the compound of formula IV, wherein the deuterated methylamine is deuterated methylamine free base or deuterated methylamine salt. Form participates in reaction.
4. The alkaline auxiliary conditions as claimed in claim 3, wherein the alkaline auxiliary is DBU, DMAP, TEA, DIPEA.
5. As claimed in claim 1, the compound of formula VII and the compound of formula IV are subjected to coupling reaction conditions, wherein the coupling reaction condition is a coupling reaction catalyzed by transition metal participation.
6. A method of reducing compound X-a under cheap metal conditions to obtain compounds of formula VI:

   , where the cheap metal is Raney nickel/hydrogen or reduced iron powder conditions.
7. A method for preparing a compound of formula

   , where R ¹ is hydroxyl or methoxy, and R ² is hydrogen or a removable nitrogen protecting group.
8. As claimed in claim 7, the base is an organic base, and the R ² group is a tert-butoxycarbonyl group.
9. A low-cost method for preparing compounds of formula VI, which includes the following steps: step 1: preparing compounds of formula Compound VIII-a and methylhydrazine derivatives are synthesized into compounds of formula IX-a under the action of a base. In step 4, compound IX-a is ring-closed under formic acid conditions to prepare compound X-a. In step 5, compound VI is prepared from compound X-a under reducing conditions. ,

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10. Compounds with the following structure can be applied to the synthesis of deuterated colexitinib or its related intermediates:

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