Process for the preparation of (6S)-3-[(4S)-4-cyano-2-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide

Abstract

The present invention provides compounds (I) useful for the prevention and treatment of viral diseases in patients associated with hepatitis B infection or diseases caused by hepatitis B infection. TIFF2022520993000065.tif4946, or a pharmaceutically acceptable salt thereof.

Description

[Technical field]

[0001] The present invention relates to (6S)-3-[(4S)-4-cyano-2-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Compound (I)), useful for the prevention and treatment of viral diseases in patients associated with hepatitis B infection or diseases caused by hepatitis B infection. [ka] or a process for the preparation of a pharma- ceutically acceptable salt thereof. [Background technology]

[0002] A related synthesis method for compound (I) was disclosed in patent WO2016113273 as Example 240, but it is not suitable for commercial use due to the following problems: 1. Chiral separation is required. 2. Excess and toxic I2 is not removed during the synthesis of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate, making it extremely dangerous for large-scale production. 3. When a chiral starting material ((3S)-5-oxopyrrolidine-3-carbonitrile) is used, the chirality is sensitive to the Ullmann reaction conditions and is prone to epimerization. Summary of the Invention

[0003] Based on the above problems, one object of the present invention is therefore to find an efficient alternative synthetic approach that can be applied on a technical scale and / or that can result in obtaining products in higher yields and / or in the desired purity and required chiral configuration. It is also an object of the present invention to address any of the above mentioned problems.

[0004] Further advantages of the current method of the present invention over those previously disclosed in the prior art include: 1. No chiral separation is required and the synthesis of a chiral starting material ((3S)-5-oxopyrrolidine-3-carbonitrile) is reported for the first time in this invention, which can be easily done on a large scale, thus shortening the overall process; 2. Compared with the prior art, excess and toxic I2 was removed in step 1) using a reducing agent, and the amount was then carefully controlled to avoid product loss; 3. The Ullmann reaction conditions were carefully optimized to keep the chirality of the (3S)-5-oxopyrrolidine-3-carbonitrile moiety unchanged throughout the reaction; 4. The BOC removal reaction was carried out under environmentally friendly conditions It is. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005] definition The term "pharmaceutical acceptable salt" refers to conventional acid or base addition salts that retain the biological effects and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid addition salts include those derived from inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base addition salts include those derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides such as, for example, tetramethylammonium hydroxide. Chemical modification of pharmaceutical compounds into salts is a technique well known to pharmaceutical scientists to obtain improved physical and chemical stability, hygroscopicity, flowability, and solubility of the compounds. This is described, for example, in Bastin RJ et al., Organic Process Research & Development 2000, 4, 427-435; or Ansel, H. et al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th Edition (1995), pages 196 and 1456-1457.

[0006] Abbreviation ACN Acetonitrile eq equivalent DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DMEDA N,N'-Dimethyl-1,2-ethanediamine IPA Isopropyl Alcohol IPAc Isopropyl acetate MeTHF 2-Methyltetrahydrofuran MTBE Methyl tert-butyl ether NIS N-iodosuccinimide TEA Triethylamine TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride V Volume wt% Weight percent

[0007] The present invention provides methods for preparing compound (I), as outlined in Scheme 1, and compound (IV), as outlined in Scheme 2. [ka] [ka]

[0008] The synthesis of compound (I) comprises the following steps: Step 1) Compound (II) [ka] Compound (III) [ka] Formation of Step 2) Compound (III) and Compound (IV) [ka] via the Ullmann reaction between compound (V) [ka] Formation of Step 3) Deprotection of compound (V) to give compound (VI). [ka] Formation of Step 4) Compound (VII) via the reaction between 3,4,5-trifluoroaniline and phenyl carbonochloridate. [ka] Formation of Step 5) Compound (I) via a substitution reaction between compound (VI) and compound (VII). [ka] Formation Includes one or more of:

[0009] A detailed description of the process steps for the synthesis of compound (I) of the present invention is as follows: Step 1) Compound (II) [ka] Compound (III) [ka] Formation The formation of compound (III) is usually carried out in the presence of a suitable iodination reagent and a suitable organic solvent. The conversion is usually carried out at room temperature or under heating conditions.

[0010] A suitable iodination reagent is selected from NIS and I2, in particular the reagent is NIS. Excess I2 formed during the reaction by using an iodination reagent is removed by addition of Na2SO3 in an amount of 0.4-0.8 equivalents, in particular 0.55-0.6 equivalents.

[0011] Suitable organic solvents are selected from DCM, THF, ACN and MeTHF, in particular the organic solvent is ACN.

[0012] The iodination reaction is usually carried out at 10 to 60°C, particularly at 25 to 30°C.

[0013] The reaction was quenched by Na2SO3 to remove excess I2 formed during the reaction, which is very important for the safety of large-scale production. However, during testing, it was found that excess Na2SO3 reduces the product and converts compound (III) back to compound (II), whereas insufficient Na2SO3 cannot quench the reaction efficiently. A series of tests were conducted and summarized in the table below, concluding that 0.55-0.6 equivalents of Na2SO3 can meet the above criteria and thus be considered as the optimal conditions. [Table 1]

[0014] Step 2) Compound (III) and Compound (IV) [ka] via the Ullmann reaction between compound (V) [ka] Formation The formation of compound (V) is usually carried out in the presence of a suitable base, a suitable catalyst, a suitable ligand and a suitable organic solvent. The conversion is usually carried out under heating conditions.

[0015] Suitable bases are selected from K2CO3, K3PO4 and Cs2CO3, in particular the base is K2CO3.

[0016] A preferred catalyst is CuI, and the amount of the catalyst is 0.05 to 0.5 equivalents, particularly 0.1 equivalent. A preferred ligand is DMEDA, and the amount of the ligand is 0.2 to 2.0 equivalents, particularly 1.0 equivalent.

[0017] Suitable organic solvents are selected from 1,4-dioxane, ACN, toluene, THF and MeTHF, in particular the organic solvent is THF.

[0018] The dehydration reaction is usually carried out at 60°C to 120°C, particularly at 70°C to 75°C.

[0019] The chiral center adjacent to the cyano group of compound (V) is prone to epimerization under Ullmann reaction conditions, and therefore it is necessary to optimize the conditions to keep the chirality of compound (V) constant during the reaction. However, it is very difficult to control the reaction parameters such as base, solvent, catalyst and ligand loading, reaction time, etc. to achieve the best conversion and chiral purity. To solve the above problems, the following tests were carried out.

[0020] i) Effect of bases on conversion and chirality [Table 2] Based on the above tests, Cs2CO3 could not achieve sufficient conversion, K3PO4 could achieve higher conversion but the chiral purity decreased in the meantime, K2CO3 did not achieve satisfactory conversion at first, but the conversion could be promoted by adding more catalyst and ligand, and the chiral purity was stable and excellent throughout the tests. Therefore, K2CO3 was selected as the preferred base.

[0021] ii) Effect of solvent on conversion and chiral purity [Table 3] Based on the above studies, the study with THF (Table 3, Study No. 2, Entry 1)) had a higher conversion than the study with MeTHF (Table 3, Study No. 1) at 18 hours. By comparing the studies with THF (Table 3, Study No. 2) and MeCN (Table 2, Study No. 2), when the same final amounts of CuI and DMEDA were reached, the study with THF took less reaction time to achieve a similar conversion than the study with MeCN. Therefore, THF was selected as the preferred solvent.

[0022] iii) Effect of catalyst and ligand loading on conversion and chiral purity [Table 4-1] [Table 4-2] Based on the above test numbers 1-3, the ligand loading has little effect on the conversion and chiral purity, and for cost reasons, 1.0 equivalent is finally determined as the optimal ligand loading. By comparing test numbers 2 in Table 1, 2 in Table 3, 4 and 5 in Table 4, it is clear that increasing the catalyst loading can increase the conversion and shorten the reaction time, but 0.1 equivalent catalyst loading is already sufficient to reach a satisfactory conversion and chiral purity. Meanwhile, the minimum catalyst loading is environmentally friendly and can be beneficial during heavy metal removal.

[0023] Step 3) Deprotection of compound (V) to give compound (VI). [ka] Formation The formation of compound (VI) is usually carried out in the presence of a suitable acid and a suitable solvent. The conversion is usually carried out at room temperature or under heating conditions.

[0024] Suitable acids are selected from H3PO4, NH4Cl, TFA and acetic acid, in particular the acid is acetic acid, and the amount of acid is 1-3 equivalents, in particular 1.5-2 equivalents.

[0025] Preferred solvents are selected from DCM, EtOH, water and toluene, in particular the solvent is water.

[0026] The deprotection reaction is usually carried out at room temperature or at 60 to 100°C, particularly at 90 to 95°C.

[0027] Step 4) Compound (VII) via the reaction between 3,4,5-trifluoroaniline and phenyl carbonochloridate. [ka] Formation The formation of compound (VII) is usually carried out in the presence of a suitable base and a suitable organic solvent. The conversion is usually carried out under cooling conditions.

[0028] Suitable bases are selected from K2CO3, KHCO3, NaHCO3 and Na2CO3, in particular the base is NaHCO3.

[0029] Suitable organic solvents are selected from MTBE, IPAc, dioxane, MeTHF and THF, in particular the organic solvent is THF.

[0030] The reaction is usually carried out at -10 to 10°C, particularly at -5 to 0°C.

[0031] Step 5) Compound (I) via a substitution reaction between compound (VI) and compound (VII). [ka] Formation The formation of compound (I) is usually carried out in the presence of a suitable base and a suitable organic solvent. The conversion is usually carried out under heating conditions.

[0032] Suitable bases are selected from K2CO3, K3PO4, DIPEA and TEA, in particular the base is DIPEA.

[0033] Suitable organic solvents are selected from MTBE, EA, IPAc, MeTHF and mixtures of IPAc / acetone, in particular the organic solvent is a mixture of IPAc / acetone.

[0034] The substitution reaction is usually carried out at 30 to 80°C, particularly at 45 to 50°C.

[0035] The synthesis of compound (IV) comprises the following steps: Step a) Compound (VIII) [ka] and compound (IX) [ka] via a cyclization reaction between compound (X) [ka] Formation of Step b) via substitution of compound (X), compound (XI) [ka] Formation of Step c) Compound (XII) via elimination reaction of compound (XI). [ka] Formation of Step d) Deprotection of compound (XII) to give compound (XIII) [ka] Formation of Step e) Dehydration of compound (XIII) to give compound (IV). [ka] Formation Includes one or more of:

[0036] A detailed description of the process steps for the synthesis of compound (IV) of the present invention is as follows: Step a) Compound (VIII) [ka] and compound (IX) [ka] via a cyclization reaction between compound (X) [ka] Formation The formation of compound (X) is usually carried out in the presence of a suitable organic solvent. The conversion is usually carried out under heating conditions.

[0037] Suitable organic solvents are selected from THF, ACN and MeTHF, in particular the organic solvent is ACN.

[0038] The cyclization reaction is usually carried out at 80 to 140°C, in particular at 100 to 110°C.

[0039] Step b) via substitution of compound (X), compound (XI) [ka] Formation The formation of compound (XI) is usually carried out in the presence of a chlorinating agent and a suitable organic solvent. The conversion is usually carried out at room temperature.

[0040] Suitable chlorinating reagents are selected from acetyl chloride, thionyl chloride and oxalyl chloride, in particular the reagent is thionyl chloride, and the amount of chlorinating reagent is 1 to 5 equivalents, in particular 3 equivalents.

[0041] Suitable organic solvents are selected from IPAc, DCM, toluene, THF and MeTHF, in particular the organic solvent is DCM.

[0042] The substitution reaction is usually carried out at 10 to 40°C, particularly at 20 to 25°C.

[0043] Step c) Compound (XII) via elimination reaction of compound (XI). [ka] Formation The formation of compound (XII) is usually carried out in the presence of a suitable base and a suitable solvent. The conversion is usually carried out under heating conditions.

[0044] Suitable bases are selected from K3PO4, TEA, DBU and DIPEA, in particular the base is DBU, and the amount of base is 1 to 2 equivalents, in particular 1.5 equivalents.

[0045] Suitable solvents are selected from DCM, ACN, THF and Me-THF, in particular the solvent is THF.

[0046] The elimination reaction is usually carried out at 20 to 80°C, particularly at 40 to 45°C.

[0047] Step d) Deprotection of compound (XII) to give compound (XIII) [ka] Formation The formation of compound (XIII) is usually carried out in the presence of a suitable acid and a suitable organic solvent. The conversion is usually carried out at room temperature.

[0048] Suitable acids are selected from H2SO4, H3PO4, HCl and TFA, in particular the acid is HCl, and the amount of acid is 0.05-0.5 equivalents, in particular 0.1 equivalents.

[0049] Suitable organic solvents are selected from EtOH, MeOH, IPA and IPAc, in particular the organic solvent is MeOH.

[0050] The deprotection reaction is usually carried out at room temperature, particularly at 20 to 25°C.

[0051] Step e) Dehydration of compound (XIII) to give compound (IV). [ka] Formation The formation of compound (IV) is usually carried out in the presence of a suitable dehydrating reagent and a suitable organic solvent. The conversion is usually carried out at room temperature.

[0052] A suitable dehydrating reagent is selected from P2O5, TFAA and acetic anhydride, in particular the dehydrating reagent is TFAA, and the amount of the dehydrating reagent is 2.5 equivalents.

[0053] Suitable organic solvents are selected from EA, IPAc, MTBE and MeTHF, in particular the organic solvent is MTBE.

[0054] The dehydration reaction is usually carried out at room temperature, particularly at 20 to 25°C. EXAMPLES

[0055] Example 1 tert-Butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (Compound (III)) [ka] A 1000 L jacketed reactor was charged with tert-butyl (6S)-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (14.1 kg, 59.5 mol, WuXi AppTec) and ACN (115 kg) at room temperature. The mixture was then charged with NIS (20.0 kg, 88.9 mol) at room temperature under N2 protection. After stirring at 20-30°C for 18 hours, the reaction mixture was slowly cooled to -5-5°C and aqueous Na2SO3 solution (1.5 wt%, 4.3 kg) was added to quench the reaction. The mixture was then slowly charged with water (140 kg) at 5-25°C over 1 hour and the resulting mixture was stirred at 5-25°C for 1 hour. The resulting suspension was separated via centrifugation in small portions to collect the wet cake. The wet cake was washed again with ACN / water (22.3 kg, v / v=1 / 2.4) and then dried using an air oven (45-50° C.) for 48 h to give the desired product as a white solid, which was used directly in the preparation of compound (V) to give 19.4 kg of tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate. The purity was 99.7% and the yield was 90%. MS m / e=363.2[M+H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ = 7.78 (s, 1H), 4.73 (m, 1H), 4.54 (d, J = 16.8 Hz, 1H), 4.42 (dd, J = 12.1, 12.5 Hz, 1H), 4.07 (dd, J = 6.8, 12.1 Hz, 1H), 3.69 (d, J = 16.8 Hz, 1H), 1.53 (d, J = 6.6 Hz, 3H), 1.41 (s, 9H).

[0056] Example 2 (3S)-5-Oxopyrrolidine-3-carbonitrile (Compound (IV)) [ka] Step a) Synthesis of (3S)-5-oxo-1-[(1R)-2-hydroxy-1-phenyl-ethyl]pyrrolidine-3-carboxylic acid (compound (X)) [ka] In a 1000L jacketed reactor, itaconic acid (62.5kg, 480mol, Qingdao Kehai Co.LTD), (R)-(-)-2-phenylglycinol (70kg, 510mol, Jiangsu Senxuan pharmaceutical chemical co.,LTD) and ACN (450kg) were charged at room temperature under N2 atmosphere. The mixture was heated to 100-110℃ and stirring was maintained for 5 hours. Then, the mixture was cooled to 5-10℃ and stirring was maintained for 3 hours. The solid was filtered off and washed with ACN (25kg) to obtain the desired product as a light yellow solid, which was directly used for the preparation of compound XI to obtain 31kg of (3S)-5-oxo-1-[(1R)-2-hydroxy-1-phenyl-ethyl]pyrrolidine-3-carboxylic acid. The purity was 98.7%, the chiral purity was 99.7%, the yield was 25%, and the MS m / e=250.1 [M+H] + It was. 1 H-NMR (400 MHz, DMSO-d 6 ) δ 7.40 (d, 1H), 7.40 (d, 1H), 7.38 (dd, 1H), 7.38 (dd, 1H), 7.27 (t, 1H), 5.83 (dd, 1H), 4.05 (m, 1H), 3.98 (m, 1H), 3.58 (dd, 1H, J=8.5, 13.8 Hz), 3.39 (dd, 1H, J=8.5, 13.8 Hz), 3.15 (m, 1H), 2.71 (dd, 1H, J=9.4, 18.8 Hz), 2.51 (dd, 1H, J=9.3, 18.8 Hz).

[0057] Step b) Synthesis of (3S)-5-oxo-1-[(1R)-2-chloro-1-phenyl-ethyl]pyrrolidine-3-carboxamide (compound (XI)) [ka] A 500 L jacketed reactor was charged with (3S)-5-oxo-1-[(1R)-2-hydroxy-1-phenyl-ethyl]pyrrolidine-3-carboxylic acid (23.2 kg, 93.2 mol) and DCM (162.4 kg) under N2 atmosphere at room temperature. To the stirred mixture, thionyl chloride (31 kg, 260.5 mol) was slowly charged at room temperature. The mixture was stirred at 20-25 °C for another 4 h. The reaction mixture was concentrated in vacuum at 45 °C (0.09-0.1 MPa) until no more solvent was distilled. To the residue, DCM (162.4 kg) and ammonia (7 kg, 410 mol) were charged below 20 °C. The mixture was stirred at 20-25 °C for 16 h. To the mixture, water (115 kg) and HOAc (3.5 kg) were charged to adjust the pH to 6-7. The mixture was then concentrated under vacuum at 30-40° C. to evaporate DCM. The mixture was then cooled to 10-15° C. and stirred at 10-15° C. for 2 h. The solid was filtered off and washed with water (50 kg) to give the desired product as a light yellow solid, which was used directly in the preparation of compound XII to give 22 kg of (3S)-5-oxo-1-[(1R)-2-chloro-1-phenyl-ethyl]pyrrolidine-3-carboxamide. The purity was 98%, the chiral purity was 99.9%, the yield was 88%, and MS m / e=267.1 [M+H]. + It was. 1 H-NMR (400 MHz, DMSO-d 6) δ 7.38 (dd, 1H, J=7.3, 7.4 Hz), 7.38 (dd, 1H, J=7.3, 7.4 Hz), 7.34 (d, 1H, J=7.4 Hz), 7.34 (d, 1H, J=7.4 Hz), 7.25 (t, 1H, J=7.3 Hz), 5.63 (dd, 1H, J=3.3, 8.3 Hz), 3.88 (dd, 1H, J=3.3, 12.4 Hz), 3.69 (dd, 1H, J=8.3, 12.4 Hz), 3.33 (dd, 1H, J=8.5, 13.8 Hz), 3.29 (dd, 1H, J=8.5, 13.8 Hz), 3.21 (m, 1H), 2.59 (dd, 1H, J=9.4, 18.8 Hz), 2.21 (dd, 1H, J=9.3, 18.8 Hz).

[0058] Step c) Synthesis of (3S)-5-oxo-1-(1-phenylvinyl)pyrrolidine-3-carboxamide (compound (XII)) [ka] A 200 L jacketed reactor was charged with (3S)-5-oxo-1-[(1R)-2-chloro-1-phenyl-ethyl]pyrrolidine-3-carboxamide (22 kg, 82.5 mol), THF (88 kg) and DBU (18.5 kg, 121.6 mol) under N2 atmosphere at room temperature. The mixture was stirred using a magnetic stirrer at 40-45°C for 8 hours. The mixture was then charged with HOAc (2.7 kg, 45.4 mol) to adjust the pH to 6-7. The mixture was concentrated under reduced pressure at 40-45°C to evaporate excess THF. Water (40 kg) was charged to the mixture and the mixture was stirred at 10-15°C for 3 hours. The solid was filtered off and washed with water (25 kg) to give the desired product as a light yellow solid, which was used directly in the preparation of compound XIII to give 15.4 kg of (3S)-5-oxo-1-(1-phenylvinyl)pyrrolidine-3-carboxamide with a purity of 99%, chiral purity of 99.9%, yield of 82%, MS m / e=231.1 [M+H]. + It was.1 H-NMR (400 MHz, DMSO-d 6 ) δ 7.39 (t, 1H, J=7.3 Hz), 7.33 (dd, 1H, J=7.3, 7.4 Hz), 7.33 (dd, 1H, J=7.3, 7.4 Hz), 7.28 (d, 1H, J=7.4 Hz), 7.28 (d, 1H, J=7.4 Hz), 4.77 (s, 1H), 4.57 (s, 1H), 3.77 (dd, 1H, J=8.5, 13.8 Hz), 3.48 (dd, 1H, J=8.5, 13.8 Hz), 3.20 (m, 1H), 2.59 (dd, 1H, J=9.4, 18.8 Hz), 2.21 (dd, 1H, J=9.3, 18.8 Hz).

[0059] Step d) Synthesis of (3S)-5-oxopyrrolidine-3-carboxamide (compound (XIII)) [ka] A 500 L jacketed reactor was charged with (3S)-5-oxo-1-(1-phenylvinyl)pyrrolidine-3-carboxamide (38.7 kg, 168 mol), methanol (108 kg) and hydrochloric acid (1.66 kg, 16.4 mol) at room temperature under N2 atmosphere. The mixture was stirred at 20-25°C for 4 hours using a magnetic stirrer. The mixture was then cooled to 0-5°C and stirred at that temperature for 3 hours. The solid was filtered off and washed with methanol (40 kg) to give the desired product as an off-white solid, which was used directly in the preparation of compound IV to give 17 kg of (3S)-5-oxopyrrolidine-3-carboxamide. The purity was 99%, the chiral purity was 100%, the yield was 80%, and MS m / e=129.1 [M+H]. + It was. 1 H-NMR (400 MHz, DMSO-d 6) δ 3.83 (dd, 1H, J=8.5, 13.8 Hz), 3.40 (dd, 1H, J=8.5, 13.8 Hz), 3.03 (m, 1H), 2.52 (dd, 1H, J=9.4, 18.8 Hz), 2.13 (dd, 1H, J=9.3, 18.8 Hz).

[0060] Step e) Synthesis of (3S)-5-oxopyrrolidine-3-carbonitrile (compound (IV)) [ka] A 200 L jacketed reactor was charged with (3S)-5-oxopyrrolidine-3-carboxamide (17 kg, 132.7 mol) and MTBE (63 kg) at room temperature under N2 atmosphere. The mixture was cooled to -5 to 0 °C using a Huber chiller. To the stirred mixture was charged TFAA (70 kg, 333 mol) at -5 to 0 °C. The mixture was agitated using a magnetic stirrer at 20 to 25 °C for another 4 h. The mixture was then cooled again to -5 to 0 °C. The solid was filtered off and washed with MTBE (30 kg) to obtain the desired product as an off-white solid, which was used directly in the preparation of compound (V) to give 11.7 kg of (3S)-5-oxopyrrolidine-3-carbonitrile. The purity was 99.3%, the chiral purity was 100%, and the yield was 81%. MS m / e=110.1[M+H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ = 3.71 (dd, J = 5.6, 9.2 Hz, 1H), 3.44 (dd, J = 7.5, 9.2 Hz, 1H), 3.32 (m, 1H), 2.97 (dd, J = 8.5, 18.2 Hz, 1H), 2.88 (dd, J = 8.4, 18.2 Hz, 1H).

[0061] Example 3 tert-Butyl (6S)-6-methyl-3-[(4S)-4-cyano-2-oxo-pyrrolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (compound (V)) [ka] A 100 L jacketed reactor was charged with THF (36 L), K2CO3 (5.14 kg), tert-butyl (6S)-3-iodo-6-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (4.5 kg, 12.4 mol), (3S)-5-oxopyrrolidine-3-carbonitrile (2.04 kg, 18.5 mol), CuI (236 g, 1.24 mol) and N,N'-dimethyl-1,2-ethanediamine (218 g, 2.5 mol) under N2 atmosphere at room temperature. The reaction mixture was heated to 75°C and stirring was maintained for 1 hour. Another portion of N,N'-dimethyl-1,2-ethanediamine (872 g, 10 mol) was added dropwise to the mixture under reflux. After stirring at reflux for another 20 hours, the reaction mixture was slowly cooled to room temperature and water (10 L) and IPAc (15 L) were added. After another 20 minutes, the two layers were separated and the organic layer was washed with 1N citric acid solution (6 L), 8% NaHCO3 (8 L) solution and 10% brine (15 L). The organic layer was filtered through a Na2SO4 pad and concentrated under reduced pressure to give the desired product as a light yellow solid, which was used directly to prepare compound (VI) to give 2.87 kg of tert-butyl (6S)-6-methyl-3-[(4S)-4-cyano-2-oxo-pyrrolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate. The purity was 99% and the yield was 67%, with MS m / e=345.2 [M+H]. + It was. 1 H-NMR (400 MHz, DMSO-d 6) δ = 7.33 (s, 1H), 4.71 (d, J = 16.8 Hz, 1H), 4.62 (m, 1H), 4.34 (dd, J = 12.1, 12.5 Hz, 1H), 4.05 (dd, J = 5.6, 9.2 Hz, 1H), 3.96 (dd, J = 6.8, 12.1 Hz, 1H), 3.86 (d, J = 16.8 Hz, 1H), 3.77 (dd, J = 7.5, 9.2 Hz, 1H), 3.44 (m, 1H), 3.22 (dd, J = 8.5, 18.2 Hz, 1H), 3.13 (dd, J = 8.4, 18.2 Hz, 1H), 1.52 (d, J = 6.6 Hz, 3H), 1.41 (s, 9H).

[0062] Example 4 (3S)-5-oxo-1-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]pyrrolidine-3-carbonitrile (Compound (VI)) [ka] A 1 L flask was charged with (6S)-6-methyl-3-[(4S)-4-cyano-2-oxo-pyrrolidin-1-yl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (124 g, 359 mmol), HOAc (32.3 g, 539 mmol) and deionized water (620 mL) at room temperature. After stirring at 95° C. for 20 h, the reaction mixture was cooled to room temperature and water was azetroped with toluene (300 mL×3). The resulting residue was triturated in MTBE (150 mL) / IPAc (150 mL) to give the desired product as a white solid, which was used directly in the preparation of compound (I) to give 1.6 kg of (3S)-5-oxo-1-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]pyrrolidine-3-carbonitrile. The purity was 99.3% and the yield was 95%. MS m / e=245.1[M+H] + . 1H-NMR (400 MHz, DMSO-d 6 ) δ = 7.32 (s, 1H), 4.19 (dd, J = 11.1, 16.4 Hz, 1H), 4.06 (dd, J = 4.3, 16.4 Hz, 1H), 4.00 (dd, J = 5.6, 9.2 Hz, 1H), 3.96 (dd, J = 3.5, 12.4 Hz, 1H), 3.72 (dd, J = 7.5, 9.2 Hz, 1H), 3.63 (dd, J = 10.5, 12.4 Hz, 1H), 3.28 (m, 1H), 3.28 (m, 1H), 3.17 (dd, J = 8.5, 18.2 Hz, 1H), 3.08 (dd, J = 8.4, 18.2 Hz, 1H), 1.02 (d, J = 6.4 Hz, 3H).

[0063] Example 5 Phenyl N-(3,4,5-trifluorophenyl)carbamate (Compound (VII)) [ka] A 20 L jacketed reactor was charged with 3,4,5-trifluoroaniline (1 kg, 3.8 mol) and THF (10 L) at room temperature under N2 atmosphere. The mixture was cooled to -5 to 0 °C. To the stirred mixture was charged an aqueous solution of NaHCO3 (856 g, 10.2 mol) in water (5 L) and phenyl carbonochloridate (1.2 kg, 7.48 mol) at -5 to 0 °C. After the addition, the reaction mixture was stirred at 0 to 10 °C for another hour, then EtOAc (5 L) and water (2 L) were added. The two layers were separated and the organic layer was washed with saturated NaCl (6 L), filtered through a Na2SO4 pad, and concentrated under reduced pressure to give the desired product as a white solid, which was used directly in the preparation of compound (I) to give 0.9 kg of phenyl N-(3,4,5-trifluorophenyl)carbamate. The purity was 99%, the yield was 92%, and the MS m / e=267.1 [M+H] + It was. 1H-NMR (400 MHz, CDCl3) δ = 7.43 (dd, J = 7.5, 8.1 Hz, 1H), 7.43 (dd, J = 7.5, 8.1 Hz, 1H), 7.28 (dd, J = 7.5, 12.3 Hz, 1H), 7.28 (dd, J = 7.5, 12.3 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.19 (dd, J = 2.7, 8.1 Hz, 1H), 7.19 (dd, J = 2.7, 8.1 Hz, 1H).

[0064] Example 6 (6S)-3-[(4S)-4-cyano-2-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide (Compound (I)) [ka] A 50 L jacketed reactor was charged with (3S)-5-oxo-1-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl]pyrrolidine-3-carbonitrile (2.2 kg, 9 mol), phenyl N-(3,4,5-trifluorophenyl)carbamate (2.4 kg, 9 mol), IPAc (19.1 kg), acetone (3.3 kg) and DIPEA (1.39 kg) under N2 atmosphere. The mixture was stirred at 45-50 °C using a magnetic stirrer for 20 h. The mixture was then cooled slowly to room temperature. The white solid was filtered off and washed with IPAc:MTBE (V / V=2 / 1, 6.7 kg). The wet cake was dried in a vacuum oven (IT=50° C.) to give the desired product as a white solid, 3.5 kg of (6S)-3-[(4S)-4-cyano-2-oxo-pyrrolidin-1-yl]-6-methyl-N-(3,4,5-trifluorophenyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxamide. The purity was 98.5%, the chiral purity was 100%, and the yield was 93%. MS m / e=418.1 [M+H]+ . 1 H-NMR (400 MHz, DMSO-d 6 ) δ = 7.38 (s, 1H), 7.16 (dd, J = 7.4, 13.4 Hz, 1H), 7.16 (dd, J = 7.4, 13.4 Hz, 1H), 4.43 (m, 1H), 4.29 (d, J = 16.8 Hz, 1H), 4.13 (dd, J = 12.1, 12.5 Hz, 1H), 3.99 (dd, J = 5.6, 9.2 Hz, 1H), 3.84 (d, J = 16.8 Hz, 1H), 3.80 (dd, J = 6.8, 12.1 Hz, 1H), 3.71 (dd, J = 7.5, 9.2 Hz, 1H), 3.44 (m, 1H), 3.22 (dd, J = 8.5, 18.2 Hz, 1H), 3.13 (dd, J = 8.4, 18.2 Hz, 1H), 1.31 (d, J = 6.6 Hz, 3H). Aspects of the invention [Aspect 1] Compound (I) [ka] or a pharma- ceutically acceptable salt thereof, comprising the steps of: The process is as follows: Step 1) Compound (II) [ka] Compound (III) [ka] Formation of Step 2) Compound (III) and Compound (IV) [ka] via the Ullmann reaction between compound (V) [ka] Formation of Step 3) Deprotection of compound (V) to give compound (VI). [ka] Formation of Step 4) Compound (VII) via the reaction between 3,4,5-trifluoroaniline and phenyl carbonochloridate. [ka] Formation of Step 5) Compound (I) via a substitution reaction between compound (VI) and compound (VII). [ka] Formation A method comprising: [Aspect 2] The method according to aspect 1, characterized in that the formation of compound (III) in step 1) is carried out in the presence of an iodination reagent, the iodination reagent being selected from NIS and I2, in particular the iodination reagent being NIS. [Embodiment 3] The method according to embodiment 1 or 2, characterized in that excess I2 formed during the reaction due to the use of an iodination reagent in step 1) is removed by Na2SO3, the amount of Na2SO3 being 0.4-0.8 equivalents, in particular 0.55-0.6 equivalents. [Aspect 4] A method according to any one of aspects 1 to 3, characterized in that the formation of compound (V) in step 2) is carried out in an organic solvent in the presence of a base, a catalyst and a ligand, the base being selected from K2CO3, K3PO4 and Cs2CO3, in particular the base is K2CO3, the catalyst is CuI, the amount of the catalyst is 0.05 to 0.5 equivalents, in particular 0.1 equivalent, the ligand is DMEDA, the amount of the ligand is 0.2 to 2.0 equivalents, in particular 1.0 equivalent, and the organic solvent is selected from 1,4-dioxane, ACN, toluene, THF and MeTHF, in particular the organic solvent is THF. [Embodiment 5] The method according to any one of embodiments 1 to 4, characterized in that the formation of compound (VI) in step 3) is carried out in the presence of an acid, the acid being selected from H3PO4, NH4Cl, TFA and acetic acid, in particular the acid being acetic acid, and the amount of acid being 1 to 3 equivalents, in particular 1.5 to 2 equivalents. [Embodiment 6] The method according to any one of embodiments 1 to 5, characterized in that the formation of compound (VII) in step 4) is carried out in the presence of a base, the base being selected from K2CO3, KHCO3, NaHCO3 and Na2CO3, in particular the base being NaHCO3. [Aspect 7] The method according to aspect 6, characterized in that the formation of compound (VII) in step 4) is carried out at -10°C to 10°C, particularly at -5 to 0°C. [Embodiment 8] The method according to any one of embodiments 1 to 7, characterized in that the formation of compound (I) in step 5) is carried out in the presence of a base, the base being selected from K2CO3, K3PO4, DIPEA and TEA, in particular the base being DIPEA. [Aspect 9] Compound (IV) [ka] or a pharma- ceutically acceptable salt thereof, comprising the steps of: The process is as follows: Step a) Compound (VIII) [ka] and compound (IX) [ka] via a cyclization reaction between compound (X) [ka] Formation of Step b) via substitution of compound (X), compound (XI) [ka] Formation of Step c) Compound (XII) via elimination reaction of compound (XI). [ka] Formation of Step d) Deprotection of compound (XII) to give compound (XIII) [ka] Formation of Step e) Dehydration of compound (XIII) to give compound (IV). [ka] Formation A method comprising: [Aspect 10] The method according to aspect 9, characterized in that the formation of compound (X) in step a) is carried out via a cyclization reaction in an organic solvent, the solvent being selected from THF, ACN and MeTHF, in particular the organic solvent is ACN, and the cyclization reaction is carried out at 80 to 140°C, in particular 100 to 110°C. [Embodiment 11] The method according to embodiment 9 or 10, characterized in that the formation of compound (XI) in step b) is carried out in the presence of a chlorinating reagent, the chlorinating reagent being selected from acetyl chloride, thionyl chloride and oxalyl chloride, in particular the reagent being thionyl chloride, and the amount of the chlorinating reagent being 1 to 5 equivalents, in particular 3 equivalents. [Embodiment 12] The method according to any one of embodiments 9 to 11, characterized in that the formation of compound (XII) in step c) is carried out in the presence of a base, the base being selected from K3PO4, TEA, DBU and DIPEA, in particular the base being DBU, and the amount of base being 1 to 2 equivalents, in particular 1.5 equivalents. [Embodiment 13] The method according to any one of embodiments 9 to 12, characterized in that the formation of compound (XIII) in step d) is carried out in the presence of an acid, the acid being selected from H2SO4, H3PO4, HCl and TFA, in particular the acid being HCl, and the amount of acid being 0.05 to 0.5 equivalents, in particular 0.1 equivalents. [Embodiment 14] The method according to any one of embodiments 9 to 13, characterized in that the formation of compound (IV) in step e) is carried out in the presence of a dehydrating reagent, the dehydrating reagent being selected from P2O5, TFAA and acetic anhydride, in particular the dehydrating reagent being TFAA and the amount of the dehydrating reagent being 2.5 equivalents.

Claims

1. Compound (I) 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, comprising the steps of: The process is as follows: Step 1) Compound (II) 【Chemistry 2】 Compound (III) 【Chemistry 3】 Formation of Step 2) Compound (III) and Compound (IV) 【Chemistry 4】 via an Ullmann reaction between 【Chemistry 5】 Formation of Step 3) Compound (VI) via deprotection of compound (V). 【Chemistry 6】 Formation of Step 4) Compound (VII) via the reaction between 3,4,5-trifluoroaniline and phenyl carbonochloridate 【Chemistry 7】 Formation of Step 5) Compound (I) via a substitution reaction between compound (VI) and compound (VII). 【Chemistry 8】 Formation A method comprising:

2. The formation of compound (III) in step 1) is carried out in the presence of an iodination reagent, which is N-iodosuccinimide and I ２ The method according to claim 1, characterized in that the compound is selected from the group consisting of:

3. Excess I formed during the reaction due to the use of an iodination reagent in step 1) ２ But Na ２ SO ３ is removed by Na ２ SO ３ The process according to claim 1 or 2, characterized in that the amount of is between 0.4 and 0.8 equivalents.

4. The formation of compound (V) in step 2) is carried out in an organic solvent in the presence of a base, a catalyst and a ligand, wherein the base is K ２ CO ３ , K ３ P.O. ４ and Cs ２ CO ３ The method according to any one of claims 1 to 3, characterized in that the catalyst is CuI, the amount of the catalyst is 0.05 to 0.5 equivalents, the ligand is N,N'-dimethyl-1,2-ethanediamine, the amount of the ligand is 0.2 to 2.0 equivalents, and the organic solvent is selected from 1,4-dioxane, acetonitrile, toluene, tetrahydrofuran and 2-methyltetrahydrofuran.

5. The formation of compound (VI) in step 3) is carried out in the presence of an acid, which is H ３ P.O. ４ , N.H. ４ 5. The process according to claim 1, characterized in that the amount of acid is selected from Cl, trifluoroacetic acid and acetic acid, and is between 1 and 3 equivalents.

6. The formation of compound (VII) in step 4) is carried out in the presence of a base, the base being K ２ CO ３ , KHCO ３ , NaHCO ３ and Na ２ CO ３ 6. The method according to claim 1 , wherein the compound is selected from the group consisting of:

7. The process according to claim 6, characterized in that the formation of compound (VII) in step 4) is carried out at -10°C to 10°C.

8. The formation of compound (I) in step 5) is carried out in the presence of a base, the base being K ２ CO ３ , K ３ P.O. ４ 8. The process according to claim 1, wherein the amine is selected from the group consisting of N,N-diisopropylethylamine and triethylamine.

9. The process is as follows: Step a) Compound (VIII) 【Chemistry 9】 and compound (IX) 【Chemistry 10】 via a cyclization reaction between compound (X), 【Chemistry 11】 Formation of Step b) Compound (XI) via substitution of compound (X). 【Chemistry 12】 Formation of Step c) Compound (XII) via elimination reaction of compound (XI). 【Chemistry 13】 Formation of Step d) Deprotection of compound (XII) to give compound (XIII). 【Chemistry 14】 Formation of Step e) Dehydration of compound (XIII) to give compound (IV). 【Chemistry 15】 Formation The method of claim 1 further comprising:

10. 10. The process according to claim 9, characterized in that the formation of compound (X) in step a) is carried out via cyclization reaction in an organic solvent, the solvent being selected from tetrahydrofuran, acetonitrile and 2-methyltetrahydrofuran, and the cyclization reaction is carried out at 80-140°C.

11. The process according to claim 9 or 10, characterized in that the formation of compound (XI) in step b) is carried out in the presence of a chlorinating reagent, which is selected from acetyl chloride, thionyl chloride and oxalyl chloride, and the amount of the chlorinating reagent is between 1 and 5 equivalents.

12. The formation of compound (XII) in step c) is carried out in the presence of a base, the base being K ３ P.O. ４ 12. The process according to any one of claims 9 to 11, characterized in that the base is selected from the group consisting of triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and N,N-diisopropylethylamine, and the amount of base is between 1 and 2 equivalents.

13. The formation of compound (XIII) in step d) is carried out in the presence of an acid, which is ２ SO ４ , H ３ P.O. ４ 13. The process according to any one of claims 9 to 12, characterized in that the amount of acid is selected from the group consisting of HCl and trifluoroacetic acid, and the amount of acid is between 0.05 and 0.5 equivalents.

14. The formation of compound (IV) in step e) is carried out in the presence of a dehydrating reagent, which is ２ O ５ 14. The process according to claim 9, characterized in that the amount of dehydrating reagent is selected from the group consisting of trifluoroacetic anhydride and acetic anhydride, and the amount of dehydrating reagent is 2.5 equivalents.

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