An asymmetric process for the preparation of (S) or (R)-Ugi amine and its tartrate salt

Abstract

The application provides an asymmetric preparation process of (S) or (R)-Ugi amine and a tartrate thereof. The chiral Ugi amine can be used for synthesizing a series of chiral phosphine ligands with a ferrocene skeleton structure, and has a wide application in asymmetric hydrogenation reactions. The application obtains the Ugi amine with single optical activity and the tartrate thereof through acetylation, asymmetric reduction hydrogenation, esterification, amination, salification and other steps with ferrocene as raw material. The raw material is cheap and easy to obtain, the reaction condition is mild, the synthesis route is simple, the yield and chiral purity are high, the generation of "three wastes" is small, the application is suitable for industrial production, and the application has great economic value and social benefits.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of chiral chemical synthesis, and particularly relates to an asymmetric preparation process of (S) or (R)-Ugi amine and a tartrate thereof. BACKGROUND

[0002] Optically active Ugi amine is a key intermediate for preparing chiral organocatalysts with ferrocene skeleton and chiral bidentate or tridentate ligands. For example, chiral phosphine organocatalysts derived from (S)-Ugi amine exhibit excellent catalytic activity and enantioselectivity in promoting asymmetric Morita-Baylis-Hillman reaction, stereoselective S N 2 substitution reaction and [3+2] cycloaddition reaction involving Morita-Baylis-Hillman adduct. Meanwhile, chiral bidentate or tridentate ligands with ferrocene skeleton derived from optically active Ugi amine can efficiently catalyze asymmetric hydrogenation reduction of unsaturated bonds (C=O, C=C and C=N) after being coordinated with noble metals. The bidentate (Wudaphos) and tridentate ligands (f-amphol, f-ampha and f-amphox-t-Bu) with ferrocene skeleton invented by Zhang Xumu group have extremely important applications in asymmetric catalytic hydrogenation, such as preparation of sitagliptin and (S)-naproxen. In addition, Josiphos is one of the representative ligands, which has excellent catalytic performance and is suitable for various reactions. Syngenta successfully realized the asymmetric industrial production of herbicide metolachlor by using Ir-Josiphos complex to perform asymmetric hydrogenation on imine. Therefore, the preparation of optically active Ugi amine has attracted much attention.

[0003] The preparation methods reported in the literature mainly include three types:

[0004] I. Chiral resolution method: racemic Ugi amine is resolved by using chiral tartaric acid, as described in the literature Catal Sci Technol, 2016, 6(1): 118-124. and Fine Chemical Intermediates, 2015, 45(6): 48-51. However, this method usually needs multiple resolutions, has low efficiency and does not meet the requirements of green chemistry.

[0005] II. Chiral substrate induction method: in the patent CN107286202A, acetylferrocene is used as raw material, and in the presence of titanium tetraisopropylate [Ti(O- i Pri)4] and NaBH4, it is condensed and reduced with optically active α-phenethylamine, and then subjected to aminomethylation, esterification and diethylamine substitution to obtain the target compound. The operation is complicated, and the overall yield is not high.

[0006] III. Asymmetric carbonyl reduction method: In recent years, many methods for asymmetric synthesis of chiral Ugi amine have been developed, that is, chiral ferrocenyl ethanol is obtained by asymmetric hydrogenation of acetylated ferrocene, and then the target compound can be obtained by simple esterification and dimethylamine substitution. The CBS reduction method in the literature Tetrahedron Lett, 2003, 44(4): 801-804 has the disadvantages of expensive chiral catalyst and low conversion rate in Ru(II)-(R,R)-TsDPEN catalytic asymmetric hydrogen transfer method in the master's thesis (Nie Hufang. Synthesis of chiral ferrocene bisphosphine ligand and its asymmetric hydrogenation reaction research[D]. Xi'an: Fourth Military University Master's Thesis, 2011.). Some methods can only synthesize one type of Ugi amine, and can only be prepared on a gram scale, such as Org Lett., 2016, 18, 2938-2941. and Chem Cat Chem, 2017, 9, 1744-1748. In 2018, the group of Zhong Weihui of Zhejiang University of Technology reported a preparation process of (S)-Ugi amine, which achieved good results, and the reaction scale could reach kilogram level (CN 108409802).

[0007] For the industrial scale preparation of (S) or (R)-Ugi amine, the existing catalytic system often has the problems of large amount of catalyst and low enantioselectivity. Therefore, it is of great significance to develop a simple and large-scale method for preparing optically active Ugi amine. SUMMARY

[0008] The present application provides an asymmetric preparation process of (S) or (R)-Ugi amine and its tartrate salt, and the synthesis route is as follows:

[0009]

[0010] The method uses ferrocene (I) as raw material, acetylated ferrocene (II) is obtained by acylation reaction; acetylated ferrocene (II) is used as raw material, under the action of complex formed by metal [Ir(COD)Cl]2 and chiral ligand (L1-L25) as catalyst, sodium hydroxide as base, isopropyl alcohol as solvent, asymmetric hydrogenation reaction is carried out under 3.0 MPa hydrogen pressure, the conversion rate is more than 99%, the optical purity of obtained 1-ferrocenyl ethanol (III) reaches 97% ee, and the TON reaches 20000-50000, realizing the preparation on a hundred kilogram scale; then simple esterification, dimethylamine substitution and salt formation can prepare Ugi amine salt on a hundred kilogram scale, and the total yield reaches 53.2%, and the optical purity of finished product is further improved to 99.5% ee.

[0011] The present application has the following beneficial effects compared with the prior art:

[0012] (1) The present application successfully develops an asymmetric preparation method of (S) or (R)-Ugi amine and its tartrate salt, the present application starts from easily available ferrocene, the raw material is cheap, the cost is low, and the synthesis of optical pure Ugi amine and its tartrate salt on a hundred-kilogram industrial scale is realized through acetylation, asymmetric hydrogenation, esterification, substitution, salt formation and other steps.

[0013] (2) Through a large number of experimental researches, it is found that the asymmetric hydrogenation reaction has very high reaction stability and activity, and excellent stereocontrol is realized by using the preferred catalyst system.

[0014] (3) The present application has the characteristics of high yield, good stereoselectivity, small amount of catalyst, etc. compared with the traditional resolution method, and has high industrial value and economic benefit. DETAILED DESCRIPTION

[0015] The present application is further illustrated by the following non-limiting examples, but the present application is not limited thereto. The experimental methods not specified in the examples are usually carried out according to the conventional conditions and the conditions described in the manual, or according to the conditions recommended by the manufacturer; the materials, reagents, etc. used, if not specifically stated, can be obtained from commercial channels.

[0016] Example 1: Synthesis of compound II

[0017] Weigh 6.0 g (32 mmol) of ferrocene (I) into a 100 mL three-necked round-bottom flask; then add 30 mL of 1,2-dichloroethane, and wait for the ferrocene (I) to completely dissolve; add 42 g (31.5 mmol) of anhydrous aluminum chloride; cool to -10℃ to -15℃, and stir for 0.5 h; slowly add 23.55 g (2.1 mL, 30 mmol) of acetyl chloride, and maintain the temperature at -10℃ to -15℃ during the addition; after the addition is completed, continue to stir the reaction at -10℃ to -15℃ for 4 h, and track the reaction progress using TLC, PE:EA = 10:1; after the reaction is completely finished, slowly add 15% aqueous HCl solution at -10℃ to -15℃ to quench, and try to maintain low temperature to prevent the material from being washed away; after the addition is completed, move to room temperature, and stir at room temperature for 0.5 h; stand for about 15 minutes, and separate the organic phase and the aqueous phase, each with a volume of about 40 mL; wash the aqueous phase with 1,2-dichloroethane 40 mL*2 twice; combine the organic phases, and wash with water 40 mL*2 twice; dry the organic phase with anhydrous sodium sulfate, store overnight, and dry sufficiently; concentrate under reduced pressure to remove 1,2-dichloroethane, and try to completely remove it; obtain 6.4 g of red solid, with a yield of 93.5%.

[0018] Example 2: Synthesis of compound II

[0019] Take 60 g (0.32 mol) of ferrocene (I) into a 1000 mL three-necked round-bottom flask; then add 300 mL of dichloromethane, wait for the ferrocene (I) to completely dissolve; add 42 g (315 mmol) of anhydrous aluminum chloride; cool to -10℃ to -15℃, stir for 0.5 h; slowly add 23.55 g (21.33 mL, 300 mmol) of acetyl chloride, maintain the temperature at -10℃ to -15℃ during the dropwise addition; after the addition is complete, continue to stir the reaction at -10℃ to -15℃ for 4 h, use TLC to track the progress of the reaction, PE:EA = 10:1; after the reaction is completely finished, slowly add 15% aqueous HCl solution at -10℃ to -15℃ to quench, try to maintain low temperature to prevent rush; after the dropwise addition is complete, move to room temperature, stir at room temperature for 0.5 h; stand to separate, the volumes of the organic and aqueous phases are about 400 mL each; wash the aqueous phase with 1,2-dichloroethane 400 mL*2 twice; combine the organic phases, then wash with water 400 mL*2 twice; dry the organic phase with anhydrous sodium sulfate, store overnight, dry thoroughly; concentrate under reduced pressure to remove 1,2-dichloroethane, try to completely remove it; obtain 60 g of red solid, yield 88%.

[0020] Example 3: Synthesis of compound II

[0021] Take ferrocene (I) (1 kg, 5.375 mol) into a 20 L glass reaction kettle; add dichloromethane (5 L), wait for the ferrocene (I) to completely dissolve; add anhydrous zinc chloride (1.61 kg, 11.825 mol), stir at 30℃ for 15 min, maintain an inert gas atmosphere to prevent moisture in the air from entering; add acetic anhydride in 3 batches, dropwise add acetic anhydride (0.165 kg*3, 1.6125 mol, 0.3 eq.), control the temperature during dropwise addition not to exceed 35℃, prevent rush, continue to react for 3 h until HPLC shows that the reaction is basically complete, quench with purified water (10 L), do not exceed 35℃, prevent rush, stir evenly, then stand to separate; add dichloromethane (2.5 L) to the aqueous phase, stir evenly, then stand to separate; combine the organic phases, add purified water (10 L) to the organic phase, stir evenly, then stand to separate; add dilute sodium hydroxide solution (4 L) to the organic phase, stir evenly, then stand to separate; wash the organic phase with purified water (5 L) again to separate; dry the organic phase with anhydrous sodium sulfate (300 g), filter to remove anhydrous sodium sulfate, remove dichloromethane under reduced pressure to dryness, obtain about 1.0 kg of red solid, yield 80%.

[0022] Example 4: Synthesis of compound II

[0023] Dry the reactor (2000L) A, and then add compound I (120 kg), zinc chloride (200 kg), and dichloromethane (600 L) at room temperature. Stir for 15 min at below 30 °C, maintain the inert gas environment in the reactor to prevent moisture in the air from entering, and add acetic anhydride (35 kg*2) in two batches dropwise, with each dropwise addition taking 15 min. Control the internal temperature during dropwise addition to be below 35 °C to prevent material from being washed away. Continue to react for 4 h, and use HPLC to track the progress of the reaction until the starting material is substantially completely reacted.

[0024] Open the condensate water (7 °C), and then slowly add water (800 L) to quench the reaction after the reactor is vented, with the temperature being below 30 °C to prevent material from being washed away. After stirring uniformly, allow the reaction to stand and separate, and then observe the color of the reaction system. Transfer the organic phase (red-brown) to a 2000 L storage tank B, add dichloromethane (300 L) to the water phase in the reactor, stir uniformly, allow the reaction to stand and separate, and then transfer the organic phase to the storage tank B. Combine the organic phases, add purified water (500 L) to the organic phase, stir for 30 min, allow the reaction to stand for 30 min, separate, transfer the lower organic phase to the washed reactor A, add sodium hydroxide solution (50 kg / 500 L) to the organic phase, stir uniformly, allow the reaction to stand and separate, and then remove the solvent dichloromethane under reduced pressure. Slurry the reaction with n-heptane (800 L), centrifuge by using a centrifuge, collect the solid, and then dry the solid under reduced pressure at 40 °C until the weight is constant. The yield of the solid is 120 kg, the yield is 81.6%, and the purity is 99.9%.

[0025] Example 5: Synthesis of compound III (Entry 1~Entry 25)

[0026] Weigh acetylferrocene (compound II) 1.14 g (5 mmol) and place it in a 50 mL stainless steel hydrogenation reactor; introduce the raw material into the glove box; add isopropanol (10 mL); add Cs2CO3 (16.3 mg); add the chiral ligand (L1~L25) of example 5 and the catalyst previously complexed with [Ir(COD)Cl]2; close the hydrogenation reactor and exit the glove box; replace with hydrogen gas for 3 times; fill with hydrogen gas to make the pressure in the reactor 40 atm; react at 25 °C~30 °C for 24 h; after 24 h, open the reactor, take 0.2 mL of the reaction solution, and use HPLC to monitor the reaction progress (liquid phase conditions are as follows: Agilent 1260 (equipped with DAD), Daicel IC, 4.6*250 mm, 5 μm, 30 °C, 254 nm, 5 μl, take 1 mL of the reaction solution, take 50 μL of it, dissolve in 1 mL of isopropanol, pass through a 0.22 μm organic filter membrane, and then measure; mobile phase gradient: Hexanes (0.1% DEA): IPA = 95:5, time: 30 min, flow rate: 1 mL / min) to determine the conversion rate and ee value. The results are shown in Table 1.

[0027] Table 1

[0028]

[0029]

[0030]

[0031] Example 6: Synthesis of compound (S)-III (Entry 26 ~ Entry 45)

[0032] Take acetylferrocene (compound II) 1.14 g (5 mmol) into a 50 mL stainless steel hydrogenation tank; bring the raw material into the glove box; add isopropanol (10 mL); add the corresponding base in Table II; add the chiral ligand (R C ,R C ,S FC )-L18 and [Ir(COD)Cl]2 are pre-complexed catalyst; close the hydrogenation tank and leave the glove box; replace hydrogen three times; fill hydrogen to make the pressure in the tank 40 atm; react for 24 h at 25 ~ 30 °C; after 24 h, open the tank, take 0.2 mL of the reaction solution, and determine the conversion rate and ee value by HPLC monitoring (the liquid phase conditions are the same as in Example 5), and the results are shown in Table II.

[0033] Table II

[0034]

[0035]

[0036]

[0037] Example 7: Synthesis of compound (S)-III (Entry 46 ~ Entry 58)

[0038] Take acetylferrocene (compound II) 1.14 g (5 mmol) into a 50 mL stainless steel hydrogenation tank; bring the raw material into the glove box; add the corresponding solvent (10 mL) in Table III; add sodium hydroxide (2 mg); add the chiral ligand (R C ,R C ,S FC )-L18 and [Ir(COD)Cl]2 are pre-complexed catalyst; close the hydrogenation tank and leave the glove box; replace hydrogen three times; fill hydrogen to make the pressure in the tank 40 atm; react for 24 h at 25 ~ 30 °C; after 24 h, open the tank, take 0.2 mL of the reaction solution, and determine the conversion rate and ee value by HPLC monitoring (the liquid phase conditions are the same as in Example 5), and the results are shown in Table III.

[0039] Table III

[0040]

[0041]

[0042] Example 8: Synthesis of compound (S)-III (Entry 59 ~ Entry 65)

[0043] Take acetylferrocene (compound II) 1.14 g (5 mmol) into a 50 mL stainless steel hydrogenation tank; bring the raw material into the glove box; add isopropanol (10 mL); add sodium hydroxide (2 mg); add the chiral ligand (R C ,R C ,S FC )-L18 and [Ir(COD)Cl]2 pre-complexed catalyst; close the hydrogenation tank and leave the glove box; replace hydrogen three times; fill hydrogen to make the pressure in the tank 40 atm; react for 24 h at 25 ~ 30 °C; after 24 h, open the tank, take 0.2 mL of the reaction solution, and measure the conversion rate and ee value by HPLC monitoring (the liquid phase conditions are the same as in Example 5), and the results are shown in Table IV.

[0044] Table IV

[0045]

[0046]

[0047] Example 9: Synthesis of compound (S)-III (Entry 66 ~ Entry 68)

[0048] Take acetylferrocene (compound II) 1.14 g (5 mmol) into a 50 mL stainless steel hydrogenation tank; bring the raw material into the glove box; add isopropanol (10 mL); add different proportions of different enantiomers of the base in Table V; add the chiral ligand (R C ,R C ,S FC )-L18 and [Ir(COD)Cl]2 pre-complexed catalyst; close the hydrogenation tank and leave the glove box; replace hydrogen three times; fill hydrogen to make the pressure in the tank 40 atm; react for 24 h at 25 ~ 30 °C; after 24 h, open the tank, take 0.2 mL of the reaction solution, and measure the conversion rate and ee value by HPLC monitoring (the liquid phase conditions are the same as in Example 5), and the results are shown in Table V.

[0049] Table V

[0050]

[0051]

[0052]

[0053] Synthesis of compound (S)-III (Entry 69 ~ Entry 74)

[0054] Weigh acetylferrocene (compound II) 1.14 g (5 mmol) into a 50 mL stainless steel hydrogenation bomb; bring the material into the glove box; add isopropanol (10 mL); add sodium hydroxide (8 mg); add the chiral ligand (R C ,R C ,S FC )-L18 pre-complexed with [Ir(COD)Cl]2; close the hydrogenation bomb and exit the glove box; replace the hydrogen gas three times; charge the hydrogen gas to a pressure of 40 atm; follow the reaction temperature and time in Table Six; monitor the reaction for the time indicated in Table Six; measure the conversion and ee values by HP LC (same liquid phase conditions as in Example 5); the results are shown in Table Six.

[0055] Table Six

[0056]

[0057]

[0058] Synthesis of compound (S)-III (Entry 75 ~ Entry 79)

[0059] Weigh acetylferrocene (compound II) 1.14 g (5 mmol) into a 50 mL stainless steel hydrogenation bomb; bring the material into the glove box; add isopropanol (10 mL); add sodium hydroxide (8 mg); add the chiral ligand (R C ,R C ,S FC )-L18 pre-complexed with [Ir(COD)Cl]2; close the hydrogenation bomb and exit the glove box; replace the hydrogen gas three times; charge the hydrogen gas to a pressure of 40 atm; follow the reaction temperature and time in Table Seven; monitor the reaction for 24 h; measure the conversion and ee values by HP LC (same liquid phase conditions as in Example 5); the results are shown in Table Seven.

[0060] Table Seven

[0061]

[0062] Entry [H2 (atm)] Conv. (%) ee (%) 75 10 15 97 76 20 60 97 77 30 ＞95 97 78 50 ＞95 97 79 60 ＞95 97

[0063] Synthesis of compound (S)-III

[0064] Acetylferrocene (compound II) 11.4 g (50 mmol) was weighed into a 300 mL stainless steel hydrogenation vessel; the vessel was brought into the glove box; isopropanol (50 mL) was added; sodium hydroxide (100 mg) was added; the chiral ligand (R C C FC )-L18 was added to the vessel; the vessel was closed and removed from the glove box; the vessel was purged with hydrogen three times; the vessel was charged with hydrogen to a pressure of 30 atm; the reaction was allowed to proceed for 24 h; the conversion and ee were determined by HPLC (same conditions as Example 5); the conversion was >95% and the ee was 96.5%.

[0065] Example 13: Synthesis of compound (S)-III

[0066] Acetylferrocene (compound II) 60 g (263 mmol) was weighed into a 500 mL stainless steel hydrogenation vessel; the vessel was brought into the glove box; isopropanol (260 mL) was added; sodium hydroxide (526 mg) was added; the chiral ligand (R C C FC )-L18 was added to the vessel; the vessel was closed and removed from the glove box; the vessel was purged with hydrogen three times; the vessel was charged with hydrogen to a pressure of 30 atm; the reaction was allowed to proceed for 24 h; the conversion and ee were determined by HPLC (same conditions as Example 5); the conversion was >95% and the ee was 96.5%; the reaction was transferred to a 500 mL flask and concentrated under reduced pressure; the isopropanol was removed; the product was dried as a yellow solid; the yield was 60.3 g, 99%.

[0067] Example 14: Synthesis of compound (S)-III

[0068] Acetylferrocene (compound II) (640 g, 2.81 mol) was completely dissolved in isopropanol (3.0 L); the acetylferrocene solution was added to a 5 L hydrogenation vessel under an inert atmosphere at room temperature; sodium hydroxide (5.6 g) was added; the chiral ligand (R C C FC ​​​​​​)-L18 and [Ir(COD)Cl]2 are pre-complexed with solid catalyst; the feed inlet is flushed with a small amount of isopropanol (0.2 L) to ensure that the catalyst and sodium hydroxide are completely introduced into the reaction system; the hydrogenation reactor is closed and inert gas is bubbled for 15 min to ensure that there is no air in the system; hydrogen is charged to 10 atm to replace the inert gas, and the operation is repeated 3 times to ensure that there is no inert gas in the system; hydrogen is charged to make the pressure in the reactor 30 atm; the reaction is carried out at 25-30 °C for 8 h, and the reaction progress is monitored by HPLC (the liquid chromatography conditions are the same as in Example 5), once every 8 h; if the hydrogen pressure drops to less than 20 atm during the reaction, hydrogen is supplemented to 30 atm until the HPLC shows that the ratio of the peak area of the raw material to that of the product is less than 3:97, and the reaction is carried out for about 36 h; after the reaction is completed, the reactor is opened and the material is discharged, and the reactor is flushed with isopropanol (2 L) to ensure that there is no residual material in the reactor; isopropanol is removed under reduced pressure to dryness at a temperature of 50-60 °C and a pressure of < -0.1 MPa; petroleum ether (1.5 L) is added, and the system is stirred and slurried at room temperature until there are no large particles in the system; filtration; the solid is dried to constant weight; the mother liquor is concentrated and the solvent is removed under reduced pressure, and then recovered; 550 g of solid is obtained with a yield of 84%; the ee value is about 96.7% as measured by HPLC.

[0069] Example 15: Synthesis of compound (S)-III

[0070] Compound II (120 kg) is completely dissolved in isopropanol (500 L) in a solution kettle at room temperature, and sodium hydroxide (1.0 kg) is added. Under an inert gas atmosphere at room temperature, the above mixture is added to a 2000 L hydrogenation reactor, and the solution kettle is flushed with a small amount of isopropanol (100 L) to ensure that there is no material remaining in the solution kettle. Nitrogen is replaced 3 times, and the chiral ligand (R C ,R C ,S FC)-L18 and [Ir(COD)Cl]2 were pre-complexed with solid catalyst, the feeding port was washed with a small amount of isopropyl alcohol (50 L) to ensure that the catalyst was completely into the reaction system, the hydrogenation reactor was closed, and the inert gas was bubbled for 15 min to ensure that there was no air in the system. Hydrogen was filled to 1.0 MPa, the inert gas was replaced, and the operation was repeated three times to ensure that there was no inert gas in the system. Hydrogen was filled to maintain the pressure in the reactor at 2.5 MPa. Continuous hydrogen was passed, and the pressure in the reactor was maintained at 2.5 MPa at 30-35°C for 22 h. The sample was taken, and the reaction progress was monitored by HPLC. HPLC showed that there was no raw material left, and the ee value was 96.7% (the liquid phase conditions were the same as in Example 5). After the reaction was completed, the reactor was opened, and the material was discharged. The reactor was washed with isopropyl alcohol (300 L) to ensure that there was no residual material in the reactor. The ferrocene ethanol isopropyl alcohol solution was added to a 3000 L reaction kettle, and concentrated under reduced pressure to dryness. Ethyl acetate (200 L) was added to a 3000 L reaction kettle, and concentrated under reduced pressure to dryness to ensure that there was no isopropyl alcohol residue.

[0071] Example 16: Synthesis of compound (S)-IV

[0072] Compound III (1.15 g, 5 mmol) was weighed into a round-bottom flask (50 mL) at room temperature; sodium acetate trihydrate (0.68 g, 5 mmol) was added; isopropyl acetate (3.0 mL) was added; the temperature was raised to 40°C, and stirring was performed for about 5 min to completely dissolve compound III; acetic anhydride (1.53 g, 15 mmol) was added, and reaction was performed at 40°C for 12 h. The sample was taken, and HPLC monitoring was performed (the liquid phase conditions were the same as in Example 5). Acetic anhydride (1.02 g, 10 mmol) was added at 40°C, and reaction was performed for another 12 h. The sample was taken, and HPLC monitoring was performed (the liquid phase conditions were the same as in Example 5). It was found that compound III was completely reacted, and compound IV did not need to be treated and could be directly used for the next reaction.

[0073] Examples 17-22: Synthesis of compound (S)-IV

[0074] Compound III (1.15 g, 5 mmol) was weighed into a round-bottom flask (50 mL) at room temperature; sodium acetate trihydrate (0.68 g, 5 mmol) was added; different solvents in Table 8 (3.0 mL) were added respectively; the temperature was raised to 40°C, and stirring was performed for about 5 min to completely dissolve compound III; acetic anhydride (1.53 g, 15 mmol) was added, and reaction was performed at 40°C for 12 h. The sample was taken, and HPLC monitoring was performed (the liquid phase conditions were the same as in Example 5). Acetic anhydride (1.02 g, 10 mmol) was added at 40°C, and reaction was performed for another 6 h. The sample was taken, and HPLC monitoring was performed (the liquid phase conditions were the same as in Example 5). It was found that compound III was completely reacted, and compound IV did not need to be treated and could be directly used for the next reaction. The subsequent results are shown in Table Eight.

[0075] Example 23: Synthesis of compound (S)-IV

[0076] Compound III (60 g, 0.26 mol) was weighed into a round bottom flask (1000 mL) at room temperature; sodium acetate trihydrate (35.5 g, 0.26 mol) was added; ethyl acetate (150 mL) was added; the temperature was raised to 40 °C and stirred for 5 min to ensure complete dissolution of compound III; acetic anhydride (80 g, 0.78 mol) was added and the reaction was carried out at 40 °C for 12 h. The sample was taken and monitored by HPLC (same as example 5). Acetic anhydride (26.5 g, 0.26 mol) was added at 40 °C and the reaction was carried out for another 6 h. The sample was taken and monitored by HPLC (same as example 5). It was found that compound III was completely reacted and compound IV was ready for the next step without further purification.

[0077] Example 24: Synthesis of compound (S)-IV

[0078] Compound III (1.0 kg, 4.35 mol) was weighed into a reaction kettle (20 L) at room temperature; sodium acetate trihydrate (0.6 kg, 4.35 mol) was added; ethyl acetate (3.0 L) was added; the temperature was raised to 40 °C and stirred for 5 min to ensure complete dissolution of compound III; acetic anhydride (1.33 kg, 13.05 mol) was added and the reaction was carried out at 40 °C for 12 h. The sample was taken and monitored by HPLC (same as example 5). Acetic anhydride (0.44 kg, 4.35 mol) was added at 40 °C and the reaction was carried out for another 12 h. The sample was taken and monitored by HPLC (same as example 5). It was found that compound III was completely reacted and compound IV was ready for the next step without further purification.

[0079] Example 25: Synthesis of compound (S)-IV

[0080] To the compound III (1.0 kg, 4.35 mol) from example 15 step which was concentrated to dryness under reduced pressure, ethyl acetate (3.0 L) was added, sodium acetate trihydrate (0.6 kg) was added and stirred for 5 min to ensure complete dissolution of ferrocene ethanol. Acetic anhydride (1.33 kg, 13.05 mol) was added at room temperature and the temperature was raised to 40 °C. The reaction was carried out for 12 h. The sample was taken and monitored by HPLC (same as example 5). Acetic anhydride (0.44 kg, 4.35 mol) was added at 40 °C and the reaction was carried out for another 12 h. The sample was taken and monitored by HPLC (same as example 5). It was found that compound III was completely reacted and compound IV was ready for the next step without further purification.

[0081] Example 26: Synthesis of compound (S)-V

[0082] To the reaction solution of compound IV obtained in step of example 16, isopropanol (1.0 mL) was added, n-heptane (3.0 mL) was added, stirred for about 30 minutes, cooled to 0 °C, 40% dimethylamine aqueous solution (6.4 mL) was added, then warmed to 50 °C for 12 h, sampling, HPLC monitoring reaction progress ((liquid phase conditions are the same as example 5)), until HPLC shows that the peak area ratio IV:V at 254 nm is <5%:95%;

[0083] After the reaction was completed, it was cooled to room temperature, and an appropriate amount of sodium chloride (0.5 g) was added. Then, it was continuously stirred for about 30 min, and then it was allowed to stand. The aqueous phase was washed with ethyl acetate (10 mL), stirred for 30 min, allowed to stand for 30 min, separated, and the organic phases were combined. Anhydrous sodium sulfate (1.0 g) was added, stirred at room temperature for 5 min, filtered, and the anhydrous sodium sulfate was removed. The organic solvent was removed under reduced pressure to obtain a red-black oily liquid, which was compound V, with a theoretical yield of 1.285 g, an actual yield of 1.7 g, a crude product yield of >100%, and an ee value of 92.3% for the crude product (liquid phase conditions: Agilent 1260 (equipped with DAD), Daicel ID-3, 4.6*250 mm, 5 μm, 30 °C, 254 nm, 5 μl, 1 mg of crude product was dissolved in 1 mL of isopropanol, filtered through a 0.22 μm organic filter, and then tested; mobile phase gradient: Hexanes (0.1% DEA): IPA = 95:5, Time: 30 min, flow rate 0.5 mL / min).

[0084] Examples 27-32: Synthesis of compound (S)-V

[0085] To the reaction solution of compound IV obtained in step of example 17-22, isopropanol (1.0 mL) was added, n-heptane (3.0 mL) was added, stirred for about 30 minutes, cooled to 0 °C, 40% dimethylamine aqueous solution (6.4 mL) was added, then warmed to 50 °C for 12 h, sampling, HPLC monitoring reaction progress ((liquid phase conditions are the same as example 5)), until HPLC shows that the peak area ratio IV:V at 254 nm is <5%:95%; the subsequent treatment was the same as example 27, and the yield of crude compound V was >100%, and the ee value is shown in Table Eight:

[0086] Table Eight

[0087] Example 17 18 19 20 21 22 Solvent Ethyl acetate DCM 1,2-DCE THF MTBE n-Heptane Reaction completion time (h) 18 23 21 19 24 22 Example 27 28 29 30 31 32 ee value of compound V crude 95.3 92.1 93.4 91.7 93.8 91.5

[0088] Example 33: Synthesis of compound (S)-V

[0089] To the reaction solution of compound IV obtained in the step of example 24, isopropanol (100 mL) was added, n-heptane (150 mL) was added, stirred for about 30 minutes, cooled to 0°C, 40% dimethylamine aqueous solution (400 mL) was added, then warmed to 50°C for 12 hours, sampled, HPLC was used to monitor the progress of the reaction (the liquid phase conditions were the same as those in example 5), until HPLC showed that the peak area ratio IV:V at 254 nm was less than 5%:95%;

[0090] After the reaction was completed, the temperature was lowered to room temperature, and an appropriate amount of sodium chloride (20 g) was added, and then stirring was continued for about 30 minutes, and then it was allowed to stand, and the water phase was washed with ethyl acetate (300 mL), stirred for 30 minutes, allowed to stand for 30 minutes, separated, and the organic phase was combined, anhydrous sodium sulfate (10 g) was added, stirred at room temperature for 5 minutes, filtered, removed the anhydrous sodium sulfate, concentrated under reduced pressure, and the organic solvent was removed, to obtain a red-black oily liquid, which was compound V, the theoretical yield was 67 g, the actual yield was 87 g, the crude product yield was >100%, the ee value of the sample was detected by HPLC, and the ee value of the crude product was 96.2%; (the liquid phase conditions were as follows: Agilent 1260 (equipped with DAD), Daicel ID-3, 4.6*250 mm, 5 μm, 30°C, 254 nm, 5 μl, 1 mg of crude product was dissolved in 1 mL of isopropanol, filtered through a 0.22 μm organic filter membrane, and then detected; the mobile phase gradient: Hexanes (0.1% DEA): IPA = 95:5, time: 30 min, flow rate 0.5 mL / min).

[0091] Example 34: Synthesis of compound (S)-V

[0092] To the reaction solution of compound IV obtained in the step of example 25, isopropanol (2.0 L) was added, n-heptane (3.0 L) was added, stirred for about 30 minutes, cooled to 0°C, 40% dimethylamine aqueous solution (8.0 L) was added, then warmed to 50°C for 12 hours, sampled, HPLC was used to monitor the progress of the reaction (the liquid phase conditions were the same as those in example 5), until HPLC showed that the peak area ratio IV:V at 254 nm was less than 5%:95%;

[0093] After the reaction is completed, cool to room temperature, add an appropriate amount of sodium chloride (20 g), continue to stir for about 30 min, then stand, separate the liquid, wash the water phase with ethyl acetate (300 mL), stir for 30 min, stand for 30 min, separate the liquid, combine the organic phases, add anhydrous sodium sulfate (10 g), stir at room temperature for 5 min, filter, remove the anhydrous sodium sulfate, concentrate under reduced pressure, remove the organic solvent, to obtain a red-black oily liquid, which is compound V, the theoretical yield is 1.12 kg, the actual yield is 1.34 kg, the crude product yield is >100%, the ee value of the sample is 95.3% (liquid phase conditions are as follows: Agilent 1260 (equipped with DAD), Daicel ID-3, 4.6*250 mm, 5 μm, 30 °C, 254 nm, 5 μl, take 1 mg of the crude product, dissolve in 1 mL of isopropyl alcohol, pass through a 0.22 μm organic filter membrane, and then test; the mobile phase gradient: Hexanes (0.1% DEA): IPA = 95:5, time: 30 min, flow rate 0.5 mL / min).

[0094] Example 35: Synthesis of compound (S)-V

[0095] Add n-heptane (360 L) to the reaction solution of compound IV obtained in the step of Example 26, stir for 30 min, add isopropyl alcohol (200 L), stir for 30 min, cool the reaction kettle to 15-20 °C, slowly add 40% dimethylamine aqueous solution (800 L), control the temperature below 25 °C to prevent material from being washed out, heat to 50 °C, and react at 50 °C for 8 h. HPLC detection shows that HPLC shows IV:V = 0.5%:99.5% (the liquid phase conditions are the same as those in Example 5).

[0096] After the reaction is completed, cool to room temperature, add an appropriate amount of sodium chloride (40 kg), continue to stir for about 30 min, then stand, separate the liquid, wash the water phase with ethyl acetate (360 L), stir for 30 min, stand for 30 min, separate the liquid, combine the organic phases, add purified water (400 L), stir for about 30 min, then stand, separate the liquid, combine all the organic phases, add anhydrous sodium sulfate (20 kg), stir at room temperature for 1 hour, filter, remove the anhydrous sodium sulfate, and transfer the filtrate to a reaction kettle (2000 L), concentrate under reduced pressure to remove the organic solvent, to obtain a red-black oily liquid, which is compound V, the theoretical yield is 134 kg, and the actual yield is between 150 kg and 180 kg, the crude product yield is >100%, the ee value of the crude product is 94.6% (the liquid phase conditions are as follows: Agilent 1260 (equipped with DAD), Daicel ID-3, 4.6*250 mm, 5 μm, 30°C, 254 nm, 5 μl, take 1 mg of the crude product, dissolve in 1 mL of isopropyl alcohol, pass through a 0.22 μm organic filter membrane, and then test; the mobile phase gradient: Hexanes (0.1% DEA): IPA = 95:5, time: 30 min, flow rate: 0.5 mL / min).

[0097] Example 36: Synthesis of compound (S,L)-VI

[0098] Dissolve the crude compound V (5.0 g) in methanol (25 mL) at room temperature, add to a round-bottom flask (100 mL), heat to reflux, continue to reflux for about 15 min, dissolve L-tartaric acid (3.0 g) in methanol (50 mL), slowly add the L-tartaric acid methanol solution under reflux, after the addition is completed, continue to reflux for 2-4 hours, stop heating, slowly cool to room temperature at about 20-25°C, stir overnight, crystallize for 12-16 hours, centrifuge, and wash the filter cake with ethyl acetate (30 mL); dry the filter cake under reduced pressure for 4 hours to obtain (S)-Ugi's amine tartaric acid salt 4.8 g, with a yield of 80%;

[0099] Take 100 mg of (S)-Ugi's amine tartaric acid salt, add 2 mL of water, dissociate with 100 mg of sodium hydroxide, add 2 mL of dichloromethane, separate the liquid, and concentrate the dichloromethane under reduced pressure to dryness; sample and measure the ee value to be 99.6% (the liquid phase conditions are as follows: Agilent 1260 (equipped with DAD), Daicel ID-3, 4.6*250 mm, 5 μm, 30°C, 254 nm, 5 μL, take 1 mg of the product, dissolve in 1 mL of isopropyl alcohol, pass through a 0.22 μm organic filter membrane, and then test; the mobile phase gradient: Hexanes (0.1% DEA): IPA = 95:5, time: 30 min, flow rate: 0.5 mL / min).

[0100] Example 37-40: Synthesis of compound (S,L)-VI

[0101] The crude compound V (5.0 g) was dissolved in MTBE (350 mL) at room temperature, and was added into a round bottom flask (1000 mL). The L-tartaric acid (21.6 g) was dissolved in methanol (175 mL), and was added into the flask at reflux. After the addition was completed, reflux was continued for 2-4 hours. The heating was stopped, and the temperature was slowly decreased to room temperature (20-25 °C). The stirring was continued overnight. The crystallization was continued for 12-16 hours. The filter cake was centrifuged, and was washed with MTBE (150 mL). The filter cake was dried under reduced pressure for 4 hours. The (S)-Ugi’s amine tartaric acid salt was obtained in a yield of 43.3 g (98%).

[0102] Table IX

[0103] Example 37 39 40 40 Solvent MTBE Ethyl acetate THF i-PrOH Yield / yield 6.32g，＞100％ 5.88g，96％ 5.35g，87％ 5.3g，86％ ee value 99.29％ 99.73％ 99.73％ 99.65％

[0104] Example 41: Synthesis of compound (S,L)-VI

[0105] The crude compound V (5.0 g) was dissolved in MTBE (350 mL) at room temperature, and was added into a round bottom flask (1000 mL). The L-tartaric acid (21.6 g) was dissolved in methanol (175 mL), and was added into the flask at reflux. After the addition was completed, reflux was continued for 2-4 hours. The heating was stopped, and the temperature was slowly decreased to room temperature (20-25 °C). The stirring was continued overnight. The crystallization was continued for 12-16 hours. The filter cake was centrifuged, and was washed with MTBE (150 mL). The filter cake was dried under reduced pressure for 4 hours. The (S)-Ugi’s amine tartaric acid salt was obtained in a yield of 43.3 g (98%).

[0106] The (S)-Ugi’s amine tartaric acid salt (100 mg) was dissolved in 2 mL of water, and was neutralized with 100 mg of sodium hydroxide. 2 mL of dichloromethane was added, and the mixture was separated. The dichloromethane was dried under reduced pressure. The ee value was determined to be 99.65% by HPLC (the same conditions as in Example 37).

[0107] Example 42: Synthesis of compound (S,L)-VI

[0108] Dissolve the crude compound V (28 g) in ethyl acetate (350 mL) at room temperature, add to a round bottom flask (1000 mL), heat to reflux, continue refluxing for about 15 min, dissolve L-tartaric acid (21.6 g) in methanol (175 mL), slowly add the L-tartaric acid methanol solution at reflux, after the addition is complete, continue refluxing for 2-4 hours, stop heating, slowly cool to room temperature 20-25 °C, stir overnight, crystallize for 12-16 hours, centrifuge, wash the filter cake with ethyl acetate (150 mL); dry the filter cake under reduced pressure for 4 hours, obtain (S)-Ugi's amine tartaric acid salt 41 g, yield 93%;

[0109] Take 100 mg of (S)-Ugi's amine tartaric acid salt, add 2 mL of water, dissociate with 100 mg of sodium hydroxide, add 2 mL of dichloromethane, separate the liquid, and dry the dichloromethane under reduced pressure; sample and measure the ee value as 99.85%. (The liquid phase conditions are the same as in Example 37).

[0110] Example 43: Synthesis of compound (S,L)-VI

[0111] Dissolve the crude compound V (28 g) in ethyl acetate (350 mL) at room temperature, add to a round bottom flask (1000 mL), heat to reflux, continue refluxing for about 15 min, dissolve L-tartaric acid (21.6 g) in methanol (175 mL), slowly add the L-tartaric acid methanol solution at reflux, after the addition is complete, continue refluxing for 2-4 hours, stop heating, slowly cool to room temperature 20-25 °C, stir overnight, crystallize for 12-16 hours, centrifuge, wash the filter cake with ethyl acetate (150 mL); dry the filter cake under reduced pressure for 4 hours, obtain (S)-Ugi's amine tartaric acid salt 41 g, yield 93%;

[0112] Take 100 mg of (S)-Ugi's amine tartaric acid salt, add 2 mL of water, dissociate with 100 mg of sodium hydroxide, add 2 mL of dichloromethane, separate the liquid, and dry the dichloromethane under reduced pressure; sample and measure the ee value as 99.85%. (The liquid phase conditions are the same as in Example 37).

[0113] Example 43: Synthesis of compound (S,L)-VI

[0114] The crude compound V (1.34 kg) was dissolved in ethyl acetate (12.5 L) at room temperature, and was added into a reaction kettle (20 L) and heated to reflux for about 15 min. L-tartaric acid (0.72 kg) was dissolved in methanol (2.5 L), and the L-tartaric acid methanol solution was slowly added dropwise under reflux. After the dropwise addition was completed, reflux was continued for 2-4 h. The heating was stopped, and the temperature was slowly lowered to about 20-25 °C. The stirring was continued overnight, and the crystallization was continued for 12-16 h. The filter cake was washed with ethyl acetate (2.5 L). The filter cake was dried under reduced pressure for 4 h to obtain (S)-Ugi's amine L-tartrate 1.5 kg with a yield of 85%.

[0115] 100 mg of (S)-Ugi's amine L-tartrate was taken, 2 mL of water was added, 100 mg of sodium hydroxide was added to dissociate, 2 mL of dichloromethane was added, and the mixture was separated. The dichloromethane was concentrated and dried under reduced pressure. The sample was taken, and the ee value was measured to be 99.55%. (The liquid phase conditions were the same as those in Example 37)

[0116] Example 45: Synthesis of compound (S, L)-VI

[0117] The crude compound V (1.34 kg) was dissolved in ethyl acetate (12.5 L) at room temperature, and was added into a reaction kettle (20 L) and heated to reflux for about 15 min. L-tartaric acid (0.72 kg) was dissolved in methanol (2.5 L), and the L-tartaric acid methanol solution was slowly added dropwise under reflux. After the dropwise addition was completed, reflux was continued for 2-4 h. The heating was stopped, and the temperature was slowly lowered to about 20-25 °C. The stirring was continued overnight, and the crystallization was continued for 12-16 h. The filter cake was washed with ethyl acetate (2.5 L). The filter cake was dried under reduced pressure for 4 h to obtain (S)-Ugi's amine L-tartrate 1.5 kg with a yield of 85%.

[0118] 100 mg of (S)-Ugi's amine L-tartrate was taken, 2 mL of water was added, 100 mg of sodium hydroxide was added to dissociate, 2 mL of dichloromethane was added, and the mixture was separated. The dichloromethane was concentrated and dried under reduced pressure. The sample was taken, and the ee value was measured to be 99.55%. (The liquid phase conditions were the same as those in Example 37)

[0119] Example 46: Synthesis of pure compound (S)-V

[0120] Into a 2000 L reactor, dichloromethane (750 L) was added, then compound VI (150 kg) was added, stirred for 30 min, into a 2000 L reactor, mass fraction dilute sodium hydroxide solution (750 kg) was added at room temperature, stirred for 4 h, stood for 60 min, separated, dichloromethane (250 L) was added to the aqueous phase, stirred for 1 h, stood for 60 min, separated, all the organic phases were combined, anhydrous sodium sulfate (20 kg) was added, stirred for 1 h at room temperature, filtered, the anhydrous sodium sulfate was removed, the filtrate was transferred to a 2000 L reactor, concentrated under reduced pressure, dichloromethane was removed, a red-black oily liquid was obtained, which was compound V pure product, the total amount was 95 kg, the yield was 99%. 1 g was taken for sample, the ee value and purity were measured, the chemical purity was 98%, the ee value was 99.6% (the liquid phase conditions were the same as those in Example 37). The total yield of compound V pure product was 53%.

[0121] Example 47: Synthesis of compound (R)-III

[0122] Acetylferrocene (compound II) (500 g, 2.2 mol) was completely dissolved in isopropyl alcohol (2.5 L); under an inert gas atmosphere, the acetylferrocene isopropyl alcohol solution was added into a 5 L hydrogenation reactor at room temperature; sodium hydroxide (4.4 g) was added; a chiral ligand (S C ,S C ,R FC )-L18 was pre-complexed with [Ir(COD)Cl]2; a small amount of isopropyl alcohol (0.1 L) was used to rinse the feeding port to ensure that the catalyst and sodium hydroxide completely entered the reaction system; the hydrogenation reactor was closed, and inert gas was bubbled for 15 min to ensure that there was no air in the system; hydrogen was charged to 10 atm, and the inert gas was replaced for 3 times to ensure that there was no inert gas in the system; hydrogen was charged to make the pressure in the reactor 30 atm; the reaction was carried out at 25-30°C for 8 h, samples were taken, and the reaction progress was monitored by HPLC (the liquid phase conditions were the same as those in Example 5), which was monitored every 8 h; if the hydrogen pressure decreased to less than 20 atm during the reaction, hydrogen was supplemented to 30 atm until the HPLC showed that the ratio of the peak area of the raw material to that of the product was less than 3:97, and the reaction was carried out for about 36 h; after the reaction was completed, the reactor was opened, and the material was discharged, and the reactor was rinsed with isopropyl alcohol (1.5 L) to ensure that there was no residual material in the reactor; isopropyl alcohol was removed under reduced pressure to dryness at a temperature of 50-60°C and a pressure of < -0.1 MPa; petroleum ether (1.2 L) was added, and the system was stirred and slurried at room temperature until there were no large particles in the system; filtration; the solid was dried to constant weight; the mother liquor was concentrated and the solvent was removed under reduced pressure, and was recovered; 425 g of solid was obtained, the yield was 84.3%; the ee value was about 96.5% as measured by HPLC.

[0123] Example 48: Synthesis of compound (R)-IV

[0124] At room temperature, compound III (600 g, 2.6 mol) was weighed into a glass reactor (10 L); sodium acetate trihydrate (355 g, 2.6 mol) was added; ethyl acetate (1.80 L) was added; the temperature was raised to 40 °C and stirred for 5 min to dissolve compound III completely; acetic anhydride (800 g, 7.8 mol) was added and the reaction was carried out at 40 °C for 12 h. The sample was taken and HPLC monitoring was carried out (the liquid phase conditions were the same as in Example 5). Acetic anhydride (265 g, 2.6 mol) was added at 40 °C and the reaction was carried out for another 6 h. The sample was taken and HPLC monitoring was carried out (the liquid phase conditions were the same as in Example 5). It was found that compound III was completely reacted and compound IV was directly used for the next step without any treatment.

[0125] Example 49: Synthesis of compound (R)-V

[0126] Isopropanol (1.2 L) and n-heptane (1.8 L) were added to the reaction solution of compound IV obtained in the step of Example 48. The temperature was lowered to 0 °C and 40% dimethylamine aqueous solution (6.4 L) was added. The temperature was raised to 50 °C and the reaction was carried out for 12 h. The sample was taken and HPLC monitoring was carried out (the liquid phase conditions were the same as in Example 5) until HPLC showed that the peak area ratio of IV:V at 254 nm was <5%:95%.

[0127] After the reaction was completed, the temperature was lowered to room temperature and an appropriate amount of sodium chloride (100 g) was added. The stirring was continued for another 30 min and then the solution was allowed to stand. The aqueous phase was washed with ethyl acetate (3.6 L) and stirred for 30 min. The solution was allowed to stand for 30 min and the organic phases were combined. Anhydrous sodium sulfate (100 g) was added and stirred at room temperature for 5 min. The anhydrous sodium sulfate was removed by filtration and the organic solvent was removed by concentration under reduced pressure to obtain a red-black oily liquid, which was compound V. The theoretical yield was 0.67 kg and the actual yield was 0.89 kg. The crude product yield was >100% and the ee value of the sample was 94.7% (the liquid phase conditions were as follows: Agilent 1260 (equipped with DAD), Daicel ID-3, 4.6*250 mm, 5 μm, 30 °C, 254 nm, 5 μl, 1 mg of crude product was dissolved in 1 mL of isopropanol and filtered through a 0.22 μm organic filter before being tested; the mobile phase gradient was Hexanes (0.1% DEA):IPA = 95:5, time: 30 min, flow rate: 0.5 mL / min).

[0128] Example 50: Synthesis of compound (R,D)-VI

[0129] The crude compound V (0.89 kg) was dissolved in ethyl acetate (8.0 L) at room temperature, and was added into a reaction kettle (20 L) and heated to reflux for about 15 min. D-tartaric acid (0.48 kg) was dissolved in methanol (1.66 L), and the L-tartaric acid methanol solution was slowly added dropwise under reflux. After the dropwise addition was completed, reflux was continued for 2-4 h. The heating was stopped, and the temperature was slowly lowered to about 20-25 °C. The mixture was stirred overnight, and crystallization was continued for 12-16 h. The mixture was centrifuged, and the filter cake was washed with ethyl acetate (2.5 L). The filter cake was dried under reduced pressure for 4 h to obtain (S)-Ugi's amine tartaric acid salt 0.9 kg with a yield of 85%.

[0130] 100 mg of (R)-Ugi's amine-D-tartaric acid salt was taken, 2 mL of water was added, and 100 mg of sodium hydroxide was added to dissociate it. 2 mL of dichloromethane was added, and the mixture was separated. The dichloromethane was concentrated and dried under reduced pressure. The sample was analyzed, and the ee value was found to be 99.63%. (The liquid phase conditions were the same as in Example 37)

[0131] The above examples are preferred embodiments of the present application, but the embodiments of the present application are not limited to the above examples. Any changes, modifications, substitutions, combinations, simplifications, etc. made without departing from the spirit and principles of the present application are equivalent replacement methods, and are included in the scope of the present application.

Claims

1. An asymmetric process for the preparation of (S) or (R)-Ugi amine and its tartrate salt, characterized in that, The reaction process is shown as follows: Comprising the following steps: (1) Using ferrocene I as raw material, acetylation reaction to obtain acetyl ferrocene II; (2) asymmetric hydrogenation of acetylferrocene II in the presence of a chiral catalyst, said catalyst being obtained by complexing a metal salt selected from one of [Ir(NBD)2Cl]2, [Ir(NBD)2]X, [Ir(COD)Cl]2, [Ir(COD)2]X, wherein X represents an anion selected from BF4 - , ClO4 - , SbF6 - , PF6 - , TfO - , with a chiral ligand selected from: wherein the reaction is carried out in a solvent comprising ethanol, isopropanol, tetrahydrofuran, dichloromethane, toluene, one or a mixture of any proportion; The base used in the reaction is potassium tert-butoxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, or a mixture thereof in any proportion; (3) The esterification of formula III to obtain optically pure (S) or (R) ferrocene ethyl acetate IV, without separation, directly reacts with dimethylamine to obtain optically pure formula V, (S) or (R)-Ugi amine; (4) The free (S) or (R)-Ugi amine is salted with the corresponding configuration of tartaric acid to obtain (S)-Ugi amine-L-tartrate VI or (R)-Ugi amine-D-tartrate, wherein "*" represents (S) or (R) two configurations.

2. The manufacturing process of claim 1, wherein, The temperature of the reaction in step (2) is 20-80 degrees Celsius; the hydrogen pressure of the reaction is 2-8 Mpa.

3. The manufacturing process of claim 1, wherein, The reaction time in step (2) is 8-60 hours.

4. The manufacturing process of claim 1, wherein, The molar ratio of acetyl ferrocene to catalyst in step (2) is 2 mmol: 0.01-1 nmol.

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