Preparation method of pyrazolopyridine derivative

Abstract

The invention provides a preparation method of a pyrazolopyridine derivative (formula (I)). The method has the advantages of mild reaction conditions, simple operation, high reaction yield, high product purity and convenient post-treatment, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a method for preparing a pharmaceutical compound, specifically a method for preparing a pyrazolopyridine derivative, belonging to the field of pharmaceutical chemistry technology. Background Technology

[0002] Protein ubiquitination is a key protein modification that regulates multiple cellular processes. It is synergistically controlled by E3 ubiquitin ligases and deubiquitinating enzymes (DUBs). DUBs cleave the isopeptide bonds between ubiquitin and the modified protein, removing ubiquitin from the target protein and rescuing it from degradation pathways; they also participate in the editing, maturation, and recycling of ubiquitin molecules after degradation. More than 100 deubiquitinating enzymes are currently known, and these proteins are subdivided into six subfamilies. The ubiquitin-specific protease (USP) subfamily is the largest, with 58 known members. USPs are cysteine ​​proteases containing highly conserved catalytic domains; USP1 is a member of the USP subfamily of DUBs.

[0003] The Fanconi Anemia (FA) and DNA Translesion Synthesis (TLS) pathways were among the first discovered DNA damage tolerance and repair pathways regulated by reversible ubiquitination. USP1 can regulate the deubiquitination of specific proteins in the FA and TLS pathways to participate in the regulation of DNA damage-repair pathways. USP1 plays an important role in DNA repair in tumor cells; reports indicate that USP1 deficiency leads to reduced survival and replication fork degradation in BRCA1-deficient cells. UAF1 (USP1-associated factor 1), as a cofactor of USP1, USP12, and USP46, can enhance their deubiquitinase activity by forming a stable USP / UAF1 protein complex. The USP1 / UAF1 complex deubiquitinates various substrates and is involved in DNA repair processes, tumor pathogenesis, and the regulation of antiviral innate immunity. Currently, there are no marketed drugs targeting the USP1 protein, making the research on USP1 inhibitors a promising area for application.

[0004] Patent WO2023155866 describes a compound of formula (I) that exhibits good USP1 inhibitory activity. The synthetic route for compound (I) is described below:

[0005]

[0006] The above preparation method requires purification via silica gel column chromatography in several steps, including steps six, seven, and eight. This process is inefficient, yields low, and costs high, making it unsuitable for industrial-scale production. Summary of the Invention

[0007] This invention provides a method for preparing a compound of formula (I), comprising the following steps:

[0008]

[0009] Wherein, R and R' are leaving groups selected from halogens -X, -OCOR1, -OTs, -ONO2, -OH, preferably from halogen -X, more preferably from -F, -Cl, and R1 is an alkyl group.

[0010] Optionally, in some embodiments, the reaction is carried out in the presence of a ligand selected from at least one of 2,2'-bipyridine, 1,10-phenanthroline, L-proline, and dimethylethylenediamine, preferably 2,2'-bipyridine; when the ligand is 2,2'-bipyridine, the molar ratio of the compound of formula (III) to 2,2'-bipyridine is 1:0.2-2, preferably 1:1;

[0011] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of cesium carbonate, potassium carbonate, and anhydrous potassium phosphate, preferably cesium carbonate;

[0012] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from at least one of cuprous iodide, cuprous bromide, and cuprous chloride, preferably cuprous iodide;

[0013] Optionally, in some embodiments, the solvent for the reaction is selected from at least one of N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone, preferably N-methylpyrrolidone;

[0014] Optionally, in some embodiments, the reaction temperature is 85°C-135°C, preferably 120±5°C.

[0015] According to one embodiment of the present invention, the preparation of compound (I) further includes the following reaction:

[0016]

[0017] Wherein, R is a leaving group selected from halogens -X, -OCOR1, -OTs, -ONO2, -OH, preferably from halogens -X, more preferably from -F, -Cl, and R1 is an alkyl group;

[0018] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from Xphos-Pd-G2, Xphos-Pd-G3, Pd(OAc)2, Pd[P(C6H5)3]4, Pd(dppf)Cl2, and PdCl2;

[0019] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from NaOH, LiOH, potassium carbonate, cesium carbonate, and anhydrous potassium phosphate, preferably NaOH;

[0020] Optionally, in some embodiments, the molar ratio of the compound of formula (II) to the compound of formula (A) is 1:1 to 1:1.5, preferably 1:1, 1:1.15, 1:1.25, 1:1.5, and more preferably 1:1.25;

[0021] Optionally, in some embodiments, the solvent for the reaction is selected from at least one of acetonitrile, water, ethanol, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, and 2-methyltetrahydrofuran, preferably acetonitrile and water;

[0022] Optionally, in some embodiments, the reaction temperature is 20°C-75°C, preferably 50±5°C.

[0023] Optionally, the method for preparing the compound of formula (I) above further includes the following purification step:

[0024]

[0025] 1) Dissolve the crude product of compound (I) in an organic solvent;

[0026] 2) Add purified water and allow crystals to form;

[0027] 3) Filtration yields the purified compound of formula (I);

[0028] Optionally, in some embodiments, the organic solvent described in the above purification step is selected from at least one of ethanol, isopropanol, water, and methanol, with ethanol being preferred;

[0029] Optionally, in some embodiments, the dissolution in step 1) is carried out at 70±5°C;

[0030] Optionally, in some embodiments, step 2) crystallization is performed at 20±5°C.

[0031] The present invention also provides a method for preparing a compound of formula (II), comprising the following reaction:

[0032]

[0033] Wherein, R and R' are leaving groups selected from halogens -X, -OCOR1, -OTs, -ONO2, -OH, preferably from halogen -X, more preferably from -F, -Cl, and R1 is an alkyl group;

[0034] Optionally, in some embodiments, the reaction is carried out in the presence of a ligand selected from at least one of 2,2'-bipyridine, 1,10-phenanthroline, L-proline, and dimethylethylenediamine, preferably 2,2'-bipyridine; when the ligand is 2,2'-bipyridine, the molar ratio of the compound of formula (III) to 2,2'-bipyridine is 1:0.2-2, preferably 1:1;

[0035] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of cesium carbonate, potassium carbonate, and anhydrous potassium phosphate, preferably cesium carbonate;

[0036] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from at least one of cuprous iodide, cuprous bromide, and cuprous chloride, preferably cuprous iodide;

[0037] Optionally, in some embodiments, the solvent for the reaction is selected from at least one of N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone, preferably N-methylpyrrolidone;

[0038] Optionally, in some embodiments, the reaction temperature is 85°C-135°C, preferably 120±5°C.

[0039] The present invention also provides a method for preparing a compound of formula (III), comprising the following reaction:

[0040]

[0041] Wherein, R and R' are leaving groups selected from halogens -X, -OCOR1, -OTs, -ONO2, -OH, preferably from halogen -X, more preferably from -F, -Cl, and R1 is an alkyl group;

[0042] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from at least one of sodium acetate, potassium acetate, triethylamine, and N,N-diisopropylethyl acetate, preferably sodium acetate;

[0043] Optionally, in some embodiments, the molar ratio of the compound of formula (IV) to the compound of formula (B) is 1:1 to 1:1.2, preferably 1:1, 1:1.1, 1:1.2, and more preferably 1:1;

[0044] Optionally, in some embodiments, the solvent for the reaction is selected from at least one of acetic acid, water, tetrahydrofuran, anhydrous methanol, anhydrous ethanol, N,N-dimethylacetamide, and acetonitrile, preferably acetic acid and water;

[0045] Optionally, in some embodiments, the reaction temperature is 15°C-65°C, preferably 25±5°C.

[0046] The present invention also provides a method for preparing a compound of formula (II), comprising the following steps:

[0047]

[0048] Wherein, R and R' are leaving groups selected from halogens -X, -OCOR1, -OTs, -ONO2, -OH, preferably from halogen -X, more preferably from -F, -Cl, and R1 is an alkyl group.

[0049] The present invention also provides a method for preparing a compound of formula (I), comprising the following steps:

[0050]

[0051] Wherein, R and R' are leaving groups selected from halogens -X, -OCOR1, -OTs, -ONO2, -OH, preferably from halogen -X, more preferably from -F, -Cl, and R1 is an alkyl group.

[0052] The present invention also provides a method for preparing a compound of formula (VI), comprising the following reaction:

[0053]

[0054] Optionally, in some embodiments, the reaction is carried out in the presence of an oxidant selected from at least one of sulfur trioxide pyridine, oxalyl chloride / triethylamine, 2-iodobenzoic acid, and pyridine dichromate, preferably sulfur trioxide pyridine.

[0055] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of dichloromethane, dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, and dioxane, preferably from at least one of dichloromethane, dimethyl sulfoxide, and acetonitrile;

[0056] Optionally, in some embodiments, the reaction temperature is -78°C to 50°C, preferably 25±5°C.

[0057] The present invention also provides a method for preparing a compound of formula (V), comprising the following reaction:

[0058]

[0059] Optionally, in some embodiments, the reaction is carried out in the presence of a reducing agent selected from at least one of sodium cyanoborohydride, sodium borohydride acetate, sodium borohydride, boranepyridine, H2, and hesperidin, preferably at least one of sodium cyanoborohydride and sodium borohydride acetate.

[0060] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of methanol, ethanol, N,N-dimethylacetamide, dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, and tetrahydrofuran, preferably from at least one of methanol, ethanol, dichloromethane, and tetrahydrofuran;

[0061] Optionally, in some embodiments, the reaction temperature is 0-50°C, preferably 25±5°C.

[0062] The present invention also provides a method for preparing a compound of formula (IV), comprising the following reaction:

[0063]

[0064] The reaction was carried out in the presence of hydrogen bromide;

[0065] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of methanol, ethanol, N,N-dimethylacetamide, dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, and tetrahydrofuran, preferably from at least one of methanol, ethanol, and N,N-dimethylacetamide;

[0066] Optionally, in some embodiments, the reaction temperature is 0-50°C, preferably 35±5°C.

[0067] This invention also provides a method for preparing a compound by sequentially combining the above steps, for example:

[0068] The method for preparing compound (V) includes the steps of (VII) → (VI) → (V);

[0069] The method for preparing compound (IV) includes the steps of (VI)→(V)→(IV);

[0070] The method for preparing compound (IV) includes the steps of (VII) → (VI) → (V) → (IV);

[0071] The preparation method of compound (III) includes the steps of (V)→(IV)→(III);

[0072] The preparation method of compound (III) includes the steps of (VI)→(V)→(IV)→(III);

[0073] The method for preparing compound (III) includes the steps of (VII)→(VI)→(V)→(IV)→(III);

[0074] The method for preparing compound (II) includes the steps (IV) → (III) → (II);

[0075] The method for preparing compound (II) includes the steps of (V)→(IV)→(III)→(II);

[0076] The method for preparing compound (II) includes the steps of (VI)→(V)→(IV)→(III)→(II);

[0077] The method for preparing compound (II) includes the steps of (VII)→(VI)→(V)→(IV)→(III)→(II);

[0078] The method for preparing compound (I) includes the steps (III) → (II) → (I);

[0079] The method for preparing compound (I) includes the steps (IV)→(III)→(II)→(I);

[0080] The method for preparing compound (I) includes the steps of (V)→(IV)→(III)→(II)→(I);

[0081] The method for preparing compound (I) includes the steps of (VI)→(V)→(IV)→(III)→(II)→(I);

[0082] The method for preparing compound (I) includes the steps of (VII)→(VI)→(V)→(IV)→(III)→(II)→(I).

[0083] In addition, the present invention also provides compounds of the following formulas (III), (IV'), (B), (V), (VI) or salts thereof:

[0084]

[0085] Wherein, R and R' are leaving groups selected from halogens -X, -OCOR1, -OTs, -ONO2, -OH, preferably from halogen -X, more preferably from -F, -Cl, and R1 is an alkyl group.

[0086] Definitions of abbreviations and key terms in this invention:

[0087]

[0088] Technical effects of the present invention:

[0089] 1. The synthetic formula (I) of this invention has a novel process route, mild reaction conditions at each step, simple operation, high yield, high product purity, and convenient post-processing, making it suitable for industrial production.

[0090] 2. The process route for preparing formula (III) from formula (IV) is novel. Silica gel column chromatography is not required during the preparation process, which improves reaction efficiency and yield, reduces costs, and is suitable for industrial-scale production. Furthermore, by controlling the reaction conditions, the stability of the product is improved.

[0091] 3. The process route for preparing formula (II) from formula (III) is novel. Silica gel column chromatography is not required during the preparation process, which improves reaction efficiency and yield. The conversion rate reaches 100%, the yield reaches over 90%, and the cost is reduced, making it suitable for industrial-scale production.

[0092] 4. The raw materials for the process of this invention are readily available and the steps are simple. The entire synthesis process does not use silica gel column chromatography or other preparative chromatographic methods, resulting in low cost, good stability, high purity, and high yield of intermediates, making it suitable for large-scale industrial production. Detailed Implementation

[0093] The present invention will be further described in detail below with reference to embodiments, but this is not intended to limit the present invention. Any equivalent substitutions made in the art in accordance with the disclosure of the present invention shall fall within the protection scope of the present invention.

[0094] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0095] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

[0096] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0097] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

[0098] Example 1

[0099] 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-fluoro-1-((4-(1-isopropyl-4-(trifluoromethyl)-1-hydro-imidazol-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)-1-hydro-pyrazolo[4,3-c]pyridine (compound of formula (I))

[0100] 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-fluoro-1-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1H-pyrazolo[4,3-c]pyridine (compound of formula (I))

[0101]

[0102] Step 1: tert-butyl(E)-2-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]oct-1-yl)methylene)hydrazone-1-carboxylic acid ester (compound of formula (VI))

[0103] tert-butyl-(E)-2-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methylene)hy drazine-1-carboxylate (compound of formula (VI))

[0104]

[0105] Reaction: 64.95 kg of dichloromethane, 23.21 kg of triethylamine, and 12.10 kg of compound (VII) (prepared according to the method disclosed in PCT / CN2023 / 076700) were added to the reaction vessel and stirred until homogeneous; 59.75 kg of [unspecified substance] was added to a transfer container. Add 18.26 kg of pyridine sulfur trioxide to DMSO and stir until dissolved. Add the prepared pyridine sulfur trioxide / DMSO solution dropwise to the reactor, maintaining the reactor temperature at 0±5℃ during the addition process. After the addition is complete, maintain the reactor temperature at 0±5℃ and continue stirring for 1-2 hours. Take samples for monitoring. Raise the temperature of reactor 1 to 20±5℃. Add tert-butyl hydrazine carbamate in batches, maintaining the reactor temperature at 25±5℃ during the addition process. After the addition is complete, maintain the reactor temperature at 25±5℃ and continue stirring for 2 hours. When the reactor temperature drops to 10±5℃, add 151.88 kg of DMSO solution to the reactor. A 5% citric acid aqueous solution was used, and the organic phase was separated and dried with anhydrous sodium sulfate. The external temperature of the reaction vessel was adjusted to 35±5℃, and solvent was removed under reduced pressure until the residual solvent in the vessel was approximately 2-3V. 30.65 kg of n-heptane was added to the reaction vessel, and the external temperature was adjusted to 40±5℃, and solvent was removed under reduced pressure until the residual solvent in the vessel was 3-4V. The filter cake was dried in a blower at 40℃ until the moisture content was <1.0%. 15.5 kg of compound (VI) was collected as a white solid with a purity of 97% and a yield of 87%.

[0106] Step 2: Tert-butyl 2-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)hydrazine-1-carboxylic acid ester (compound of formula (V))

[0107] tert-butyl-2-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)hydrazine-1-carboxylate (compound of formula (V))

[0108]

[0109] Reaction: Add 61.45 kg methanol, 13.09 kg acetic acid, and 15.50 kg of compound (VI) to the reactor and stir until homogeneous; control the reactor temperature at 25±5℃; add 4.11 kg sodium cyanoborohydride in batches, controlling the reactor temperature at 25±5℃ during the addition process; after addition, adjust the reactor temperature to 25±5℃ and maintain the temperature at 25±5℃ for 16 hours; transfer the reaction solution to a temporary storage container; add 124.23 kg water and 24.41 kg sodium bicarbonate to the reactor and start stirring; transfer the temporary storage container... The reaction solution was slowly added to the reactor, and the temperature inside the reactor was controlled at 20±5℃ during the addition process. After the addition was complete, stirring was continued for half an hour. 216.03 kg of ethyl acetate was added to the reactor, and the mixture was separated. The organic phase was dried with anhydrous sodium sulfate. The external temperature of the reactor was adjusted to 35±5℃, and the solvent was removed under reduced pressure until the solvent content was 2-3V. 29.12 kg of n-heptane was added to the reactor, and the external temperature of the reactor was adjusted to 40±5℃, and the solvent was removed under reduced pressure until the residual solvent in the reactor was 2-3V. The filter cake was dried in a blower at 50℃ until the moisture content was <1.0%. 12.5 kg of compound of formula (V) was obtained with a purity of 97% and a yield of 80%.

[0110] Step 3: 2-(4-(methylhydrazine)bicyclo[2.2.2]oct-1-yl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazolium dihydrobromide (compound of formula (IV))

[0111] 2-(4-(hydrazineylmethyl)bicyclo[2.2.2]octan-1-yl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole di-hydrobromate (compound of formula (IV))

[0112]

[0113] Reaction: 49.35 kg of methanol and 12.50 kg of compound (V) were added to the reactor, and stirring was started. The reactor temperature was controlled at 25±5℃, and 24.49 kg of 48% hydrogen bromide aqueous solution was added dropwise. After the addition was complete, the reactor temperature was adjusted to 35±5℃ and maintained at 35±5℃ for 10 h. The reactor temperature was adjusted to 40±5℃ and desolvation was carried out under reduced pressure until no obvious distillate flowed out. 20.08 kg of ethanol and 20.49 kg of methyl tert-butyl ether were added to the reactor, and the reactor temperature was controlled at 20±5℃. Stirring was started and carried out for 1-2 h. The mixture was centrifuged, and the filter cake was dried in a forced-air oven at 45℃ until the moisture content was <1.0%. 12.5 kg of compound (IV) with a purity of 99% and a yield of 80% was obtained.

[0114] Step 4: (Z)-2,4-dichloro-3-fluoro-5-((2-((4-(1-isopropyl-4-(trifluoromethyl-1-hydro-imidazol-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)hydrazine)methyl)pyridine (compound of formula (III))

[0115] (Z)-2,4-dichloro-3-fluoro-5-((2-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)hydrazineylidene)methyl)pyridine (compound of formula (III))

[0116]

[0117] The internal temperature was controlled at 25±5℃. 16.326 kg of acetic acid and 0.662 kg of sodium acetate were added sequentially to a 50 L reactor. After the addition was complete, the mixture was stirred at room temperature. Then, 0.776 kg of compound (B) was added and stirred until dissolved. Then, 2.003 kg of compound (IV) and 16.153 kg of purified water were slowly added dropwise over approximately 1 hour. After the addition was complete, the reaction was allowed to proceed for 2 hours. 6.034 kg of methanol was added to the reaction mixture. After the addition was complete, the mixture was stirred for 1 hour. The mixture was filtered, and the filter cake was washed three times with purified water. The filter cake was then dried under vacuum to obtain 1.908 kg of intermediate product compound (III) (yield: 90%).

[0118] 1 H NMR (400MHz, DMSO) δ8.57(t,J=4.7Hz,1H),8.53(s,1H),7.91(d,J=1.0Hz,1H),7.60(s,1H),4.84(dt,J =13.2,6.6Hz,1H),3.04(d,J=4.7Hz,2H),1.97–1.87(m,6H),1.60–1.50(m,6H),1.37(d,J=6.5Hz,6H).

[0119] LCMSm / z = 506.1 [M+H] +

[0120] Step 5: 6-Chloro-7-fluoro-1-((4-(1-isopropyl-4-(trifluoromethyl)-1-hydro-imidazol-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)-1-hydro-pyrazolo[4,3-c]pyridine (compound of formula (II))

[0121] 6-chloro-7-fluoro-1-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1H-pyrazolo[4,3-c]pyridine (compound of formula (II))

[0122]

[0123] 13.186 kg N-methylpyrrolidone, 2.379 kg cesium carbonate, 0.707 kg cuprous iodide, and 0.571 kg 2,2'-bipyridine were added sequentially to the reaction vessel. Stirring was started, and the temperature was raised to 120±5℃. While maintaining an internal temperature ≥110℃, a solution of N-methylpyrrolidone of formula (III) (1.843 kg of formula (III) + 4.586 kg N-methylpyrrolidone) was slowly added dropwise over approximately 2 hours. After the addition was complete, the reaction continued for 1.5 hours. The temperature was then lowered to 20±5℃, and the reaction solution was transferred to a 100 L reaction vessel. 16.740 kg of ammonia water was added, and the mixture was stirred at 20±5℃ for approximately 1 hour. Then, 30.678 kg of purified water and 52.204 kg of isopropyl acetate were added. After separation, the organic phase was washed twice with 20.139 kg of 10% citric acid solution. Another 20.098 kg of citric acid solution was then added to the organic phase. Wash once with 10% sodium chloride solution; concentrate under vacuum at 50±5℃ until the final volume is about 14L, add 7.901kg of anhydrous methanol to switch solvents, continue to concentrate until the final volume is about 14L, stop concentration, cool to 20±5℃ and stir for about 1h, filter, wash the filter cake once with 0.711kg of anhydrous methanol; dry the filter cake under vacuum at 55±5℃ and ≤-0.08MPa for 10h to obtain 1.441kg of intermediate product of formula (II) compound (yield: 84.3%).

[0124] 1 H NMR (400MHz, DMSO) δ8.57(t,J=4.7Hz,1H),8.53(s,1H),7.91(d,J=1.0Hz,1H),7.60(s,1H),4.84(dt,J =13.2,6.6Hz,1H),3.04(d,J=4.7Hz,2H),1.97–1.87(m,6H),1.60–1.50(m,6H),1.37(d,J=6.5Hz,6H).

[0125] LCMSm / z = 470.2[M+1] +

[0126] Step 6: 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-fluoro-1-((4-(1-isopropyl-4-(trifluoromethyl)-1-hydro-imidazol-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)-1-hydro-pyrazolo[4,3-c]pyridine (compound of formula (I))

[0127] 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-fluoro-1-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1H-pyrazolo[4,3-c]pyridine (compound of formula (I))

[0128]

[0129] 10.790 kg acetonitrile, 1.016 kg compound (A), 0.116 kg Xphos-Pd-G2, and 1.391 kg compound (II) were added sequentially to the reactor. Stirring was started, and nitrogen purging was performed for 30 min. The temperature was raised to 50 ± 5 °C, and sodium hydroxide solution (0.237 kg sodium hydroxide + 2.780 kg purified water, bubbling with nitrogen for 20 min) was slowly added dropwise under nitrogen protection over approximately 0.5 h. After the addition was complete, the reaction continued for another 0.5 h. The reaction solution was transferred to a 50 L reactor, and 18.002 kg ethyl acetate and 20.473 kg 3% sodium chloride solution were added. After separation, 11.271 kg of organic phase was added. Wash twice with 10% sodium chloride solution (11.271 kg × 2); collect the organic phase, concentrate under vacuum at 50 ± 5 °C until the final volume is about 6 L, stop the concentration, add 0.750 kg isopropanol, cool to 20 ± 5 °C and stir for about 2 h, filter, and dry the filter cake under vacuum at 50 ± 5 °C and ≤ -0.08 MPa for about 16 h to obtain 1.228 kg of crude product of compound (I) (yield: 82.6%).

[0130] 1H NMR (400MHz, CDCl3) δ8.99(d,J=1.6Hz,1H),8.69(s,1H),8.21(d,J=2.0Hz,1H ),7.21(d,J=1.0Hz,1H),4.68–4.75(m,1H),4.37(s,2H),3.93(s,3H),1.99–2. 04(m,6H),1.73(td,J=8.2,4.2Hz,1H),1.68–1.60(m,6H),1.41(d,J=6.6Hz,6H ),1.36–1.27(m,1H),1.23–1.15(m,1H),0.94–1.00(m,1H),0.90–0.82(m,1H).

[0131] LCMSm / z = 584.70 [M+1] + .

[0132] Step 7: 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-fluoro-1-((4-(1-isopropyl-4-(trifluoromethyl)-1-hydro-imidazol-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)-1-hydro-pyrazolo[4,3-c]pyridine (compound of formula (I))

[0133] 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-fluoro-1-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1H-pyrazolo[4,3-c]pyridine (compound of formula (I))

[0134] 1.228 kg of crude compound (I) and 9.988 kg of anhydrous ethanol were added to the reactor. Stirring was started, and the temperature was raised to 80±5℃ and maintained for approximately 1 hour. The reaction solution was then hot-filtered to remove a small amount of insoluble matter. The filtrate was collected and added to a 50 L reactor. The temperature was raised to 70±5℃, and the internal temperature was controlled to be ≥65℃. 1.994 kg of purified water was slowly added dropwise over approximately 0.5 hours. After the addition was complete, the temperature was lowered to 60℃, and 2.41 g of compound (I) seed crystals were added. The mixture was then stirred for 20 minutes. Add 4.971 kg of purified water dropwise over approximately 0.5 h, cool to approximately 20 ± 5 °C, and continue stirring for 2 h. After stirring for approximately 2 h, filter the reaction mixture. Wash the filter cake with 0.516 kg of anhydrous ethanol / purified water in a 2:1 ratio, then rinse with 0.600 kg of purified water. Filter until no more droplets flow out. Dry the filter cake under reduced pressure at 55 ± 5 °C and vacuum ≤ -0.08 MPa for approximately 36 h to obtain 0.997 kg of compound (I) (molar yield: 81.2%).

[0135] 1 H NMR (400MHz, CDCl3) δ8.99(d,J=1.6Hz,1H),8.69(s,1H),8.21(d,J=2.0Hz,1H ),7.21(d,J=1.0Hz,1H),4.68–4.75(m,1H),4.37(s,2H),3.93(s,3H),1.99–2. 04(m,6H),1.73(td,J=8.2,4.2Hz,1H),1.68–1.60(m,6H),1.41(d,J=6.6Hz,6H ),1.36–1.27(m,1H),1.23–1.15(m,1H),0.94–1.00(m,1H),0.90–0.82(m,1H).

[0136] LCMSm / z = 584.70 [M+1] + .

Claims

1. A method for preparing a compound of formula (I), comprising the following steps: in, R and R' are leaving bases.

2. A method for preparing a compound of formula (III), comprising the following reaction: in, R and R' are leaving bases.

3. A method for preparing a compound of formula (I), comprising the following steps: in, R and R' are leaving bases.

4. A method for preparing a compound of formula (VI), comprising the following reaction:

5. A method for preparing a compound of formula (V), comprising the following reaction:

6. A method for preparing a compound of formula (IV), comprising the following reaction: The reaction was carried out in the presence of hydrogen bromide.

7. A compound of formula (III), (IV'), (B), (V), (VI) or a salt thereof: in, R and R' are leaving bases.

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