Preparation method for pyrrolo[2,3-d]pyrimidine derivative and novel intermediate

Abstract

The present invention relates to a preparation method for pyrrolo[2,3-d]pyrimidine derivative and a novel intermediate. The preparation method comprises the following steps: step 1: performing a substitution reaction between compound VII and compound VIII to obtain compound VI; step 2: under Lewis acid catalysis, subjecting compound VI to a Strecker reaction with an ammonia source and a cyanide and then hydrolyzing a cyano group of a product of the Strecker reaction, and converting the cyano group into a carboxyl group to obtain compound V; step 3: using trifluoroacetyl to protect an amino group of compound V to obtain compound III; step 4: performing a condensation dehydration reaction between intermediate III and compound IV to obtain compound II; and step 5: subjecting compound II to basic hydrolysis to remove the trifluoroacetyl protecting group and obtain AZD5363. The reaction conditions of the preparation method are mild and easy to control, the reaction process is easy to monitor, low cost of starting material is achieved, a work-up method of each step of the reaction is simple, high yield and good purity are achieved, and good application prospects and value are achieved.

Description

A process for the preparation of pyrrolo[2,3-d]pyrimidine derivatives and novel intermediates TECHNICAL FIELD

[0001] The present invention belongs to the field of pharmaceutical chemistry and relates to a process for the preparation of pyrrolo[2,3-d]pyrimidine derivatives and novel intermediates. BACKGROUND

[0002] AZD5363 (trade name: Capivasertib; chemical name: (S)-4-amino-N-(1-4-chlorophenyl)-3- hydroxypropyl)-I-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide, chemical structure as shown below) is a highly potent and selective AKT isoform (AKT1 / 2 / 3) inhibitor developed by AstraZeneca, which was granted priority review by FDA in June 2023 for the treatment of hormone receptor-positive (HR + ), human epidermal growth factor receptor 2-negative (HER 2- ) locally advanced or metastatic breast cancer patients who have relapsed or progressed on or after endocrine-based regimens.

[0003] Currently, there are 2 patent literatures reported the synthesis of AZD5363, patent WO 2009047563 (route 1) uses 6-chloro-7-azapurine (compound 1) and N-Boc-amino-piperidyl-1,1-carboxylic acid (compound 2) as starting materials, compound 3 is obtained by substitution reaction, then condensation reaction with chiral amino intermediate (compound 4), and finally the target product I is obtained by removing the Boc protecting group. This synthesis process has small reaction scale, low yield, and many impurities. Then the chemical reagents and solvents used are not environmentally friendly, polluting and high cost, and the post-treatment is difficult. In addition, the key starting material 4-(tert-butoxy carbonylamino)piperidine-4-carboxylic acid lacks large-scale commercial supply and needs to be prepared separately. Its preparation process also has many problems such as inconvenient monitoring of reaction progress, poor solubility of product with large polarity; finally, the post-treatment of Boc deprotection step is long and the purity is poor.

[0004] Route 1 (WO 2009047563)

[0005] Patent CN 106661033 B (Route 2) made some improvements on the basis of Route 1. Under the action of trichloroacetyl chloride, intermediate 3 was deprotected and intramolecularly cyclized to obtain Liuqi's anhydride (compound 6), and then subjected to ring-opening reaction with a chiral amine intermediate (compound 4) to obtain the target compound I. The synthesis of this patent also uses the expensive 4-(tert-butoxycarbonylamino)piperidine-4-carboxylic acid intermediate as the starting material to synthesize compound 3, but the preparation of Liuqi's anhydride (compound 6) from compound 3 requires more stringent control of process conditions, requiring strict water-free treatment of the reaction solvent, reaction device, and reaction environment, which leads to increased production costs and other problems.

[0006] Route 2 (CN 106661033 B)

[0007] The existing synthesis method of AZD5363 faces various challenges, including low yield, difficult-to-control impurity generation, complex purification steps, and the use of potentially harmful chemical reagents to the environment and operating personnel. These problems not only limit the large-scale production of AZD5363, but also affect the quality and cost-effectiveness of the final product. Therefore, it is necessary to develop a new production process.

[0008] SUMMARY

[0009] In view of the problems of the prior art, the present application aims to provide a preparation method for AZD5363 and a novel intermediate, wherein the preparation method for AZD5363 is a new preparation method of AZD5363, and the preparation method comprises the following steps:

[0010] Step 1: substituting 6-chloro-7-azapurine (compound VII) with 4-piperidone hydrochloride (compound VIII) to obtain compound VI;

[0011] Step 2: performing Strecker reaction on compound VI with an ammonia source and cyanide under the catalysis of a Lewis acid, and then hydrolyzing the cyano group of the Strecker reaction product to convert it into a carboxyl group to obtain compound V, i.e. intermediate V;

[0012] Step 3: protecting the amino group of compound V with trifluoroacetyl to obtain compound III;

[0013] Step 4: performing condensation and dehydration reaction on intermediate III with compound IV (chiral amine intermediate) to obtain compound II;

[0014] Step 5: hydrolyzing compound II with a base to remove the trifluoroacetyl protecting group to obtain the AZD5363, i.e. compound I.

[0015] Further, in step 1, the substitution reaction is carried out in an alcohol solvent; and / or;

[0016] The alcohol solvent is any one or a combination of at least two of methanol, ethanol, n-propanol, isopropanol, n-butanol or t-butanol, and is further preferably ethanol; and / or;

[0017] The reaction temperature of the substitution reaction is 60-120°C (e.g., 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, etc.), and is preferably 70-90°C; and / or;

[0018] The molar ratio of 6-chloro-7-azapurine (compound VII) to 4-piperidone hydrochloride (compound VIII) is 1:(1-1.2), wherein 1-1.2 can be 1.05, 1.1, 1.15, etc.

[0019] Further, the reaction solvent of the Strecker reaction in the first stage of step 2 is any one or a combination of at least two of dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane, and is preferably dichloromethane; and / or;

[0020] The ammonia source is any one or a combination of at least two of aqueous ammonia, an ammonia organic solution (e.g., an ammonia methanol solution, an ammonia ethanol solution, an ammonia tetrahydrofuran solution) or an ammonium salt (e.g., ammonium chloride, ammonium formate, ammonium carbonate or ammonium acetate), and is preferably an ammonia tetrahydrofuran solution; and / or;

[0021] The cyanide is any one or a combination of at least two of sodium cyanide, potassium cyanide or cyanotrimethylsilane, and is preferably cyanotrimethylsilane.

[0022] Further, in step 2, the Strecker reaction is carried out at 0-60°C (e.g., 10°C, 20°C, 30°C, 40°C, 50°C, etc.), and is preferably 0-25°C; and / or;

[0023] The reaction time of the Strecker reaction is 1-36h, e.g., 5h, 10h, 20h, 30h, etc.

[0024] Further, the molar ratio of compound IV, cyanide and ammonia source is 1:(1-1.5):(1-4), wherein 1-1.5 can be 1.1, 1.2, 1.3, 1.4, etc., 1-4 can be 1.5, 2, 2.5, 3, 3.5, etc., and is preferably 1:1-1.8, and more preferably 1:1.2:1.5; and / or;

[0025] The Lewis acid is zinc iodide and / or titanium tetraisopropoxide, and the amount of the Lewis acid is 5% to 20% (e.g., 10%, 15%, etc.) of the molar amount of compound IV, preferably 10%.

[0026] Further, in step 2, the hydrolysis of the cyano group in the second stage comprises the following steps: hydrolysis with a base, and then adjusting the pH to the isoelectric point with an acid to precipitate the product; and / or;

[0027] The base is sodium hydroxide and / or potassium hydroxide; and / or;

[0028] The acid is any one or a combination of at least two of hydrochloric acid, sulfuric acid, or phosphoric acid, preferably hydrochloric acid.

[0029] Further, in step 3, the reaction solvent used in the trifluoroacetyl protection is selected from any one or a combination of at least two of dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane, preferably dichloromethane; and / or;

[0030] The molar concentration of the mixture of compound V and the reaction solvent, i.e., the ratio of the reactant to the reaction solvent, is 0.1 mol / L to 2 mol / L (e.g., 0.5 mol / L, 1 mol / L, 1.5 mol / L, etc.), preferably 0.2 mol / L or 0.5 mol / L; and / or;

[0031] The reaction temperature for the trifluoroacetyl protection is 0°C to 60°C (e.g., 10°C, 20°C, 30°C, 40°C, 50°C, etc.), preferably 0°C to 25°C; and / or;

[0032] The reaction time for the trifluoroacetyl protection is 1 h to 24 h (e.g., 5 h, 10 h, 15 h, 20 h, etc.), preferably 3 h to 6 h; further preferably 3 h, 4 h, 10 h, or 6 h; more further preferably 3 h; and / or;

[0033] The trifluoroacetyl reagent used in the trifluoroacetyl protection is trifluoroacetyl chloride or trifluoroacetic anhydride; wherein the molar ratio of compound III to the trifluoroacetic anhydride is 1:1 to 2, wherein 1 to 2 can be 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, etc., preferably 1:1 to 1.5, more preferably 1:1.3.

[0034] Further, the reaction of the trifluoroacetyl protection comprises the following post-processing steps: extraction, washing, removal of the solvent under reduced pressure, and silica gel chromatography purification.

[0035] Further, in the condensation and dehydration reaction of step 4:

[0036] The condensation agent used in the condensation dehydration reaction is any one or a combination of at least two of carbonyl diimidazole condensing agent, carbodiimide condensing agent (such as N,N'-dicyclohexyl carbodiimide (DCC), N,N'-diisopropyl carbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI)), onium salt condensing agent (such as N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (HATU), O-(IH-benzotriazol-1-yl)-N,N,N',N'-tetramethylisourea hexafluorophosphate), benzotriazole-1-tetramethyl hexafluorophosphate (HBTU), Carter condensing agent (BOP), 1H-benzotriazole-1-yl oxytripyrrolidinyl hexafluorophosphate (PyBOP), organic phosphorus condensing agent (such as diphenylphosphinic chloride (DPP-Cl), diphenyl azide phosphate (DPPA)); further preferably 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI); and / or;

[0037] The additive used in the condensation dehydration reaction is any one or a combination of at least two of N-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 2-hydroxypyridine-N-oxide (HOPO) or N-hydroxy succinimide (HOSu), further preferably 2-hydroxypyridine-N-oxide (HOPO); and / or;

[0038] The base used in the condensation dehydration reaction is any one or a combination of at least two of triethylamine, diisopropyl ethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably diisopropyl ethylamine; and / or;

[0039] The reaction solvent used in the condensation dehydration reaction is selected from any one or a combination of at least two of dichloromethane (DCM), trichloromethane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methyl pyrrolidone (NMP) or dimethyl sulfoxide (DMSO), preferably N,N-dimethylformamide; and / or;

[0040] The molar ratio of the compound III to the condensing agent is 1:(1-2), wherein 1-2 can be 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, etc., preferably 1:1.3; and / or;

[0041] The molar concentration of the compound III is 0.1 mol / L to 2 mol / L (for example, 0.5 mol / L, 1 mol / L, 1.5 mol / L, etc.), preferably 0.3 mol / L or 0.5 mol / L; and / or;

[0042] The reaction time of the condensation dehydration reaction is 1 h to 6 h (for example, 2 h, 3 h, 4 h, 5 h, etc.), preferably 3 h to 6 h, further preferably 3 h, 4 h, 5 h or 6 h; and / or;

[0043] The reaction temperature of the condensation dehydration reaction is 10℃ to 60℃ (for example, 10℃, 20℃, 30℃, 40℃, 50℃, etc.), preferably room temperature.

[0044] Further, the condensation dehydration reaction comprises the following post-processing steps: filtration, for example, filtration with diatomite, washing, removal of solvent under reduced pressure, silica gel chromatography purification.

[0045] Further, in step 5, the reaction of hydrolytic de-trifluoroacetyl is carried out in methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl pyrrolidone, water and a mixed solvent thereof; and / or;

[0046] The base used for hydrolytic de-trifluoroacetyl protecting group is selected from any one or a combination of at least two of potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide.

[0047] The preparation method of the present application has one or more of the following advantages: mild and easy-to-control reaction conditions, easy-to-monitor reaction process, low raw material cost, simple post-processing mode after each step reaction, high yield, good purity, good application prospect and value.

[0048] The present application provides a novel intermediate, 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydropyridine, the above compound V, which has a larger conjugated system and a more significant ultraviolet coloration, which is conducive to monitoring the progress of the reaction and has a high synthesis yield.

[0049] Compared with the prior art, the present application has the following beneficial effects:

[0050] 1) No additional synthesis of 4-aminohexahydropyridine-4-carboxylic acid or 4-aminohexahydropyridine-4-carboxylic acid intermediate with a protecting group is required, which shortens the process steps and significantly reduces the raw material cost.

[0051] 2) The novel intermediate 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydropyridine (compound V) has a larger conjugated system and a more significant ultraviolet coloration, which is conducive to monitoring the progress of the reaction and has a high synthesis yield.

[0052] 3) The reaction conditions for protecting the amino group of intermediate V with trifluoroacetyl, protecting and deprotecting the group are mild, the post-treatment is convenient, the product is easier to crystallize and purify, the yield is high, and the purity is high.

[0053] 4) It has the advantages of cheap and easily available starting materials, safe and simple operation of each step, environmentally friendly production conditions, low cost, etc., and is more suitable for industrialized production. DETAILED DESCRIPTION

[0054] The technical solutions of the present application will be further illustrated by specific embodiments. Those skilled in the art should understand that the embodiments are only to help understand the present application and should not be regarded as specific limitations of the present application.

[0055] Example 1: Synthesis of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,4-dimethoxyhexahydropyridine (Compound VI)

[0056] Dissolve 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (120.0 g, 781.41 mmol) and 4-oxopiperidinone hydrochloride (106.1 g, 782.5 mmol) in anhydrous ethanol (800 mL), heat to 80°C, react for 4 hours, TLC detects that the raw material is completely reacted, the reaction liquid is cooled to room temperature, concentrated to dryness under reduced pressure, redissolved with dichloromethane, washed with saturated sodium bicarbonate, water, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is crystallized in ethanol water to obtain the title compound (159.1 g, yield 90.8%, purity 96.4%). MS (ESI, m / z): 217 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.19 (s, 1H), 7.25-7.19 (m, 1H), 6.65 (dd, 1H), 4.17 (t, 4H), 2.55-2.51 (m, 4H).

[0057] Example 2: Synthesis of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydropyridine-4-carboxylic acid (Compound V)

[0058] Dissolve 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydropyridin-4-one (50.0 g, 231.22 mmol), zinc iodide (7.4 g, 23.12 mmol) and ammonia in tetrahydrofuran solution (2 M, 173.4 mL, 346.83 mmol) in dry dichloromethane (300 mL), slowly drop trimethylsilyl cyanide (29.8 g, 300.59 mmol), stir the reaction at room temperature for 24 hours, check the reaction complete, cool the reaction to 20 °C, concentrate under reduced pressure, dissolve the residue in methanol and water (V / V = 5 / 1, 300 mL), add sodium hydroxide (27.4 g, 693.66 mmol) in portions, react at 60 °C for 3 hours, cool, concentrate under reduced pressure, dissolve in water, adjust the pH with dilute hydrochloric acid, precipitate the solid, filter and dry to obtain the title compound (55.3 g, yield 87.7%, purity 95.8%). MS (ESI, m / z): 262 [M+H] + ; 1 H NMR (400 MHz, Methanol-d4) δ 8.38 (s, 1H), 7.40 (d, 1H), 6.97 (d, 1H), 4.48 (dt, 2H), 4.14 (ddd, 2H), 2.54 (dt, 2H), 2.12 (ddd, 2H).

[0059] Dissolve 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydropyridin-4-one (50.0 g, 231.22 mmol), titanium tetraisopropoxide (6.6 g, 23.12 mmol) and ammonia in tetrahydrofuran solution (2 M, 173.4 mL, 346.83 mmol) in dry dichloromethane (300 mL), slowly drop trimethylsilyl cyanide (29.8 g, 300.59 mmol), stir the reaction at room temperature for 24 hours, check the reaction complete, cool the reaction to 20 °C, concentrate under reduced pressure, dissolve the residue in methanol and water (V / V = 5 / 1, 300 mL), add sodium hydroxide (27.4 g, 693.66 mmol) in portions, react at 60 °C for 3 hours, cool, concentrate under reduced pressure, dissolve in water, adjust the pH with dilute hydrochloric acid, precipitate the solid, filter and dry to obtain the title compound (56.6 g, yield 90.1%, purity 96.2%). MS (ESI, m / z): 262 [M+H] + .

[0060] Example 3: Synthesis of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-(2,2,2- trifluoroacetamido)piperidine-4-carboxylic acid (Compound III)

[0061] Dissolve 4-amino-l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydropyridine-4- carboxylic acid (80.0 g, 306.18 mmol) in anhydrous dichloromethane (350 mL), cool to 5 °C, slowly drop trifluoroacetic anhydride (83.6 g, 398.03 mmol), then warm to 25 °C, stir the reaction for 3 hours, TLC test shows the reaction is complete, cool the reaction to 5 °C, quench with water, separate the layers, wash the organic phase with saturated brine, water, dry over anhydrous sodium sulfate, concentrate under reduced pressure to give the title compound (107.5 g, yield 96.7%, purity 98.4%). MS (ESI, m / z): 358 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.72 (s, 1H), 8.30 (d, 1H), 7.38 (s, 1H), 6.84 (s, 1H), 4.29 (d, 2H), 3.66 (d, 2H), 2.23 (d, 2H), 2.15 (d, 2H).

[0062] Example 4: Synthesis of (S)-N-(l-(4-chlorophenyl)-3-hydroxypropyl)-l-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-4-(2,2,2-trifluoroacetamido)piperidine-4-carboxamide (Compound II)

[0063] Dissolve compound II (75.0 g, 209.91 mmol), (S)-3-amino-3-(4-chlorophenyl)propan-l-ol (40.9 g, 220.41 mmol), 2-hydroxypyridine-N-oxide (HOPO, 28.0 g, 251.89 mmol) and triethylamine (42.5 g, 419.82 mmol) in dry N,N-dimethylformamide (400 mL), stir to complete dissolution at room temperature, add l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 48.3 g, 251.89 mmol) in portions, continue stirring the reaction for 3 hours, TLC test shows the reaction is complete, dilute with water, extract with ethyl acetate, combine the organic phases, wash separately with dilute hydrochloric acid, 10% sodium carbonate solution, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to give the title compound (105.8 g, yield 94.7%, purity 98.6%). MS (ESI, m / z): 525 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 9.20 (s, 1H), 8.20 (d, 1H), 8.15 (d, 1H), 7.38-7.31 (m, 2H), 7.31-7.24 (m, 2H), 7.18 (dd, 1H), 6.62 (dd, 1H), 4.89 (td, 1H), 4.58 (s, 1H), 4.30 (dd, 2H), 3.56-3.46 (m, 2H), 3.36 (d, 2H), 2.26-2.03 (m, 4H), 1.91-1.73 (m, 2H).

[0064] Example 5: Preparation of (S)-4-amino-N-(l-(4-chlorophenyl)-3- hydroxypropyl)-l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (Compound I, i.e. AZD5363)

[0065] Compound II (100.0 g, 190.50 mmol, from the target compound II in Example 1) and potassium carbonate (52.7 g, 381.00 mmol) were dissolved in ethanol (500 mL), the reaction was stirred at room temperature for 5 hours, TLC detection of the raw material reaction was complete, the reaction was poured into water, the solid was precipitated, filtered and washed with water, the solid was recrystallized with ethanol water to obtain the target compound (75.2 g, yield 95.4%, purity 99.3%). MS (ESI, m / z): 429 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.45 (d, 1H), 8.11 (s, 1H), 7.37-7.34 (m, 2H), 7.33-7.30 (m, 2H), 7.15 (d, 1H), 6.57 (d, 1H), 4.87 (q, 1H), 4.56 (s, 1H), 4.38 (dd, 2H), 3.53 (q, 2H), 3.36 (t, 2H), 2.01-1.77 (m, 3H), 1.41 (dd, 2H).

[0066] Alternatively, compound II (40.0 g, 76.20 mmol, from the target compound II in Example 1) and sodium hydroxide (52.7 g, 381.00 mmol) were dissolved in tetrahydrofuran / methanol (V / V = 10 / 1, 200 mL), the reaction was stirred at room temperature for 5 hours, TLC detection of the raw material reaction was complete, the reaction was poured into water, the solid was precipitated, filtered and washed with water, the solid was recrystallized with isopropanol water, dried to obtain the target compound (30.9 g, yield 93.9%, purity 99.3%). MS (ESI, m / z): 429 [M+H] + .

[0067] Alternatively, compound II (40.0 g, 76.20 mmol, from the target compound II obtained in Example 1) and cesium carbonate (24.8 g, 76.20 mmol) were dissolved in methanol (200 mL), the reaction was stirred at room temperature for 5 hours, TLC detection of the complete reaction of the starting material, the reaction was poured into water, the solid was precipitated, filtered and washed with water, the solid was recrystallized with methanol water, dried to obtain the target compound (31.2 g, yield 95.3%, purity 99.8%). MS (ESI, m / z): 429 [M+H] + .

[0068] The above merely provides a specific implementation of the present application, but the protection scope of the present application is not limited thereto, and it should be understood by those skilled in the art that any changes or replacements within the technical scope disclosed by the present application can be easily conceived by those skilled in the art, and all such changes or replacements fall within the protection scope and disclosure scope of the present application.

Claims

1. A process for the preparation of a pyrrolo[2,3-d]pyrimidine derivative, characterized by, The preparation method comprises the following steps: Step 1: substituting compound VII with compound VIII to obtain compound VI; Step 2: under the catalysis of Lewis acid, subjecting compound VI to Strecker reaction with ammonia source and cyanide, and then hydrolyzing the cyanide of the Strecker reaction product to carboxyl to obtain compound V; Step 3: protecting the amino group of compound V with trifluoroacetyl to obtain compound III; Step 4: subjecting intermediate III to condensation dehydration reaction with compound IV to obtain compound II; Step 5: hydrolyzing the trifluoroacetyl protecting group of compound II with base to obtain AZD5363, i.e. compound I.

2. The production method according to claim 1, characterized by, In step 1, the substituting reaction is carried out in an alcohol solvent; and / or; The alcohol solvent is any one or a combination of at least two of methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, and is further preferably ethanol; and / or; The reaction temperature of the substituting reaction is 60-120℃, preferably 70-90℃; and / or; The molar ratio of compound VII to compound VIII is 1:(1-1.2).

3. The production method according to claim 1 or 2, characterized by, In step 2, the reaction solvent of the Strecker reaction is any one or a combination of at least two of dichloromethane, trichloromethane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane, and is preferably dichloromethane; and / or; The ammonia source is any one or a combination of at least two of aqueous ammonia, ammonia organic solution or ammonium salt; and / or; The cyanide is any one or a combination of at least two of sodium cyanide, potassium cyanide or cyanotrimethylsilane, and is preferably cyanotrimethylsilane.

4. The production method according to any one of claims 1 to 3, characterized by, In step 2, the Strecker reaction is carried out at 0-60℃, preferably 0-25℃; and / or; The reaction time of the Strecker reaction is 1-36h.

5. The method of any one of claims 1-4, wherein, The molar ratio of compound IV, cyanide and ammonia source is 1:(1-1.5):(1-4), preferably 1:1-1.8, and more preferably 1:1.2:1.5; and / or; The Lewis acid is zinc iodide and / or titanium tetraisopropoxide, and the amount is 5%-20% of the molar amount of compound IV, preferably 10%.

6. The method of any one of claims 1-5, wherein, In step 2, the cyanide hydrolysis comprises the following steps: hydrolysis with base, and then adjusting the pH to the isoelectric point with acid to precipitate the product; and / or; The base is sodium hydroxide or potassium hydroxide; and / or; The acid is any one or a combination of at least two of hydrochloric acid, sulfuric acid or phosphoric acid, and is preferably hydrochloric acid.

7. The method of any one of claims 1-6, wherein, In step 3, the reaction solvent for trifluoroacetyl protection is selected from any one or a combination of at least two of dichloromethane, trichloromethane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane, and is preferably dichloromethane; and / or; The molar concentration of the mixture of compound V and reaction solvent is 0.1-2mol / L, preferably 0.2-0.5mol / L; and / or; The reaction temperature of trifluoroacetyl protection is 0-60℃, preferably 0-25℃; and / or; The reaction time of trifluoroacetyl protection is 1-24h, preferably 3-6h, and is further preferably 3h; and / or; The trifluoroacetyl reagent used in the trifluoroacetyl protection is trifluoroacetyl chloride and / or trifluoroacetic anhydride; wherein the molar ratio of compound III to the trifluoroacetyl reagent is 1:1-2, preferably 1:1-1.5, more preferably 1:1.

3.

8. The method of any one of claims 1-7, wherein, In step 4, the condensation dehydrating agent used in the condensation dehydrating reaction is any one or a combination of at least two of carbonyldiimidazole condensing agent, carbodiimide condensing agent, onium salt condensing agent, benzotriazole-1-tetramethyl hexafluorophosphate, Carter condensing agent, 1H-benzotriazole-1-yl oxy tripyrrolidinyl hexafluorophosphate or organic phosphorus condensing agent; and / or; The additive used in the condensation dehydrating reaction is any one or a combination of at least two of N-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, 2-hydroxypyridine-N-oxide or N-hydroxy succinimide, preferably 2-hydroxypyridine-N-oxide; and / or; The base used in the condensation dehydrating reaction is any one or a combination of at least two of triethylamine, diisopropyl ethylamine or 1,8-diazobicyclo[5.4.0]undec-7-ene, preferably diisopropyl ethylamine; and / or; The reaction solvent used in the condensation dehydrating reaction is selected from any one or a combination of at least two of dichloromethane, trichloromethane, tetrahydrofuran, 2-methyl tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl pyrrolidone or dimethyl sulfoxide, preferably N,N-dimethylformamide; and / or; The molar ratio of compound III to the condensing agent is 1:(1-2), preferably 1:1.3; and / or; The molar concentration of compound III is 0.1 mol / L-2 mol / L, preferably 0.3 mol / L or 0.5 mol / L; and / or; The reaction time of the condensation dehydrating reaction is 1 h-6 h, preferably 3 h, 4 h, 10 h or 6 h; further preferably 3 h; The reaction temperature of the condensation dehydrating reaction is 10℃-60℃, preferably room temperature.

9. The method of any one of claims 1-8, wherein, In step 5, the reaction of hydrolytic de-trifluoroacetyl protection group is carried out in methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl pyrrolidone, water and a mixture thereof; and / or; The base used in the hydrolytic de-trifluoroacetyl protection group is selected from any one or a combination of at least two of potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide.

10. A novel intermediate characterized by, The novel intermediate is 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)hexahydropyridine.

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