A process for the preparation of a deuterated cediranib intermediate

Abstract

The application provides a preparation method of a deuterium cediranib intermediate, and belongs to the technical field of chemical synthesis. The application first provides a compound shown in formula IA, a salt or a stereoisomer thereof, and then uses the compound shown in formula IA, the salt or the stereoisomer thereof to prepare a deuterium cediranib intermediate shown in formula I. The synthesis method is simple in operation, the raw materials are cheap and easy to obtain, the product has high yield and high purity, and the by-product of methyl isomerization in the key step is less, so that the problem of methyl regioselectivity in the synthesis of the compound shown in formula I in the prior art is overcome, and the method is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of a deucravacitinib intermediate. BACKGROUND

[0002] Deucravacitinib is a high-selectivity JAK inhibitor with an oral liposome structure. After excluding the effects of photosensitizers and neutral methods on the activation of the inhibitor and the influence on leukocytes and the spinal cord, the drug can reduce the side effects of inflammatory factor production and frequent activation of immune cells. It is used for treating moderate to severe psoriasis and rheumatoid arthritis and other autoimmune diseases.

[0003]

[0004] The compound shown in formula I is an important intermediate for synthesizing deucravacitinib. The patent application with the publication number CN104884454A prepares deucravacitinib by taking the compound of formula I as an intermediate, and the synthesis route is as follows:

[0005]

[0006] In the synthesis process of the compound of formula I, the main difficulty lies in the introduction of the methyl group in the 1,2,4-triazole. To solve this problem, the main synthesis routes in the prior art include:

[0007] 1) Selective methylation by using MeI, such as the US patent with the publication number US20220002267A1 and the paper Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165 (J. Med. Chem. 2019, 62 (20), 8973-8995); the route starts from methyl o-nitrobenzoate, has isomerization products, and needs column purification.

[0008] 2) In the form of Pd-catalyzed coupling, such as the international patent application with the publication number WO2021237121A1, which is realized by 3-bromo-1-methyl-1,2,4-thiazole and aryl boronic acid substrates, but the substrates and Pd selected by this route are relatively expensive, and the overall route cost is high.

[0009] 3) Synthesis by ring closure using N-methyl-N-formylhydrazine and cyano substrate under the condition of base, as disclosed in international patent application WO2023064223A1. The key step needs to be completed under strong alkaline conditions, and the reaction yield is low in actual synthesis when the substrate contains a nitro functional group.

[0010] It is of great significance for the synthesis of dacomitinib to provide a method for synthesizing the compound of formula I with high yield, high purity and low cost. SUMMARY

[0011] The purpose of the present application is to provide a method for preparing a dacomitinib intermediate.

[0012] The present application provides a dacomitinib intermediate, which is a compound of formula IA, a salt thereof or a stereoisomer thereof:

[0013]

[0014] wherein,

[0015] R1 is selected from C1-C4 alkyl;

[0016] R2 is selected from hydrogen or tert-butyloxycarbonyl.

[0017] Further, the compound is shown in formula IA1 or formula IA2:

[0018]

[0019] wherein,

[0020] R1 is selected from C1-C4 alkyl;

[0021] Preferably, the compound is shown in formula IA1-1 or formula IA2-1:

[0022]

[0023] The present application also provides a method for preparing the aforementioned dacomitinib intermediate, which comprises the following steps:

[0024] Step 1:

[0025]

[0026] Compound 1 and compound 2 are dissolved in a solvent respectively to prepare a solution, then the solution containing compound 1 is added to the solution containing compound 2, and the reaction is carried out until completion to obtain a reaction liquid, which is purified to obtain a compound of formula IA1.

[0027] Step 2:

[0028]

[0029] reacting the compound of formula IA1 with an acid in a solvent to obtain a reaction solution, purifying the reaction solution to obtain the compound of formula IA2;

[0030] wherein R1 is as defined above.

[0031] Further,

[0032] In step 1, the equivalent ratio of the compound 1 to the compound 2 is 1:0.9-2.0;

[0033] And / or, in step 1, the solvent is methyl tert-butyl ether, diethyl ether or tetrahydrofuran;

[0034] And / or, in step 1, the reaction temperature is -20-20℃, and the reaction time is 0.5-5h;

[0035] And / or, in step 2, the acid is trifluoroacetic acid, hydrochloric acid or glacial acetic acid;

[0036] And / or, in step 2, the mass-volume ratio of the compound of formula IA1 to the acid is 1g:1-10mL;

[0037] And / or, in step 2, the solvent is dichloromethane or toluene;

[0038] And / or, in step 2, the reaction temperature is 10-110℃, and the reaction time is 10-12h;

[0039] Preferably,

[0040] In step 1, the equivalent ratio of the compound 1 to the compound 2 is 1:1.3;

[0041] And / or, in step 1, the solvent is tetrahydrofuran;

[0042] And / or, in step 1, the reaction temperature is 0-5℃;

[0043] And / or, in step 1, the purification comprises the following steps: concentrating the reaction solution, adding an organic solvent and saturated sodium carbonate solution to the concentrate, stirring and washing, separating and collecting the organic phase, dissolving the organic phase in an organic solvent after concentration, washing the organic phase with hydrochloric acid, drying and filtering to obtain the compound of formula IA1; the organic solvent is dichloromethane, methyl tert-butyl ether or ethyl acetate;

[0044] And / or, in step 2, the acid is trifluoroacetic acid;

[0045] And / or, in step 2, the mass-volume ratio of the compound of formula IA1 to the acid is 1g:4mL;

[0046] And / or, in step 2, the purifying comprises the following steps: concentrating the reaction solution, adding an organic solvent and saturated sodium bicarbonate solution in the concentrate, washing after stirring, taking the organic phase, washing with water and saturated brine again, drying and filtering to obtain the compound shown in formula IA2; the organic solvent is dichloromethane, methyl tert-butyl ether or ethyl acetate.

[0047] Further, the preparation method of the compound 1 comprises the following steps:

[0048]

[0049] Step (1): reacting compound 3, base and dimethyl sulfate in a solvent, filtering after the reaction is completed to obtain filtrate, adding base solution to the filtrate to react, adjusting pH to 3-4 by adding acid after the reaction is completed, directly extracting, drying the organic phase, filtering and concentrating to obtain compound 4;

[0050] Step (2): reacting compound 4 and chlorinating agent in a solvent to obtain compound 1;

[0051] Preferably,

[0052] In step (1), the equivalent ratio of compound 3, base and dimethyl sulfate is 1: (2.5-5): (2.5-5);

[0053] And / or, in step (1), the equivalent ratio of compound 3 and base in the base solution is 1: (3-5);

[0054] And / or, in step (2), the equivalent ratio of compound 4 and chlorinating agent is 1: (1.5-3).

[0055] Further,

[0056] In step (1), the solvent is acetone, ethyl acetate or acetonitrile;

[0057] And / or, in step (1), the base is potassium carbonate, sodium carbonate or sodium hydroxide;

[0058] And / or, in step (1), the reaction temperature of compound 3, base and dimethyl sulfate is 50-60℃;

[0059] And / or, in step (1), after the reaction is completed, diatomite is used for filtering to obtain filtrate;

[0060] And / or, in step (1), the base in the base solution is sodium hydroxide or potassium hydroxide;

[0061] And / or, in step (1), the reaction temperature of adding base solution is 20-40℃;

[0062] And / or, in step (1), the acid is hydrochloric acid;

[0063] And / or, in step (1), the solvent used in the extraction is ethyl acetate or dichloromethane;

[0064] And / or, in step (2), the chlorinating agent is dichlorosulfoxide, phosphorus oxychloride or oxalyl chloride;

[0065] And / or, in step (2), the solvent is dichloromethane or toluene;

[0066] And / or, in step (2), the temperature of the reaction is 40-60℃;

[0067] Preferably,

[0068] In step 1, the solvent is acetone;

[0069] And / or, in step 1, the base is potassium carbonate;

[0070] And / or, in step 1, the base in the base solution is sodium hydroxide;

[0071] And / or, in step (1), the solvent used in the extraction is ethyl acetate;

[0072] And / or, in step (2), the chlorinating agent is dichlorosulfoxide;

[0073] And / or, in step (2), the solvent is dichloromethane.

[0074] Further, the method for preparing the compound 2 comprises the following steps:

[0075]

[0076] In a solvent, a base is added to the compound 5, and the pH is adjusted to 10-12, a Boc2O solution is dropped in after the reaction, the reaction solution is extracted, and the organic phase after extraction is dried to obtain the compound 2;

[0077] Preferably,

[0078] The solvent is water;

[0079] And / or, the equivalent ratio of the compound 5, the base and Boc2O is 1:(1.1-1.5):(1.2-1.5);

[0080] And / or, the base is any one or a mixture of two of sodium carbonate, potassium carbonate, sodium bicarbonate and sodium hydroxide;

[0081] And / or, the pH adjustment uses sodium hydroxide;

[0082] And / or, the solvent of the Boc2O solution is tetrahydrofuran;

[0083] And / or, the temperature when the Boc2O solution is dropped is 0-5℃;

[0084] And / or, the temperature of the reaction is 20-30℃, and the reaction time is 10-20h;

[0085] And / or, the solvent used in the extraction is dichloromethane, methyl tert-butyl ether or ethyl acetate;

[0086] More preferably,

[0087] The equivalent ratio of the compound 5, the base and Boc2O is 1:1.1:1.2;

[0088] And / or, the base is sodium bicarbonate;

[0089] And / or, the solvent used in the extraction is ethyl acetate.

[0090] The application also provides the use of the aforementioned deucalixitin intermediate in the preparation of the compound shown in formula I and / or deucalixitin;

[0091]

[0092] The application also provides a method for preparing the compound shown in formula I, which comprises the following steps:

[0093]

[0094] Step a: the compound shown in formula IA, formamidinium acetate, acetic acid and anhydride are reacted in a solvent to obtain the compound shown in formula IC;

[0095] Step b: the compound shown in formula IC and hydrogen are reacted under the action of a catalyst to obtain the compound shown in formula I;

[0096] R1, R2 are as described above.

[0097] Further,

[0098] In step a, the equivalent ratio of the compound shown in formula IA, formamidinium acetate and anhydride is 1:(2-5):(0-0.5);

[0099] And / or, in step a, the mass-volume ratio of the compound shown in formula IA and acetic acid is 1g:5-10mL;

[0100] And / or, in step a, the solvent is toluene, acetonitrile or tetrahydrofuran;

[0101] And / or, in step a, the temperature of the reaction is 100-120℃, and the reaction time is 15-72h;

[0102] And / or, in step a, the obtained compound of formula IC is purified before, and the purification comprises the following steps: cooling the reaction solution to 0-4 DEG C, adding the reaction solution into excess saturated sodium carbonate aqueous solution, collecting the organic layer by liquid separation, washing the organic phase after extraction, drying and concentrating;

[0103] And / or, in step b, the solvent is methanol.

[0104] And / or, in step b, the catalyst is Pd / C or Raney Ni.

[0105] And / or, in step b, the mass ratio of the compound of formula IC and the catalyst is 1:0.1-0.5.

[0106] And / or, in step b, the reaction temperature is 40-60 DEG C, and the reaction time is 10-20 h.

[0107] And / or, in step b, the reaction pressure is 2-10 MPa.

[0108] Preferably,

[0109] In step a, the equivalent ratio of the compound of formula IA, formamidine acetate and anhydride is 1:2:(0.1-0.5).

[0110] And / or, in step a, the mass-volume ratio of the compound of formula IA and acetic acid is 1g:5mL.

[0111] And / or, in step a, the solvent is toluene.

[0112] And / or, in step a, the anhydride is acetic anhydride.

[0113] And / or, in step b, the catalyst is Pd / C.

[0114] Compared with the prior art, the present application has the following beneficial effects:

[0115] The method for synthesizing the deuterium crenoxin intermediate of the present application starts from commercially available 3-nitrosalicylic acid, and the entire route does not involve unconventional materials, the rapid construction of 1,2,4-triazole is realized by using formamidine, the operation is easy to obtain, and a methyl group is carried in the ring formation process, thereby avoiding the problem of regioselectivity when the triazole is first constructed and then the methyl group is introduced.

[0116] In summary, the present application provides a method for synthesizing the deuterium crenoxin intermediate of formula I, the synthetic method of the present application is simple to operate, the raw materials used are cheap and easy to obtain, the product has high yield and high purity, the key step of methyl isomerization has less by-products, the problem of methyl regioselectivity in the synthesis of the compound of formula I in the prior art is overcome, and the method is suitable for industrial production.

[0117] Obviously, according to the above content of the present application, other various forms of modification, replacement or change can be made according to the common technical knowledge and usual means in the art without departing from the above basic technical idea of the present application.

[0118] The above content of the present application will be further explained in detail through the specific embodiments in the form of examples. However, it should not be understood that the above subject matter of the present application is limited to the following examples. Any technology realized based on the above content of the present application belongs to the scope of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0119] Figure 1 H NMR spectrum of the compound prepared in step 4. 1 H NMR spectrum of the compound prepared in step 4.

[0120] Figure 2 H NMR spectrum of the compound prepared in step 4. 1 H NMR spectrum of the compound prepared in step 4. DETAILED DESCRIPTION

[0121] The raw materials and equipment used in the specific embodiments of the present application are known products, which are obtained by purchasing commercially available products.

[0122] The optimal synthesis route of the deuterium canrexibine intermediate of the present application is as follows:

[0123]

[0124] Preparation of the deuterium canrexibine intermediate of the present application

[0125] Step 1:

[0126]

[0127] A 3000 mL three-necked flask with mechanical stirring and thermometer was prepared, and 3-nitrosalicylic acid (200 g, 1.09 mol, 1 eq.) and acetone (2000 mL, 10V) were added to the three-necked flask at room temperature, and then potassium carbonate (377.37 g, 2.73 mol, 2.5 eq.) and dimethyl sulfate DMS (344.40 g, 2.73 mol, 2.5 eq.) were added in sequence; under stirring, the temperature was increased to 55°C, and TLC (petroleum ether: ethyl acetate = 5:1, Rf=0.5) detection showed no footboard point, indicating that the reaction was complete. The reaction solution was cooled to room temperature, filtered with diatomite, and the filter cake was washed with acetone (100 mL x 3), and the combined filtrate was collected. f

[0128] ​Add approximately 1000 mL of an aqueous solution containing sodium hydroxide (174.74 g, 4.37 mol, 4 eq.) to the filtrate; stir at room temperature for approximately 1.5 h; and perform TLC (petroleum ether: ethyl acetate = 5:1). f The disappearance of the point at 0.5 indicates that the reaction is complete. Finally, 6N HCl was added to the reaction solution to adjust the pH to 3-4. The solution changed from orange-red to pale yellow and produced a large amount of precipitate. Ethyl acetate (1L × 3) was added, stirred to dissolve the precipitate, and extracted. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. A pale yellow solid was obtained, dried in a 60℃ oven, and weighed to obtain 205g (yield 95%, purity 99.78%).

[0129] Step 2:

[0130]

[0131] Add 200 g (1.01 mol, 1.0 eq.) of 2-methoxy-3-nitrobenzoic acid prepared in step 1 to a 3 L three-necked flask, and add dichloromethane (600 mL, 3V); stir continuously at room temperature, and slowly add thionyl chloride (181.04 g, 1.52 mol, 1.5 eq.); then heat to reflux (45 °C) and maintain the reaction at this temperature for 8 h. Take a small amount of the reaction solution, dilute with ethanol, and perform TLC (ethanol, ethyl acetate as the developing solvent, RL). f =0.3) After the reaction is complete, the reaction solution is cooled to room temperature and concentrated for later use.

[0132] Step 3:

[0133]

[0134] Methylhydrazine sulfate (200 g, 1.39 mol, 1.0 eq.) was added to a three-necked flask containing 900 mL of water. NaHCO3 (128.21 g, 1.53 mol, 1.1 eq.) was added in portions while stirring. Then, 150 mL of 40% sodium hydroxide solution was slowly added at 0–5 °C to adjust the pH to 10. Finally, Boc2O (363.37 g, 1.66 mol, 1.2 eq.) was dissolved in THF (1 L, 5V) and added dropwise to the three-necked flask while maintaining the temperature at 0–5 °C. The ice-water bath was removed, and the mixture was stirred overnight. The next day, THF in the reaction solution was concentrated, and ethyl acetate (400 mL) was added and the mixture was stirred and extracted separately. The mixture was then extracted twice more with ethyl acetate (2*1L, 5V). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 171 g of white liquid with a yield of 66.7% and a purity of 79%. It can be used directly in the next step without further purification.

[0135] Step 4:

[0136]

[0137] Preparation Implementation Case 1 (Optimal Scheme): Freshly prepared 1-tert-butoxycarbonyl-1-methylhydrazine (51.85 g, 301.50 mmol, 1.3 eq.) was dissolved in a three-necked flask containing THF (363 mL, 7 V) and cooled to 0 °C using an ice-salt bath for later use; simultaneously, 2-methoxy-3-nitrobenzoyl chloride (50 g, 231.92 mmol, 1 eq.) was dissolved in THF (150 mL, 3 V) and transferred to a dry constant pressure funnel; under controlled temperature of 0-5 °C, the THF solution of 2-methoxy-3-nitrobenzoyl chloride was added dropwise to the three-necked flask containing the THF solution of 1-tert-butoxycarbonyl-1-methylhydrazine, taking approximately 3 hours in total. After the addition is complete, the reaction solution is concentrated. Then, ethyl acetate (250 mL, 5V) is added to the concentrated mixture, followed by the slow addition of saturated sodium carbonate solution (450 mL). The mixture is stirred and washed, and the organic phase is separated and collected. The aqueous phase is then extracted with ethyl acetate (200 mL * 2). The collected organic phases are combined and concentrated to obtain 85 g of a yellow oil. The yellow oil is dissolved in ethyl acetate and washed four times with 2N hydrochloric acid (30 mL). Each wash is followed by extraction with ethyl acetate. The mixture is dried over anhydrous Na2SO4, filtered, and concentrated to obtain 70 g of a yellow solid with a yield of 82.57% and a product purity of 98.62%. 1 H NMR (400MHz, CDCl3) δ = 9.12 (s, 1H), 8.24 (dd, J = 8.0, 2.0Hz, 1H), 7.93 (dd, J = 7 .9, 1.9Hz, 1H), 7.34 (t, J = 7.9Hz, 1H), 4.04 (s, 3H), 3.19 (s, 3H), 1.44 (s, 9H).

[0138] Preparation Implementation Case 2 (Replacement of Solvent): Freshly prepared 1-tert-butoxycarbonyl-1-methylhydrazine (30 g, 205.22 mmol, 1.3 eq.) was dissolved in a three-necked flask containing methyl tert-butyl ether (210 mL, 7 V) and cooled to 0 °C using an ice-salt bath for later use; simultaneously, 2-methoxy-3-nitrobenzoyl chloride (34.03 g, 157.86 mmol, 1 eq.) was dissolved in methyl tert-butyl ether (102 mL, 3 V) and transferred to a dry constant pressure funnel; under controlled temperature of 0-5 °C, the methyl tert-butyl ether solution of 2-methoxy-3-nitrobenzoyl chloride was added dropwise to the three-necked flask containing the methyl tert-butyl ether solution of 1-tert-butoxycarbonyl-1-methylhydrazine, taking approximately 2 hours in total. After the addition is complete, the reaction solution is concentrated. Then, ethyl acetate (170 mL, 5V) is added to the concentrated mixture, followed by the slow addition of saturated sodium carbonate solution (270 mL). The mixture is stirred and washed, and the organic phase is separated and collected. The aqueous phase is then extracted with ethyl acetate (150 mL * 2). The collected organic phases are combined and concentrated to obtain 51 g of yellow oil. The yellow oil is dissolved in ethyl acetate and washed four times with 2N hydrochloric acid (18 mL). Each wash is followed by extraction with ethyl acetate. The mixture is dried over anhydrous Na2SO4, filtered, concentrated, and then passed through a column to obtain 20 g of yellow solid. The yield is 39.0%, and the product purity is 98.5%.

[0139] The total yield of the product (yellow solid) obtained in steps 1 to 4 above was 24.71-52.32%. The total yield was 52.32% and the purity was 98.62% when using Example 1, and the total yield was 24.71% and the purity was 98.5% when using Example 2.

[0140] Step 5:

[0141]

[0142] Preparation Implementation Case 1 (Optimal Scheme): The starting material 1-tert-butoxycarbonyl-N-[2-(methoxy-3-nitro-benzoyl)amino]-N-methyl-carbamic acid (50 g, 153.70 mmol, 1 eq.) was transferred to a 500 mL three-necked flask. Toluene (250 mL, 5V), formamidine acetate (32.00 g, 307.39 mmol, 2 eq.), acetic acid (250 mL, 5V), and acetic anhydride (1.57 g, 15.37 mmol, 0.1 eq.) were added sequentially. The reaction was carried out at 110 °C for 48 h, at which point the TLC plate showed complete reaction. The mixture was then cooled to 0 °C using an ice-water bath. Simultaneously, a 1 L beaker was prepared and 500 mL of a 1.54 mol / L sodium carbonate aqueous solution was poured in. Under ice bath conditions, the reaction solution was slowly added to an aqueous sodium carbonate solution. After the addition was complete, the organic layer was collected by separation. Ethyl acetate (200 mL * 2) was added for extraction, and the organic phases were combined. The organic phase was washed with saturated sodium carbonate solution until the yellow impurity spots on the TLC plate were removed. After drying and concentration, 22.8 g of yellow solid product was obtained, with a yield of 63.3%.

[0143] Preparation Implementation Case 2 (Increasing Acetic Anhydride Amount): The starting material 1-tert-butoxycarbonyl-N-[2-(methoxy-3-nitro-benzoyl)amino]-N-methyl-carbamic acid (50 g, 153.70 mmol, 1 eq.) was transferred to a 500 mL three-necked flask. Toluene (250 mL, 5V), formamidine acetate (32.00 g, 307.39 mmol, 2 eq.), acetic anhydride (7.85 g, 76.85 mmol, 0.5 eq.), and acetic acid (250 mL, 5V) were added sequentially. The reaction was carried out at 110 °C for 48 h, at which point the TLC plate showed complete reaction. The mixture was then cooled to 0 °C using an ice-water bath. Simultaneously, a 1 L beaker was prepared, and 500 mL of a 1.54 mol / L sodium carbonate aqueous solution was poured in. Under ice bath conditions, the reaction solution was slowly added to an aqueous sodium carbonate solution. After the addition was complete, the organic layer was collected by separation. Ethyl acetate (200 mL * 2) was added for extraction, and the organic phases were combined. The organic phase was washed with saturated sodium carbonate solution until the yellow impurity spots on the TLC plate were removed. After drying and concentration, 19.1 g of yellow solid product was obtained, with a yield of 53.1%.

[0144] Preparation Implementation Case 3 (Replacement of Solvent): The starting material 1-tert-butoxycarbonyl-N-[2-(methoxy-3-nitro-benzoyl)amino]-N-methyl-carbamic acid (50 g, 153.70 mmol, 1 eq.) was transferred to a 500 mL three-necked flask. Tetrahydrofuran (THF) (250 mL, 5V), formamidine acetate (32.00 g, 307.39 mmol, 2 eq.), acetic anhydride (1.57 g, 15.37 mmol, 0.1 eq.), and acetic acid (250 mL, 5V) were added sequentially. The reaction was carried out at 110 °C for 72 h, at which point the TLC plate showed complete reaction. The mixture was then cooled to 0 °C using an ice-water bath. Simultaneously, a 1 L beaker was prepared and 500 mL of a 1.54 mol / L sodium carbonate aqueous solution was poured in. Under ice bath conditions, the reaction solution in the flask was slowly added to an aqueous sodium carbonate solution. After the addition was complete, the reaction solution was concentrated to remove most of the tetrahydrofuran, and the organic layer was collected by separation with ethyl acetate (500 mL, 10V). Then, ethyl acetate (200 mL * 2) was added for extraction, and the organic phases were combined. The organic phase was washed with saturated sodium carbonate solution until the yellow impurity spots on the TLC plate were removed. After drying and concentration, 12.1 g of yellow solid product was obtained, with a yield of 33.6%.

[0145] Preparation Implementation Case 4 (Replacement of Solvent): The starting material 1-tert-butoxycarbonyl-N-[2-(methoxy-3-nitro-benzoyl)amino]-N-methyl-carbamic acid (50 g, 153.70 mmol, 1 eq.) was transferred to a 500 mL three-necked flask. Acetonitrile (250 mL, 5V), formamidinium acetate (32.00 g, 307.39 mmol, 2 eq.), acetic anhydride (1.57 g, 15.37 mmol, 0.1 eq.), and acetic acid (250 mL, 5V) were added sequentially. The reaction was carried out at 110 °C for 72 h, at which point the TLC plate showed complete reaction. The mixture was then cooled to 0 °C using an ice-water bath. Simultaneously, a 1 L beaker was prepared, and 500 mL of a 1.54 mol / L sodium carbonate aqueous solution was poured in. Under ice bath conditions, the reaction solution in the flask was slowly added to an aqueous sodium carbonate solution. After the addition was complete, the solution was transferred to a round-bottom flask, and the reaction solution was concentrated to remove most of the acetonitrile. Ethyl acetate (500 mL, 10V) was added, and the organic layer was collected by separation. Ethyl acetate (200 mL * 2) was then added for extraction, and the organic phases were combined. The organic phase was washed with saturated sodium carbonate solution until the yellow impurity spots on the TLC plate were removed. After drying and concentration, 15 g of yellow solid product was obtained, with a yield of 41.6%.

[0146] Preparation and Implementation Case 5:

[0147] Phase 1:

[0148]

[0149] The starting material, 1-tert-butoxycarbonyl-N-[2-(methoxy-3-nitro-benzoyl)amino]-N-methyl-carbamic acid (45 g, 138.33 mmol, 1 eq.), was dissolved in a round-bottom flask containing DCM (90 mL, 2 V). Trifluoroacetic acid (TFA) (180 mL, 4 V) was added at 10–15 °C. After reacting overnight, the reaction was completed by TLC. After concentrating the reaction solution, ethyl acetate (180 mL, 4 V) was added. The organic phase was washed twice with saturated sodium bicarbonate, then washed once with water and saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give 25.20 g of a white solid, with a yield of 78.8% and a purity of 98.3%.

[0150] Phase Two:

[0151]

[0152] The product obtained in the first stage, 2-methoxy-N'-methyl-3-nitrobenzoylhydrazine (25 g, 111.01 mmol, 1.0 eq.), was added to a 500 mL round-bottom flask, followed by toluene (125 mL, 5V), formamidine acetate (23.11 g, 222.02 mmol, 2 eq.), acetic acid (125 mL, 5V), and acetic anhydride (1.13 g, 11.10 mmol, 0.1 eq.). The reaction was carried out at 110 °C for 15 h, at which point the TLC plate showed complete reaction. The mixture was then cooled to 0 °C using an ice-water bath. Simultaneously, a 1 L beaker was prepared, and 250 mL of a 1.54 mol / L sodium carbonate aqueous solution was poured in. Under ice bath conditions, the reaction solution in the flask was slowly added to the sodium carbonate solution; after the addition was complete, the organic layer was collected by separation; ethyl acetate (200 mL * 2) was added for extraction, and the organic phases were combined; the organic phase was washed with saturated sodium carbonate solution until the yellow impurity spots on the TLC plate were removed; after drying and concentration, 16.4 g of yellow solid product was obtained, with a yield of 63.4%.

[0153] Step 6:

[0154]

[0155] The unpurified starting material from the previous step, 1-tert-butoxycarbonyl-N-[(2-methoxy-3-nitro-benzoyl)amino]-N-methyl-carbamic acid (5 g, 15.37 mmol, 1 eq.), was dissolved in methanol (50 mL, 10 V) and added to a 100 mL autoclave. Pd / C (0.5 g, 0.1 M) was added, and the pressure was increased to 2 MPa with hydrogen at 45 °C. The reaction was allowed to proceed overnight, and TLC was performed to confirm complete reaction. After filtration and concentration, the direct yield was 95%, with a purity of 98.6%. 1H NMR (400MHz, CDCl3) δ=8.09(s,1H),7,34(dd,J=8.0,2.0Hz,1H),6.99(t,J=8.0Hz),6.81(dd,J=8.0,2.0Hz),4.00(s,3H),3.77(s,3H).

[0156] The total yield of the products prepared in steps 1-6 above was 7.89% to 31.46%, with an optimal total yield of 31.46% and a product purity of 98.6%.

[0157] In summary, this invention provides a method for synthesizing the intermediate of deuterocelexitinib shown in Formula I. The synthesis method of this invention is simple to operate, uses inexpensive and readily available raw materials, and has high product yield and high purity. The key step of methyl isomerization produces fewer byproducts, making it suitable for industrial production.

Claims

1. A process for the preparation of a deuterated cediranib intermediate characterized in that: It comprises the following steps: Step 1: Compound 1 and compound 2 are dissolved in a solvent respectively to prepare a solution, then the solution containing compound 1 is added to the solution containing compound 2, and the reaction is carried out until completion to obtain a reaction liquid, and the reaction liquid is purified to obtain a compound shown in formula IA1; Step 2: The compound shown in formula IA1 and an acid are reacted in a solvent to obtain a reaction liquid, and the reaction liquid is purified to obtain a compound shown in formula IA2; Wherein, R1 is selected from C1-C4 alkyl; In step 1, the equivalent ratio of the compound 1 and the compound 2 is 1:0.9-2.0; In step 1, the solvent is tetrahydrofuran; In step 1, the reaction temperature is-20-20℃, and the reaction time is 0.5-5h.

2. The preparation method according to claim 1, characterized in that: In step 2, the acid is trifluoroacetic acid, hydrochloric acid or glacial acetic acid; And / or, in step 2, the mass-volume ratio of the compound shown in formula IA1 and the acid is 1g:1-10mL; And / or, in step 2, the solvent is dichloromethane or toluene; And / or, in step 2, the reaction temperature is 10-110℃, and the reaction time is 10-12h.

3. The preparation method according to claim 2, characterized in that: In step 1, the equivalent ratio of the compound 1 and the compound 2 is 1:1.3; And / or, in step 1, the solvent is tetrahydrofuran; And / or, in step 1, the reaction temperature is 0-5℃; And / or, in step 1, the purification comprises the following steps: the reaction liquid is concentrated, an organic solvent and a saturated sodium carbonate solution are added to the concentrate, and after stirring and washing, the organic phase is separated and collected, the organic phase is concentrated and then dissolved in an organic solvent, the organic phase is washed with hydrochloric acid, and after drying and filtration, the compound shown in formula IA1 is obtained; the organic solvent is dichloromethane, methyl tert-butyl ether or ethyl acetate; And / or, in step 2, the acid is trifluoroacetic acid; And / or, in step 2, the mass-volume ratio of the compound shown in formula IA1 and the acid is 1g:4mL; And / or, in step 2, the purification comprises the following steps: the reaction liquid is concentrated, an organic solvent and a saturated sodium bicarbonate solution are added to the concentrate, and after stirring and washing, the organic phase is taken and washed with water and saturated brine, and after drying and filtration, the compound shown in formula IA2 is obtained; the organic solvent is dichloromethane, methyl tert-butyl ether or ethyl acetate.

4. The method of claim 1, wherein: The preparation method of the compound 1 comprises the following steps: Step (1): compound 3, a base and dimethyl sulfate are reacted in a solvent, after filtration, a filtrate is obtained, a base solution is added to the filtrate, after the reaction is completed, the pH is adjusted to 3-4 by adding an acid, direct extraction, drying of the organic phase, filtration and concentration to obtain compound 4; Step (2): compound 4 and a chlorinating agent are reacted in a solvent to obtain compound 1.

5. The preparation method according to claim 4, characterized in that: In step (1), the equivalent ratio of compound 3, the base and dimethyl sulfate is 1:(2.5-5):(2.5-5); And / or, in step (1), the equivalent ratio of compound 3 and the base in the base solution is 1:(3-5). And / or, in step (2), the equivalent ratio of the compound 4 and the chlorinating agent is 1: (1.5~3).

6. The preparation method of claim 5, wherein: In step (1), the solvent is acetone, ethyl acetate or acetonitrile; And / or, in step (1), the base is potassium carbonate, sodium carbonate or sodium hydroxide; And / or, in step (1), the reaction temperature of the compound 3, the base and dimethyl sulfate is 50~60℃; And / or, in step (1), after the reaction is completed, diatomite is used to filter to obtain a filtrate And / or, in step (1), the base in the base solution is sodium hydroxide or potassium hydroxide; And / or, in step (1), the reaction temperature of the addition of the base solution is 20~40℃; And / or, in step (1), the acid is hydrochloric acid; And / or, in step (1), the solvent used in the extraction is ethyl acetate or dichloromethane; And / or, in step (2), the chlorinating agent is dichloro sulfoxide, phosphorus oxychloride or oxalyl chloride; And / or, in step (2), the solvent is dichloromethane or toluene; And / or, in step (2), the reaction temperature is 40~60℃.

7. The preparation method of claim 6, wherein: In step 1, the solvent is acetone; And / or, in step 1, the base is potassium carbonate; And / or, in step 1, the base in the base solution is sodium hydroxide; And / or, in step (1), the solvent used in the extraction is ethyl acetate; And / or, in step (2), the chlorinating agent is dichloro sulfoxide; And / or, in step (2), the solvent is dichloromethane.

8. The method of claim 1, wherein: The preparation method of the compound 2 comprises the following steps: In a solvent, a base is added to the compound 5, and the pH is adjusted to 10~12, a Boc2O solution is dropped after reaction, the reaction solution is extracted, and the organic phase after extraction is dried to obtain the compound 2.

9. The preparation method of claim 8, wherein: The solvent is water; And / or, the equivalent ratio of the compound 5, the base and Boc2O is 1: (1.1~1.5): (1.2~1.5); And / or, the base is any one or a mixture of two of sodium carbonate, potassium carbonate, sodium bicarbonate and sodium hydroxide; And / or, the pH is adjusted using sodium hydroxide; And / or, the solvent of the Boc2O solution is tetrahydrofuran; And / or, the temperature when the Boc2O solution is dropped is 0~5℃; And / or, the reaction temperature is 20~30℃, and the reaction time is 10~20h; And / or, the solvent used in the extraction is dichloromethane, methyl tert-butyl ether or ethyl acetate.

10. The preparation method of claim 9, wherein: The equivalent ratio of the compound 5, the base and Boc2O is 1:1.1:1.2; And / or, the base is sodium bicarbonate; And / or, the solvent used in the extraction is ethyl acetate.

11. A method for preparing the compound shown in Formula I, characterized in that: It comprises the following steps: Step a: in a solvent, a compound of formula IA, formamidinium acetate, acetic acid and an anhydride are reacted to obtain a compound of formula IC; Step b: the compound of formula IC and hydrogen gas are reacted under the action of a catalyst to obtain the compound of formula I; R1is selected from C1-C4 alkyl; R2is selected from hydrogen or tert-butyloxycarbonyl; In step a, the solvent is toluene.

12. The method of claim 11, wherein: In step a, the equivalent ratio of the compound of formula IA, formamidine acetate and acid anhydride is 1: (2-5): (0-0.5); and / or, in step a, the mass-volume ratio of the compound of formula IA and acetic acid is 1 g: 5-10 mL; and / or, in step a, the temperature of the reaction is 100-120 ℃, and the reaction time is 15-72 h; and / or, in step a, the compound of formula IC is obtained after purification, and the purification comprises the following steps: cooling the reaction solution to 0-4 ℃, adding the reaction solution into excess saturated sodium carbonate aqueous solution, collecting the organic layer by liquid-liquid separation, washing the organic phase after extraction, drying and concentrating; and / or, in step b, the solvent is methanol; and / or, in step b, the catalyst is Pd / C or Raney Ni; and / or, in step b, the mass ratio of the compound of formula IC and the catalyst is 1:0.1-0.5; and / or, in step b, the temperature of the reaction is 40-60 ℃, and the reaction time is 10-20 h; and / or, in step b, the reaction is under a pressure of 2-10 MPa.

13. The method of claim 12, wherein: In step a, the equivalent ratio of the compound of formula IA, formamidine acetate and acid anhydride is 1:2: (0.1-0.5); and / or, in step a, the mass-volume ratio of the compound of formula IA and acetic acid is 1 g: 5 mL; and / or, in step a, the solvent is toluene; and / or, in step a, the acid anhydride is acetic anhydride; and / or, in step b, the catalyst is Pd / C.

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