Process for preparation of cyclic dinucleotide

Abstract

To provide an improved processes for the preparation of a cyclic dinucleotide which is useful as a STING agonist.SOLUTION: As illustrated in the following formula, compound A is used to introduce a phosphate group into a nucleoside protected with an appropriate protecting group to yield compound 3, which is then reacted with the 5'-hydroxyl group of another nucleoside, and a phosphate group is introduced again into the 3'-amino group of the 3'-amino ribose portion. Subsequently, a cyclization reaction is induced between the 5'-hydroxyl group and the phosphate group, followed by deprotection to create the cyclic dinucleotide. This invention offers advantages in terms of its shorter synthesis process and reduced use of toxic reagents.SELECTED DRAWING: None

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 62 / 775,094, filed December 4, 2018, the contents of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present invention relates generally to improved methods for producing cyclic dinucleotides, which are useful as STING agonists. [Background technology]

[0003] formula: [ka] There is disclosed an improved method for preparing compound I represented by the formula:

[0004] Compound I, compositions comprising Compound I, and alternative methods of making Compound I are disclosed in commonly assigned U.S. Application No. 15 / 748,685, filed January 30, 2018, the contents of which are incorporated herein by reference. Compound I may be useful in treating conditions associated with STING activity, both alone and in combination with other anti-cancer agents for the treatment of various types of cancer. Summary of the Invention

[0005] In one aspect, the present invention provides a compound of formula: [ka] A method for producing compound I represented by the following formula: a) reacting compound I with TBSCl and Et3N in DMF to obtain compound 2; [ka] b) reacting compound 2 with a base, such as imidazole, DBU, diisopropylethylamine, triazole, tetrazole or a metal alkoxide base, in a solvent, such as THF, 2-MeTHF, MeCN or DMF, and then with compound A to obtain compound 3; [ka] c) then dissolving compound 3 and compound 9 in a solvent such as THF, MeCN or DMF followed by addition of a base such as potassium t-butoxide, DBU or other metal alkoxide base, followed by quenching with a suitable acid such as acetic acid to give compound 4; [ka] d) thereafter, reacting compound 4 in a solvent such as THF, 2-MeTHF, MeCN or DMF, followed by addition of a base such as imidazole, DBU, triazole, tetrazole, diisopropylethylamine or a metal alkoxide base, followed by addition of compound B to obtain compound 5 of formula; [ka] e) thereafter treating a solution of compound 5 in a solvent such as THF, MeTHF or MeCN with an acid such as TFA, MSA, p-TSA or utilizing fluoride deprotection to obtain compound 6 of formula; [ka] f) solubilizing it in a suitable solvent such as THF, MeCN, NMP or DMF, then mixing with a suitable base such as lithium t-butoxide, potassium t-butoxide, DBU, LiHMDS or other HMDS bases or other metal alkoxide bases, followed by quenching by stirring with a suitable quench solution such as glacial acetic acid / MeCN to obtain compound of formula 7; [ka] g) thereafter combining said compound with a suitable base, such as methylamine, ammonia or other alkylamine base, stirring and concentrating to obtain compound of formula 8; [ka] The present invention provides a method comprising:

[0006] In a second aspect of the present invention, novel intermediate compounds and their diastereomers are provided as shown in the table below. The compounds are shown with specific protecting groups, i.e., Bz for the amine protecting group and TBS for the alcohol substituent, but a wider range of protecting groups or none at all can be utilized. For amine protecting groups (X), the protecting group can be selected from amide, thioamide, sulfonamide, carbamate, imine, formamidine, alkyl (e.g., benzyl, allyl), phosphate and silyl compounds. For alcohol protecting groups (Y), the protecting group can be selected from silyl, alkyl (e.g., allyl or benzyl), alkoxymethyl ether (e.g., TOM), alkoxyethyl ether (e.g., cyanoethyl) and ester. These lists of protecting groups are not considered limiting, but will encompass additional protecting groups known to those skilled in the art. The leaving groups as part of compounds A and B may be selected from any of the reagents set forth in U.S. Patent Application No. 16 / 382,692, filed April 12, 2019, the contents of which are incorporated herein.

[0007] [Table 1] [Table 2] These intermediates are used in the methods of the present invention.

[0008] Alternatively, compound 8 can be prepared from the following sequence of steps. [ka] [ka]

[0009] In one embodiment of the present invention, a method is disclosed, wherein the base in step b) is imidazole, DBU, diisopropylethylamine, triazole, tetrazole or a metal alkoxide base. In a preferred embodiment, the base in step b) is imidazole. In one embodiment of the present invention, a method is disclosed, wherein the solvent in step c) is THF, MeCN or DMF. In a preferred embodiment, the solvent in step c) is THF.

[0010] In another embodiment of the present invention, a method is disclosed, wherein the base in step c) is potassium t-butoxide, DBU or other alkoxide base. In a preferred embodiment, the base in step c) is sodium tert-pentoxide.

[0011] In another embodiment of the present invention, a method is disclosed, wherein the solvent in step d) is THF, 2-MeTHF, MeCN or DMF. In a preferred embodiment, the solvent in step d) is 2-MeTHF. In another embodiment of the present invention, a method is disclosed, wherein the base in step d) is imidazole, DBU, triazole, tetrazole, diisopropylethylamine, or other alkoxide. In a preferred embodiment, the base in step d) is imidazole.

[0012] In another embodiment of the present invention, a process is disclosed, wherein the solvent in step f) is THF, MeCN, NMP or a mixture thereof or DMF. In a preferred embodiment, the solvent in step f) is a mixture of THF and NMP. In another embodiment of the present invention, a method is disclosed, wherein the base in step f) is potassium t-butoxide, lithium t-butoxide, DBU or other metal alkoxide base. In a preferred embodiment, the base in step f) is lithium t-butoxide.

[0013] In another embodiment of the present invention, a method is disclosed, wherein the base in step g) is methylamine, ammonia or butylamine. In a preferred embodiment, the base in step g) is methylamine.

[0014] Advantages of the disclosed methods include a significant reduction in the length of the synthesis, as well as reduced use of harmful reagents such as H2S and CCl4. In addition, the disclosed methods are highly diastereoselective, resulting in the ability to produce a single (preferred) diastereoisomer in improved yield and properties compared to synthetic methods that lack diastereoselectivity. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Working Example The present invention will now be further illustrated by the following examples, which are preferred embodiments of the invention. Unless otherwise specified, all temperatures are in degrees Celsius (° C.). It should be understood that these examples are illustrative rather than limiting, and that other embodiments are possible which are within the spirit and scope of the invention as defined by the claims appended hereto.

[0016] Although the compounds contained herein are depicted with a particular stereochemistry, the methods disclosed herein can be used to provide any diastereomer.

[0017] For ease of reference, the following abbreviations may be used herein: [Table 3] [Table 4]

[0018] Example 1 Preparation of compound 2 [ka]

[0019] Compound 1 (25.0 g) was dissolved in DMF (180 mL). TBSCl (26.9 g, 3.35 equiv.) and Et3N (29 mL, 4.0 equiv.) were added to the solution, and the thick suspension was stirred at room temperature overnight. UPLC showed complete conversion. The crude was then diluted with MTBE and washed with 5% H3PO4 solution (100 mL), 5% K2HPO4 (100 mL) and brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated to a crude oil. The crude was purified by silica chromatography. The isolated product was a yellow amorphous solid (25.1 g, 81.2%). LCMS of 2: m / z (M+H) + :599

[0020] Example 2 Preparation of compound 3 (laboratory scale) [ka]

[0021] To a mixture of imidazole (2.37 g, 8 equiv., 34.9 mmol) and compound 2 (2.90 g, 4.36 mmol, 90 wt%) was added MeCN (42 mL) at ambient temperature followed by (R)-SO4P(V) (compound A) (3.25 g, 1.8 equiv., 7.84 mmol). The reactor was made inert by flushing with N2 for 1 min. After 2 h, the reaction mixture was concentrated and the resulting residue was purified by column chromatography with 0-20% EtOAc in DCM to give 2.82 g of a white solid as compound 3 (dr 98:2) in 77% yield. LCMS of 3: m / z (M+H) + :813

[0022] Preparation of compound 3 (large scale) Compound 2 (1 kg, 1.0 eq.), imidazole (0.81 kg, 7.2 eq.) and 2-MeTHF are charged to a reactor. The reaction mixture is stirred until dissolution is complete. The reaction mixture is cooled to 0° C. and compound A (1.25 kg, 1.8 eq.) is charged to the reactor. The reaction is allowed to acclimate at 0° C. for as long as 6 hours (NLT). The reaction is quenched with acetic acid (0.72 kg, 7.2 eq.) and then diluted with 2-MeTHF (4 L / kg) and n-hexane (3 L / kg). The resulting mixture is washed with water (6 L / kg) and DMF (4 L / kg) and the aqueous layer is separated and discarded. The organic layer is then diluted with 2-MeTHF (1 L / kg) and then washed with aqueous K2HPO4 (2 kg / kg in 6 L / kg water) and DMF (4 L / kg). The layers are again separated and the aqueous layer is discarded. The organic layer is washed with aqueous K2HPO4 (1.2 kg / kg in 6 L / kg water) and DMF (4 L / kg). Again, the layers are separated and the aqueous layer is discarded. The organic layer is washed with aqueous NaCl (1 w / w, 5.5 L / kg); the aqueous layer is separated and discarded. The resulting mixture is diluted with methanol (6 L / kg) and the batch is concentrated to a total volume of 6 L / kg. The resulting mixture is diluted with methanol (6 L / kg). Water (0.75 L / kg) is charged to the reactor and crystalline seeds of compound 3 are added. The batch is conditioned for 1 hour at 20° C. and water (2.75 L / kg) is added. The batch is conditioned and the resulting slurry is filtered. The cake is washed with 1:1 MeOH:water (4 L / kg) and dried under reduced pressure at 40° C. The dried cake is dissolved in toluene (5 L / kg) and heated to 40° C. The batch is cooled to 20° C. over 90 minutes. Compound 3 crystalline seeds are charged and conditioned at 20° C. for 2 hours. n-Heptane (15 L / kg) is charged to the reactor over 2 hours and conditioned at 20° C. for 1 hour. The resulting slurry is filtered and washed with 3:1 n-heptane:toluene (4 L / kg). The solid is dried under vacuum at 50° C. to give 1.05 kg of white solid as compound 3 in 77% yield.

[0023] Example 3 Preparation of compound 4 (laboratory scale) [ka]

[0024] Intermediate compound 9 (0.408 g, 1.35 eq, 0.830 mmol, 95 wt%) and compound 3 (0.500 g, 0.615 mmol) were dissolved in THF (5.0 mL) at 45° C., and the solvent was removed by flushing the reactor with nitrogen. THF (7.5 mL) was added to the residue, and the resulting mixture was heated at 45° C. to dissolve most of the solids, and then cooled to ambient temperature. Potassium tert-butoxide in THF (1 mol / L) (1.84 mL, 3.0 eq, 1.84 mmol) was added slowly over 5 min. After 1.5 h, additional potassium tert-butoxide in THF (1 mol / L) (0.31 mL, 0.5 eq, 0.31 mmol) was added to the reaction mixture, and the mixture was mixed for 0.5 h. The reaction mixture was then quenched by the addition of acetic acid (0.15 mL, 4 eq.). The mixture was concentrated and the resulting residue was purified by column chromatography using 0-10% MeOH in DCM to give 0.46 g of a white solid as compound 4 in 65% yield. LCMS of compound 4: m / z (M+H) + :1143

[0025] Preparation of compound 4 (large scale) A slurry of THF (12.7 L, Karl Fischer value (KF) <100 ppm) and compound 9 (0.786 kg, 95 wt%, 1.1 equiv) was heated at 40-55 °C and concentrated under vacuum to a batch volume of 3-4 L. Dry THF (KF <100 ppm) was added to the original batch volume (12.7 L). The mixture was then cooled to 0 °C and intermediate 3 (1.27 kg, 93 wt%, 1.0 equiv) was added. A solution of sodium t-pentoxide in THF (2.3 L, 2.3 M, 4.0 equiv) was then added over 30 min. < The mixture was stirred at 0-5° C. until the reaction was complete. Acetic acid (469 g, 5.0 eq.) was added and the reaction was <The mixture was quenched at 10° C. The resulting mixture was treated with a solution of sodium phosphate monobasic (10 wt%, 12.7 L). The layers were separated and the organic layer was washed with a solution of sodium phosphate monobasic (10 wt%, 7.6 L). The layers were separated and the resulting organic layer was distilled under vacuum to 10 L while maintaining the batch temperature at 10-20° C. Acetonitrile (3.8 L) was added. A constant volume distillation was performed at 10-20° C. under vacuum with a batch volume of approximately 12.7 L. The solvent ratio of THF / acetonitrile was 100%. < Distillation was stopped when 10% v / v was reached. The batch was allowed to warm to 20°C and water was charged over 30 minutes until the KF of the batch was in the range of 35-50%. The slurry was allowed to settle for 1 hour before filtering. The cake was washed with acetonitrile / water mixture (75 / 25 v / v, 2.54Lx2), acetonitrile (2.54Lx2) and concentrated under vacuum. < Drying at 25° C. gave 1.16 kg (92% by weight) of product, a yield of 65%.

[0026] Example 4 Preparation of compound 5 (laboratory scale) [ka]

[0027] To a solution of compound 4 (0.150 g, 0.131 mmol) in THF (3.3 mL, 22v) was added imidazole (71 mg, 8 equiv, 1.05 mmol) at ambient temperature, followed immediately by (S)-SO 3 P(V) (136 mg, 2.5 equiv, 0.328 mmol). The reactor was then inerted by flushing with N2 for 1 min. After 1 h, imidazole (50 mg) and (S)-SO 3 P(V) (50 mg) were added. 4 h after the last charge, (S)-SO 3 P(V) (50 mg) was added and the mixture was agitated for 1 h and then concentrated. The residue was purified by column chromatography with 0-20% MeOH in DCM to give compound 5 as a white solid (148 mg, 81% yield). LCMS of compound 5: m / z (M+H) + :1357

[0028] Example 4a Preparation of compound 6 (laboratory scale) [ka]

[0029] Water (0.15 mL) was added to a solution of 5 (0.15 g, 0.11 mmol) in DCM (3 mL, 20v) followed by trifluoroacetic acid (0.30 mL, 4.0 mmol). The mixture was stirred at ambient temperature for 2 h, then diluted with DCM (2 mL) and the resulting mixture was washed with an aqueous solution of K2HPO4 (10%, 3 mL x 2). The organic phase was dried over MgSO4 and concentrated. The resulting residue was purified by column chromatography with 0-20% MeOH in DCM to give 6 (66 mg, 48% yield) as a white solid. LCMS of 6: m / z (M+H) + :1243

[0030] Preparation of compound 6 (large scale) [ka]

[0031] Preparation of compound 6 (large scale) An anhydrous solution of compound 4 (1.0 equiv.) in 2-MeTHF (5 L / kg) plus imidazole (8.0 equiv.) is prepared. The solution is cooled to 0° C. and solid compound B is added to the reaction in one portion with stirring. The solution is allowed to acclimate for 16 hours or until compound 4 is consumed. The reaction stream is diluted with additional MeTHF (4 L / kg) and then MSA (11.0 equiv.) is added as a solution in 2-MeTHF (5 L / kg) while maintaining the internal temperature below 0° C. and stirred. The solution is allowed to acclimate at −5° C. for 5 hours or until compound 5 is consumed. The reaction is quenched with aqueous sodium phosphate buffer at pH 4.5 (4 L / kg) and then the aqueous layer is separated. The organic layer is washed two more times with additional aqueous sodium phosphate buffer at pH 4.5 (2×4 L / kg) and then with saturated aqueous sodium chloride solution (4 L / kg). The washed organic layer is concentrated under reduced pressure to a final volume of 5 L / kg, then the water content of the stream is reduced to only (NMT) 0.7% by weight using co-distillation with 2-MeTHF or molecular sieves. MTBE (15 L / kg) is added dropwise over 1 hour with stirring, and the resulting slurry is allowed to settle at 20°C for as long as (NLT) 1 hour. The slurry is filtered, the cake is washed with MTBE (2x4 L / kg), and the resulting solid is then dried under reduced pressure with a slow stream of N2 at about 30°C.

[0032] The large scale production of compound 6, unlike the laboratory scale production described above, does not involve the isolation of compound 5.

[0033] Example 5 Preparation of compound 7 (laboratory scale) [ka]

[0034] To a solution of compound 6 (5.0 mg, 0.0040 mmol) in THF (1.0 mL) (alternative solvents: MeCN, DMF), potassium tert-butoxide in THF (1 mol / L) (0.012 mL, 3.0 equiv, 0.012 mmol) was added slowly at ambient temperature. The mixture was stirred at room temperature for 17 h. The reaction mixture was then quenched with a solution of HOAc in MeCN (5% v / v, 0.3 mL). HPLC analysis showed that the major peak was formed as the desired product 7. LCMS of 7: m / z (M+H) + The resulting stream was used in subsequent step 7 without further purification.

[0035] Preparation of compound 7 (large scale) A reactor under nitrogen protection is charged with THF (15 L, 15 L / kg) and the temperature is adjusted to 20° C. BMT-433600 (1.0 kg, 1.0 eq, LR) is charged continuously to the reactor. The solution is distilled to 5 L / kg under vacuum (150-200 torr) at 20-25° C. until the mixture has a KF of only 600 ppm. If the KF cannot be reached, more THF (10 L, 10 L / kg) is added and the distillation is repeated. NMP (7.5 L, 7.5 L / kg) is added to the solution, followed by LiOtBu (3.0 L, 3.0 eq, 1M in THF) in several portions while maintaining the internal temperature at 20-30° C. After 1 hour, acetic acid (241 g, 5.0 eq) is added to quench the reaction. After 15 minutes, the mixture is treated with water (5 L, 5 L / kg), cyclohexane (10 L, 10 L / kg), and conditioned at 20-30° C. for 0.5 hours. The layers are separated, and 2-MeTHF (10 L, 10 L / kg) and 20 wt % aqueous NaCl (3.0 L, 3.0 L / kg) are added to the aqueous layer. The resulting mixture is conditioned at 20-30° C. for 0.5 hours. The layers are separated, and the aqueous layer is back-extracted with 2-MeTHF (10 L, 10 L / kg). The organic layers are combined and then concentrated to 2-3 L / kg at 20-30° C. and 100 Torr. The resulting stream is used in the next step without further purification.

[0036] Example 6 Preparation of compound 8 [ka]

[0037] To the above solution from step 6 was added a solution of methylamine in EtOH (33 wt%, 0.5 mL). The mixture was stirred at ambient temperature for 0.5 h and then concentrated. The resulting residue was subjected to preparative TLC and purified with 15% MeOH in DCM to give compound 8 as a white solid (1.0 mg, 27% yield over two steps, steps 6 and 7). LCMS of compound 8: m / z (M+H) + :933

[0038] Preparation of compound 8 (large scale) A solution of compound 7 in NMP (2-3 L / kg) is charged with 33 wt% MeNH2 in ethanol (1 L / kg, 10 eq. MeNH2). The reaction mixture is agitated at 20°C for 5 hours or until compound 7 is completely consumed. The reaction mixture is charged with 6N aqueous HCl (6 eq.) and citric acid in water (1 eq.) (1.5 L / kg). The resulting slurry is agitated at 20°C for 2 hours. The slurry is filtered and the cake is washed with tetrahydrofuran (3 L / kg) followed by water (3 L / kg). The cake is dried under reduced pressure at 55°C with a slow stream of nitrogen. The dried cake is dissolved in THF (4 L / kg), water (4 L / kg) and NH4OH (3 eq.) and then agitated at 20°C for 1 hour. Citric acid (3 eq) in water (2 L / kg) is charged to the reactor and the resulting slurry is conditioned for 2 hours at 20° C. The slurry is filtered and the cake is washed with THF (2×3 L / kg). The cake is dried under reduced pressure at 55° C. with a slow stream of nitrogen.

[0039] Example 7 Compound I (Lab Scale) [ka]

[0040] Intermediate 8 (0.25 g, 0.25 mmol) was suspended in THF (1.25 mL, 5v) at ambient temperature. Triethylamine·hydrogen trifluoride (0.41 mL, 10 equiv, 2.51 mmol) was added to the suspension to obtain a homogeneous solution. Triethylamine (0.18 mL, 5 equiv, 1.26 mmol) was then added and the solution was heated to 40° C. The reaction mixture was agitated at 40° C. for 6 h to give compound I in >90% in-process yield.

[0041] Preparation of Compound I (large scale) A reactor was charged with intermediate 8 and 3 equivalents of TBAF trihydrate followed by acetonitrile; the batch was heated to 50° C. and held at that temperature for up to 18 hours. At the end of the reaction, the batch was cooled to room temperature and the crude product was purified to give compound (I) in 75-80% yield.

[0042] Spectral data: Compound 2: 1 H NMR (400MHz, CDCl3) δ 9.12(s,1H), 8.80(s,1H), 8.56(s,1H), 8.02(d,J=7.5Hz,2H), 7.62-7.4 9(m,3H), 6.11(s,1H), 4.40(d,J=4.3Hz,1H), 4.11(dd,J=11.5, 2.1Hz,1H ), 3.98-3.89(m,2H), 3.61(dd,J=8.3, 4.6Hz,1H), 1.60(brs,2H), 0.95(s ,18H), 0.79(s,1H), 0.22(s,3H), 0.15(s,3H), 0.14(s,3H), 0.13(s,3H); 13 C NMR(100MHz,CDCl3) δ 164.6, 152.6, 151.0, 149.3, 141.6, 133.9, 132.7, 128.8, 127.8, 123.2, 90 .0, 85.1, 77.9, 61.9, 52.2, 26.1, 25.8, 18.6, 18.1, -4.4, -4.9, -5.3, -5.4 m / z(M+H) + 600

[0043] Compound 3: 1 H NMR: 11H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.63 (s, 1H), 8.38 (s, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.46 (t, J = 7.2 Hz, 1H), 7.38 (t, J = 7.2 Hz, 2H), 7.22 (brs, 5H), 6.02 (d, J = 2.0 Hz, 1H), 5.10 - 4.87 (brm, 1H), 4.55 - 4.36 (brm, 3H), 4.12 (q, J = 9.7 Hz, 1H), 4.07 - 4.00 (brm, 2H), 3.98 (brd, J = 11.9 Hz, 1H), 3.80 (dd, J = 11.9, 2.8 Hz, 1H), 0.80 (s, 9H), 0.80 (s, 9H), 0.00 (s, 12H); 13 13C NMR (100 MHz, CDCl3) δ 164.7, 152.7, 151.2, 149.6, 141.5, 134.7, 134.6, 133.8, 132.8, 129.3, 129.2, 128.9, 127.9, 127.7, 123.3, 89.8, 84.9, 84.8, 76.6, 76.5, 74.2, 74.1, 61.9, 57.0, 56.9, 54.1, 26.2, 25.8, 18.6, 18.0, -4.7, -4.8, -5.1, -5.4; 31 31P NMR (160 MHz, CDCl3) δ 95.9 m / z (M + H) + 813

[0044] Compound 4: 11H NMR: (500 MHz, DMSO-d6) δ 12.24 - 11.76 (m, 2H), 11.13 (s, 1H), 8.74 - 8.35 (m, 4H), 8.25 - 8.19 (m, 1H), 7.99 - 7.89 (m, 2H), 7.65 - 7.52 (m, 1H), 7.51 - 7.41 (m, 2H), 6.09 - 5.99 (m, 1H), 5.77 - 5.67 (m, 1H), 5.14 - 5.05 (m, 1H), 4.55 - 4.44 (m, 1H), 4.32 - 4.21 (m, 1H), 4.20 - 4.06 (m, 3H), 3.98 - 3.71 (m, 4H), 3.30 - 3.25 (m, 2H), 2.87 - 2.73 (m, 1H), 1.09 - 0.99 (m, 6H), 0.80 (s, 9H), 0.74 (s, 9H), 0.68 (s, 9H), 0.00 (s, 6H), -0.01 (s, 3H), -0.06 - -0.12 (m, 6H), -0.29 - -0.34 (m, 3H); 13 13C NMR: (126 MHz, DMSO-d6) δ 180.3, 165.6, 154.8, 151.8, 151.7, 150.4, 148.5, 148.0, 141.6, 138.8, 133.3, 132.4, 128.5, 128.4, 125.6, 120.8, 88.6, 88.1, 85.0, 84.9, 80.5, 80.5, 76.0, 76.0, 73.1, 64.4, 64.4, 63.1, 53.4, 52.9, 34.6, 25.9, 25.6, 18.9, 18.8, 18.1, 17.7, 17.5, -5.0, -5.1, -5.2, -5.3, -5.5; 31 31P NMR (202 MHz, DMSO-d6) δ 59.9 m / z (M + H) + 1143

[0045] Compound 5: 11H NMR (500 MHz, DMSO-d6) δ 12.32 - 12.06 (m, 1H), 11.41 - 11.10 (m, 1H), 8.71 (s, 1H), 8.53 - 8.42 (m, 1H), 8.23 - 8.19 (m, 1H), 8.06 (brd, J = 7.6 Hz, 2H), 7.66 - 7.62 (m, 1H), 7.57 - 7.47 (m, 5H), 7.31 (s, 2H), 7.31 (d, J = 4.8 Hz, 2H), 6.21 (brt, J = 11.4 Hz, 1H), 6.11 (d, J = 3.5 Hz, 1H), 5.89 (d, J = 5.5 Hz, 1H), 5.23 (brt, J = 7.8 Hz, 1H), 5.04 - 4.92 (m, 1H), 4.62 - 4.57 (m, 1H), 4.48 - 4.40 (m, 1H), 4.38 - 4.20 (m, 4H), 4.19 - 4.14 (m, 1H), 3.87 - 3.69 (m, 3H), 2.92 - 2.83 (m, 1H), 1.96 - 1.89 (m, 1H), 1.84 - 1.76 (m, 2H), 1.36 - 1.26 (m, 2H), 1.07 - 1.04 (m, 3H), 0.86 (s, 9H), 0.82 - 0.79 (m, 9H), 0.75 (s, 9H), 0.10 - 0.03 (m, 9H), -0.01 (d, J = 4.9 Hz, 6H), -0.17 (s, 3H); 31 31P NMR (202 MHz, DMSO-d6) δ 95.2, 57.8 m / z (M + H) + 1357

[0046] Compound 6: 11H NMR (500 MHz, DMSO-d6): δ 12.14 (s, 1H), 11.58 (brs, 1H), 11.22 (brs, 1H), 8.73 (d, J = 6.4 Hz, 2H), 8.22 (s, 1H), 8.04 (d, J = 7.3 Hz, 2H), 7.63 (m, 1H), 7.59 - 7.52 (m, 4H), 7.43 - 7.32 (m, 3H), 6.48 (dd, J = 13.0, 10.5 Hz, 1H), 6.10 (d, J = 3.0 Hz, 1H), 5.87 (d, J = 5.1 Hz, 1H), 5.30 (dd, J = 8.4, 5.7 Hz, 1H), 4.71 (t, J = 6.0 Hz, 1H), 4.65 - 4.52 (m, 3H), 4.37 (q, J = 9.5 Hz, 1H), 4.33 - 4.15 (m, 6H), 4.10 - 3.91 (m, 3H), 3.71 (m, 1H), 3.59 (m, 1H), 2.79 (quin, J = 6.8 Hz, 1H), 1.09 (appt, 6H), (m, 18H), 0.80 (s, 9H), 0.75 (s, 9H), 0.06 (s, 3H), 0.02 (s, 3H), 0.00 (s, 3H), -0.15 (s, 3H); 13 13C NMR (125 MHz, DMSO-d6): δ 180.1, 165.6, 151.6, 151.5, 150.4, 148.8, 148.2, 142.2, 137.7, 135.2 (2C), 133.4, 132.4, 128.8 (2C), 128.7, 128.5 (2C), 128.4 (3C), 128.2 (2C), 125.6, 120.3, 88.9, 87.5, 84.5, 82.1, 75.5, 73.9, 73.6, 65.6, 60.3, 55.9, 55.1, 52.8, 34.6, 25.8, 25.6 (6C), 18.8, 17.7, -4.7, -4.9, -5.1, -5.2 m / z (M + H) + 1243

[0047] Compound 7: 11H NMR (400 MHz, DMSO-d6) δ 12.13 (brs, 1H), 11.76 - 11.49 (m, 1H), 11.17 (brs, 1H), 9.10 (s, 1H), 8.73 (s, 1H), 8.10 (brs, 1H), 8.04 (d, J = 10.0 Hz, 2H), 7.65 - 7.59 (m, 1H), 7.62 (t, J = 10.0 Hz, 1H), 7.53 (t, J = 10.0 Hz, 2H), 6.17 (s, 1H), 5.83 (s, 1H), 4.59 (brs, 1H), 4.22 - 4.07 (m, 4H), 4.07 - 3.94 (m, 4H), 3.87 (brdd, J = 10.9, 3.1 Hz, 1H), 2.82 (dt, J = 13.7, 6.8 Hz, 1H), 1.90 (s, 1H), 1.05 (d, J = 10.0 Hz, 6H), 0.99 (s, 9H), 0.94 (s, 9H), 0.33 (s, 3H), 0.25 (s, 3H), 0.23 (s, 3H), 0.16 (s, 3H); 13 13C NMR: (101 MHz, DMSO-d6) δ 180.7, 172.5, 166.0, 155.4, 151.8, 150.6, 148.5, 148.4, 142.7, 134.0, 132.8, 129.0, 128.9, 125.9, 90.0, 81.4, 77.5, 76.0, 62.3, 53.6, 51.2, 34.8, 26.5, 26.4, 26.3, 23.0, 21.6, 19.2, 18.3, 18.2, -2.7, -3.7, -4.1, -4.2, -4.3; 31 31P NMR (202 MHz, DMSO-d6) δ 55.8, 52.4 m / z (M + H) + 1107

[0048] Compound 8: 1 1H NMR (500 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.34 (s, 1H), 7.87 (s, 1H), 6.01 (s, 1H), 5.75 (s, 1H), 4.50 (brs, 1H), 4.10 - 3.86 (m, 9H), 0.93 (s, 9H), 0.90 (s, 9H), 0.23 (s, 3H), 0.21 (s, 6H), 0.16 (s, 3H); 13C NMR: (126MHz, DMSO-d6) δ 157.2, 154.0, 152.0, 150.7, 148.3, 147.2, 141.1, 134.9, 119.0, 116.3, 90.1, 89.2, 81.0 ,79.9,77.2,75.7,62.8,61.0,52.6,51.0,26.3,26.3,18.2,18.1,-4.3,-3.8-4.4,-4.4; 31 P NMR (202MHz, DMSO-d6) δ 57.1, 53.9 m / z(M+H) + 933

[0049] Compound I: 1 H NMR(500MHz,DMSO-d6):δ 10.76(brs,1H), 8.73(s,1H), 8.31(s,1H), 7.80(s,1H), 6.54(brs,2H), 6.06(s,1H), 5.79(s,1H), 4.36(brd,J=4.2 Hz,1H), 4.25(brd,J=10.5Hz,1H), 4.19(brd,J=10.5Hz,1H), 4.10(repeat,3H), 4.02(brdd,J=10.2,3.6Hz,1H), 3.95(v brm,1H), 3.90(repeat,2H); 13 C NMR (126MHz, DMSO-d6, 25℃): δ 156.8, 153.9, 153.2, 150.5, 149.0, 148.1, 139.9, 134.3, 118.7, 116.3, 89.9, 88.6, 80.4, 79.2, 74.7, 73.3, 62.3, 61.2, 52.2, 50.8; 31 P NMR (206MHz, DMSO-d6, 25℃): δ 62.8. m / z (M+H) + 705

[0050] Compound 8に to Kabetsu Road (Project 1および2)

change

[0051] Project 1: To a mixture of imidazole (1.93 g, 8 equiv., 28.3 mmol) and intermediate A (2.04 g, 1.0 equiv., 3.51 mmol) was added MeCN (25 mL) at ambient temperature. The mixture was concentrated. To the resulting residue was added MeCN (15 mL) followed by (S)-SO 3 P(V) (compound B) (2.85 g, 2.0 equiv., 7.02 mmol) under nitrogen atmosphere. After 2 h, the reaction mixture was concentrated and the resulting residue was purified by column chromatography with 0-25% EtOAc in DCM to give 1.80 g of a white solid as compound 9 (dr 97:3), 65% yield; m / z (M+H). + Got it for :795.

[0052] Step 2: Compound 9 (0.600 g, 1.0 equiv, 0.755 mmol) and compound 1 (0.345 g, 1.2 equiv, 0.906 mmol) were dissolved in THF (10.0 mL) and the solvent was removed by concentration under vacuum. THF (12 mL) was added to the resulting residue and the mixture was cooled to 0° C. Potassium tert-butoxide (1 mol / L) in THF (2.3 mL, 3.0 equiv, 2.3 mmol) was added slowly over 5 min. The reaction mixture was stirred at 0° C. for 16 h, after which acetic acid (0.173 mL, 4.0 equiv) was added. The reaction mixture was concentrated and the resulting residue was purified by column chromatography using 0-10% MeOH in DCM to give 0.50 g of white solid as compound 10 in 56% yield; LCMS (M+H) of compound 10 + Obtained at :1143.

Claims

1. formula: 【Chemistry 1】 A method for producing compound I represented by the following formula: a) Compound 1 was dissolved in TBSCl and Et ３ reacting with N to obtain compound 2; 【Chemistry 2】 b) reacting compound 2 with compound A to obtain compound 3; 【Chemistry 3】 c) reacting compound 3 with compound 9 to obtain compound 4; 【Chemistry 4】 d) reacting compound 4 in a solvent, then adding a base, followed by adding compound B, to obtain compound 5 of the formula: 【Chemistry 5】 e) selectively deprotecting compound 5 to obtain compound 6 of formula: 【Chemistry 6】 f) cyclizing it under basic conditions in a suitable solvent to obtain compound 7 of formula; 【Chemistry 7】 g) which is then mixed in a suitable base, stirred and concentrated to give a compound of the formula: 【Chemistry 8】 and then subjecting the compound to deprotection to obtain compound I. A manufacturing method comprising:

2. 2. The process according to claim 1, wherein the base in step b) is imidazole, DBU, diisopropylethylamine, triazole, tetrazole or a metal alkoxide base, or lithium diisopropylamide, sodium bis(trimethylsilyl)amide or other amide base.

3. 3. The method of claim 2, wherein the base is imidazole.

4. 2. The process of claim 1, wherein the solvent in step c is THF, MeCN or DMF.

5. The method of claim 4, wherein the solvent is THF.

6. 2. The process of claim 1, wherein the base in step c) is lithium diisopropylamide, sodium bis(trimethylsilyl)amide or other amide base, or potassium t-butoxide, DBU or other alkoxide base.

7. The process of claim 6, wherein the base in step c) is sodium tert-pentoxide or sodium t-amylate.

8. The process of claim 1, wherein the solvent in step d) is THF, 2-MeTHF, MeCN or DMF.

9. The process of claim 8, wherein the solvent in step d) is 2-MeTHF.

10. 2. The process of claim 1, wherein the base in step d) is imidazole, DBU, triazole, tetrazole, diisopropylethylamine or other t-butoxide.

11. 11. The process according to claim 10, wherein the base in step d) is imidazole.

12. 2. The process according to claim 1, wherein the solvent in step f) is THF, MeCN, NMP or DMF or a mixture thereof.

13. 13. The process according to claim 12, wherein the solvent in step f) is a mixture of THF and NMP.

14. 2. The process of claim 1, wherein the base in step f) is lithium diisopropylamide, potassium bis(trimethylsilyl)amide or other amide base, or potassium t-butoxide, DBU or other alkoxide base, or NaHMDS or other alkylsilylamine.

15. The method of claim 14, wherein the base in step f) is lithium t-butoxide.

16. 2. The process of claim 1, wherein the base in step g) is a methylamine, ammonium or other alkylamine base.

17. 17. The method of claim 16, wherein the base in step g) is methylamine.

18. The table below: 【Table 1】 【Table 2】 and diastereomers thereof.

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