Method for preparing androgen receptor targeted degradation compound and salt thereof

Abstract

The invention provides a method for preparing androgen receptor targeted degradation compounds and salts thereof, and belongs to the field of medicines. Compared with the prior art, the method for preparing the androgen receptor targeted degradation compound and the salt thereof has the advantages that the obtained product is higher in purity, safer and stable in quality, the production period is shortened, industrial production is facilitated, and the method has a wide market prospect.

Description

A method for preparing androgen receptor targeted degradation compound and its salt Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a method for preparing an androgen receptor targeted degradation compound and a salt thereof. Background Art

[0002] Amidst a growing and aging global population, the incidence of prostate cancer continues to increase. Currently, androgen deprivation therapy (ADA) is the primary treatment. The androgen receptor (AR) belongs to the nuclear receptor family and is a ligand-dependent transcription factor. Dysregulation of the AR signaling pathway plays a crucial role in the development and progression of prostate cancer. Studies have shown that castration-resistant prostate cancer (CRPC) is still AR-dependent. The androgen receptor (AR) comprises 918 amino acids and shares similar structure and function with other nuclear receptors. It is composed of three key domains: the DNA-binding domain (DBD), the ligand-binding domain (LBD), and the N-terminal domain (NTD). The DBD and LBD are connected by a hinge. The LBD, located at the carbon terminus of the AR, is the site of ligand binding, determining the specificity of ligand-AR binding. Ligand binding to the LBD activates the AR. Two transcriptional activation domains have been identified in AR: activation function 1 (AF1) in the NTD domain and activation function 2 (AF2), a highly conserved hydrophobic pocket in the LBD domain. Before 2010, docetaxel-based chemotherapy was the only treatment option that could prolong the survival of patients with metastatic CRPC.

[0003] Protein degradation targeting chimeras (PROTACs) have attracted widespread attention as small molecules that can induce the degradation of target proteins. As bifunctional molecules, PROTACs include a small molecule compound that can bind to the target protein (protein of interest, POI), a linker group is introduced at its appropriate position, and then connected to a small molecule compound that can bind to the ubiquitin protease. The resulting small molecule probe can bind to the target protein and the ubiquitin protease at the same time, thereby promoting the ubiquitination of the target protein. The multi-ubiquitinated protein can be recognized and degraded by the proteasome. Using the PROTACs strategy, a protein degradation targeting chimera that can target and recognize / bind to the androgen receptor is prepared. It can regulate the level of the androgen receptor through the intracellular ubiquitin-proteasome degradation system and induce the degradation of the androgen receptor, thereby achieving the effect of treating prostate cancer and other related diseases regulated by the androgen receptor.

[0004] Chinese patent application number CN202010301601.1 discloses a class of bifunctional chimeric heterocyclic compounds (e.g., compound 279) that can target androgen receptor degradation in prostate cancer cells and inhibit their proliferation. However, the preparation method for this class of compounds is not conducive to industrial production, and the resulting product has a low purity. Summary of the Invention

[0005] In order to solve the above problems, the object of the present invention is to provide a method for preparing an androgen receptor targeted degradation compound and its salts, which is conducive to industrial production and has a higher purity of the obtained product.

[0006] The present invention provides a method for preparing an androgen receptor targeted degradation compound, which comprises the following steps:

[0007] The compound of formula III reacts with the compound of formula II to obtain the compound of formula I, which is an androgen receptor targeted degradation compound;

[0008] Wherein, X is selected from halogen or C 1-3 Alkyl or CF3;

[0009] Y is selected from CH or N;

[0010] W is selected from O, S, NMe or NH;

[0011] Ring A is selected from substituted or unsubstituted 3-8 membered cycloalkyl groups, wherein the substitution is that one or more hydrogen atoms on the ring are replaced by halogen or C 1-3 Alkyl substitution;

[0012] R 1 Selected from hydrogen or C 1-3 alkyl;

[0013] Ring B is selected from a 5- to 6-membered heteroaromatic ring or a 6-membered aromatic ring;

[0014] Selected from

[0015] G 2 ,G 3 Independently selected from CR 2 or N; R 2 Selected from H, halogen, hydroxyl;

[0016] n1, n2, n3, n4, n5, n6 are independently selected from 1 or 2;

[0017] M is selected from CR 3 R 4 , where R 3 ,R 4 are independently selected from H or Me;

[0018] Z is selected from H, halogen or C 1-3 alkyl.

[0019] Furthermore, the reaction temperature is 50-140° C., and the reaction time is 3-20 hours; the reaction solvent is water, an organic solvent, or a mixture of water and an organic solvent; the molar ratio of the compound of formula III to the compound of formula II is 1:(0.5-3); the reaction is carried out under the action of a base, and the molar ratio of the compound of formula III to the base is 1:(0.5-2.5), preferably 1:(1.0-2.5).

[0020] Furthermore, the reaction temperature is 93-105° C., and the reaction time is 5-16 hours; the reaction solvent is N-methylpyrrolidone, dimethyl sulfoxide, or a mixture of both; the molar ratio of the compound of formula III to the compound of formula II is 1:(1.3-1.5); and the base is sodium bicarbonate, and the molar ratio of the compound of formula III to the base is 1:(1.3-1.5).

[0021] Furthermore, the preparation method of the compound of formula III comprises the following steps: hydrolyzing and deprotecting the compound of formula IV to obtain the compound of formula III;

[0022] Furthermore, the reaction temperature is 20-65° C., the reaction time is 1-16 hours, preferably 1-6 hours; the reaction solvent is water, an organic solvent, or a mixture of water and an organic solvent; the hydrolysis is carried out under the action of an acid, and the molar ratio of the compound of formula IV to the acid is 1:(5-15).

[0023] Furthermore, the reaction temperature is 25-35° C., and the reaction time is 3 hours; the reaction solvent is an alcohol solvent, preferably one or a mixture of methanol and ethanol; the acid is concentrated hydrochloric acid or trifluoroacetic acid, and the molar ratio of the compound of formula IV to the acid is 1:10.

[0024] Furthermore, the preparation method of the compound of formula IV comprises the following steps: reacting the compound of formula V with the compound of formula VI to obtain the compound of formula IV;

[0025] Among them, R5 is C 1-20 Alkyl, phenyl or C 1-20 Alkyl-substituted phenyl.

[0026] Furthermore, R5 is methyl or p-tolyl; the reaction temperature is 50-110°C, and the reaction time is 3-10 hours, preferably 4-10 hours; the reaction solvent is water, an organic solvent, or a mixture of water and an organic solvent; the molar ratio of the compound of formula V to the compound of formula VI is 1:(0.5-3); the reaction is carried out in the presence of a base and a halide salt, and the molar ratio of the compound of formula V to the base and the halide salt is 1:(0.5-2.5):(0.05-0.5).

[0027] Furthermore, the reaction temperature is 80-85° C., and the reaction time is 6 hours; the reaction solvent is one or a mixture of two or more of N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, and N-methylpyrrolidone; the molar ratio of the compound of formula V to the compound of formula VI is 1:1.2; the base is one or a mixture of two of sodium carbonate and potassium carbonate, the halide salt is sodium iodide, and the molar ratio of the compound of formula V to the base and the halide salt is 1:1.5:0.1.

[0028] Furthermore, the preparation method of the compound of formula V comprises the following steps: reacting the compound of formula VIII with the compound of formula VII to obtain the compound of formula V;

[0029] Furthermore, the reaction temperature is -10 to 40°C, and the reaction time is 5 to 20 hours; the reaction solvent is water, an organic solvent, or a mixture of water and an organic solvent; the molar ratio of the compound of formula VIII to the compound of formula VII is 1:(0.5-3); the reaction is carried out in the presence of a base and a basic catalyst, and the molar ratio of the compound of formula VIII to the base and the basic catalyst is 1:(1-5):(0.05-0.3).

[0030] Furthermore, the reaction temperature is -5-5°C, the reaction time is 10-16 hours; the reaction solvent is dichloromethane; the molar ratio of the compound of formula VIII to the compound of formula VII is 1:1.3; the base is triethylamine, the alkaline catalyst is 4-dimethylaminopyridine, and the molar ratio of the compound of formula VIII to the base and the alkaline catalyst is 1:2.5:0.1.

[0031] Furthermore, the preparation method of the compound of formula VIII comprises the following steps: reacting the compound of formula X-1 with the compound of formula X-2 to obtain the compound of formula VIII;

[0032] Furthermore, the reaction temperature is 40-60°C, the reaction time is 2-20 hours, preferably 2-6 hours; the reaction solvent is water, an organic solvent or a mixture of water and an organic solvent; the molar ratio of the compound of formula X-1 to the compound of formula X-2 is 1:(1-3); the reaction is carried out under the action of a base, and the molar ratio of the compound of formula X-1 to the base is 1:(1-3).

[0033] Furthermore, the reaction temperature is 50° C., the reaction time is 4 hours; the reaction solvent is N,N-dimethylformamide; the molar ratio of the compound of formula X-1 to the compound of formula X-2 is 1:2; the base is potassium carbonate, and the molar ratio of the compound of formula X-1 to the base is 1:2.

[0034] Furthermore, the preparation method of the compound of formula VIII comprises the following steps: (i) reacting the compound of formula Y-2 with an oxidizing agent to obtain the compound of formula Y-1; (ii) reacting the compound of formula Y-1 with the compound of formula X-2 to obtain the compound of formula VIII;

[0035] Among them, R6 is C 1-20 alkyl.

[0036] Furthermore, in step (i), the oxidant is m-chloroperbenzoic acid; the reaction temperature is 10-40°C, preferably 25±5°C, the reaction time is 4-20 hours, preferably 8-16 hours; the reaction solvent is an organic solvent, preferably dichloromethane;

[0037] In step (ii), the reaction temperature is 60-110° C., preferably 80-90° C., and the reaction time is 1-4 hours, preferably 2 hours; the reaction solvent is an organic solvent, preferably dichloromethane; the reaction is carried out in the presence of a base, preferably sodium carbonate, potassium carbonate, or a mixture of both;

[0038] The molar ratio of the compound of formula Y-2, the oxidizing agent, and the compound of formula X-2 is 1:(1-3):(2-5), preferably 1:2:3.5.

[0039] Furthermore, the preparation method of the compound of formula X-1 comprises the following steps: reacting the compound of formula X-3 with dimethyl disulfide to obtain the compound of formula X-1;

[0040] Furthermore, the reaction temperature is 40-60°C, and the reaction time is 3-7 hours; the reaction solvent is water, an organic solvent, or a mixture of water and an organic solvent; the molar ratio of the compound of formula X-3 to dimethyl disulfide is 1:(1-5); the reaction is carried out under the action of a diazotizing agent, and the molar ratio of the compound of formula X-3 to the diazotizing agent is 1:(1-5).

[0041] Furthermore, the reaction temperature is 50° C., the reaction time is 5 hours; the reaction solvent is acetonitrile; the molar ratio of the compound of formula X-3 to dimethyl disulfide is 1:3.29; the diazotization reagent is tert-butyl nitrite, and the molar ratio of the compound of formula X-3 to tert-butyl nitrite is 1:3.1.

[0042] Furthermore, the preparation method of the compound of formula X-3 comprises the following steps: reacting the compound of formula X-4 with the compound of formula X-5 to obtain the compound of formula X-3;

[0043] Furthermore, the reaction temperature is -10 to 80°C, the reaction time is 10-30 hours, preferably 15-30 hours; the reaction solvent is water, an organic solvent or a mixture of water and an organic solvent; the molar ratio of the compound of formula X-4 to the compound of formula X-5 is 1:(0.5-2); the reaction is carried out under the action of a base, a palladium catalyst and a phosphine ligand, and the molar ratio of the compound of formula X-4 to the base, the palladium catalyst and the phosphine ligand is 1:(1-3):(0.001-0.1):(0.003-0.1), preferably 1:(1-3):(0.001-0.1):(0.01-0.1).

[0044] Furthermore, the reaction temperature is 40 to 65° C., the reaction time is 20 to 24 hours; the reaction solvent is dioxane; the molar ratio of the compound of formula X-4 to the compound of formula X-5 is 1:1.1; the base is triethylamine, the palladium catalyst is palladium acetate, the phosphine ligand is 4,5-bis(diphenylphosphine)-9,9-dimethylanthracene, and the molar ratio of the compound of formula X-4 to the base, palladium catalyst and phosphine ligand is 1:2:0.015:0.03.

[0045] Furthermore, the preparation method of the compound of formula X-4 comprises the following steps: reacting the compound of formula X-6 with the compound of formula X-7 to obtain the compound of formula X-4;

[0046] Furthermore, the reaction temperature is -20 to 30°C, and the reaction time is 6 to 20 hours; the reaction solvent is water, an organic solvent, or a mixture of water and an organic solvent; the molar ratio of the compound of formula X-6 to the compound of formula X-7 is 1:(0.5-1.5); the reaction is carried out under the action of a base, and the molar ratio of the compound of formula X-6 to t-BuOK and potassium carbonate is 1:(0.5-1.5):(1-2).

[0047] Furthermore, the reaction temperature is 10-20°C, and the reaction time is 8-16 hours; the reaction solvent is dichloromethane, dimethyl sulfoxide, N-methylpyrrolidone or acetonitrile; the molar ratio of the compound of formula X-6 to the compound of formula X-7 is 1:0.95; the base is t-BuOK and potassium carbonate, and the molar ratio of the compound of formula X-6 to t-BuOK and potassium carbonate is 1:1:1.4.

[0048] Further, the X is selected from F, Cl, Br;

[0049] Y is CH;

[0050] W is O;

[0051] Ring A is selected from the following substituted or unsubstituted groups: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane; the substitution is that one to five hydrogen atoms on the carbon ring are replaced by C 1-3 Alkyl substitution;

[0052] R 1 Selected from hydrogen or C 1-3 alkyl;

[0053] Ring B is selected from a 5- to 6-membered N-containing heteroaromatic ring;

[0054] Selected from

[0055] Z is selected from H, F, Cl or C 1-3 alkyl.

[0056] Furthermore, the 5- to 6-membered N-containing heteroaromatic ring is selected from

[0057] Furthermore, the androgen receptor targeted degradation compound is one of the following compounds:

[0058] The present invention also provides a method for preparing a salt of an androgen receptor targeted degradation compound, which comprises the following steps:

[0059] (a) obtaining an androgen receptor targeted degradation compound according to the above method;

[0060] (b) The androgen receptor targeted degradation compound is salted with an acid to obtain a salt of the androgen receptor targeted degradation compound.

[0061] Furthermore, the acid is an organic acid or an inorganic acid.

[0062] Furthermore, the acid is citric acid, mandelic acid, fumaric acid, maleic acid, phosphoric acid, sulfuric acid, D-camphorsulfonic acid, nicotinic acid, benzoic acid, L-malic acid or L-tartaric acid.

[0063] The androgen receptor targeted degradation compound refers to a compound that can target and degrade the androgen receptor.

[0064] Compared with existing methods, the method for preparing androgen receptor targeted degradation compounds of the present invention has higher purity, is safer and has stable quality, shortens the production cycle, is conducive to industrial production, and has broad market prospects.

[0065] The method of the present invention is suitable for small-scale production in laboratories and also suitable for large-scale industrial production.

[0066] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0067] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0068] The raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.

[0069] In the embodiments of the present invention, unless otherwise specified, the operations are carried out at room temperature, which is 25±5°C.

[0070] Overnight reaction refers to reaction for 8-16 hours.

[0071] Example 1 Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-3-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-1,2,4-triazine-6-carboxamide citrate

[0072] Step 1: Preparation of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile

[0073] Weigh t-BuOK (107 g, 0.955 mol) and THF (500 mL) into a three-necked flask and cool to 0-5°C. Add trans-4-aminocyclohexanol (100 g, 0.868 mol) in batches and stir for 1 hour. Add potassium carbonate (179.7 g, 1.302 mol), cool to -10--5°C, and add a mixed solution of 2-chloro-4-fluorobenzonitrile (141.8 g, 0.912 mol) and THF (500 mL) dropwise. After the addition is complete, react for 1 hour, then allow the temperature to rise naturally and react overnight. Water (500 mL) was added to the reaction solution, stirred and separated, and the aqueous phase was extracted with ethyl acetate (500 mL). The organic phases were combined and washed with 100 mL*2 water. The organic phase was concentrated to dryness to obtain an oily substance, which was washed several times with n-hexane to obtain 213 g of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile solid, with a yield of 97% and a purity of 98%. LC-MS: [M+H] + =250.9.

[0074] Step 2: Preparation of 3-amino-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1,2,4-triazine-6-carboxamide

[0075] In a 5 L three-necked flask, 3-amino-6-bromo-1,2,4-triazine (230 g, 1.32 mol), 4-((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (300 g, 1.2 mol), triethylamine (341 mL, 2.45 mol), palladium acetate (4.0 g, 18.0 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylanthracene (20 g, 36.0 mmol) were added to dioxane (3000 mL). The atmosphere was replaced with argon twice, and then with carbon monoxide twice, with carbon monoxide protection. Heated to 65°C with stirring for 24 h, and the reaction was complete after a plate tap. The reaction solution was cooled to room temperature. Filtered with a thicker layer of silica gel and a thinner layer of celite, the filter cake was washed with EA:MeOH = 20:1 (5 L), and then washed with DCM:MeOH = 20:1 (5 L). The filtrate was dried by rotary evaporation, 1.5 L of acetonitrile was added to the slurry, and the mixture was filtered. The filter cake was washed with acetonitrile and the solid was dried to obtain 315 g of 3-amino-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1,2,4-triazine-6-carboxamide as a solid. The yield was 70%, the purity was 93%, and the LC-MS showed [M+H] + =373.0.

[0076] Step 3: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-3-(methylthio)-1,2,4-triazine-6-carboxamide

[0077] In a 5L three-necked flask, add 3-amino-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1,2,4-triazine-6-carboxamide (353.0 g, 947 mmol) and dimethyl disulfide (294.0 g, 3.12 mol) to acetonitrile (3500 mL). Add tert-butyl nitrite (336 g, 90%, 2.94 mol) dropwise. Heat to 50°C, stir for 5 hours, and complete the reaction by tapping the plate. Cool the reaction mixture to room temperature. Add 135 mL of methanol dropwise and stir for 10 minutes. The solvent is evaporated to dryness to obtain a crude solid. Add 40 mL of ethyl acetate and sonicate for 1 minute. Add 400 mL of n-hexane and sonicate for 5 minutes. Pour off the supernatant and repeat this process twice more. The solid was dried to give 470 g of crude N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-3-(methylthio)-1,2,4-triazine-6-carboxamide, yield: 122%, purity: 92%, LC-MS: [M+H] + =404.1.

[0078] Step 4: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-3-(4-(hydroxymethyl)piperidin-1-yl)-1,2,4-triazine-6-carboxamide

[0079] The compound N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-3-(methylthio)-1,2,4-triazine-6-carboxamide (382.0 g, 945 mmol), K2CO3 (261.0 g, 1.89 mol), and 4-hydroxymethylpiperidine (217 g, 1.89 mol) were added to DMF (2000 mL) in sequence. The mixture was heated to 50°C and stirred for 4 hours. The reaction was complete as determined by TLC. The reaction solution was cooled to room temperature. Ethyl acetate and water were added for extraction. The aqueous layer was extracted once more with ethyl acetate. The organic layers were combined, washed twice with saturated brine and once with water, dried, and spin-dried to obtain a crude product. The crude product was slurried in 800 mL of acetonitrile. The solid was filtered and dried to obtain 780 g of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-3-(4-(hydroxymethyl)piperidin-1-yl)-1,2,4-triazine-6-carboxamide solid, with a yield of 58% and a purity of 97%. LC-MS: [M+H] + =471.1.

[0080] Step 5: Preparation of (1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)-1,2,4-triazin-3-yl)piperidin-4-yl)methyl-4-methylbenzenesulfonate

[0081] Add dichloromethane (2 L) to a 3 L reaction flask, start mechanical stirring, add N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-3-(4-(hydroxymethyl)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (200.0 g, 0.4247 mol), add triethylamine (107.44 g, 1.0618 mol), 4-dimethylaminopyridine (5.19 g, 0.04247 mol), add p-toluenesulfonyl chloride (105.25 g, 0.5521 mol) in batches, control the temperature at -5-5 ° C, and stir the reaction for 10 to 16 hours. After the reaction was completed, purified water was added to the reaction solution to quench the reaction, stirred, allowed to stand and separate, washed once with 5% citric acid aqueous solution, washed once with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. Ethyl acetate / n-hexane was added for crystallization. The resulting solid was transferred to an oven and dried in vacuo to obtain 245 g of solid (1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)-1,2,4-triazin-3-yl)piperidin-4-yl)methyl-4-methylbenzenesulfonate, with a yield of 92% and a purity of 99%. LC-MS: [M+H] + =625.1.

[0082] Step 6: Preparation of tert-butyl 7-((1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)-1,2,4-triazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0083] To a 500 mL reaction flask, add DMF (80 mL) and start mechanical stirring. Then add (1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)-1,2,4-triazin-3-yl)piperidin-4-yl)methyl-4-methylbenzenesulfonate (20.0 g, 32 mmol), 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane (8.69 g, 38.4 mmol), sodium iodide (0.719 g, 4.8 mmol), and sodium carbonate (5.1 g, 48.1 mmol). The reaction mixture was heated to 80-85°C and reacted for 6 hours. Remove from heat, add DMF (120 mL), add purified water (100 mL) dropwise, stir, cool and crystallize, control the temperature at 20-30°C and stir for 1 hour, filter, rinse the filter cake with purified water (40 mL), and filter dry. Add DMF (200 mL) to a 500 mL reaction flask, start mechanical stirring, add the filter cake obtained in the previous step, heat to 90-100°C to dissolve and clarify, add purified water (100 mL) dropwise, remove from heat, stir, cool and crystallize, control the temperature at 20-30°C and stir for 1 hour, filter, rinse the filter cake with purified water (40 mL), and filter dry. The obtained solid was transferred to an oven and vacuum dried for 6 hours to obtain 20.0 g of tert-butyl 7-((1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)-1,2,4-triazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate solid, with a yield of 92% and a purity of 97%. LC-MS: [M+H] + =679.2.

[0084] Step 7: 3-(4-((2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1,2,4-triazine-6-carboxamide

[0085] Anhydrous ethanol (28.48 g) was added to a 500 mL reaction flask, and mechanical stirring was started. Tert-butyl 7-((1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)-1,2,4-triazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (18 g, 26.5 mmol) was then added. The reaction mixture was temperature controlled at 25-35°C, and concentrated hydrochloric acid (26.28 g, 265 mmol) was added dropwise. After reacting for 3 hours, purified water (45 g) was added to the reaction mixture, and the reaction mixture was extracted with dichloromethane (90 g * 3 times). The temperature of the reaction mixture was controlled at ≤20°C, and sodium carbonate (9 g) was added batchwise to adjust the pH of the reaction mixture to 4-6. Add 28.48g of ethanol, control the external temperature to ≤20℃ and concentrate until there are no bubbles, then stop concentrating. The pH of the reaction solution in the previous step is continued to be adjusted to 7-8 with saturated sodium carbonate aqueous solution. When the reaction solution gradually turns milky white, control the temperature at 10-20℃ and stir for 1-2 hours to precipitate a white solid; filter and filter the filter cake to dryness. The resulting solid is transferred to an oven and vacuum dried to obtain 18.365g of a crude solid of 3-(4-((2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1,2,4-triazine-6-carboxamide, yield: 126%, purity: 98%, LC-MS: [M+H] + =579.3.

[0086] Step 8: N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-3-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-1,2,4-triazine-6-carboxamide

[0087] Weigh 40 mL of N-methylpyrrolidone into a 100 mL reaction flask, start mechanical stirring, and heat to 93-105°C. Then weigh 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (5.01 g, 18.15 mmol), NaHCO₃ (1.52 g, 18.15 mmol), and 3-(4-((2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1,2,4-triazine-6-carboxamide (8 g (87.6% content), 13.81 mol) into the reaction flask. Control the temperature at 93-105°C and react for 5-16 hours. After 11 hours, turn off the heat and cool to crystallize. Ethyl acetate (36 g) and purified water (8 g) were added to the reaction solution, and stirring and crystallization were continued for 1 hour. Filter and rinse the filter cake with purified water (14 g). The filter cake from the previous step was transferred to an oven and vacuum dried for 4 to 8 hours to obtain 8.2 g of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-3-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-1,2,4-triazine-6-carboxamide as a solid, with a yield of 82% and a purity of 97%. LC-MS: [M+H] + =835.3.

[0088] Step 9: N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-3-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-1,2,4-triazine-6-carboxamide citrate

[0089] Start mechanical stirring and add dichloromethane (1.1 kg), anhydrous methanol (64 g), and N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-3-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (8 g) to the reactor. Stir and dissolve. Concentrate to remove the solvent. Stop concentrating when the solvent in the reactor is less than one-fifth of the total volume. Add citric acid / methanol solution dropwise, stir and crystallize for 16-24 hours, filter, transfer the filter cake to the reactor, add acetone / purified water / acetonitrile mixed solvent in sequence, slurry, filter, rinse the filter cake with the mixed solution, and drain. The filter cake was transferred to an oven and vacuum dried for 16 to 24 hours to obtain 7.2 g of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-3-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-1,2,4-triazine-6-carboxamide citric acid solid. Yield: 73%, purity: 99%, LC-MS: [M+H] + =835.3.

[0090] Example 2 Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxindol-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)pyrazine-2-carboxamide citrate

[0091] Refer to the method of Example 1, except that step 4 is replaced by the following steps:

[0092] 200 mg (1.0 eq) of raw material N-((1r, 4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(methylthio)pyrazine-2-carboxamide was added to the reaction flask, 3 mL of dichloromethane was added, m-chloroperbenzoic acid (170 mg, 2.0 eq) was added, and stirred overnight. Potassium carbonate (138 mg, 2.0 eq) and 4-hydroxymethylpiperidine (200 mg, 3.5 eq) were added, and the reaction was stopped at 80-90 ° C for 2 hours. Ethyl acetate and water were added for extraction. The organic layers were combined and concentrated to obtain a crude product, which was purified on a preparative plate (i.e., preparation 薄层 The product was purified by chromatography) to give 116 mg of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carboxamide, with a yield of 50%.

[0093] Example 3 Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-3-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-1,2,4-triazine-6-carboxamide

[0094] The target product was prepared by referring to the method of Example 1. The specific operation was as follows: 1 kg of N-methylpyrrolidone was weighed, and 3-(4-((2,7-diazaspiro[3.5]nonane-7-yl)methyl)piperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-1,2,4-triazine-6-carboxamide (100 g, 172.7 mmol), 2-(2,6-dioxo-piperidin-3-yl)-5,6-difluoro-isoindole-1,3-dione (56 g, 189.9 mmol), sodium bicarbonate (16 g, 189.9 mmol) were added in sequence. mmol), heated to 90 ° C and reacted overnight. After the reaction was completed, ethyl acetate and water were added, stirred for crystallization, and filtered to obtain 122 g of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-3-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-1,2,4-triazine-6-carboxamide with a purity of 98% and a yield of 83%. LC-MS: [M+H] + =853.3.

[0095] Example 4 Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)-2,7-diazaspiro[4.4]nonan-2-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0096] The target product was prepared by referring to the method of Example 1. The specific steps are as follows:

[0097] Step 1: Preparation of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile

[0098] The operation is the same as step 1 in Example 1.

[0099] Step 2: Preparation of 5-amino-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyrazine-2-carboxamide

[0100] In a 5 L three-necked flask, 2-amino-5-bromo-pyrazine (69.3 g, 0.40 mol), 4-((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile (100 g, 0.40 mol), triethylamine (80.5 g, 0.80 mol), palladium acetate (0.13 g, 0.0006 mol), and 4,5-bis(diphenylphosphino)-9,9-dimethylanthracene (0.69 g, 0.0012 mol) were added to dioxane (1000 mL). The atmosphere was replaced with argon twice, and then with carbon monoxide twice, with a carbon monoxide shield. Heated to 50-60°C with stirring for 24 h, and the reaction was complete after a plate was tapped. The reaction mixture was cooled to room temperature. Filtered with a thicker layer of silica gel and a thinner layer of celite, the filter cake was washed with EA:MeOH = 20:1, and then with DCM:MeOH = 20:1. The filtrate was dried by rotary evaporation, acetonitrile was added to make pulp, and suction was filtered. The filter cake was washed with acetonitrile and the solid was dried to obtain 74 g of 5-amino-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-pyrazine-2-carboxamide as a solid with a yield of 50%.

[0101] Step 3: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(methylthio)pyrazine-2-carboxamide

[0102] 5-Amino-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-pyrazine-2-carboxamide (14.83 g, 1.0 eq) was added to the reaction flask, 150 mL of acetonitrile was added, stirring was started, dimethyl disulfide (12.4 g, 3.3 eq) was added, tert-butyl nitrite (12.74 g, 3.1 eq) was added dropwise, the temperature was raised to 40-50°C and the reaction was carried out for 6 hours, the reaction was stopped, 6 ml of methanol was added and stirred for 10 minutes, the mixture was concentrated to dryness at 40°C, and purified by column chromatography (filler: 200 mesh silica gel, mobile phase: petroleum ether / ethyl acetate = 4 / 1 to 3 / 1) to give 3.2 g of solid product N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(methylthio)pyrazine-2-carboxamide with a purity of 90% and a yield of 20%.

[0103] Step 4: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-hydroxypiperidin-1-yl)pyrazine-2-carboxamide

[0104] The compound N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(methylthio)-pyrazine-2-carboxamide (15.0 g, 1.0 eq), K2CO3 (10.3 g, 2.0 eq), and 4-hydroxypiperidine (7.5 g, 2.0 eq) were added sequentially to 150 mL of DMF, heated to 50°C, and stirred for 10 hours. The reaction solution was cooled to room temperature. Ethyl acetate and water were added for extraction. The aqueous layer was extracted once with ethyl acetate. The organic layers were combined, washed twice with saturated brine and once with water, dried, and spin-dried to obtain a crude product. The crude product was purified by column chromatography to obtain 4.8 g of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(hydroxy)piperidin-1-yl)-pyrazine-2-carboxamide as a solid, with a yield of 42%.

[0105] Step 5: Preparation of 1-(5-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyrazin-2-yl)piperidin-4-yl 4-methylbenzenesulfonate

[0106] Add 20 mL of dichloromethane to the reaction flask, start stirring, add N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(hydroxy)piperidin-1-yl)-pyrazine-2-carboxamide (2.0 g, 1.0 eq), add triethylamine (1.33 g, 3.0 eq), 4-dimethylaminopyridine (0.11 g, 0.2 eq), add p-toluenesulfonyl chloride (1.25 g, 1.5 eq) in batches, control the temperature at -5-5°C, and stir the reaction for 10 to 16 hours. After the reaction was completed, purified water was added to the reaction solution to quench the reaction, stirred, allowed to stand and separate, washed once with 5% citric acid aqueous solution, washed once with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 2.3 g of solid (1-(5-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)-pyrazin-2-yl)piperidin-4-yl)methyl-4-methylbenzenesulfonate with a purity of 95.9% and a yield of 86%. LC-MS: [M+H] + =609.9.

[0107] Step 6: Preparation of tert-butyl 7-(1-(5-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyrazin-2-yl)piperidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

[0108] DMF (10 mL) was added to the reaction flask, and stirring was initiated. (1-(5-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)-pyrazin-2-yl)piperidin-4-yl)methyl-4-methylbenzenesulfonate (1.8 g, 1.0 eq), 2-tert-butyloxycarbonyl-2,7-diazaspiro[4.4]nonane (8.69 g, 1.2 eq), sodium iodide (0.72 g, 0.15 eq), and sodium carbonate (5.1 g, 1.5 eq) were added. The reaction mixture was heated to 90-95°C and reacted for 3 hours. The mixture was removed from heat and cooled to room temperature. Ethyl acetate and water were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed twice with water, concentrated to dryness, and purified by column chromatography to obtain 1.27 g of tert-butyl 7-(1-(5-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyrazin-2-yl)piperidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate as a solid with a purity of 96.2% and a yield of 65%. LC-MS: [M+H] + =664.1.

[0109] Step 7: Preparation of 5-(4-(2,7-diazaspiro[4.4]nonan-2-yl)piperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyrazine-2-carboxamide

[0110] 1.25 g (1.0 eq) of tert-butyl 7-(1-(5-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyrazin-2-yl)piperidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate was added to the reaction flask, and 25 mL of anhydrous ethanol was added. 1 mL of concentrated hydrochloric acid was added dropwise at 20 ° C. After reacting for 1 hour, the temperature was raised to 40 ° C. and the reaction was continued for 1.5 hours. The solvent was removed by concentration. The mixture was stirred for 2 h, and dichloromethane and water were added. The dichloromethane layer was separated and the aqueous layer was alkaline. Sodium bicarbonate was added to the aqueous layer until it became alkaline and the mixture was extracted with dichloromethane. The organic layers were combined to obtain 0.83 g of 5-(4-(2,7-diazaspiro[4.4]non-2-yl)piperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyrazine-2-carboxamide with a purity of 95.6% and a yield of 76%. LC-MS: [M+H] + =536.1.

[0111] Step 8: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)-2,7-diazaspiro[4.4]nonan-2-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0112] 0.80 g (1.0 eq) of 5-(4-(2,7-diazaspiro[4.4]non-2-yl)piperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyrazine-2-carboxamide was added to the reaction flask, and 8 mL NMP, sodium bicarbonate (0.18 g, 1.5 eq) and 2-(2,6-dioxo-piperidin-3-yl)-5,6-difluoro-isoindole-1,3-dione (0.63 g, 1.5 eq) were added, the temperature was raised to 85-90°C for reaction for 4 hours, ethyl acetate and water were added, the organic layers were extracted and combined, concentrated to dryness, and purified by column to obtain 1.1 g of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)-2,7-diazaspiro[4.4]non-2-yl)piperidin-1-yl)pyrazine-2-carboxamide with a purity of 85.8% and a yield of 92%. LC-MS: [M+H] + =838.0.

[0113] Example 5 N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide

[0114] The target product was prepared by referring to the method of Example 1. The specific steps are as follows:

[0115] Step 1: Preparation of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile

[0116] The operation is the same as step 1 in Example 1.

[0117] Step 2: Preparation of 6-amino-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide

[0118] To a reaction flask, 10 grams (1.0 eq) of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile, 100 mL of 1,4-dioxane, 3-amino-6-bromopyridazine (6.93 g, 1.0 eq), triethylamine (8.05 g, 2.0 eq), palladium acetate (13 mg, 0.0015 eq), and 4,5-bis(diphenylphosphino)-9,9-dimethylanthracene (69 mg, 0.003 eq) were added. The atmosphere was replaced with argon twice, and then with carbon monoxide twice, with carbon monoxide protection. Heat to 50-60°C and stir for 10 hours, concentrate to dryness, add dichloromethane to dissolve, add water to wash, separate the liquids, dry over anhydrous sodium sulfate, filter, concentrate to dryness, and pulp to obtain the product 6-amino-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide.

[0119] Step 3: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(methylthio)pyridazine-3-carboxamide

[0120] To a reaction flask, add 400 mL of acetonitrile and stir. Add 6-amino-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide (40 g, 1.0 eq), then dimethyl disulfide (33 g, 3.0 eq) and dropwise add tert-butyl nitrite (30 g, 3.0 eq). Heat to 55°C and react for 6 hours. After completion of the reaction, concentrate to dryness and purify by column chromatography to obtain 24.5 g of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(methylthio)pyridazine-3-carboxamide as a solid product in a yield of 56.6%.

[0121] Step 4: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide

[0122] To a reaction flask, 15 g (1.0 eq) of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(methylthio)pyridazine-3-carboxamide was added, along with 150 mL of DMF, 4-hydroxymethylpiperidine (8.6 g, 2.0 eq), and potassium carbonate (10.3 g, 2.0 eq). The temperature was raised to 50-60°C and the reaction was allowed to stand for 20 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layers were combined, concentrated, and purified by column chromatography to yield 5.6 g of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide in a 32% yield.

[0123] Step 5: Preparation of (1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl-4-methylbenzenesulfonate

[0124] 5.6 g (1.0 eq) of N-((1r, 4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxamide was added to the reaction flask, 30 mL of dichloromethane was added, and the mixture was cooled to 0°C. Triethylamine (3.6 g, 3.0 eq) and DMAP (0.44 g, 0.3 eq) were added, and p-toluenesulfonyl chloride (3.4 g, 1.5 eq) were added. The mixture was kept warm for 16 hours. When the reaction mixture was stirred for 24 hours, triethylamine and p-toluenesulfonyl chloride were added, and the reaction was continued at this temperature for 24 hours. A citric acid aqueous solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was concentrated and purified on a preparative plate to obtain 5.2 g of the product (1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl-4-methylbenzenesulfonate with a purity of 85.2% and a yield of 70%. LC-MS: [M+H] + =623.9.

[0125] Step 6: Preparation of tert-butyl 7-((1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0126] To the reaction flask was added 2.5 g (1.0 eq) of (1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl-4-methylbenzenesulfonate, 25 mL of DMF, and 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane (1.1 g, 1.2 eq). Stirring was started, and sodium iodide (0.12 g, 0.2 eq) and sodium carbonate (0.85 g, 2.0 eq) were added. The reaction was heated to 80-85°C for 7 hours, the reaction was stopped, ethyl acetate and water were added for extraction, the organic layers were combined and washed once with water, concentrated to dryness, and purified on a preparative plate to obtain 2.4 g of tert-butyl 7-((1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate with a purity of 90.9% and a yield of 88%. LC-MS: [M+H] + =678.1.

[0127] Step 7: Preparation of 6-(4-(((2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide

[0128] To the reaction flask, 2.35 g (1.0 eq) of tert-butyl 7-((1-(6-(((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate was added, 2 ml of dichloromethane and 3 ml of anhydrous ethanol were added, 1 mL of concentrated hydrochloric acid was added dropwise at 20 ° C, the reaction was allowed to proceed for 16 hours, and water was added to quench the reaction. The mixture was stirred for 2 hours, and dichloromethane was added to extract and remove impurities once; sodium bicarbonate was added to the aqueous layer until it became alkaline, and the mixture was extracted with dichloromethane. The organic layers were combined to obtain 1.6 g of 6-(4-(((2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide with a purity of 79.6% and a yield of 80%. LC-MS: [M / 2+H] + =289.7, [M+H] + =578.3.

[0129] Step 8: Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide

[0130] 1.3 g (1.0 eq) of 6-(4-(((2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide was added to the reaction flask, and 13 mL of To the mixture of NMP, sodium bicarbonate (0.21 g, 1.1 eq) and 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (0.68 g, 1.1 eq) were added, and the mixture was heated to 90-95°C for 3 hours. Ethyl acetate and water were added, and the organic layers were extracted and combined, concentrated to dryness, dissolved in dichloromethane, washed twice with water, concentrated to dryness, and purified by column chromatography to obtain 1.0 g of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide with a purity of 92.2% and a yield of 53%. LC-MS: [M+H] + =834.0.

[0131] Example 6 N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((1r,5S,6S)-6-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperazin-1-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridazine-3-carboxamide

[0132] The target product was prepared by referring to the method of Example 1. The specific steps are as follows:

[0133] Steps 1-3:

[0134] The operation is the same as steps 1-3 of Example 5.

[0135] Step 4: Preparation of N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((1r,5S,6R)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridazine-3-carboxamide

[0136] To the reaction flask, 15 g (1.0 eq) of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(methylthio)pyridazine-3-carboxamide was added, followed by 150 mL of DMF and ((1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-yl)methanol (8.4 g, 2.0 eq), and potassium carbonate (10.3 g, 2.0 eq). The reaction was heated to 50-60 degrees and then stopped after 20 hours. Water was added to quench the reaction, and ethyl acetate was added for extraction. The organic layers were combined and concentrated, and the product was purified by column chromatography to obtain 5.6 g of N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((1r,5S,6R)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridazine-3-carboxamide with a yield of 32%.

[0137] Step 5: Preparation of ((1R,5S,6R)-3-(6-(((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl-4-methylbenzenesulfonate

[0138] 2.0 g (1.0 eq) of N-((1r, 4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((1r, 5S, 6R)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hex-3-yl)pyridazine-3-carboxamide was added to the reaction flask, 30 mL of dichloromethane was added, and the mixture was cooled to 0°C. Triethylamine (1.29 g, 3.0 eq) and DMAP (0.16 g, 0.3 eq) were added, and p-toluenesulfonyl chloride (1.22 g, 1.5 eq) were added. The reaction mixture was stirred for 16 hours at room temperature, and triethylamine and p-toluenesulfonyl chloride were added. The reaction mixture was kept warm for 24 hours. A citric acid aqueous solution was added to quench the reaction. The mixture was extracted with dichloromethane, and the organic phase was concentrated. The mixture was purified on a preparative plate to obtain 2.1 g of the product ((1R,5S,6R)-3-(6-(((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl-4-methylbenzenesulfonate in a yield of 79%.

[0139] Step 6: Preparation of tert-butyl 4-(((1R,5S,6S)-3-(6-(((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)piperazine-1-carboxylate

[0140] To the reaction flask was added 2.1 g (1.0 eq) of ((1R,5S,6R)-3-(6-(((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl-4-methylbenzenesulfonate, 10 mL of DMF, and tert-butyl piperazine-1-carboxylate (0.75 g, 1.2 eq). Stirring was started, and sodium iodide (0.076 g, 0.15 eq) and sodium carbonate (0.54 g, 1.5 eq) were added. The reaction mixture was heated to 80-85°C for 1 hour, and then the reaction was stopped. Ethyl acetate and water were added for extraction. The organic layers were combined, washed once with water, concentrated to dryness, and purified by column chromatography to obtain 1.9 g of tert-butyl 4-(((1R,5S,6S)-3-(6-(((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)piperazine-1-carboxylate with a purity of 86.4% and a yield of 90%. LC-MS: [M+H] + =636.0.

[0141] Step 7: Preparation of N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((1r,5S,6S)-6-(piperazin-1-ylmethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridazine-3-carboxamide

[0142] 1.9 g (1.0 eq) of tert-butyl 4-(((1R,5S,6S)-3-(6-(((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)-3-azabicyclo[3.1.0]hexane-6-yl)methyl)piperazine-1-carboxylate was added to the reaction flask, 5 mL of dichloromethane and 5 mL of anhydrous methanol were added, 1 mL of concentrated hydrochloric acid was added dropwise at 20°C, the reaction was carried out at 30°C for 7 hours, and the mixture was concentrated to remove the residue. The solvent was removed, dichloromethane and water were added, and sodium bicarbonate was added to the aqueous layer until it became alkaline. The mixture was extracted with dichloromethane. The organic layers were combined and concentrated to give 1.6 g of N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((1r,5S,6S)-6-(piperazin-1-ylmethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridazine-3-carboxamide with a purity of 93.7% and a yield of 100%. LC-MS: [M+H] + =536.1.

[0143] Step 8: Preparation of N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((1r,5S,6S)-6-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperazin-1-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridazine-3-carboxamide

[0144] 1.6 g (1.0 eq) of N-((1r, 4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-((1r, 5S, 6S)-6-(piperazin-1-ylmethyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyridazine-3-carboxamide was added to the reaction flask, 13 mL of NMP was added, sodium bicarbonate (0.28 g, 1.1 eq) and 2-(2,6-dioxo-piperidin-3-yl)-5,6-difluoro-isoindole-1,3-dione (1.32 g, 1.5 eq) were added, the temperature was raised to 90-95 ° C for 3 hours, and ethyl acetate was added. The mixture was stirred for 2 hours, and the mixture was stirred for 3 hours. The mixture was stirred for 2 hours. The mixture was stirred for 3 hours. The mixture was stirred for 3 hours. The mixture was stirred for 4 hours. The mixture was stirred for 5 hours. The mixture was stirred for 3 hours. The mixture was stirred for 4 hours. The mixture was stirred for 5 hours. The mixture was stirred for 3 hours. The mixture was stirred for 3 hours. The mixture was stirred for 4 hours. The mixture was stirred for 5 hours. The mixture was stirred for 3 hours. The mixture was stirred for 4 hours. The mixture was stirred for 5 hours. + =810.0.

[0145] In summary, the present invention provides a method for preparing an androgen receptor targeted degradation compound and its salts. Compared with existing methods, the product obtained by the method of the present invention has higher purity, is safer and has stable quality, shortens the production cycle, is conducive to industrial production, and has broad market prospects.

Claims

1. A method for preparing androgen receptor-targeted degrading compounds, characterized in that: It comprises the following steps: The compound of formula III reacts with the compound of formula II to obtain the compound of formula I, and the compound of formula I is an androgen receptor targeted degrading compound; wherein X is selected from halogen or C 1-3 alkyl or CF3; Y is selected from CH or N; W is selected from O, S, NMe or NH; Ring A is selected from substituted or unsubstituted 3- to 8-membered cycloalkyl groups, where the substitution is that one or more hydrogens on the ring are substituted by halogen or C 1-3 alkyl groups; R 1 selected from hydrogen or C 1-3 alkyl; Ring B is selected from a 5- to 6-membered heteroaryl ring or a 6-membered aryl ring; Selected from G 2 , G 3 are each independently selected from CR 2 or N; R 2 is selected from H, halogen, hydroxyl; n1, n2, n3, n4, n5, n6 are each independently selected from 1 or 2; M is selected from CR 3 R 4 , where R 3 , R 4 are each independently selected from H or Me; Z is selected from H, halogen or C 1-3 alkyl group.

2. The method according to claim 1, wherein: The temperature of the reaction is 50-140 °C, and the reaction time is 3-20 hours; the reaction solvent is water, an organic solvent or a mixture of water and an organic solvent; the molar ratio of the compound of formula III to the compound of formula II in the reaction is 1:(0.5-3); the reaction is carried out under the action of a base, and the molar ratio of the compound of formula III to the base is 1:(0.5-2.5), preferably 1:(1.0-2.5).

3. The method according to claim 2, wherein: The temperature of the reaction is 93-105 °C, and the reaction time is 5-16 hours; the reaction solvent is one or a mixture of two of N-methylpyrrolidone and dimethyl sulfoxide; the molar ratio of the compound of formula III to the compound of formula II in the reaction is 1:(1.3-1.5); the base is sodium bicarbonate, and the molar ratio of the compound of formula III to the base is 1:(1.3-1.5).

4. The method according to any one of claims 1-3, characterized in that: The preparation method of the compound of formula III It includes the following steps: the compound of formula III is obtained after the compound of formula IV is hydrolyzed to remove the protecting group; 5. The method according to claim 4, wherein: The temperature of the reaction is 20-65 °C, and the reaction time is 1-16 hours, preferably 1-6 hours; the reaction solvent is water, an organic solvent or a mixture of water and an organic solvent; the hydrolysis is carried out under the action of an acid, and the molar ratio of the compound of formula IV to the acid is 1:(5-15).

6. The method according to claim 5, characterized in that: The temperature of the reaction is 25-35 °C, and the reaction time is 3 hours; the reaction solvent is an alcohol solvent, preferably one or a mixture of two of methanol and ethanol; the acid is concentrated hydrochloric acid or trifluoroacetic acid, and the molar ratio of the compound of formula IV to the acid is 1:

10.

7. The method according to claim 4, characterized in that: The preparation method of the compound of formula IV comprises the following steps: reacting a compound of formula V with a compound of formula VI to obtain a compound of formula IV; Among them, R5 is C 1-20 alkyl, phenyl or C 1-20 alkyl-substituted phenyl.

8. The method according to claim 7, wherein: R5 is methyl or p-tolyl; the temperature of the reaction is 50-110 °C, and the reaction time is 3-10 hours, preferably 4-10 hours; the reaction solvent is water, an organic solvent or a mixture of water and an organic solvent; the molar ratio of the compound of formula V to the compound of formula VI in the reaction is 1:(0.5-3); the reaction is carried out under the action of a base and a halogenated salt, and the molar ratio of the compound of formula V to the base and the halogenated salt is 1:(0.5-2.5):(0.05-0.5).

9. The method according to claim 8, wherein: The temperature of the reaction is 80-85 °C, and the reaction time is 6 hours; the reaction solvent is one or a mixture of two or more of N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, and N-methylpyrrolidone; the molar ratio of the compound of formula V to the compound of formula VI in the reaction is 1:1.2; the base is one or a mixture of two of sodium carbonate and potassium carbonate, and the halogenated salt is sodium iodide, and the molar ratio of the compound of formula V to the base and the halogenated salt is 1:1.5:0.

1.

10. The method according to claim 7, characterized in that: The preparation method of the compound of formula V comprises the following steps: reacting the compound of formula VIII with the compound of formula VII to obtain the compound of formula V; 11. The method according to claim 10, characterized in that: The temperature of the reaction is -10 to 40 °C, and the reaction time is 5 to 20 hours; the reaction solvent is water, an organic solvent, or a mixture of water and an organic solvent; the molar ratio of the compound of formula VIII to the compound of formula VII is 1:(0.5 - 3); the reaction is carried out under the action of a base and a basic catalyst, and the molar ratio of the compound of formula VIII to the base and the basic catalyst is 1:(1 - 5):(0.05 - 0.3).

12. The method according to claim 11, wherein: The temperature of the reaction is -5 to 5 °C, and the reaction time is 10 to 16 hours; the reaction solvent is dichloromethane; the molar ratio of the compound of formula VIII to the compound of formula VII is 1:1.3; the base is triethylamine, and the basic catalyst is 4-dimethylaminopyridine, and the molar ratio of the compound of formula VIII to the base and the basic catalyst is 1:2.5:0.

1.

13. The method according to claim 10, wherein: The preparation method of the compound of formula VIII comprises the following steps: reacting a compound of formula X-1 with a compound of formula X-2 to obtain the compound of formula VIII; 14. The method according to claim 13, characterized in that: The temperature of the reaction is 40 - 60 °C, the reaction time is 2 - 20 hours, preferably 2 - 6 hours; the reaction solvent is water, an organic solvent, or a mixture of water and an organic solvent; the molar ratio of the compound of formula X-1 to the compound of formula X-2 is 1:(1 - 3); the reaction is carried out under the action of a base, and the molar ratio of the compound of formula X-1 to the base is 1:(1 - 3).

15. The method according to claim 14, characterized in that: The temperature of the reaction is 50 °C, and the reaction time is 4 hours; the reaction solvent is N,N-dimethylformamide; the molar ratio of the compound of formula X-1 to the compound of formula X-2 is 1:2; the base is potassium carbonate, and the molar ratio of the compound of formula X-1 to the base is 1:

2.

16. The method according to claim 10, characterized in that: The preparation method of the compound of formula VIII comprises the following steps: (i) reacting the compound of formula Y-2 with an oxidant to obtain the compound of formula Y-1; (ii) The compound of formula Y-1 reacts with the compound of formula X-2 to obtain the compound of formula VIII; Among them, R6 is C 1-20 alkyl group.

17. The method according to claim 16, wherein: In step (i), the oxidant is m-chloroperbenzoic acid; the temperature of the reaction is 10 - 40 °C, preferably 25 ± 5 °C, the reaction time is 4 - 20 hours, preferably 8 - 16 hours; the reaction solvent is an organic solvent, preferably dichloromethane; In step (ii), the temperature of the reaction is 60 - 110 °C, preferably 80 - 90 °C, the reaction time is 1 - 4 hours, preferably 2 hours; the reaction solvent is an organic solvent, preferably dichloromethane; the reaction is carried out under the action of a base, and the base is preferably one or a mixture of two of sodium carbonate and potassium carbonate; The molar ratio of the compound of formula Y-2, the oxidant, and the compound of formula X-2 is 1:(1 - 3):(2 - 5), preferably 1:2:3.

5.

18. The method according to claim 13, wherein: The preparation method of the compound of formula X-1 comprises the following steps: reacting the compound of formula X-3 with dimethyl disulfide to obtain the compound of formula X-1; 19. The method according to claim 18, wherein: The temperature of the reaction is 40 - 60 °C, the reaction time is 3 - 7 hours; the reaction solvent is water, an organic solvent, or a mixture of water and an organic solvent; the molar ratio of the compound of formula X-3 to dimethyl disulfide is 1:(1 - 5); the reaction is carried out under the action of a diazotizing reagent, and the molar ratio of the compound of formula X-3 to the diazotizing reagent is 1:(1 - 5).

20. The method according to claim 19, wherein: The temperature of the reaction is 50 °C, and the reaction time is 5 hours; the reaction solvent is acetonitrile; the molar ratio of the compound of formula X-3 to dimethyl disulfide is 1:3.29; the diazotizing reagent is tert-butyl nitrite, and the molar ratio of the compound of formula X-3 to tert-butyl nitrite is 1:3.

1.

21. The method according to claim 18, wherein: The preparation method of the compound of formula X-3 comprises the following steps: reacting the compound of formula X-4 with the compound of formula X-5 to obtain the compound of formula X-3; 22. The method according to claim 21, wherein: The temperature of the reaction is -10 to 80 °C, the reaction time is 10 - 30 hours, preferably 15 - 30 hours; the reaction solvent is water, an organic solvent, or a mixture of water and an organic solvent; the molar ratio of the compound of formula X-4 to the compound of formula X-5 is 1:(0.5 - 2); the reaction is carried out under the action of a base, a palladium catalyst, and a phosphine ligand, and the molar ratio of the compound of formula X-4 to the base, the palladium catalyst, and the phosphine ligand is 1:(1 - 3):(0.001 - 0.1):(0.003 - 0.1), preferably 1:(1 - 3):(0.001 - 0.1):(0.01 - 0.1).

23. The method according to claim 22, characterized in that: The temperature of the reaction is 40 to 65 °C, the reaction time is 20 - 24 hours; the reaction solvent is dioxane; the molar ratio of the compound of formula X-4 to the compound of formula X-5 is 1:1.1; the base is triethylamine, the palladium catalyst is palladium acetate, the phosphine ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylanthracene, and the molar ratio of the compound of formula X-4 to the base, the palladium catalyst, and the phosphine ligand is 1:2:0.015:0.

03.

24. The method according to claim 21, wherein: The preparation method of the compound of formula X-4 comprises the following steps: reacting the compound of formula X-6 with the compound of formula X-7 to obtain the compound of formula X-4; 25. The method according to claim 24, characterized in that: The temperature of the reaction is -20 to 30 °C, the reaction time is 6 - 20 hours; the reaction solvent is water, an organic solvent, or a mixture of water and an organic solvent; the molar ratio of the compound of formula X-6 to the compound of formula X-7 is 1:(0.5 - 1.5); the reaction is carried out under the action of a base, and the molar ratio of the compound of formula X-6 to t-BuOK and potassium carbonate is 1:(0.5 - 1.5):(1 - 2).

26. The method according to claim 25, characterized in that: The temperature of the reaction is 10 - 20 °C, the reaction time is 8 - 16 hours; the reaction solvent is dichloromethane, dimethyl sulfoxide, N-methylpyrrolidone, or acetonitrile; the molar ratio of the compound of formula X-6 to the compound of formula X-7 is 1:0.95; the base is t-BuOK and potassium carbonate, and the molar ratio of the compound of formula X-6 to t-BuOK and potassium carbonate is 1:1:1.

4.

27. The method according to any one of claims 1-26, characterized in that: X is selected from F, Cl, Br; Y is CH; W is O; Ring A is selected from the following substituted or unsubstituted groups: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane; the substitution is that one to five hydrogens on the carbocyclic ring are substituted by C 1-3 alkyl groups; R 1 selected from hydrogen or C 1-3 alkyl; Ring B is selected from 5 - to 6-membered N-containing heteroaromatic rings; Selected from Z is selected from H, F, Cl or C 1-3 alkyl group.

28. The method according to claim 27, wherein: The 5- or 6-membered N-containing heteroaryl ring is selected from 29. The method according to any one of claims 1-26, characterized in that: The androgen receptor-targeting degrading compound is one of the following compounds:

30. A method for preparing a salt of an androgen receptor-targeting degrading compound, characterized in that: It comprises the following steps: (a) Obtaining an androgen receptor-targeted degrading compound according to the method described in any one of claims 1 - 29; (b) Forming a salt of the androgen receptor-targeted degrading compound with an acid to obtain a salt of the androgen receptor-targeted degrading compound.

31. The method according to claim 30, wherein: The acid is an organic acid or an inorganic acid.

32. The method according to claim 31, wherein: The acid is citric acid, mandelic acid, fumaric acid, maleic acid, phosphoric acid, sulfuric acid, D-camphorsulfonic acid, nicotinic acid, benzoic acid, L-malic acid, or L-tartaric acid.