SACUBITRIL INTERMEDIATE, PREPARATION METHOD THEREFOR, AND USE THEREOF

Abstract

A sacubitril intermediate, a preparation method therefor, and use thereof. A key intermediate N-Boc amino alcohol represented by formula (10) or formula (10-a) can be efficiently prepared. The intermediate can be used to prepare a neutral endopeptidase (NEP) inhibitor or a prodrug thereof, particularly a NEP inhibitor comprising a skeleton of -amino--biphenyl--methylalkanoic acid or ester, such as sacubitril. Also provided are intermediates for preparing formula (10) or formula (10-a). Raw materials of the process route are cheap, the operation is simple and convenient, the production cost is low, and the method is suitable for industrial production

##STR00001##

Claims

1. A preparation process for compound (10), comprising the following steps: ##STR00059## step a: reacting compound (6) with compound (M) under an action of a catalyst to give compound (7), wherein * represents that compound (6) and compound (7) are both in R configuration or S configuration; preferably, * represents that compound (6) and compound (7) are both in R configuration; R.sup.1 is F, Cl, Br, I, or OR.sup.3, and R.sup.3 represents C.sub.1-6 alkyl or C.sub.1-6 heteroalkyl; R.sup.2 is ##STR00060## wherein X is Cl, Br, or I; Pg.sub.1 is an amino protective group; and compound (10) has a structure: ##STR00061## wherein * represents that compound (10) is in R configuration or S configuration, preferably, * represents that compound (10) is in R configuration.

2. The process according to claim 1, wherein the catalyst is a cuprous salt; the amino protective group is benzyloxycarbonyl, tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, or trimethylsilylethoxycarbonyl.

3. The process according to claim 2, wherein the cuprous salt is CuI, CuBr, CuCl, or CuCN.

4. The process according to claim 1, wherein the reaction is performed under dry and oxygen-free conditions; preferably, the reaction is performed under dry and oxygen-free conditions with introduction of nitrogen for protection.

5. The process according to claim 1, wherein the reaction temperature of the reaction is 60 to 0 C.; preferably, the reaction temperature is 45 to 0 C.; more preferably, the reaction temperature is 30 to 10 C.

6. The process according to claim 1, wherein the reaction solvent of the reaction is a first solvent, and the first solvent is an organic aprotic solvent.

7. The process according to claim 6, wherein the organic aprotic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, toluene, cyclopentyl methyl ether, dichloromethane, methyl tert-butyl ether, or diethyl ether, or any combination thereof.

8. The process according to claim 1, wherein the molar ratio of compound (6) to compound (M) is 1:0.7-2.

9. The process according to claim 1, further comprising the following steps: ##STR00062## wherein * represents that compound (7), compound (8), and compound (9) are all in R configuration or S configuration; preferably, * represents that compound (7), compound (8), and compound (9) are all in R configuration; step b: reacting compound (7) in a second solvent under a first heating condition to give compound (8), wherein step c: subjecting compound (8) and a base to a hydrolysis reaction in a third solvent under a second heating condition to give compound (9), wherein the base is sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, or sodium methoxide, or any combination thereof, the molar ratio of compound (8) to the base is 1:(0.9-5).

10. The process according to claim 9, wherein the heating temperatures under the first heating condition and the second heating condition are each independently 80-150 C., preferably 100-150 C.

11. The process according to claim 9, wherein the second solvent and the third solvent are each independently n-butanol, benzene, toluene, ethylene glycol dimethyl ether, N,N-dimethylformamide, or N,N-dimethylacetamide, or any combination thereof.

12. The process according to claim 9, wherein the reaction of step c is performed by adding a base directly without any post-treatment after the reaction of step b.

13. The process according to claim 9, further comprising the following steps: ##STR00063## wherein * represents that compound (9) and compound (10) are both in R configuration or S configuration; preferably, * represents that compound (9) and compound (10) are both in R configuration; and step d: subjecting compound (9) to an amino protection reaction to give compound (10).

14. The process according to claim 1, wherein compound (6) is prepared by the following steps: ##STR00064## wherein * on compound (2), compound (3), compound (4a), compound (4), and compound (5) represents that compound (2), compound (3), compound (4a), compound (4), and compound (5) are all in S configuration, and * on compound (6) represents that compound (6) is in R configuration; or * on compound (2), compound (3), compound (4a), compound (4), and compound (5) represents that compound (2), compound (3), compound (4a), compound (4), and compound (5) are all in R configuration, and * on compound (6) represents that compound (6) is in S configuration; Pg.sub.2 is a hydroxyl protective group, preferably methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, or nitrosulfonyl; R.sup.1 and Pg.sub.1 have the definitions according to claim 1; step a: subjecting compound (2) and a hydroxyl protective reagent to a hydroxyl protection reaction to give compound (3); preferably, the feeding molar ratio of compound (2) to the hydroxyl protective reagent is 1:(1-3); more preferably, the feeding molar ratio of compound (2) to the hydroxyl protective reagent is 1:(1-2); even more preferably, the feeding molar ratio of compound (2) to the hydroxyl protective reagent is 1:(1.2-1.5); most preferably, the feeding molar ratio of compound (2) to the hydroxyl protective reagent is 1:1.3; step b: reacting compound (3) with acid HY to give compound (4a); preferably, the acid HY is hydrochloric acid, hydrobromic acid, formic acid, hydroiodic acid, p-toluenesulfonic acid, or trifluoromethanesulfonic acid; step c: reacting compound (4a) under an action of a base to give compound (4); preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate; step d: subjecting compound (4) and an amino protective reagent to an amino protection reaction to give compound (5); preferably, the feeding molar ratio of compound (4) to the amino protective reagent is 1:1-1.5; and step e: reacting compound (5) in a fourth solvent under an action of a basic reagent to give compound (6); preferably, the basic reagent is sodium hydride, sodium methoxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, or sodium ethoxide; preferably, the feeding molar ratio of compound (5) to the basic reagent is 1:(1-3).

15. The process according to claim 1, wherein compound (6) is prepared by the following steps: ##STR00065## wherein * on compound (4-1-a) and compound (5-1) represents that compound (4-1-a) and compound (5-1) are both in S configuration, and * on compound (6) represents that compound (6) is in R configuration; or * on compound (4-1-a) and compound (5-1) represents that compound (4-1-a) and compound (5-1) are both in R configuration, and * on compound (6) represents that compound (6) is in S configuration; step a: subjecting compound (4-1-a) and an amino protective reagent to an amino protection reaction under an action of a base to give compound (5-1); preferably, the feeding molar ratio of compound (4-1-a) to the amino protective reagent is 1:(0.7-2); preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate, or potassium carbonate; and step b: reacting compound (5-1) at a low temperature under an action of triphenylphosphine and ethyl azodicarboxylate and under nitrogen atmosphere to give compound (6), wherein the low temperature is 40 to 0 C., preferably 30 to 10 C., and more preferably 20 to 10 C.

16. The process according to claim 1, wherein compound (6) is prepared by the following steps: ##STR00066## wherein * on compound (4a) represents that compound (4a) is in S configuration, and * on compound (5-2) and compound (6) represents that compound (5-2) and compound (6) are both in R configuration; or * on compound (4a) represents that compound (4a) is in R configuration, and * on compound (5-2) and compound (6) represents that compound (5-2) and compound (6) are both in S configuration; step a: reacting compound (4a) under an action of a base to give compound (5-2); preferably, the base is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate, or potassium carbonate; preferably, the feeding molar ratio of compound (4a) to the base is 1:(1-3), more preferably 1:(1.2-2.5), and most preferably 1:1.5; preferably, the reaction temperature is 10-100 C.; more preferably, the reaction temperature is 30-80 C.; even more preferably, the reaction temperature is 40-60 C.; most preferably, the reaction temperature is 50 C.; and step b: continuously subjecting compound (5-2) and an amino protective reagent to an amino protection reaction to give compound (6); preferably, the feeding molar ratio of compound (5-2) to the amino protective reagent is 1:(0.7-2); preferably, the reaction is a low-temperature reaction, and the low temperature is 5 to 15 C.; more preferably, the low temperature is 0-10 C.

17. A compound, having a structure of formula (7a) or (7b) below: ##STR00067## wherein R.sup.1a is F, Cl, Br, I, or OR.sup.3, and R.sup.3 represents C.sub.1-6 alkyl or C.sub.1-6 heteroalkyl; Pg.sub.1a is an amino protective group, preferably benzyloxycarbonyl, tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, or trimethylsilylethoxycarbonyl; and when R.sup.1a is Br or I, Pg.sub.1a is not tert-butoxycarbonyl.

18. The compound according to claim 12, having one of the following structures: ##STR00068##

19. A compound, having a structure of formula (8-a) or (8-b) below: ##STR00069##

20. Use the compound according to claim 19 in the preparation of sacubitril.

Description

DETAILED DESCRIPTION

[0141] Generally, the compounds of the present disclosure may be prepared by the methods described in the present disclosure. The following reaction schemes and examples serve to further illustrate the context of the present disclosure. It should be understood by those skilled in the art that the examples are only intended to help understand the present disclosure and should not be construed as the specific limitation of the present disclosure.

[0142] Unless otherwise indicated, all temperatures in the examples described below are given in Celsius degrees. The room temperature of the present disclosure is 10-30 C. or 15-25 C. Unless otherwise stated, reagents are conventional and commercially available. The chromatographic column is a silica gel column. Nuclear magnetic resonance spectroscopy is performed using CDCl.sub.3 or DMSO-d.sub.6 as the solvent (reported in ppm) and TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. Coupling constants Jare expressed in hertz (Hz).

[0143] The following abbreviations are used throughout the present disclosure:

TABLE-US-00001 Benzyloxycarbonyl Cbz tert-Butoxycarbonyl Boc Methoxycarbonyl COOMe or CO.sub.2Me Ethoxycarbonyl COOEt or CO.sub.2Et Isobutyloxycarbonyl COO.sup.iBu or CO.sub.2.sup.iBu Fluorenylmethoxycarbonyl Fmoc Isopropyloxycarbonyl COO.sup.iPr or CO.sub.2.sup.iPr Trimethylsilylethoxycarbonyl -Teoc Allyloxycarbonyl -Alloc Trifluoromethanesulfonyl -OTf Methanesulfonyl -OMs Nitrosulfonyl -Ns p-Toluenesulfonyl -Ts Ethyl acetate EA, EtOAc Petroleum ether PE Tetrahydrofuran THF Chloroform-d deuterated chloroform DMSO-d.sub.6 deuterated dimethyl sulfoxide M, mol/L mol/liter

EXAMPLES

Example 1: Synthesis of Compound (6-a)

Step 1: Synthesis of Compound (2-a)

##STR00036##

[0144] Benzaldehyde (50 g, 0.47 mol) was added to ethanol (300 mL), and the mixture was stirred at room temperature. Aqueous ammonia (25%, 50 mL) was dropwise added to the reaction system at 15-20 C. After the dropwise addition was completed, the mixture was warmed to room temperature and stirred for 20 min, and then (S)-epichlorohydrin (52 g, 0.56 mol, 1.2 eq) was diluted with ethanol (50 mL) and slowly and dropwise added to the reaction system under nitrogen atmosphere. After the dropwise addition was completed, the system was stirred at room temperature (25-30 C.) for 12 h. After epichlorohydrin disappeared as monitored by GC, the reaction was completed. Ethanol was recovered by distillation under reduced pressure to give a yellow oily product, and ethanol (100 mL) was added for distillation again to give a pale yellow oily liquid (113 g), which was crude compound (2-a).

[0145] Screening of different process conditions in step 1 of Example 1: According to the reagent feeding amounts shown in Table 1, the rest of operations were performed as described in step 1 to give compound (2-a). A GC content of the compound (2-a) obtained was detected, and the results are shown in Table 1.

TABLE-US-00002 TABLE 1 Screening of different process conditions in step 1 of Example 1 Aqueous Epichloro- ammonia Nitro- GC Benzaldehyde hydrin (25%) Ethanol gen content 01 18.7 g 24 g (1.5 eq) 14.7 g 50 mL Absent 79% 02 18.7 g 24 g (1.5 eq) 14.7 g 50 mL Present 92% 03 18.7 g 24 g (1.2 eq) 14.7 g 50 mL Present 91% 04 100 g 104 g (1.2 eq) 120 g 400 mL Present 94%

[0146] The screening and optimizing of the reaction conditions show that, with all other conditions being identical to the paragraph immediately preceding Table 1, use of nitrogen protection during the dropwise addition of epichlorohydrin can effectively reduce the formation of impurities and increase the yield. Simultaneously, the reaction scale-up yielded similar results to the small-scale experiment, indicating good reaction stability.

Step 2: Synthesis of Compound (4-a)

##STR00037##

[0147] The crude compound (2-a) (113 g, 0.42 mol, 1.0 eq) obtained in the previous step (step 1) was added to dichloromethane (400 mL), and the mixture was stirred at room temperature until a small amount of a white insoluble substance was observed. The mixture was filtered, and triethylamine (63.7 g, 0.629 mol, 1.5 eq) was added to the filtrate. The mixture was cooled to an internal temperature of 0-10 C., and methanesulfonyl chloride (62.5 g, 0.545 mol, 1.3 eq) diluted with dichloromethane (100 mL) was dropwise added. The system was heated to an internal temperature of 12 C., and a white solid precipitated. After the dropwise addition was completed, the system was cooled to 4 C. and stirred for 1 h with the temperature maintained. Then the starting materials disappeared as monitored by normal phase HPLC. Water (400 mL) was added to the system, and the mixture was uniformly stirred for 30 min and extracted. The organic phase was washed twice with water (400 mL2). Concentrated hydrochloric acid (120 g) diluted with water (240 mL) was added to the organic phase. The mixture was uniformly stirred at room temperature for 3-4 h and left to stand for liquid separation. The organic phase was washed with water (50 mL), and the aqueous phases were combined to give an aqueous solution of crude compound (4-a), which was directly used for the subsequent reaction.

[0148] Screening of different process conditions in step 2 of Example 1: According to the reagent feeding amounts shown in Table 2, the rest of operations were performed as described in step 2 of Example 1 to give an aqueous solution of compound (4-a). Conversion rates of compound (2-a) were detected, and the results are shown in Table 2.

TABLE-US-00003 TABLE 2 Screening of different process conditions in step 2 of Example 1 Methanesulfonyl Conversion 2-a (crude product) chloride Triethylamine Dichloromethane rate 01 113 g (0.4 mol) 67 g (1.4 eq) 63.7 g (1.5 eq) 500 mL 100% 02 113 g (0.4 mol) 62 g (1.3 eq) 63.7 g (1.5 eq) 500 mL 100% 03 113 g (0.4 mol) 57 g (1.2 eq) 63.7 g (1.5 eq) 500 mL 98% 04 113 g (0.4 mol) 48 g (1 eq) 63.7 g (1.5 eq) 500 mL 80%

[0149] Under reaction conditions similar to those in the paragraph immediately preceding Table 2, it was found that the conversion rate of the hydroxyl protection reaction for the same batch of (2-a) was related to the amount of methanesulfonyl chloride used. When using an equivalent of 1.3 eq, the reaction can be completely converted.

Step 3: Synthesis of Compound (5-a)

##STR00038##

[0150] The aqueous solution of the crude compound (4-a) (0.374 mol, 1.0 eq) of step 2 was added to a 2 L reaction flask and cooled to an internal temperature of 0-10 C., and then an aqueous sodium hydroxide solution (sodium hydroxide (17 g) dissolved in water (100 mL), 1.1 eq) was dropwise added to adjust the pH to 8-9. The system gradually turned into a white turbid state, and after the dropwise addition was completed, the system was maintained at 0-10 C. Di-tert-butyl dicarbonate (82 g, 1 eq) diluted with dichloromethane (100 mL) was dropwise added to the reaction system. The system generated gas and released heat, and the system was heated to an internal temperature of 10-15 C. After the dropwise addition was completed, the mixture was left to react for 2 h with the temperature maintained. After the starting materials disappeared as monitored by LC-MS, the reaction was completed. The mixture was left to stand for liquid separation, and dichloromethane (137 g) was added to the aqueous phase for extraction. The organic phases were separated, combined, and washed with water. The organic phase was dried, filtered, and concentrated under reduced pressure to give a pale yellow oily liquid, which became a white waxy solid (126 g) after standing, which was crude compound (5-a).

[0151] Characterization data for (5-a): .sup.1H NMR (600 MHz, Chloroform-d) 5.09 (s, 1H), 4.89 (s, 1H), 3.81-3.76 (m, 1H), 3.70 (dd, J=12.4, 6.1 Hz, 1H), 3.55 (dq, J=10.2, 5.2 Hz, 1H), 3.45 (dt, J=14.2, 6.2 Hz, 1H), 3.13 (s, 3H), 1.45 (s, 9H). .sup.13C NMR (151 MHz, CDCl.sub.3) 155.92, 80.16, 79.85, 43.58, 42.36, 38.38, 28.22.

[0152] Screening of different process conditions in step 3 of Example 1: According to the reagent feeding amounts shown in Table 3, the rest of operations were performed as described in step 3 of Example 1 to give crude compound (5-a). Conversion rates of the compound (4-a) were detected, and the results are shown in Table 3.

TABLE-US-00004 TABLE 3 Screening of different process conditions in step 3 of Example 1 Di-tert-butyl Conversion 4-a (crude product) Sodium hydroxide dicarbonate Dichloromethane rate 01 Aqueous solution 15 g (1.1 eq) 74 g (1 eq) 500 mL 100% (0.34 mol) 02 Aqueous solution 15 g (1.1 eq) 140 g (1.5 eq) 500 mL 100% (0.34 mol)

[0153] Under reaction conditions similar to those in the paragraph immediately preceding Table 3, when the amount of di-tert-butyl dicarbonate used was 1-1.5 eq, the reactions can all be completely converted.

Step 4: Synthesis of Compound (6-a)

##STR00039##

[0154] The crude compound (5-a) (126 g) obtained in step 3 was added to tetrahydrofuran (500 mL) and completely dissolved by stirring at room temperature. The mixture was cooled to 0-10 C., and a sodium hydride solid (60%, 20 g, 0.83 mol, 2 eq) was added to the reaction. The system generated gas foam, and was warmed to room temperature (25-30 C.) and left to react for 1 h. Then the starting materials disappeared as monitored by LC-MS. Tetrahydrofuran was recovered under reduced pressure. Dichloromethane and water were added to the residue for extraction. The organic phase was dried and precipitated to give a pale yellow oily liquid (85 g), which was purified by distillation under reduced pressure to give a colorless oily liquid (51.6 g) as compound (6-a) with a GC purity of 92%, and a total yield from the reaction of the compound PhCHO in step 1 to the final synthesis of the compound (6-a) in step 4 was 58.3%.

[0155] Characterization data for (6-a): .sup.1H NMR (600 MHz, Chloroform-d) 3.63 (dd, J=10.0, 4.1 Hz, 1H), 3.46 (dd, J=11.3, 5.9 Hz, 1H), 2.78-2.70 (m, 1H), 2.38 (d, J=4.0 Hz, 1H), 2.12 (s, 1H), 1.46 (s, 9H). .sup.13C NMR (151 MHz, CDCl.sub.3) 160.96, 81.15, 44.50, 37.12, 30.92, 27.43.

[0156] Screening of different process conditions in step 4 of Example 1: According to the reagent feeding amounts shown in Table 4, the rest of operations were performed as described in step 4 of Example 1 to give compound (6-a). The yield results are shown in Table 4.

TABLE-US-00005 TABLE 4 Screening of different process conditions in step 4 of Example 1 A total yield from the reaction of Base the compound PhCHO to the final 5-a (2 eq) Solvent synthesis of the compound (6-a) 01 500 mg NaOH DCM <30% 02 500 mg K.sub.2CO.sub.3 DCM 0% 03 500 mg t-BuOK DCM <30% 04 500 mg Cs.sub.2CO.sub.3 DCM 30~40% 05 500 mg NaOH EtOH 0% 06 500 mg t-BuOK EtOH <10% 07 500 mg NaOH THF 50~60% 08 500 mg t-BuOK THF <30% 09 5 g NaH THF 80~90% 10 5 g NaH DCM <10% 11 5 g NaH DMF 70~80% 12 20 g NaH THF 84%

[0157] Under reaction conditions similar to those in the paragraph immediately preceding Table 4, the reaction yield was the highest when NaH was used as the base and THE was used as the solvent.

Example 2: Synthesis of Compound (6-a)

Step 1: Synthesis of Compound (5-1-a)

##STR00040##

[0158] The crude product (2-a) (113 g, 0.4 mol, 1.0 eq) prepared in step 1 of Example 1 was added to dichloromethane (200 mL) serving as a solvent. Concentrated hydrochloric acid (86 g, 1.0 eq) diluted with water (100 mL) was added dropwise to the reaction. After the dropwise addition was completed, the mixture was uniformly stirred for 1 h at room temperature (25-30 C.) and left to stand for phase separation. The organic phase was washed with water (50 mL) and then the aqueous phases were combined. The aqueous phase was cooled to an internal temperature of 0-10 C., and sodium hydroxide (17 g) dissolved in water (50 mL) was slowly and dropwise added to the reaction. After the dropwise addition was completed, di-tert-butyl dicarbonate (65 g, 0.417 mol, 1 eq) diluted with dichloromethane (100 mL) was slowly and dropwise added to the reaction system. The system released heat and generated gas. After the dropwise addition was completed, the mixture was warmed to room temperature and stirred for 2 h. Then the starting materials were completely converted as detected by LC-MS. The mixture was left to stand for phase separation, the aqueous phase was washed with dichloromethane (100 mL), and the organic phases were combined, dried, filtered, and precipitated under reduced pressure to give a white solid (98 g), which was crude compound (5-1-a).

Step 2: Synthesis of Compound (6-a)

##STR00041##

[0159] The crude compound (5-1-a) (98 g, 0.376 mol, 1 eq) obtained in the previous step (step 1 of Example 2) was added to toluene (300 mL) and completely dissolved by stirring at room temperature. Triphenylphosphine (108 g, 0.413 mol, 1.1 eq) was added under nitrogen atmosphere, and the mixture was cooled to an internal temperature of 10 to 20 C. Diethyl azodicarboxylate (68.7 g, 0.394 mol, 1.05 eq) was slowly and dropwise added to the reaction system. The system gradually changed from colorless to yellow, and a solid precipitated. After the dropwise addition was completed, the mixture was left to react for 2 h with the temperature maintained, and the starting materials disappeared as monitored by LC-MS. For the post-treatment, water (150 mL) was added to the reaction, and the mixture was stirred at room temperature and left to stand for phase separation. The organic phase was precipitated under reduced pressure to give a yellow oily liquid (115 g), which was purified by distillation under reduced pressure to give a colorless oily liquid (64 g), which was pure compound (6-a). The GC purity was 93%. A total yield of the reactions from step 1 of Example 1 to the final synthesis of the compound (6-a) of Example 2 was calculated to be 73%.

Example 3: Synthesis of Compound (6-a)

##STR00042##

[0160] The aqueous solution of the crude compound (4-a) obtained in step 2 of Example 1 (0.356 mol, 1 eq) was cooled to 5-10 C. Sodium hydroxide (15 g, 0.392 mol, 1.1 eq) diluted with water (50 mL) was slowly and dropwise added to the reaction system. After the dropwise addition was completed, the system was supplemented with toluene (200 mL), heated to 50 C., and left to react for 1-2 h. Then the starting materials were completely converted as monitored by LC-MS. The system was cooled to 0-10 C., and di-tert-butyl dicarbonate (71.5 g, 0.327 mol, 1 eq) was dropwise added to the reaction system. After the dropwise addition was completed, the system was warmed to room temperature and left to react for 2-3 h, and then LC-MS indicated the disappearance of the starting materials and the generation of the desired product. The mixture was left to stand for liquid separation, and the aqueous phase was washed with toluene (100 mL). Then the organic phases were combined and precipitated under reduced pressure to give a yellow oil (85 g). The compound (6-a) was obtained as a colorless oily liquid (60 g) by purifying by distillation under reduced pressure with a GC purity of 95%; and a total yield of the reactions from step 1 of Example 1 to the final synthesis of the compound (6-a) of Example 3 was calculated to be 68%.

Example 4: Synthesis of Compound (10-a)

Step 1: Synthesis of Compound (7-a)

##STR00043##

[0161] The compound (6-a) (51.6 g, 0.27 mol, 1.0 eq) obtained in step 4 of Example 1 was dissolved in tetrahydrofuran (200 mL) to give a solution of the compound (6-a) in tetrahydrofuran for later use. Copper(I) iodide (0.5 g, 0.003 mol, 0.01 eq) was added to a dry and oxygen-free reaction flask, and biphenylmagnesium bromide (134 mL, 2.0 M, 1.0 eq) was added to the reaction system under nitrogen atmosphere. The system was cooled to an internal temperature of 15 to 20 C., and then the solution of the compound (6-a) in tetrahydrofuran was dropwise added to the reaction system. The system gradually changed to green. After the dropwise addition was completed, the mixture was left to react for 1 h with the temperature maintained at 5 to 10 C. GC monitoring indicated that the reaction was completed, and the reaction was quenched by adding water (50 mL). Tetrahydrofuran was recovered under reduced pressure. Then dichloromethane (300 mL) r (400 mL) were added for extraction. Liquid separation was performed, and the organic phase was dried and precipitated to give a white flocculent solid, which was slurried with n-heptane to give pure compound (7-a) (74 g) with a yield of 79%.

[0162] Characterization data for (7-a): .sup.1H NMR (600 MHz, Chloroform-d) 7.56 (dd, J=19.0, 7.5 Hz, 4H), 7.43 (t, J=7.4 Hz, 2H), 7.33 (dd, J=15.2, 7.4 Hz, 3H), 4.85 (d, J=6.8 Hz, 1H), 4.17 (s, 1H), 3.65 (d, J=10.0 Hz, 1H), 3.54 (d, J=11.1 Hz, 1H), 2.94 (dt, J=21.5, 8.7 Hz, 2H), 1.44 (s, 9H). .sup.13C NMR (151 MHz, CDCl.sub.3) 155.03, 140.75, 139.72, 136.13, 129.71, 128.76, 127.36, 127.23, 126.98, 79.84, 51.98, 46.96, 37.41, 28.33.

[0163] Screening of different process conditions in step 1 of Example 4: According to the reagent feeding amounts shown in Table 5, the rest of operations were performed as described in step 1 of Example 4 to give compound (7-a). The results are shown in Table 5.

TABLE-US-00006 TABLE 5 Screening of different process conditions in step 1 of Example 4 Biphenylmagnesium Reaction 6-a bromide Copper(I) iodide THF temperature 01 4 g 11 mL(2.0M) 0.3 g (0.1 eq) 20 mL 10 C..fwdarw.40 C. 02 4 g 11 mL(2.0M) 0.3 g (0.1 eq) 20 mL 10 C. 03 30 g 75 mL(2.0M) 220 mg (0.01 eq) 150 mL 10~5 C.

[0164] The price of copper(I) iodide was high, researches show that the copper(I) iodide can still effectively catalyze the reaction when the using amount was 0.01 eq, and the reaction effect was almost the same as that of the small-scale experiment when the reaction was preliminarily scaled up.

Step 2: Synthesis of Compound (10-a)

##STR00044##

[0165] Compound (7-a) (70 g, 0.2 mol, 1 eq) was added to toluene (200 mL). The mixture was heated to 110 C. at reflux for 0.5 h, and then (7-a) disappeared, and compound (8-a) was generated as monitored by LC-MS.

[0166] Characterization data for compound (8-a): .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.83 (s, 1H), 7.69-7.64 (m, 2H), 7.61 (d, J=8.2 Hz, 2H), 7.46 (t, J=7.6 Hz, 2H), 7.40-7.31 (m, 3H), 4.30 (t, J=8.2 Hz, 1H), 4.15-4.05 (m, 1H), 4.03 (dd, J=8.2, 5.4 Hz, 1H), 2.84 (qd, J=13.6, 6.1 Hz, 2H); .sup.13C NMR (101 MHz, DMSO) 159.11, 140.35, 138.87, 136.34, 130.49, 129.40, 127.79, 127.14, 127.00, 68.57, 52.95, 40.35.

[0167] Sodium hydroxide (24 g, 0.6 mol, 3 eq) was added to the reaction, and the mixture was left to react for 3 h with the temperature maintained at 80 C. Then compound (8-a) disappeared, and compound (9-a) was generated as monitored by LC-MS.

[0168] The system was cooled to 25-30 C., and after the addition of water (100 mL), di-tert-butyl dicarbonate (44 g, 0.2 mol, 1 eq) was dropwise added. The system gradually became turbid, and a white solid precipitated. After the dropwise addition was completed, the mixture was left to react for 2 h with the temperature maintained. HPLC indicated the disappearance of compound (9-a) and the generation of compound (10-a). The system was supplemented with toluene (200 mL), heated to 60 C., stirred for 30 min, and left to stand for liquid separation with the temperature maintained. The aqueous phase was discarded, and the organic phase was slowly cooled to 0 C. to precipitate a white solid. The solid was filtered and dried to give compound (10-a) (white solid) (53 g) with a purity of 99.5%. A total yield for the three steps was 85.5%.

Example 5: Synthesis of Compound (8-a)

Step 1: Synthesis of Compound (5-2-a)

##STR00045##

[0169] The aqueous solution of the crude compound (4-a) (0.374 mol, 1.0 eq) obtained in step 2 of Example 1 was added to a 2 L reaction flask and cooled to an internal temperature lower than 10 C., and then an aqueous sodium hydroxide solution (sodium hydroxide (17 g) dissolved in water (100 mL), 1.1 eq) was dropwise added to adjust the pH to 8-9. The system gradually turned into a white turbid state, and after the dropwise addition was completed, the system was cooled to 0-10 C. Methyl chloroformate (37 g, 1.1 eq) diluted with dichloromethane (100 mL) was dropwise added to the reaction system. The system generated gas and released heat, and the system was heated to an internal temperature of 10-15 C. After the dropwise addition was completed, the mixture was left to react for 2 h with the temperature maintained. After the starting materials disappeared as monitored by LC-MS, the reaction was completed. The mixture was left to stand for liquid separation, and dichloromethane (137 g) was added to the aqueous phase for extraction. The organic phases were separated, combined, and washed with water. The organic phase was dried, filtered, and concentrated under reduced pressure to give a pale yellow oily liquid, which became a white waxy solid (105 g) after standing, which was crude compound (5-2-a).

[0170] Characterization data for compound (5-2-a): .sup.1H NMR (600 MHz, Chloroform-d) 5.79 (s, 1H), 4.89 (s, 1H), 3.81 (d, J=11.6 Hz, 1H), 3.73 (dd, J=11.9, 6.0 Hz, 1H), 3.68 (s, 3H), 3.58 (d, J=14.4 Hz, 1H), 3.54-3.47 (m, 1H), 3.14 (s, 3H); .sup.13C NMR (151 MHz, CDCl.sub.3) 157.12, 79.40, 52.15, 43.36, 42.30, 38.04.

Step 2: Synthesis of Compound (6-2-a)

##STR00046##

[0171] The crude compound (5-2-a) (105 g, 0.32 mol, 1 eq) obtained in step 2 of Example 5 was added to tetrahydrofuran (400 mL), and the compound was completely dissolved by stirring at room temperature. The mixture was cooled to 0-10 C., and a sodium hydride solid (60%, 19.2 g, 0.48 mol, 1.5 eq) was added to the reaction. The system generated gas foam, and was warmed to room temperature (25-30 C.) and left to react for 1 h. Then the starting materials disappeared as monitored by LC-MS. Tetrahydrofuran was recovered under reduced pressure. Then dichloromethane and water were added for extraction. The organic phase was dried and precipitated to give a pale yellow oily liquid (58 g). The colorless oily liquid (43.5 g) was obtained as compound (6-2-a) by purifying by distillation under reduced pressure with a GC purity of 95%, and a total yield of the first five steps of Example 1 was calculated to be 62.5%.

[0172] Characterization data for compound (6-2-a): .sup.1H NMR (600 MHz, Chloroform-d) 3.74 (s, 3H), 3.65 (dd, J=11.6, 6.0 Hz, 1H), 3.51 (dd, J=11.6, 5.7 Hz, 1H), 2.82 (dt, J=5.4, 2.5 Hz, 1H), 2.47 (d, J=6.0 Hz, 1H), 2.20 (s, 1H). .sup.13C NMR (151 MHz, CDCl.sub.3) 162.60, 53.39, 44.35, 37.17, 30.93.

Step 3: Synthesis of Compound (7-2-a)

##STR00047##

[0173] The compound (6-2-a) (43 g, 0.287 mol, 1.0 eq) obtained in step 2 was dissolved in tetrahydrofuran (200 mL) to give a solution of the compound (6-a) in tetrahydrofuran for later use.

[0174] Copper(I) iodide (0.5 g, 0.0028 mol, 0.01 eq) was added to a dry and oxygen-free reaction flask, and biphenylmagnesium bromide (158 mL, 2.0 M, 1.1 eq) was added to the reaction system under nitrogen atmosphere. The system was cooled to an internal temperature of 15 to 20 C., and then the solution of the compound (6-a) in tetrahydrofuran was dropwise added to the reaction system. After the dropwise addition was completed, the mixture was left to react for 1 h with the temperature maintained at 10 to 5 C. GC monitoring indicated that the reaction was completed, and the reaction was quenched by adding water (50 mL). Tetrahydrofuran was recovered under reduced pressure. Then dichloromethane (300 mL) and water (400 mL) were added for extraction. Liquid separation was performed, and the organic phase was dried and precipitated to give a white flocculent solid, which was slurried with n-heptane to give pure compound (7-2-a) (70 g) with a yield of 80%.

[0175] Characterization data for compound (7-2-a): .sup.1H NMR (400 MHz, Chloroform-d) 7.60-7.51 (m, 4H), 7.43 (t, J=7.6 Hz, 2H), 7.37-7.27 (m, 3H), 5.03 (d, J=7.4 Hz, 1H), 4.22 (s, 1H), 3.68 (s, 3H), 3.64 (d, J=3.5 Hz, 1H), 3.54 (dd, J=11.2, 3.2 Hz, 1H), 2.96 (t, J=6.4 Hz, 2H); .sup.13C NMR (101 MHz, CDCl.sub.3) 156.19, 140.63, 139.81, 135.82, 129.63, 128.75, 127.40, 127.25, 126.95, 52.48, 52.24, 46.71, 37.30.

Step 4: Synthesis of Compound (8-a)

##STR00048##

[0176] The compound (7-2-a) (70 g) obtained in step 3 was added to a 500 mL reaction flask, and toluene (200 mL) was added. The mixture was heated to 110 C. and stirred at reflux for 2-3 h. Compound (7-2-a) disappeared, and compound (8-a) was generated as monitored by LC-MS. Toluene was recovered under reduced pressure to give a pale yellow solid (59.5 g), which could be directly used for the subsequent reaction.

Example 6: Synthesis of Compound (8-a)

Step 1: Synthesis of Compound (5-3-a)

##STR00049##

[0177] The aqueous solution of the crude compound (4-a) (0.374 mol, 1.0 eq) of step 2 of Example 1 was added to a 2 L reaction flask and cooled to an internal temperature lower than 10 C., and then an aqueous sodium hydroxide solution (sodium hydroxide (17 g) dissolved in water (100 mL), 1.1 eq) was dropwise added to adjust the pH to 8-9. The system gradually turned into a white turbid state, and after the dropwise addition was completed, the system was cooled to 0-10 C. Ethyl chloroformate (43.9 g, 1.1 eq) diluted with dichloromethane (100 mL) was dropwise added to the reaction system. The system generated gas and released heat, and the system was heated to an internal temperature of 10-15 C. After the dropwise addition was completed, the mixture was left to react for 2 h with the temperature maintained. After the starting materials disappeared as monitored by LC-MS, the reaction was completed. The mixture was left to stand for liquid separation, and dichloromethane was added to the aqueous phase for extraction. The organic phases were separated and combined. The organic phase was dried, filtered, and concentrated under reduced pressure to give a pale yellow oily liquid, which became a white waxy solid (112 g) after standing, which was crude compound (5-3-a).

[0178] Characterization data for compound (5-3-a): .sup.1H NMR (600 MHz, Chloroform-d) 5.44 (s, 1H), 4.90 (s, 1H), 4.13 (d, J=6.7 Hz, 2H), 3.80 (d, J=12.2 Hz, 1H), 3.72 (dd, J=12.2, 6.0 Hz, 1H), 3.60 (d, J=14.5 Hz, 1H), 3.51 (dt, J=13.7, 6.0 Hz, 1H), 3.13 (s, 3H), 1.25 (t, J=6.4 Hz, 3H); .sup.13C NMR (151 MHz, CDCl.sub.3) 156.76, 79.63, 61.21, 43.47, 42.50, 38.28, 14.39.

Step 2: Synthesis of Compound (6-3-a)

##STR00050##

[0179] The crude compound (5-3-a) (112 g, 0.32 mol, 1 eq) of step 3 was added to tetrahydrofuran (400 mL), and the compound was completely dissolved by stirring at room temperature. The mixture was cooled to 0-10 C., and a sodium hydride solid (60%, 26.18 g, 0.65 mol, 2 eq) was added to the reaction. The system generated gas foam, and was warmed to room temperature (25-30 C.) and left to react for 1 h. Then the starting materials disappeared as monitored by LC-MS. Tetrahydrofuran was recovered under reduced pressure. Then dichloromethane and water were added for extraction. The organic phase was dried and precipitated to give a pale yellow oily liquid (54 g). The colorless oily liquid (47.6 g) was obtained as compound (6-3-a) by purifying by distillation under reduced pressure with a GC purity of 94%, and a total yield of the first five steps of Example 1 was calculated to be 63%.

Step 3: Synthesis of Compound (7-3-a)

##STR00051##

[0180] The compound (6-3-a) (47 g, 0.287 mol, 1.0 eq) obtained in step 2 was dissolved in tetrahydrofuran (200 mL) to give a solution of the compound (6-3-a) in tetrahydrofuran for later use.

[0181] Copper(I) iodide (0.5 g, 0.0028 mol, 0.01 eq) was added to a dry and oxygen-free reaction flask, and biphenylmagnesium bromide (158 mL, 2.0 M, 1.1 eq) was added to the reaction system under nitrogen atmosphere. The system was cooled to an internal temperature of 15 to 20 C., and then the solution of the compound (6-3-a) in tetrahydrofuran was dropwise added to the reaction system. After the dropwise addition was completed, the mixture was left to react for 1 h with the temperature maintained at 5 to 10 C. GC monitoring indicated that the reaction was completed, and the reaction was quenched by adding water (50 mL). Tetrahydrofuran was recovered under reduced pressure. Then dichloromethane (300 mL) and water (400 mL) were added for extraction. Liquid separation was performed, and the organic phase was dried and precipitated to give a white flocculent solid, which was slurried with n-heptane to give pure compound (7-3-a) (77 g) with a yield of 85%.

[0182] Characterization data for compound (7-3-a): .sup.1H NMR (400 MHz, Chloroform-d) 7.60-7.51 (m, 4H), 7.42 (t, J=7.6 Hz, 2H), 7.32 (dd, J=14.0, 7.6 Hz, 3H), 5.01 (d, J=7.7 Hz, 1H), 4.21 (s, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.65 (dd, J=10.8, 3.8 Hz, 1H), 3.53 (dt, J=11.1, 3.6 Hz, 1H), 2.95 (tt, J=13.4, 6.4 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) 155.78, 140.64, 139.76, 135.89, 129.63, 128.73, 127.36, 127.22, 126.93, 61.04, 52.35, 46.75, 28.29, 14.51.

Step 4: Synthesis of Compound (8-a)

##STR00052##

[0183] The compound (7-3-a) (70 g) obtained in step 3 was added to a 500 mLreaction flask, and toluene (200 mL) was added. The mixture was heated to 110 C. and stirred at reflux for 2-3 h. (7-3-a) disappeared, and compound (8-a) was generated as monitored by LC-MS. Toluene was recovered under reduced pressure to give a pale yellow solid (63 g), which could be directly used for the subsequent reaction.

Example 7: Synthesis of Compound (10-a)

[0184] This example is a kilogram-level scale-up reaction, and the room temperature of the process is 25-35 C.

Step 1: Synthesis of Compound (2-a)

##STR00053##

[0185] Benzaldehyde (1.0 kg, 9.42 mol) was added to ethanol (4 L), and the mixture was stirred at room temperature. Aqueous ammonia (25%, 1 L) was dropwise added to the reaction system at 15-20 C. After the dropwise addition was completed, the mixture was warmed to room temperature and stirred for 20 min, and then (S)-epichlorohydrin (1.05 kg, 11.3 mol, 1.2 eq) was diluted with ethanol (2 L) and slowly and dropwise added to the reaction system under nitrogen atmosphere. After the dropwise addition was completed, the system was stirred at room temperature (25-30 C.) for 12 h. After epichlorohydrin disappeared as monitored by GC, the reaction was completed. Ethanol was recovered by distillation under reduced pressure to give a yellow oily product, and ethanol (1 L) was added for distillation again to give a pale yellow oily liquid (2.3 kg), which was crude compound (2-a).

Step 2: Synthesis of Compound (4-a)

##STR00054##

[0186] The crude compound (2-a) (2.3 kg, 8.5 mol) obtained in the previous step (step 1 of Example 7) was added to dichloromethane (8 L), and the mixture was stirred at room temperature until a small amount of a white insoluble substance was observed. The mixture was filtered, and triethylamine (1.29 kg, 12.75 mol, 1.5 eq) was added to the filtrate. The mixture was cooled to an internal temperature of 0-10 C., and methanesulfonyl chloride (1.27 kg, 11.05 mol, 1.3 eq) was dropwise added. The system was heated to an internal temperature of 12-20 C., and a white solid precipitated. After the dropwise addition was completed, the mixture was warmed to room temperature and stirred for 1 h. Then the starting materials disappeared as monitored by normal phase HPLC. Water (2 L) was added to the system, and the mixture was uniformly stirred for 30 min and extracted. The organic phase was washed twice with water (2 L2).

[0187] Concentrated hydrochloric acid (1.2 kg) diluted with water (2.4 L) was added to the organic phase treated in the previous step. The mixture was uniformly stirred at room temperature for 3-4 h and left to stand for liquid separation. The organic phase was washed with water (500 mL), and the aqueous phases were combined to give an aqueous solution of crude compound (4-a), which was then used directly for the subsequent reaction.

Step 3: Synthesis of Compound (5-a)

##STR00055##

[0188] The aqueous solution of the crude compound (4-a) (7.63 mol) obtained in step 2 of Example 7 was added to a reaction kettle and cooled to an internal temperature lower than 10 C., and then an aqueous sodium hydroxide solution (sodium hydroxide (460 g) dissolved in water (2 L)) was dropwise added. The system gradually turned into a white turbid state, and after the dropwise addition was completed, the system was cooled to 0-10 C. Di-tert-butyl dicarbonate (1.7 kg, 7.63 mol, 1 eq) was dropwise added to the reaction system. The system generated gas and released heat, and the system was heated to an internal temperature of 10-15 C. After the dropwise addition was completed, the mixture was left to react for 2 h with the temperature maintained. After the starting materials disappeared as monitored by LC-MS, the reaction was completed. The mixture was left to stand for liquid separation, and dichloromethane (2.7 kg) was added to the reaction for extraction. The organic phases were separated after standing, washed with water (2 kg), dried, and filtered, and the solvent was recovered by distillation under reduced pressure to give a pale yellow oily liquid, which became a white waxy solid (2.5 kg) after standing as crude compound (5-a).

Step 4: Synthesis of Compound (6-a)

##STR00056##

[0189] The crude compound (5-a) (2.5 kg, 7.65 mol) obtained in step 3 of Example 7 was added to tetrahydrofuran (5 L) and completely dissolved by stirring at room temperature to give a solution of the compound (5-a) in tetrahydrofuran for later use.

[0190] Tetrahydrofuran (2 L) was added to a reaction kettle and cooled to 0-10 C. A sodium hydride solid (60%, 460 g, 11.47 mol, 1.5 eq) was added to the reaction kettle, and the mixture was stirred for 30 min with the temperature maintained. Then the solution of the compound (5-a) in tetrahydrofuran was dropwise added, and the dropwise addition was completed over 2-3 h. The mixture was heated to 50 C. and left to react for 5 h. Then the starting materials disappeared as monitored by LC-MS. The reaction was quenched by adding water (500 mL), and then tetrahydrofuran was recovered under reduced pressure. Dichloromethane (4 L) and water (2.5 L) was added for extraction. The organic phase was dried and precipitated to give a pale yellow oily liquid (1.75 kg). The colorless oily liquid (1.1 kg) was obtained as compound (6-a) by purifying by distillation under reduced pressure with a GC purity of 96%, and a total yield of the first five steps was 60%.

Step 5: Synthesis of Compound (7-a)

##STR00057##

[0191] The compound (6-a) (1.1 kg) obtained in step 4 of Example 7 was dissolved in tetrahydrofuran (4.5 L) to give a solution of the compound (6-a) in tetrahydrofuran for later use. Copper(I) iodide (11 g) was added to a dry and oxygen-free reaction kettle, and biphenylmagnesium bromide (3 L, 2.0 M, 6 mol) was added to the reaction system under nitrogen atmosphere. The mixture was cooled to an internal temperature of 15 to 20 C., and then the solution of the compound (6-a) in tetrahydrofuran was dropwise added to the reaction system. The system gradually changed to grayish green. The dropwise addition was completed over 2 h, and the mixture was left to react for 1-2 h with the temperature maintained. GC monitoring indicated that the reaction was completed, and the reaction was quenched by adding water (2 L). Tetrahydrofuran was recovered under reduced pressure. Then dichloromethane (5 L) and water (6 L) were added for extraction. Liquid separation was performed, and the organic phase was dried and precipitated to give a white flocculent solid (2.1 kg), which was slurried with n-heptane to give pure compound (7-a) (1.6 kg) with a yield of 79%.

Step 6: Synthesis of Compound (10-a)

##STR00058##

[0192] The compound (7-a) (1.6 kg) obtained in step 5 of Example 7 was added to toluene (8 L), and the mixture was heated to 100-110 C. at reflux for 1-2 h. The compound (7-a) disappeared, and compound (8-a) was generated as monitored by LC-MS. The system was cooled and supplemented with toluene (2 L), and then sodium hydroxide (740 g) was added to the reaction. The mixture was left to react at reflux for 3 h. The compound (8-a) disappeared, and compound (9-a) was generated as monitored by LC-MS. The system was cooled to 25-30 C., and di-tert-butyl dicarbonate (1.1 kg) was dropwise added. The system gradually became turbid, and a white solid precipitated. After the dropwise addition was completed, the mixture was left to react for 2 h with the temperature maintained. HPLC indicated the disappearance of compound (9-a) and the generation of compound (10-a). The system was supplemented with water (2 L), heated to 50-60 C., stirred for 30 min, and left to stand for liquid separation with the temperature maintained. The organic phases were separated and slowly cooled to 0 C. to precipitate a white solid. The solid was filtered and dried to give compound (10-a) (white solid) (1.25 kg) with a purity of 99.3%. A total yield for the three steps was 87%.

[0193] The examples described above are preferred embodiments of the present disclosure, which, however, are not intended to limit the embodiments of the present disclosure. Any other changes, modifications, substitutions, combinations, and simplifications can be made without departing from the spirit and principle of the present disclosure, and should be construed as equivalent replacements and included in the protection scope of the present disclosure.