Preparation of (9S)-2-bromo-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine

Abstract

The present invention relates to a compound of formula (I) TIFF2023503509000041.tif39169 The present invention relates to a process for the large-scale synthesis of Compound (I) or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is useful as an important intermediate for synthesizing compounds for the prevention and treatment of diseases associated with the deposition of β-amyloid in the brain, particularly Alzheimer's disease, as well as other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, and Down's syndrome.

Description

[Technical Field]

[0001] The present invention relates to compound (I) [ka] In a process for producing (9S)-2-bromo-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine or a pharmaceutically acceptable salt thereof, compound (I) or a pharmaceutically acceptable salt thereof is useful as an important intermediate for synthesizing compounds for the prevention and treatment of diseases associated with β-amyloid deposition in the brain, particularly Alzheimer's disease, as well as other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, and Down's syndrome. [Background technology]

[0002] Background of the Invention Related synthetic approaches to compound (I) have been disclosed in WO 2019121434, WO 2018083050, WO 2011086098 and WO 2010083141, however, some current processes are not suitable for large-scale production due to the following issues: (a) To produce 6-chloro-2-(2,3,4-trifluorophenyl)hexanoic acid, compound (III), in lower yields, column purification with cumbersome work-up processes is required in step 1. (b) Chiral separation is ultimately required to obtain the desired chiral product, which entails significant cost concerns and process hurdles for large-scale production of compound (I). (c) For the synthesis of the key intermediate aminotriazole compound (VII), the previous synthetic route from the methyl ester of 6-chloro-2-(2,3,4-trifluorophenyl)hexanoic acid, such as that in WO2011086098, can only provide a very low yield (about 15%), whereas the method of the present invention significantly improved the yield to about 50%. (d) If the published process is used, even if a chiral center is generated in step 6, racemization and column purification are possible in later synthesis steps. (e) Safe, robust, and scalable concerns for the de novo formation of high-energy triazole rings during large-scale production.

[0003] In light of the above challenges, one objective of the present invention is to find efficient synthetic routes and approaches that address all of the above challenges and that can be applied to the large-scale production of chiral compound (I).

[0004] Another embodiment of the present invention is compound (IV) and / or compound (IVa): [ka] A novel method for producing DETAILED DESCRIPTION OF THE INVENTION

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

[0006] Abbreviation aq. aqueous solution API Active Pharmaceutical Ingredient DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DIPEA N,N-Diisopropylethylamine eq equivalent EtOAc or EA ethyl acetate IPC In-Process Control IPA Isopropanol IPAc Isopropyl acetate ML mother liquor 2-MeTHF 2-methyltetrahydrofuran MTBE Methyl tert-butyl ether NaHMDS Sodium hexamethyldisilazide in THF NMP N-methyl-2-pyrrolidone Pd / C Palladium Carbon TEA Triethylamine v. volume v / v volume ratio wt.% weight percent

[0007] The present invention provides a process for the preparation of compounds of formula (I), as outlined in Scheme 1. Scheme 1 [ka]

[0008] The synthesis comprises the following steps: Step 1) Compound (III) [ka] The formation of 2,3,4-trifluorophenylacetic acid, compound (II) [ka] with 1-chloro-4-iodobutane to form compound (III); Step 2) Compound (IVa) [ka] via chiral resolution of salt formation between a chiral base and compound (III) to form compound (IVa); Step 3) Compound (IV), which is (2S)-6-chloro-2-(2,3,4-trifluorophenyl)hexanoic acid [ka] via dissociation of compound (IVa) with an acid to form compound (IV); Step 4) Compound (V), which is (2S)-6-chloro-2-(2,3,4-trifluorophenyl)hexanoyl chloride [ka] via acyl chlorination of compound (IV) with a chlorinating agent to form compound (V); Step 5) Compound (VI) [ka] via a coupling reaction between amino-guanidine and compound (V) to form compound (VI); Step 6) Compound (VII) [ka] via intramolecular cyclization of compound (VI) in the presence of a base to form compound (VII); Step 7) Compound (I) [ka] via the Sandmeyer reaction to form compound (I). Includes:

[0009] A detailed description of the method steps of the present invention is as follows: Step 1) Compound (III) [ka] The formation of 2,3,4-trifluorophenylacetic acid, compound (II) [ka] and the formation of compound (III) via reaction with 1-chloro-4-iodobutane and a base.

[0010] Compound (III) (288 kg, 89% purity, over 90% yield) was synthesized using an appropriate base in the presence of an appropriate solvent at temperature.

[0011] Suitable solvents are selected from THF, n-heptane, MeCN and MeTHF, in particular the solvent is THF.

[0012] A suitable temperature is selected from -5 to 5°C, and a suitable reaction time is 1 to 3 hours, particularly, the temperature is 0°C and the reaction time is 2 hours.

[0013] Suitable bases are selected from NaHMDS, KOtBu and LiHMDS, a particularly suitable base is NaHMDS.

[0014] In another embodiment, the order of loading of reactants was changed for the reaction, which was important for the overall process in terms of technical-scale production and improved yield. The best conversion results by IPC could be achieved by adding NaHMDS to a solution of compound (II) in THF and 1-chloro-4-iodobutane at 0 °C under stirring for 3 h. A better and simpler workup process was also developed by replacing the HCl solution with a citric acid solution, adjusting the pH to 5-7, and subsequently extracting the mixture with IPAc to obtain a high-quality product (III) solution for the next step of large-scale production of (IVa) without column purification.

[0015] According to published conditions (WO2011086098), the methyl ester of compound (III) was used for triazole formation, but unfortunately with a very low yield (about 15.8%).

[0016] The crude product was used directly in the next step without solid isolation.

[0017] Step 2) Compound (IVa) [ka] Compound (IVa) (164 kg, chiral purity 99.4%, yield 44%) was isolated via chiral resolution of the salt formation between a chiral base and compound (III) in a suitable solvent.

[0018] Suitable chiral bases include quinidine, (R)-(+)-N-benzyl-α-methylbenzylamine, (S)-(+)-2-aminobutanol, (S)-(-)-α-methylbenzylamine, hydroquinine, (R)-(+)-2-amino-3-phenol-1-propanol, (1R,2R)-(+)-pseudoephedrine, (S)-(-)-phenylpropylamine, (R)-(-)-2-amino-1-propanol The chiral base is selected from the group consisting of (S)-(+)-phenylglycinol, N-methyl-D-glucamine, (-)-cinchonidine, (S)-(+)-phenylglycinol, dehydroabietylamine, (1R,2S)-(+)-cis-1-amino-2-indanol, (1R,2R)-(-)-1,2-diaminocyclohexane, and (1R,2R)-(+)-1,2-diphenylethylenediamine, and in particular, the chiral base is (S)-(+)-phenylglycinol.

[0019] Suitable solvents are selected from IPAc, THF, MTBE and IPA, in particular the solvent is IPAc.

[0020] The reaction is carried out at 45°C, -55°C, then cooled to 5°C, -15°C, and in particular at 50°C, then cooled to 10.4°C.

[0021] Step 3) Compound (IV), which is (2S)-6-chloro-2-(2,3,4-trifluorophenyl)hexanoic acid [ka] via dissociation of compound (IVa) with aqueous HCl to form compound (IV).

[0022] Step 4) Compound (V), which is (2S)-6-chloro-2-(2,3,4-trifluorophenyl)hexanoyl chloride [ka] via acyl chlorination of compound (IV) with a chlorinating agent to form compound (V).

[0023] Suitable chlorinating reagents are selected from (COCl)2 and SOCl2, in particular the chlorinating reagent is SOCl2.

[0024] The amount of SOCl2 is selected from 2.5 to 5 equivalents, and in particular the amount is 5 equivalents.

[0025] Suitable solvents are selected from NMP and DCM / DMF, in particular the solvent is NMP.

[0026] The reaction is carried out at 5°C, -20°C, particularly at 5°C, -15°C.

[0027] To address the concern of low yield of aminotriazole compound (VII), the newly formed (2S)-6-chloro-2-(2,3,4-trifluorophenyl)hexanoyl chloride, compound (V), was used in place of the methyl ester of (III) to generate the desired aminotriazole compound (VII). The newly developed conditions were verified as a scalable process.

[0028] Step 5) Compound (VI) [ka] via a coupling reaction between amino-guanidine and compound (V) to form compound (VI).

[0029] Suitable solvents used in this step are selected from NMP, DCM, pyridine, dioxane and MeTHF, in particular the solvent is NMP.

[0030] The reaction is carried out at 5°C to 125°C, particularly 5°C to 15°C.

[0031] The reaction is carried out for 1 to 20 hours, and the reaction time is preferably 3 hours.

[0032] The regioisomer, compound (VI-1), was also observed during the coupling of acyl chlorides with aminoguanidine and was also taken into consideration during the development process. Compound (VI-1) and another major by-product, compound (VI-2), could be removed from the developed recrystallization process. [ka]

[0033] Step 6) Compound (VII) [ka] via intramolecular cyclization of compound (VI) in the presence of a base to form compound (VII).

[0034] Suitable bases are selected from NaOH, NaHCO3, Et3N, DIEA, Na2CO3, K2CO3, DBU, and K3PO4, K3PO4 / KI, and in particular the base is K3PO4 / KI. The conditions developed are very important to avoid racemization in this step, and the base selection is particularly important. The strong base NaOH can cause more than 30% racemization in this step.

[0035] Suitable solvents are selected from DMF, MeCN, MeTHF, IPA and NMP, and in particular the solvent is IPA. Correct solvent selection is also important for the reaction and crystallization to achieve high yields.

[0036] The reaction is carried out at 60°C, -105°C, particularly 75°C, -85°C.

[0037] The reaction time is 5 to 18 hours, and in particular the reaction time is 16 hours.

[0038] Step 7) Compound (I) [ka] via the Sandmeyer reaction in the presence of a nitrate reagent and a catalyst in a suitable solvent to form compound (I). Recrystallization was performed to achieve 99.9% purity and 100.0% chiral purity in 70% yield.

[0039] Suitable nitrate reagents and catalysts are selected from NaNO / HBr and t-BuONO / CuBr, particularly t-BuONO / CuBr. The preferred equivalents of t-BuONO / CuBr are 1.7 to 1.3 equivalents, particularly 1.5 equivalents. The selection of nitrate reagents and catalysts and their equivalents was important to achieve the highest yields and the lowest by-products of Compounds (I-1) and (I-2). [Table 1]

[0040] Suitable solvents are selected from MeCN, MeTHF, THF, IPA and NMP, in particular the solvent is MeCN.

[0041] When attempting to reduce the reaction volume from 15 volumes to 5 volumes of MeCN, all reactions were able to give complete conversion, especially with a solvent volume of 6 volumes.

[0042] The reaction time is 1.5 to 22 hours, and the reaction is carried out at 25 to 60°C, and particularly the reaction is carried out at 45°C for 3 hours. [ka] (Compounds (I-1) and (I-2) were observed by HPLC and their structures were tentatively determined.) [Example]

[0043] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention.

[0044] Example 1 6-chloro-2-(2,3,4-trifluorophenyl)hexanoic acid (compound (III) [ka]

[0045] A 3000 L glass-lined (GL / 3000 L) pilot plant reactor under N2 protection was charged with 2,3,4-trifluorophenylacetic acid (Compound (II), 102.3 kg, 1.0 equiv.) and THF (590 kg) at 15°C to 25°C. After stirring for 30 minutes, 1-chloro-4-iodobutane (130 kg, 1.9 equiv.) was added to the reaction mixture, and the reactor temperature was then adjusted to -5°C to 5°C under nitrogen protection. Under nitrogen protection, NaHMDS (1 M / THF, 956 kg, 2.0 equiv.) was slowly added to the reactor at -5°C to 5°C for at least 1 hour, and the reaction mixture was stirred at -5°C to 5°C for 1 to 3 hours.

[0046] Under nitrogen protection, water (200 kg) was slowly charged in small portions to the reactor at a batch temperature of -5 to 5° C., via vacuum to the reaction mixture. Then, under nitrogen protection, the temperature was adjusted to 15 to 25° C., and 38% aqueous citric acid solution (372 kg) was charged in small portions via vacuum at 15 to 25° C. until the pH reached 7, and the reaction mixture was allowed to stand for 0.5 to 1.5 hours.

[0047] The aqueous layer was removed, and IPAc (309 kg) was charged via a charging device and a diaphragm pump. The separated organic mixture was concentrated under reduced pressure (internal temperature below 30°C) to approximately 206-515 L to remove THF. IPAc (422 kg), 25% aqueous NaCl solution (180 kg), and process water (122 kg) were then charged to the resulting residue via a charging device and a diaphragm pump at 20-30°C. The mixture was stirred for 1 hour, and then the aqueous layer was separated.

[0048] The two organic layers were combined (approximately 1000 L) and concentrated. The residue was azeotroped with IPAc (2×450 L) to remove water to the limit required by IPC, yielding a product of compound (III) in IPAc solution (net 288 kg) for use in the next step without further treatment. Roughness 1 NMR: 1 H NMR(300 MHz,CDCl3)δ=7.08-6.96(m,2H),3.98(t,J=7.2 Hz,1H),3.51(t,J=6.2 Hz,2H),2.17-2.09(m,1H),1.87-1.75(m,3H),1.51-1.37(m,2H),0.18(s,18H).

[0049] Example 2 Synthesis of (2S)-6-chloro-2-(2,3,4-trifluorophenyl)hexanoate; [(1S)-2-hydroxy-1-phenyl-ethyl]ammonium (Compound (IVa)) and Compound (IV) [ka]

[0050] An 8000 L glass-lined reactor was charged with Compound (III) in isopropyl acetate (167 kg) and IPAc (4004 kg) via a diaphragm pump, and the mixture was heated to 50°C and stirred until clear. L-phenylglycinol (27 kg) and IPAc (155 kg) were charged to the clear solution, and the mixture was stirred at 45-55°C for 2.5 hours. Crystal seeds (0.08 kg) were added to the mixture, which was stirred at 50°C for an additional 2.5 hours. Another portion of L-phenylglycinol (55.8 kg) and IPAc (155 kg) was charged to the mixture, which was stirred at 50°C for an additional 8 hours, and then cooled to 10°C with stirring for an additional 15 hours to obtain a suspension. The suspension was filtered, and the filter cake was washed in a centrifuge with cold IPAc (380 + 187 kg, 10°C) to obtain crude Compound (IVa) (228 kg, 96% ee).

[0051] Recrystallization: Crude IVa (228 kg) and IPAc (2958 kg) were charged to an 8000 L reactor. The mixture was heated to 50° C. with stirring for 8 hours, then cooled to 10° C. and stirred for 15 hours to give a suspension. The suspension was filtered and washed with cold IPAc (381 + 191 kg) at 10° C. to give pure compound (Iva) (164 kg, 99.4% ee) as a wet cake, which was used in the next step without further manipulation.

[0052] Preparation of the free acid compound (IV): 35% HCl (106 kg), process water (502 kg), and DCM (1477 L) were charged into an 8000 L reactor under N2. The mixture was stirred for 30 minutes. Compound (IVa) wet cake (164 kg) and process water (338 kg) were added to the solution at 10°C. The mixture was stirred for an additional hour, and then 2 M HCl (381 kg) was added to adjust the pH to 2 at 10°C. The temperature was then adjusted to 25°C, and the mixture was stirred for 3 hours to obtain a clear two-phase solution. The solution was allowed to settle for 1.5 hours and separated. The lower layer (organic phase) was washed with NaCl solution (10.1 kg NaCl in 328 kg water), which was then extracted with DCM (207 L), and the upper layer (inorganic phase) was extracted twice with DCM (107 kg and 106 kg). The combined DCM layers were concentrated under vacuum (below 40°C) and azeotroped twice with DCM (513 L and 514 L) to remove water, giving Compound (IV) in DCM solution (net weight 1426.6 kg, IPC water content approximately 0.04%, Compound (IV) 72.2 kg), a 44% yield for these two steps. Compound (IV) with 99.2% ee and 96% chemical purity was used directly in the next step without further manipulation.

[0053] Example 3 Preparation of Compounds (V), (VI) and (VII) from Compound IV [ka]

[0054] The preparation of compound (VII) from 72.2 kg of compound (IV) in one batch was finalized in a production facility according to the following procedure: Finally, 38.20 kg of compound (VII) was obtained in 50% yield with a purity of 99.3%, a chiral purity of 97.5% and an assay of 95.8%.

[0055] A DCM solution (1426 kg total) of compound (IV) (72.2 kg) from the previous step in a 1000 L reactor was concentrated to 71-142 L, and then NMP (225 kg) and thionyl chloride (34.8 kg, 2.5 equivalents) were charged under nitrogen protection with stirring at 5-15°C. The reaction mixture was stirred for 3 hours, and then aminoguanidine hydrochloride (31.2 kg, 1.1 equivalents) was charged under nitrogen protection at 5-15°C to form compound (VI). Process water (352 kg + 104 kg) was added in portions to the mixture at 5-15°C, followed by IPAc (622 kg + 225 kg) at 5-15°C. Next, 30% K3PO4 solution (726 + 50 kg) was slowly added to the mixture at 20 °C until the pH reached 8.1, followed by dropwise addition of process water (70 kg) to the mixture via a peristaltic pump. After stirring the mixture at 20 °C for 60 minutes, the aqueous layer was separated and extracted with IPAc (282 kg). The combined organic layers were concentrated (below 45 °C) until 71 282 L remained, and the residue (below 45 °C) was azeotroped twice with IPA (446 + 639 L) to obtain a 71 497 L solution (IPAc content approximately 0.01). To the residual solution, IPA (535 L), KI (85 kg), and K3PO4 (300 kg) were charged via a flexible isolator under nitrogen protection, followed by addition of process water (470 kg) to the mixture at 10–30 °C. The mixture was stirred at 75-85°C for 20 hours and then cooled to 45-60°C, after which the aqueous layer was separated. The organic layer was further cooled to 35-45°C, and then Compound (VII) crystal seeds (0.055 kg) were charged with stirring for an additional 2 hours. The mixture was cooled to 0-10°C over 1 hour, and then process water (289 kg) was added under N2 with stirring for 12 hours at 0-10°C to obtain a suspension. The suspension was filtered using a centrifuge, and the filter cake was washed twice (350 kg + 58 kg) with IPA / water (31 / 36 ratio, 36 kg) and process water under N2 to obtain Compound (VII) (41.25 kg, purity 99.4%, chiral purity 97.5%). The wet cake was dried under reduced pressure at 55°C for 30 hours to obtain solid Compound (VII) (38.2 kg). The impurities of compounds (VI-1) and (VI-2) were removed during recrystallization. Compound VII: 1H NMR(300 MHz,DMSO-d6)δ=7.032-7.17(m,2H),6.23(s,2H),4.34(m,1H),4.15-3.99(m,2H),2.14-1.93(m,4H),1.92-1.76(m,1H),1.60-1.48(m,1H).

[0056] Example 4 Preparation of Compound (I) [ka] (Compounds (I-1) and (I-2) were observed by HPLC and their structures were tentatively determined.)

[0057] The preparation of Compound (I) from 36.50 kg of Compound (VII) in one batch was finalized in a production facility according to the following procedure: Finally, 31.10 kg of Compound (I) was obtained in 73% yield with a purity of 99.9%, a chiral purity of 100.0% and an assay of 96.3%.

[0058] Compound (VII) (35 kg), MeCN (141 kg + 29 kg), and CuBr (41.6 kg) solids were charged into a 1000 L GL reactor via a flexible isolator under N2 protection. The mixture was heated to 40-50°C, and then tert-butyl nitrite (19.2 kg) and MeCN (7 kg) were added slowly in small portions under N2 protection. The mixture was stirred at 40-50°C for 5 hours, cooled to 15-25°C, and then IPAc (472 kg) and process water (176 kg) were added. The mixture was stirred for 10 hours and filtered through diatomaceous earth (10 kg). The filter cake was rinsed with IPAc (101 kg), and the aqueous layer was separated. The organic layer was then concentrated under vacuum to 140-210 L. The residual solution was azeotroped four times with MeOH (140, 125, 123, and 126 kg) to achieve a 140-210 L solution with the desired quality (IPAc approximately 28938 ppm). The mixture was heated to 60-70 °C to obtain a clear solution and stirred for 2 h. The solution was cooled to 5-15 °C with stirring under N2 for 24 h to obtain a suspension. The suspension was filtered, and the wet cake was rinsed with MeOH (16 kg) to obtain a solid cake of compound (I) (36.2 kg, 99.8% ee, 97.4% purity).

[0059] Recrystallization: EA (514 kg) was charged to the solid cake of crude Compound (I) in a 1000 L reactor, and the mixture was stirred at 30-40 °C to obtain a solution. The mixture was concentrated to 280-350 L below 35 °C and then cooled to the batch temperature of 20-30 °C under N2 protection. Compound (I) crystal seeds (0.058 kg) were charged to the reactor at 20-30 °C, and the solution was stirred for 2 h. The solution was azeotroped three times with MeOH (114, 108, and 106 kg) to obtain a final solution of 105-175 L with the desired IPC (EA approximately 3967 ppm). The MeOH solution (105-175 L) of crude Compound (I) was stirred at 40-50 °C for 2 h and then cooled to 5-15 °C with stirring for an additional 20 h to obtain a suspension, which was then filtered. The wet cake was rinsed with MeOH (17 kg) and dried under vacuum at 35° C. for 15 hours to give pure compound (I) (31.1 kg, 99.9% ee, 99.6% purity) as a white solid. The impurities of compounds (I-1) and (I-2) were removed during recrystallization. Compound (I): 1 H NMR(400 MHz,DMSO-d6)δ=7.38-7.28(m,1H),7.27-7.17(m,1H),4.55(dd,J=3.4,9.8 Hz,1H),4.50-4.39(m,1H),4.38-4.23(m,1H),2.14-1.93(m,4H),1.92-1.78(m,1H),1.70-1.51(m,1H)

Claims

1. Compound (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, comprising the steps of: Step 1) Compound (III) 【Chemistry 2】 The formation of 2,3,4-trifluorophenylacetic acid, compound (II) 【Transformation 3】 with 1-chloro-4-iodobutane to form compound (III); Step 2) Compound (IVa) 【Chemistry 4】 via chiral resolution of the salt formation between a chiral base and compound (III) to form compound (IVa); Step 3) Compound (IV), which is (2S)-6-chloro-2-(2,3,4-trifluorophenyl)hexanoic acid 【Transformation 5】 via dissociation of compound (IVa) with an acid to form compound (IV); Step 4) Compound (V), which is (2S)-6-chloro-2-(2,3,4-trifluorophenyl)hexanoyl chloride 【Transformation 6】 via acyl chlorination of compound (IV) with a chlorinating agent to form compound (V); Step 5) Compound (VI) 【Transformation 7】 via a coupling reaction between amino-guanidine and compound (V) to form compound (VI); Step 6) Compound (VII) 【Transformation 8】 via intramolecular cyclization of compound (VI) in the presence of a base to form compound (VII); Step 7) Compound (I) 【Chemistry 9】 via the Sandmeyer reaction to form compound (I). A method comprising any one of the following:

2. 2. The method of claim 1, wherein the formation of compound (IVa) in step 2) is carried out in the presence of a chiral base, and the chiral base is (S)-(+)-phenylglycinol.

3. 3. The method according to claim 1 or 2, wherein the formation of compound (IVa) in step 2) is carried out in a solvent, and the solvent is selected from IPAc, THF, MTBE and IPA.

4. The method of claim 3 wherein the solvent is IPAc.

5. The formation of compound (VII) in step 6) is carried out in the presence of a base, and the base is NaOH, NaHCO ３ , Et ３ N, DIEA, Na ２ CO ３ , K. ２ CO ３ , DBU and K ３ P.O. ４ , K ３ P.O. ４ 5. The method according to claim 1, wherein the hydroxybenzoate is selected from the group consisting of hydroxybenzoates, ...

6. The base is K ３ P.O. ４ The method of claim 5, wherein the hydroxyl group is hydroxyl group.

7. 7. The process according to any one of claims 1 to 6, wherein the formation of compound (VII) in step 6) is carried out in a solvent, and the solvent is selected from DMF, MeCN, MeTHF, IPA and NMP.

8. The method of claim 7 wherein the solvent is IPA.

9. The formation of compound (I) in step 7) is carried out in the presence of a nitrite reagent and a catalyst, and the nitrite reagent and the catalyst are NaNO ２ / HBr and t-BuONO / CuBr ２ The method according to any one of claims 1 to 8, wherein the compound is selected from the group consisting of:

10. The nitrite reagent and catalyst are t-BuONO / CuBr ２ The method of claim 9, wherein

11. t-BuONO / CuBr ２ The method according to claim 9 or 10, wherein the amount of equivalents is 1.7 to 1.3 equivalents.

12. 12. The method of claim 11, wherein the equivalents are 1.5 equivalents.

13. Compound (IVa) 【Chemistry 10】 a process for preparing a compound (III) comprising reacting a chiral base with a compound (III) 【Chemistry 11】 via chiral resolution of salt formation between

14. 14. The method of claim 13, wherein the formation of compound (IVa) is carried out in the presence of a chiral base, wherein the chiral base is (S)-(+)-phenylglycinol, and the reaction is carried out in a solvent, wherein the solvent is selected from IPAc, THF, MTBE, and IPA.

15. The method of claim 14, wherein the solvent is IPAc.

16. 14. The method of claim 13, wherein the formation of compound (IVa) is carried out in the presence of (S)-(+)-phenylglycinol in IPAc.

17. Compound (IVa): (2S)-6-chloro-2-(2,3,4-trifluorophenyl)hexanoic acid [(1S)-2-hydroxy-1-phenyl-ethyl]ammonium 【Chemistry 12】 A compound.

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