Vilbeglycolone intermediate compound as well as preparation method and application thereof

Abstract

The invention discloses a vibeglycolone intermediate, a preparation method thereof and application of the intermediate in preparation of vibeglycolone, and belongs to the technical field of medicinal chemistry. The structural general formula of the vibeglycolone intermediate compound II disclosed by the invention is as follows: # imgabs0 # R1 is a silicon-containing hydroxyl protecting group. The invention also develops a new synthesis route of vibeglycolone by adopting the key intermediate, and by introducing a hydroxyl protecting group at the front end of the reaction, the stability of the intermediate compound is increased, the generation of oxidation impurities in the cyclization and hydrogenation process is effectively reduced, the purification problem in the synthesis process is greatly improved, the cost is saved, and the yield is increased. The synthesis efficiency is also improved, the obtained target compound vibeglycolone has higher purity, and the newly developed synthesis route is more suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a new intermediate of vibergolone and a preparation method thereof, as well as application of the intermediate in the preparation of vibergolone. Background Art

[0002] Vibegron is a β3 adrenergic receptor (ADRB3) agonist used to treat urge incontinence, urgency and frequency in patients with overactive bladder (OAB). Vibegron was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on September 21, 2018, and is marketed in Japan by Kyorin Pharmaceutical and Kissei. It was approved for marketing by the FDA on December 23, 2020.

[0003] The chemical name of Vibegron is (6S)-N-[4-[[(2S,5R)-5-[(R)hydroxy(phenyl)methyl]pyrrolidin-2-yl]toluene]phenyl]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-α]pyrimidine-6-carboxamide, and the molecular structure is as follows:

[0004]

[0005] At present, there are mainly the following methods for preparing Vibergron:

[0006]

[0007] Method 1

[0008] Method 1: Compound patent WO2009124166A uses 5-alkyne-1-hexanoic acid (1) as the starting material, and introduces a chiral oxazolidinone auxiliary group to obtain the aldol condensation product 3 with high enantioselectivity. The intermediate is hydrolyzed and protected on the hydroxyl group to convert into the intermediate 5. The intermediate further undergoes Curtius rearrangement to obtain the intermediate 6, which is then subjected to Sonogashira coupling, enamine hydrolysis, and acidic de-Boc intramolecular imidization to obtain the intermediate 9, which is further subjected to reductive amination under NaBH3CN conditions to generate two diastereoisomers 10. The cis isomer is then subjected to Boc protecting group on the pyrrole ring, NO2 hydrogenation reduction, amidation, and deprotection to obtain the target product, vibergron. This route has poor selectivity (dr=84:16) when synthesizing the intermediate 10, which is not conducive to subsequent separation and purification, and greatly reduces the synthesis efficiency.

[0009]

[0010] Method 2

[0011] Method 2, process patents WO2013062881A and WO2013062878A1 use glycine methyl ester 1 as the starting material, and obtain intermediate 3 through amidation and intramolecular rearrangement. Under the action of carbonyl reductase, chiral amino alcohol intermediates can be quickly and efficiently constructed, followed by hydroxyl protection, ester reduction, and alcohol oxidation to obtain intermediate 7, which is then reacted with phosphate 8 to form olefin 9, and then hydrogenation reduction of double bonds, deprotection, reductive amination, and amide condensation to complete the synthesis of the target product, vibergron. This preparation process involves HWE reaction, and the raw material phosphate used therein has no industrial-grade material supply, and the dihydropyrrole hydrochloride intermediate 11 in the last step has poor stability and is easily oxidized. Based on structural similarity, the generated impurities are difficult to remove in the subsequent process.

[0012] Method 3, Patent WO2014150639A uses relatively cheap pentynol as a raw material, without purification, and quickly constructs intermediate 3 in four steps. Under the action of carbonyl reductase, the intermediate obtains the reduction product 4 with high enantioselectivity (>99.4% ee), high diastereoselectivity (dr>100:1), and high yield (95%). Subsequently, the intermediate 8 is obtained by Sonogashira coupling, cycloimidation, hydroxyl protection, hydrogenation reduction, and hydroxyl deprotection. Finally, the amine intermediate is condensed with carboxylic acid sodium salt 9 under the action of EDC to generate the target product Vibergron. The disadvantage of this process route is that the intermediates 6 and 7 generated subsequently are poorly stable and easily oxidized, generating a large amount of impurities that are difficult to remove, making compound 8 difficult to use for subsequent raw material synthesis.

[0013]

[0014] Method 3

[0015] In summary, the above described preparation method of Vibergolone is cumbersome and has many disadvantages such as poor yield, low purity, and unsuitability for economical large-scale production. In order to overcome this problem, it is necessary to develop a new and cost-effective process for large-scale production of Vibergolone with high chiral purity. Summary of the invention

[0016] In order to solve the problems of poor yield, low purity and high cost in the preparation process of Vibergolone in the prior art, the present invention provides a new intermediate II and IV of Vibergolone and a preparation method thereof, as well as the application of the new intermediate in the preparation of a key intermediate of Vibergolone and Vibergolone.

[0017] The present invention is specifically implemented by the following technical solutions:

[0018] In a first aspect, the present invention provides a compound II;

[0019]

[0020] Where R 1 A silanol-containing protective group;

[0021] Preferably, the R 1 Optional TBS, TIPS, DMPS or TBDPS;

[0022] As a further preferred embodiment, R 1 TBS is preferred.

[0023] In a second aspect, the present invention provides a method for preparing compound II, the preparation method comprising the following steps:

[0024] (1) Under alkaline conditions, compound I reacts with a silicon-containing chlorinated compound in an organic solvent to obtain compound II; the chemical reaction equation is as follows:

[0025]

[0026] Preferably, the organic solvent in step (1) is one or more of THF, DMF, DMAC, EtOAc, CH2Cl2, acetone, CH3CN, toluene; more preferably CH2Cl2. Preferably, the initial reaction concentration of Formula I in the organic solvent is 0.1-2M;

[0027] Preferably, the base in step (1) is Et3N, DIPEA, tetramethylethylenediamine, imidazole, DMAP, DBN, DBU, pyridine, N-methylmorpholine; more preferably imidazole. Preferably, the molar ratio of the base to formula I is 1 to 5:1;

[0028] In a third aspect, the present invention provides a compound IV;

[0029] In Formula IV, R 1 The definition of is the same as that of Formula II.

[0030] In a fourth aspect, the present invention provides a method for preparing compound IV, the preparation method comprising the following steps:

[0031] (2) Under the protection of inert gas, compound II and compound III react in alkaline conditions, copper salt and catalyst to obtain compound IV; the chemical reaction equation is as follows:

[0032]

[0033] Preferably, the base in step (2) is: Et3N, i-Pr2NEt, i-Pr2NH, more preferably Et3N. Preferably, the molar ratio of the base to formula II is 1 to 3:1;

[0034] Preferably, the copper salt in step (2) is: CuI, CuBr, CuCl, more preferably CuI;

[0035] Preferably, the catalyst in step (2) is: Pd(dppf)Cl2, Pd(PPh3)4, PdCl2, Pd(PPh3)2Cl2, Pd(OAc)2 / PPh3, more preferably Pd(PPh3)2Cl2;

[0036] Preferably, the reaction in step (2) needs to be carried out in a nitrogen atmosphere, so during the reaction process, the air in the reactor needs to be fully replaced with nitrogen. To achieve sufficient replacement, the nitrogen replacement operation can be carried out multiple times; the reaction temperature is 0-40°C.

[0037] In a fifth aspect, the present invention provides a method for preparing compound V, the preparation method comprising the following steps:

[0038] (3) Compound IV is reacted with a deprotecting agent to obtain compound V; the chemical reaction equation is as follows:

[0039]

[0040] Preferably, the deprotection reagent in step (3) is: TFA, TMSBr, AlCl3, ZnBr2, more preferably ZnBr2;

[0041] In a sixth aspect, the present invention provides a method for preparing compound VIII, the preparation method comprising the following steps:

[0042] (1) Under alkaline conditions, compound I reacts with a hydroxyl protecting agent in an organic solvent to obtain compound II;

[0043] (2) Under alkaline conditions, copper salt and catalyst conditions, compound II and compound III react to obtain compound IV;

[0044] (3) Compound IV is reacted with a deprotecting agent to obtain compound V;

[0045] (4) Compound V undergoes a ring-closing reaction under alkaline conditions to obtain compound VI;

[0046] (5) Under the conditions of a catalyst and a reducing agent, compound VI is reduced to compound VII;

[0047] (6) Under acidic conditions, compound VII is deprotected to obtain a salt of compound VIII, and a base is added to adjust to obtain free amine VIII; the chemical reaction equation is as follows:

[0048]

[0049] Among them, R 1 is TBS, DMPS, TBDPS or TIPS; further preferably R 1 For TBS.

[0050] The operation details of steps (1)-(3) are as shown above and will not be repeated here.

[0051] Furthermore, in step (4), the base is selected from Et3N, i-Pr2NEt, i-Pr2NH, and more preferably i-Pr2NEt.

[0052] Furthermore, the catalyst in step (5) is Pt / Al2O3, Pd / Al2O3, Pd / C, Pd(OH) 2 / C, more preferably Pd(OH)2 / C; the reducing agent in step (5) is H2, HCOONH4, more preferably HCOONH4.

[0053] Furthermore, in step (6), the acid may be TFA, HCl, HBr, H2SO4, HNO3, H3PO4, MeSO3H, and more preferably H2SO4; the base may be imidazole, pyridine, Et3N, ammonia water, NaOH, KOH, and more preferably ammonia water.

[0054] In a seventh aspect, the present invention provides a method for synthesizing Vibergron using compound IX, wherein the preparation method comprises the following steps:

[0055] (7) Compound VIII and compound IX are reacted with a condensing agent to obtain vibergron.

[0056] The chemical reaction equation is expressed as follows:

[0057]

[0058] In the condensation reaction, the condensation agent is at least one of DCC, CDI, EDCI, HATU, HBTU, EDCI / HOBT, EDCI / HOAT, and T3P.

[0059] In an eighth aspect, the present invention provides a method for preparing vibergron, the preparation method comprising the following steps:

[0060] (1) Under alkaline conditions, compound I reacts with a hydroxyl protecting agent in an organic solvent to obtain compound II;

[0061] (2) Under alkaline conditions, copper salt and catalyst conditions, compound II and compound III react to obtain compound IV;

[0062] (3) Compound IV is reacted with a deprotecting agent to obtain compound V;

[0063] (4) Compound V undergoes a ring-closing reaction to obtain compound VI;

[0064] (5) Under the conditions of a catalyst and a reducing agent, compound VI is reduced to compound VII;

[0065] (6) Under acidic conditions, compound VII is deprotected to obtain a salt of compound VIII, and a base is added to adjust the reaction to obtain free amine VIII;

[0066] (7) Compound VIII and compound IX are reacted with a condensing agent to obtain vibergron.

[0067] The chemical reaction equation is expressed as follows:

[0068]

[0069] Among them, R 1 is TBS, TBDPS or TIPS; further preferably R 1 For TBS.

[0070] The operation details of steps (1)-(6) are as shown above and will not be repeated here.

[0071] In the condensation reaction of step (7), the condensation agent is at least one of DCC, CDI, EDCI, HATU, HBTU, EDCI / HOBT, EDCI / HOAT, and T3P.

[0072] Compared with the existing preparation method of Vibergron, the present invention has the following technical advantages:

[0073] The present invention describes a new synthesis route of Vibergolone, which increases the stability of the intermediate compound by introducing a hydroxyl protecting group at the front end of the reaction, effectively reduces the generation of oxidative impurities in the cyclization and hydrogenation processes, greatly improves the purification problem in the synthesis process, saves costs, and improves the synthesis efficiency. The obtained target compound Vibergolone has higher purity, and the newly developed synthesis route is more suitable for industrial-scale production.

[0074] The present invention first adds a silanol protecting group, thereby avoiding the generation of Ullmann-type ether impurities from free hydroxyl and compound III during the Sonogashira coupling process, effectively improving the raw material conversion efficiency and avoiding the impurity removal process; at the same time, the generation of chloro-based poisonous impurities in the process from compound 4 to 5 in method three is avoided. DETAILED DESCRIPTION

[0075] In order to make the purpose, technical scheme and advantages of the present invention clearer, the technical scheme will be further described clearly and completely through examples below. If no specific conditions are specified in the examples, the experiment is carried out under conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the instruments is not specified, they are all conventional products that can be purchased commercially. If the manufacturer of the reagents is not specified, they are all conventional products that can be purchased commercially or prepared according to known literature. In the compound II used in the examples of the present invention, R 1 is TBS, TIPS, other compounds in the corresponding examples, R 1 Also known as TBS and TIPS.

[0076] Example 1: Preparation of Compound II-1

[0077]

[0078] Scheme 1: Add imidazole (2.04 g, 30.0 mmol), CH2Cl2 (10 mL) and TBSCl (3.0 g, 20 mmol) in a 100 mL three-necked flask in turn, maintain the oil bath temperature at 45 ° C, stir for 1 hour, and slowly add I (2.89 g, 10.0 mmol) / CH2Cl2 (10 mL) solution to the reaction solution. After 18 hours of reaction, the plate monitors the complete conversion of the raw material I, transfer the reaction solution to a separatory funnel, wash with water (3*100 mL), wash with saturated brine, dry with anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure, and vacuum dry at room temperature to obtain compound II-1, a light yellow liquid with a yield of 99% and a purity of 97.8%. High-resolution mass spectrometry (HR-ESI-MS), nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR), carbon nuclear magnetic resonance spectroscopy ( 13 C-NMR) confirmed the structure of compound II-1: ESI-HRMS: m / z = 404.2619 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6)δ 1 H NMR (400MHz, DMSO-d6) δ7.34–7.27(m,2H),7.27–7.19(m,3H),6.40(d,J=8.6Hz,1H),4.70(d,J=5.7Hz,1H),3.73–3.56(m,1H),2.64(t, J=2.6Hz,1H),2.21–2.08(m,1H),2.05–1.93(m,1H),1.60–1.43(m,1H),1.42–1.20(m,10H),0.84(s,9H),0.04(s,3H),-0.18(s,3H)ppm. 13C NMR (101MHz, DMSO-d6) δ155.3,141.8,127.7,127.1,126.6,84.0,77.3,75.3,70.9,55.5,28.2,25.7,25.6,17.7,14.8,-3.3,-5.1ppm.

[0079] Scheme 2: Compound I (0.10 g, 0.35 mmol) and CH3CN (1.7 mL) were added to a 10 mL reaction tube in sequence, the temperature was lowered to 0°C, DBU (0.158 g, 1.05 mmol) was added, and after stirring for 1 h, TBSCl (0.78 g, 0.53 mmol) was added in batches. After stirring at 0°C for 24 h, the raw material I was still not completely converted. Samples were taken for HPLC analysis, and the conversion rate was 84% ​​and the yield was 63%.

[0080] Scheme 3: Add imidazole (0.706 g, 1.05 mmol) and DMF (1.7 mL) in a 10 mL reaction tube, cool to 0°C, add TBSCl (0.78 g, 0.70 mmol) in batches, maintain the temperature at 0°C, stir for 0.5 h, and slowly add I (0.10 g, 0.35 mmol) to the reaction solution. After stirring at 0°C for 24 h, the raw material I was completely converted, and the sample was taken for HPLC analysis, with a conversion rate of 100% and a yield of 83%.

[0081] Example 2: Preparation of Compound IV-1

[0082]

[0083] Scheme 1: Compound II-1 (3.38 g, 8.37 mmol), compound III (2.08 g, 8.37 mmol), Pd(PPh3)2Cl2 (59 mg, 0.084 mmol) and CuI (25.6 mg, 0.168 mmol) were added in sequence into a 250 mL three-necked flask. Nitrogen was replaced in the reaction flask three times. i-PrOH (10 mL) and THF (20 mL) were slowly added. The reaction solution was stirred at 0 °C. After 10 min, Et3N (0.98 g, 9.63 mmol) was slowly added dropwise. The reaction solution was stirred at this temperature for 10 min and then warmed to room temperature. The reaction was stirred for 18 h under TLC monitoring, and the raw material II was completely converted. i-PrOAc (50 mL) was added to the reaction flask and stirred for 10 min. The reaction solution was transferred to a separatory funnel and washed with 10% ammonium chloride solution (3*30 mL), 0.6 M hydrochloric acid (30 mL), and saturated saline solution twice. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain compound IV-1 as a yellow liquid with a yield of 99% and a purity of 96%. High-resolution mass spectrometry (HR-ESI-MS), nuclear magnetic resonance hydrogen spectrum ( 1H-NMR), carbon nuclear magnetic resonance spectroscopy ( 13 C-NMR) confirmed the structure of compound IV-1: ESI-HRMS: m / z=563.2348 [M+H] + ; 1 HNMR (400MHz, DMSO-d6) δ8.23–8.14(m,2H),7.62–7.55(m,2H),7.36–7.28(m,2H),7.28–7.21(m,3H),6.52(d,J=8.6Hz,1H),4.71(d,J =5.7Hz,1H),3.82–3.63(m,1H),2.48–2.29(m,2H),1.65–1.50(m,1H),1.47–1.28(m,10H),0.82(s,9H),0.04(s,3H),-0.18(s,3H)ppm. 13 C NMR(101MHz,DMSO-d6)δ155.4,146.3,141.8,132.3,130.2,127.8,127.2,126.7, 123.6,96.3,79.3,77.4,75.5,55.6,31.2,28.2,25.6,17.7,15.9,-5.0,-5.1ppm.

[0084] Scheme 2: Compound II-1 (2.70 g, 6.70 mmol), compound III (1.66 g, 6.70 mmol), Pd(dppf)Cl2 (49 mg, 0.067 mmol) and CuI (20.5 mg, 0.134 mmol) were added in sequence into a 250 mL three-necked flask. Nitrogen was replaced in the reaction flask three times. i-PrOH (8 mL) and THF (16 mL) were slowly added. The reaction solution was stirred at 0 °C. After 10 min, Et3N (0.78 g, 7.7 mmol) was slowly added dropwise. The reaction solution was stirred at this temperature for 10 min and then warmed to room temperature. The reaction was stirred for 18 h under TLC monitoring, and the raw material II was completely converted. i-PrOAc (40 mL) was added to the reaction flask and stirred for 10 min. The reaction solution was transferred to a separatory funnel and washed with 10% ammonium chloride solution (3*20 mL), 0.6 M hydrochloric acid (20 mL), and saturated saline solution twice. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain compound IV-1 as a yellow liquid with a yield of 93% and a purity of 95%.

[0085] Example 3. Preparation of Compound V-1

[0086]

[0087] Scheme 1: Add compound IV-1 (5.0 g, 9.5 mmol), ZnBr2 (2.50 g, 1.8 mmol) and CH2Cl2 (250 mL) to a single-necked flask in sequence, and heat to 40°C with stirring. Monitor the reaction by TLC for 24 hours, and the raw material IV-1 is completely converted. The reaction solution is cooled to room temperature, filtered, washed with dichloromethane, and the filtrate is transferred to a separatory funnel, washed twice with water and saturated saline solution, respectively. The organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain compound V-1 as a light yellow solid with a yield of 95% and a purity of 97%. High-resolution mass spectrometry (HR-ESI-MS), nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR), carbon nuclear magnetic resonance spectroscopy ( 13 C-NMR) confirmed the structure of compound V-1: ESI-HRMS: m / z = 425.2367 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.24–8.18(m,2H),7.63–7.57(m,2H),7.44–7.31(m,5H),4.95(d,J=6.3Hz,1H),3.38(d,J=6 .1Hz,1H),2.65(t,J=7.3Hz,2H),1.82–1.68(m,2H),1.32–1.20(m,2H),0.82(s,9H),0.07(s,3H),-0.20(s,3H)ppm; 13 C NMR(101MHz,DMSO-d6)δ149.3,142.3,135.2,132.4,131.2(3),131.1(7),1 29.9,126.5,97.6,83.1,77.1,57.6,28.5,28.4,20.5,18.3,-0.5,-2.7ppm.

[0088] Scheme 2: Compound IV-1 (2.5 g, 4.8 mmol), CH2Cl2 (100 mL) and TFA (100 mL) were added to a single-necked flask in sequence and stirred at 0°C. The reaction was monitored by TLC for 1 h, and the raw material IV-1 was completely converted. The reaction solution was warmed to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in CH2Cl2, and ammonia water was added to adjust it to neutral. The solution was transferred to a separatory funnel, washed twice with water and saturated saline solution, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain compound V-1 as a light yellow solid with a yield of 90% and a purity of 88%.

[0089] Scheme 3: Compound IV-1 (2.5 g, 4.8 mmol), TMSBr (1.5 g, 9.6 mmol) and CH2Cl2 (100 mL) were added to a single-necked flask in sequence and stirred at 0°C. The reaction was monitored by TLC for 24 h. The raw material IV-1 was still not completely converted. A small amount of methanol was added, and the reaction solution was warmed to room temperature and transferred to a separatory funnel. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain compound V-1 as a light yellow solid with a yield of 85% and a purity of 86%.

[0090] Example 4. Preparation of Compound VI-1

[0091]

[0092] Scheme 1: Add V-1 (3.56 g, 8.39 mmol) to a 100 mL pressure bottle, replace nitrogen three times, add i-PrOH (20 mL) and i-Pr2NEt (2.17 g, 16.8 mmol) in sequence, heat and stir, keep the water bath temperature at 55-65 ° C for 6 hours. Monitor the complete conversion of raw material V-1 by spot plate, cool the reaction solution containing compound VI-1 to room temperature, and use it directly in the next step.

[0093] Scheme 2: Add V-1 (3.24 g, 7.63 mmol) to a 100 mL three-necked flask, replace nitrogen three times, add DMAC (3 mL), THF (15 mL) and i-Pr2NEt (1.97 g, 15.3 mmol) in sequence, heat and stir, keep the water bath temperature at 55-65 ° C for 6 hours. Monitor the complete conversion of raw material V-1 by spot plate, cool the reaction solution containing compound VI-1 to room temperature, and use it directly in the next step.

[0094] Scheme 3: Add V-1 (2.92 g, 6.87 mmol) to a 100 mL three-necked flask, replace nitrogen three times, add DMAC (16 mL) and i-Pr2NEt (1.77 g, 13.8 mmol) in sequence, heat and stir, keep the water bath temperature at 55-65 ° C for 6 hours. Monitor the complete conversion of raw material V-1 by spot plate, cool the reaction solution containing compound VI-1 to room temperature, and use it directly in the next step.

[0095] Example 5. Preparation of Compound VII-1

[0096]

[0097] Scheme 1: The reaction solution of Scheme 1 in Example 4 was cooled to 20°C, and i-PrOH (20 mL), Pd(OH)2 / C (10wt%, 0.89 g) and HCOONH4 (3.17 g, 50.3 mmol) were added in sequence. The reaction was sealed and the temperature was maintained at 27°C for 17 hours. The reaction temperature was then raised to 50°C for 7.5 hours. The intermediate was completely converted after monitoring by a plate. The catalyst was filtered out and washed with isopropanol (10 mL). The solvent was evaporated under reduced pressure. Water (100 mL), ethyl acetate (50 mL) and sodium chloride (5 g) were added and stirred at room temperature for 5 minutes to separate the layers. The organic phase was washed with water (2*50 mL), and the solvent was evaporated under reduced pressure to obtain compound VII-1, a light yellow or wine red liquid with a yield of 86% and a purity of 97%.

[0098] Scheme 2: The reaction solution of Scheme 2 in Example 4 was cooled to 20°C, and DMAC (11 mL), THF (55 mL) and Pt / Al2O3 (5wt%, 0.8 g) were added in sequence, transferred to a high-pressure hydrogenation reactor, pressurized to 0.71 MPa, maintained at a reaction temperature of 27°C for 17 hours, and the conversion of VI-1 was complete after the plate was monitored. The reaction temperature was raised to 50°C for 7.5 hours, and the conversion of the intermediate was complete after the plate was monitored. The hydrogenation reactor was removed, the inner tank was taken out, the catalyst was removed by filtration, washed with tetrahydrofuran (10 mL), and the solvent was evaporated under reduced pressure. Water (100 mL), ethyl acetate (50 mL) and sodium chloride (5 g) were added and stirred at room temperature for 5 minutes to separate the layers. The organic phase was washed with water (2*50 mL), and the solvent was evaporated under reduced pressure to obtain compound VII-1, a light yellow or wine red liquid with a yield of 83% and a purity of 95%.

[0099] Scheme 3: The reaction solution of Scheme 3 in Example 4 was cooled to 20°C, THF (60 mL) and Pt / Al2O3 (5wt%, 0.7 g) were added in sequence, transferred to a high-pressure hydrogenation reactor, pressurized to 0.71 MPa, maintained at a reaction temperature of 27°C for 17 hours, and the conversion of VI-1 was complete after monitoring by the plate. The reaction temperature was raised to 50°C for 7.5 hours, and the conversion of the intermediate was complete after monitoring by the plate. The hydrogenation reactor was removed, the inner tank was taken out, the catalyst was removed by filtration, washed with THF (10 mL), and the solvent was evaporated under reduced pressure. Water (100 mL), ethyl acetate (50 mL) and sodium chloride (5 g) were added and stirred at room temperature for 5 minutes to separate the layers. The organic phase was washed with water (2*50 mL), and the solvent was evaporated under reduced pressure to obtain compound VII-1, a light yellow liquid with a yield of 73% and a purity of 92%.

[0100] Example 6. Preparation of Compound VIII

[0101] Scheme 1: Add compound VII-1 (1.0 g, 2.5 mmol), isopropanol (10 mL) and water (1 mL) to a single-mouth bottle, heat to 60°C, slowly add dilute sulfuric acid (6 M, 1.0 mL), monitor the reaction by HPLC for 24 hours, the raw material VII-1 is completely converted, evaporate the solvent under reduced pressure, add a small amount of isopropanol, heat to 45°C and stir for 30 minutes, slowly cool to room temperature, filter after crystallization, add 20 mL of water to the solid, adjust the pH to 8-9 with ammonia water, extract with ethyl acetate (2*20 mL), wash with water (15 mL), dry the organic phase with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and dry to obtain compound VIII as a light yellow solid with a yield of 70% and a purity of 94%.

[0102]

[0103] Scheme 2: Add compound VII-1 (0.7 g, 1.8 mmol) and isopropanol (7 mL) to a single-mouth bottle, heat to 60°C, slowly dropwise add 85% phosphoric acid (0.25 g) in isopropanol (3 mL), monitor the reaction by HPLC for 24 hours, the raw material VII-1 is completely converted, evaporate the solvent under reduced pressure, add a small amount of isopropanol, heat to 45°C and stir for 30 minutes, slowly cool to room temperature, filter after crystallization, add 15 mL of water to the solid, adjust the pH to 8-9 with ammonia water, extract with ethyl acetate (2*15 mL), wash with water (10 mL), dry the organic phase over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and dry to obtain compound VIII as a light yellow solid with a yield of 65% and a purity of 93%.

[0104]

[0105] Scheme 3: Add compound VII-1 (1.0 g, 2.5 mmol) and ethyl acetate (5 mL) to a single-necked bottle, cool to 0°C, and slowly add HCl / EtOAc (2 mL, 4 M) solution. After 16 hours, take a sample for HPLC analysis. The residual amount of VII-1 or VII-1 hydrochloride is 18%, and the remaining raw materials are converted into VIII hydrochloride.

[0106] Example 7: Preparation of Vibergron

[0107]

[0108] Scheme 1: Add compound VIII (0.500 g, 1.77 mmol), compound IX (0.350 g, 1.95 mmol), isopropanol (2 mL) and water (1.2 mL) to a three-necked flask, stir at room temperature to dissolve, slowly add hydrochloric acid (5 M, about 0.5 mL) to adjust pH to 3.0-3.5, continue stirring at room temperature for 1 hour, slowly add EDCI (0.364 g, 1.89 mmol), HPLC monitors the reaction for 18 hours, and the raw material VIII is completely converted. 14% ammonia solution (about 2 mL) is added to the reaction solution, and a light yellow solid is precipitated. After stirring at room temperature for crystallization for 7 hours, it is filtered, washed with 30% isopropanol solution, and the solid is dried in an oven at 60°C overnight to obtain Vibegron, an off-white solid, with a yield of 89% and a purity of 99.5%.

[0109] Scheme 2: Compound IX (32.9 mg, 0.182 mmol), CDI (27.3 mg, 0.280 mmol) and acetonitrile (0.5 mL) were added to a single-necked bottle respectively, and the mixture was stirred at room temperature for 1.5 h. A solution of VIII (39.6 mg, 0.140 mmol) in acetonitrile (1 mL) was added dropwise to the reaction system. After stirring at room temperature for 24 h, the raw material VIII was still not completely converted. Sampling and HPLC analysis showed a conversion rate of 71% and a yield of 40%.

[0110] Example 8: Preparation of Compound II-2

[0111]

[0112] Imidazole (2.04 g, 30.0 mmol), CH2Cl2 (10 mL) and TIPSCl (3.0 g, 20 mmol) were added to a 100 mL three-necked flask in sequence. The oil bath temperature was maintained at 45 °C. After stirring for 1 h, I (2.89 g, 10.0 mmol) / CH2Cl2 (10 mL) solution was slowly added dropwise to the reaction solution. The plate was monitored. After 18 h, the raw material I was completely converted. The reaction solution was transferred to a separatory funnel, washed with water (3*100 mL), washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Compound II-2 was obtained as a light yellow liquid at room temperature under vacuum. The yield was 96% and the purity was 98.2%.

[0113] Example 9: Preparation of Compound IV-2

[0114]

[0115] In a 250mL three-necked flask, compound II-2 (4.28g, 9.6mmol), compound III (2.39g, 9.6mmol), Pd(PPh3)2Cl2 (66mg, 0.096mmol) and CuI (28.6mg, 0.192mmol) were added in sequence. The reaction flask was evacuated with nitrogen three times. i-PrOH (10mL) and THF (20mL) were slowly added. The reaction solution was stirred at 0°C. After 10min, Et3N (0.98g, 9.63mmol) was slowly added dropwise. The reaction solution was stirred at this temperature for 10min and then warmed to room temperature. The reaction was stirred for 18h under the monitoring of TLC. The raw material II-2 was completely converted. i-PrOAc (50 mL) was added to the reaction flask and stirred for 10 min. The reaction solution was transferred to a separatory funnel and washed with 10% ammonium chloride solution (3*30 mL), 0.6 M hydrochloric acid (30 mL), and saturated saline solution twice. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain compound IV-2 as a yellow liquid with a yield of 99% and a purity of 98%.

[0116] Example 10. Preparation of Compound V-2

[0117]

[0118] Compound IV-2 (5.4 g, 9.5 mmol), ZnBr2 (2.5 g, 1.8 mmol) and CH2Cl2 (250 mL) were added to a single-necked flask in sequence, and the temperature was raised to 40°C with stirring. The reaction was monitored by TLC for 24 hours, and the raw material IV-2 was completely converted. The reaction solution was cooled to room temperature, filtered, washed with dichloromethane, and the filtrate was transferred to a separatory funnel, washed twice with water and saturated saline solution, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain compound V-2 as a light yellow solid with a yield of 93% and a purity of 96%.

[0119] Example 11. Preparation of Compound VI-2

[0120]

[0121] Add V-2 (4.13 g, 8.84 mmol) to a 100 mL pressure bottle, replace nitrogen three times, add i-PrOH (18 mL) and i-Pr2NEt (2.28 g, 17.6 mmol) in sequence, heat and stir, keep the water bath temperature at 55-65 ° C for 6 hours. Monitor the complete conversion of raw material V-1 by spot plate, cool the reaction solution containing compound VI-2 to room temperature, and use it directly in the next step.

[0122] Example 12, Preparation of Compound VII-2

[0123]

[0124] The reaction solution of the above compound VI-2 was cooled to 20°C, and i-PrOH (20 mL), Pd(OH)2 / C (10wt%, 0.93 g) and HCOONH4 (3.33 g, 52.8 mmol) were added in sequence. The reaction was sealed and the temperature was maintained at 27°C for 17 hours. The reaction temperature was then raised to 50°C for 7.5 hours. The intermediate conversion was complete after monitoring by spot plate. The catalyst was filtered out and washed with i-PrOH (10 mL). The solvent was evaporated under reduced pressure. Water (100 mL), ethyl acetate (50 mL) and sodium chloride (5 g) were added and stirred at room temperature for 5 minutes to separate the layers. The organic phase was washed with water (2*50 mL), and the solvent was evaporated under reduced pressure to obtain compound VII-1, a light yellow or wine red liquid with a yield of 85% and a purity of 94%.

[0125] Example 13. Preparation of Compound VIII

[0126]

[0127] Compound VII-2 (1.1 g, 2.5 mmol), isopropanol (10 mL) and water (1 mL) were added to a single-mouth bottle respectively, heated to 60 ° C, and dilute sulfuric acid (6 M, 1.0 mL) was slowly added dropwise. After HPLC monitoring of the reaction for 24 hours, the raw material VII was completely converted, the solvent was evaporated under reduced pressure, a small amount of isopropanol was added, heated to 45 ° C and stirred for 30 min, slowly cooled to room temperature, filtered after crystallization, 20 mL of water was added to the solid, ammonia water was adjusted to pH = 8-9, ethyl acetate was extracted (2*20 mL), washed with water (15 mL), the organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and dried to obtain compound VIII as a light yellow solid with a yield of 74% and a purity of 95%.

[0128] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of the present invention to be protected.

Claims

1. A compound II, characterized in that The general structure is as follows: Where: R 1 Contains a silanol protecting group.

2. Compound II according to claim 1, characterized in that: The R 1 Selected from TBS, TIPS, DMPS or TBDPS.

3. The method for preparing compound II according to claim 1, characterized in that: The method comprises the following steps: under alkaline conditions, compound I reacts with a silicon-containing chlorinated compound in an organic solvent to obtain compound II; the reaction formula is as follows: The organic solvent is selected from one or more of THF, DMF, DMAC, EtOAc, CH2Cl2, acetone, CH3CN, and toluene; the base is selected from Et3N, DIPEA, tetramethylethylenediamine, imidazole, DMAP, DBN, DBU, pyridine, and N-methylmorpholine; and the molar ratio of the base to formula I is 1 to 5:

1.

4. A compound IV, characterized in that The general structure is as follows: Where: R 1 is a silanol-containing protecting group; preferably selected from TBS, TIPS, DMPS or TBDPS.

5. The method for preparing compound IV according to claim 4, characterized in that: The method comprises the following steps: in alkaline conditions, copper salt and catalyst, compound II and compound III react to obtain compound IV; the reaction formula is as follows: The base is selected from Et3N, i-Pr2NEt or i-Pr2NH; the molar ratio of the base to formula II is 1 to 3:1; the copper salt is selected from CuI, CuBr, CuCl; the catalyst is selected from Pd(dppf)Cl2, Pd(PPh3)4, PdCl2, Pd(PPh3)2Cl2 or Pd(OAc)2 / PPh3; the reaction temperature is 0-40°C.

6. A method for preparing compound V, characterized in that: The method comprises the following steps: compound IV is subjected to the action of a deprotecting agent to obtain compound V; the deprotecting agent is selected from TFA, TMSBr, AlCl3 or ZnBr2. Where: R 1 is a silanol-containing protecting group; preferably selected from TBS, TIPS, DMPS or TBDPS.

7. A method for preparing compound VIII, characterized in that: The steps include: Where: R 1 A silanol-containing protective group; preferably selected from TBS, DMPS, TBDPS or TIPS; (1) Under alkaline conditions, compound I reacts with a hydroxyl protecting agent in an organic solvent to obtain compound II; (2) Compound II and Compound III react under alkaline conditions, a copper salt and a catalyst to obtain Compound IV; (3) Compound IV is reacted with a deprotecting agent to obtain compound V; (4) Compound V undergoes a ring-closing reaction under alkaline conditions to obtain compound VI; (5) Under the conditions of a catalyst and a reducing agent, compound VI is reduced to compound VII; (6) Under acidic conditions, compound VII is deprotected to obtain compound VIII salt, which is then adjusted with base to obtain free amine VIII.

8. The method for preparing compound VIII according to claim 7, characterized in that: In step (4), the solvent is selected from one or more of THF, DMF, DMAC, CH3CN, i-PrOH, and the base is selected from Et3N, i-Pr2NEt, i-Pr2NH; in step (5), the catalyst is selected from Pt / Al2O3, Pd / Al2O3, Pd / C, Pd(OH) 2 / C, the reducing agent is selected from H2, HCOONH4; in step (6), the acid is selected from TFA, HCl, HBr, H2SO4, HNO3, H3PO4, MeSO3H, and the base is selected from imidazole, pyridine, Et3N, ammonia, NaOH or KOH.

9. A method for preparing Vibergron, characterized in that: The method comprises the following steps: obtaining compound VIII by the method of claim 7 or 8, and then reacting compound VIII with compound IX under the action of a condensing agent to obtain vibergron; the reaction equation is as follows: The condensing agent is selected from DCC, CDI, EDCI, HATU, HBTU, EDCI / HOBT, EDCI / HOAT or T3P.

10. A method for preparing Vibergron, characterized in that: The steps include:

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