5-substituted indoline chiral amine, preparation method therefor, and use thereof in preparation of silodosin

Abstract

Disclosed in the present invention are a 5-substituted indoline chiral amine compound I, a preparation method therefor, and a preparation method for silodosin. Silodosin is prepared from an indoline derivative and a (R)-2-aminopropanol derivative as starting materials by steps of converting the (R)-2-aminopropanol derivative into an aziridine derivative; halogenating the indoline derivative to obtain a compound of formula III, then forming a Grignard reagent from same, and in the presence of a Cu(I) catalyst, reacting same with the (R)-2-aziridine derivative to obtain the 5-substituted indoline chiral amine I; and performing a formylation reaction, an oximation reaction, a dehydration reaction, an N-alkylation reaction, deprotection of hydroxyl, deprotection of amino, and a hydrolysis reaction to obtain silodosin. The present invention uses an efficient chiral source introduction mode, wherein the 5-substituted indoline chiral amine is prepared by converting D-alanine into a chiral aziridine derivative and reacting same with an indoline moiety, thereby omitting an optical resolution step, such that the obtained compound has a high ee value and the yield is improved.

Description

5-substituted indoline chiral amine, its preparation method and its application in preparation of silodosin TECHNICAL FIELD

[0001] The present application belongs to the field of medicine and preparation of intermediates, and particularly relates to 5-substituted indoline chiral amine, its preparation method and its application in preparation of silodosin. BACKGROUND

[0002] Silodosin is an alpha 1A adrenergic receptor antagonist developed by Kissei and Daiichi Pharmaceutical Company for treating urinary obstruction caused by prostatic hyperplasia, and its structural formula is as shown below:

[0003] The structure of silodosin contains 5-substituted indoline chiral amine, and its preparation method is mainly developed around the structural feature. There are various preparation methods at present, and the key step is in the introduction of chiral amine, including chiral resolution, chiral induction, direct introduction of chiral source and the like. However, the existing preparation methods still have problems such as long route, low yield, high cost, and some processes unsuitable for industrialization.

[0004] SUMMARY

[0005] The present application provides a 5-substituted indoline chiral amine, its preparation method and its application in preparation of silodosin, and the process has the characteristics of simple route, high yield and suitability for large-scale industrial production, and has good industrial application prospect.

[0006] The present application first provides a preparation method of 5-substituted indoline chiral amine shown in formula I, and the method is characterized by comprising the following steps:

[0007] (1) 2,3-dihydro-1H-indole is reacted by one or more steps to obtain a compound of formula II

[0008] (2) the compound of formula II is reacted with a halogenating agent to obtain a compound of formula III

[0009] (3) the compound of formula III is first formed into a Grignard reagent, and then reacted with a aziridine derivative derived from (R)-2-aminopropanol in the presence of a Cu(I) catalyst to obtain 5-substituted indoline chiral amine I

[0010] In formula (I)-(III), R 1The hydroxyl protecting group can be an ester group, a silyl group, a tetrahydropyranyl group, a methoxymethylene group, a benzyl group, or a benzyl group with a substituent on the benzene ring, a benzoyl group, or a benzoyl group with a substituent on the benzene ring, a methyl group, a diphenylmethyl group, a triphenylmethyl group, or an allyl group; wherein, the substituent on the benzyl group's benzene ring is a C1-C4 alkyl or C1-C4 alkoxy group, a halogen group, a nitro group, an amino group, an aminoacyl group, a cyano group, a C1-C4 alkamido group, or a hydroxyl group; the ester group is R 3 CO-, where R 3 It is an alkyl group, preferably C1 to C2. 10 Alkyl; the silicon group is a trialkylsilyl group R 4 R 5 R 6 Si-, R 4 R 5 and R 6 It is an alkyl group, preferably C1 to C2. 10 Alkyl, more preferably C1-C6 alkyl, even more preferably C1-C4 alkyl, wherein R 4 R 5 and R 6 They can be the same or different.

[0011] R 2 The amino protecting group can be methanesulfonyl, substituted or unsubstituted benzylsulfonyl, tert-butoxycarbonyl, allyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, triphenylmethyl, trifluoroacetyl, or acetyl. The benzylsulfonyl and benzyloxycarbonyl can be unsubstituted, single-substituted, or multi-substituted. The substituent can be C1-C4 alkyl or C1-C4 alkoxy, halogen, nitro, amino, aminoacyl, cyano, C1-C4 alkamide, or hydroxyl.

[0012] X is a halogen, which can be chlorine, bromine, or iodine.

[0013] In some implementations, the R 1 It is a benzyl group or a benzyl group or a benzoyl group with a substituent on the benzene ring, wherein the substituent on the benzene ring is one or more of a C1-C4 alkyl or C1-C4 alkoxy group, F, Cl or Br;

[0014] The R mentioned 2 It is a tert-butoxycarbonyl, substituted or unsubstituted benzenesulfonyl group, wherein the substituent is one or more of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br or nitro.

[0015] In some embodiments, in step (1), the compound of formula II is obtained by reacting 2,3-dihydro-1H-indole with 1-benzyloxy-3-halopropane;

[0016] The 1-benzyloxy-3-halopropane is 1-benzyloxy-3-chloropropane, 1-benzyloxy-3-bromopropane, or 1-benzyloxy-3-iodopropane;

[0017] In some embodiments, step (1) is carried out in the presence of an organic base.

[0018] In some embodiments, the organic base is an organic amine, preferably a trialkylamine, and more preferably triethylamine or diisopropylethylamine;

[0019] In some embodiments, step (1) is carried out in a polar solvent, preferably DMF or DMSO;

[0020] In some embodiments, an additive bromide or iodide, preferably sodium iodide or sodium bromide, is added during the reaction in step (1).

[0021] In some embodiments, the halogenated reagent in step (2) is a halogen or NBS.

[0022] In some embodiments, the (R)-2-aminopropanol-derived aziridine derivative in step (3) is (R)-2-methyl-1-tert-butoxycarbonylaziridine, (R)-2-methyl-1-benzenesulfonylaziridine, (R)-2-methyl-1-p-nitrobenzenesulfonylaziridine, or (R)-2-methyl-1-p-toluenesulfonylaziridine.

[0023] In some embodiments, the Cu(I) catalyst in step 3) includes cuprous iodide, cuprous bromide, cuprous chloride, cuprous bromide dimethyl sulfide, and tris(triphenylphosphine)cuprous bromide.

[0024] In some embodiments, the method for preparing the 5-substituted indoline chiral amine of Formula I-1 is characterized by comprising the following steps:

[0025] (1) 2,3-Dihydro-1H-indole reacts with 1-benzyloxy-3-halopropane to give compound II-1.

[0026] (2) The reaction of compound II-1 with a halogenated reagent yields compound III-1.

[0027] (3) Compound III-1 first forms a Grignard reagent, and then reacts with the (R)-2-aminopropanol-derived aziridine derivative in the presence of a Cu(I) catalyst to give 5-substituted indoline chiral amine I-1.

[0028] A second aspect of the present invention provides a 5-substituted indoline chiral amine compound with the structure shown in Formula I:

[0029] Among them, R 1 The hydroxyl protecting group can be an ester group, a silyl group, a tetrahydropyran, a methoxymethylene (MOM), a benzyl group or a benzyl group substituted on the benzene ring, a benzoyl group or a benzoyl group substituted on the benzene ring, a methyl group, a diphenylmethyl group, a triphenylmethyl group, or an allyl group, wherein the substituent on the benzene ring is a C1-C4 alkyl or C1-C4 alkoxy group, a halogen, a nitro group, an amino group, an aminoacyl group (NH2CO-), a cyano group, a C1-C4 alkamido group, or a hydroxyl group;

[0030] R 2 The amino protecting group can be methanesulfonyl, substituted or unsubstituted benzyl, tert-butoxycarbonyl, allyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, triphenylmethyl, trifluoroacetyl, acetyl, etc. Among them, benzyl and benzyloxycarbonyl can be unsubstituted, single-substituted or multi-substituted. The substituent can be C1-C4 alkyl or C1-C4 alkoxy, halogen, nitro, amino, aminoacyl, cyano, C1-C4 alkamido, hydroxy, etc.

[0031] In the above text, the ester group is R. 3 CO-, where R 3 It is an alkyl group, preferably C1 to C2. 10 Alkyl, more preferably C1 to C6 alkyl, and even more preferably C1 to C4 alkyl.

[0032] The silicon-based group is trialkylsilyl (R 4 R 5 R 6 Si-), R 4 R 5 and R 6 It is an alkyl group, preferably C1 to C2. 10 Alkyl, more preferably C1-C6 alkyl, even more preferably C1-C4 alkyl, wherein R 4 R 5 and R 6 They can be the same or different.

[0033] In some implementations, R 1 It is a benzyl group or a benzoyl group with a substituent on the benzyl ring, wherein the substituent on the benzyl group is one or more of a C1-C4 alkyl or C1-C4 alkoxy group, F, Cl or Br.

[0034] In some implementations, the R 2 It is tert-butyloxycarbonyl, substituted or unsubstituted benzenesulfonyl;

[0035] The substituent on the benzenesulfonyl group is one or more of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br or nitro;

[0036] In some implementations, the R 2 It is a tert-butoxycarbonyl, substituted or unsubstituted benzenesulfonyl group, wherein the substituent on the benzenesulfonyl group is one or more of methyl, methoxy, F, Cl, Br or nitro.

[0037] In some embodiments, the 5-substituted indoline chiral amine compound has any of the following structural formulas:

[0038] A third aspect of the present invention provides a method for preparing serodosine, comprising the following steps:

[0039] (B) The 5-substituted indoline chiral amine I was reacted in the presence of DMF / POCl3 to give compound IV.

[0040] (C) Compound IV reacts first with hydroxylamine, and then reacts again with a dehydrating agent to obtain compound V.

[0041] (D) The reaction of compound V with 2-(2-trifluoroethoxyphenoxy)ethyl bromide yields compound VI.

[0042] (E) Compound VI is dehydroxylated to prepare compound VII.

[0043] (F) The compound of formula VII is deamino protecting to obtain the compound of formula VIII.

[0044] The hydrolysis of compound (G)VIII yields serodoxin;

[0045] Among them, R 1 The hydroxyl protecting group can be an ester group, a silyl group, a tetrahydropyranyl group, a methoxymethylene group, a benzyl group, or a benzyl group substituted on the benzene ring, a benzoyl group, or a benzoyl group substituted on the benzene ring, a methyl group, a diphenylmethyl group, a triphenylmethyl group, or an allyl group, wherein the substituent on the benzene ring is a C1-C4 alkyl or C1-C4 alkoxy group, a halogen group, a nitro group, an amino group, an aminoacyl group, a cyano group, a C1-C4 alkamido group, or a hydroxyl group; the ester group is R 3 CO-, where R 3 It is an alkyl group, preferably C1 to C2. 10 Alkyl; the silicon group is a trialkylsilyl group R 4 R5 R 6 Si-, R 4 R 5 and R 6 It is an alkyl group, preferably C1 to C2. 10 Alkyl, more preferably C1-C6 alkyl, even more preferably C1-C4 alkyl, wherein R 4 R 5 and R 6 They can be the same or different;

[0046] R 2 The amino protecting group can be methanesulfonyl, substituted or unsubstituted benzyl, tert-butoxycarbonyl, allyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, triphenylmethyl, trifluoroacetyl, or acetyl. The benzyl and benzyloxycarbonyl groups can be unsubstituted, single-substituted, or multi-substituted. The substituents can be C1-C4 alkyl or C1-C4 alkoxy, halogen, nitro, amino, aminoacyl, cyano, C1-C4 alkamide, or hydroxyl.

[0047] In some embodiments, in step (C), the reaction of compound IV with hydroxylamine is carried out in an alcohol solvent;

[0048] In some embodiments, the alcohol solvent is methanol or ethanol.

[0049] In some embodiments, the dehydrating agent in step (C) is acetic anhydride, the dehydration reaction is carried out in the presence of acetic anhydride and a base, and the solvent for the dehydration reaction is DMSO or DMF; the base is an inorganic base selected from one or more of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate, preferably potassium carbonate;

[0050] In some embodiments, step (D) is carried out in a base and an organic solvent;

[0051] In some embodiments, the alkali is potassium carbonate, sodium carbonate, or lithium carbonate;

[0052] In some embodiments, the organic solvent is acetonitrile.

[0053] In some embodiments, the dehydroxylation protection reaction described in step (E) is carried out in an acid and an organic solvent;

[0054] In some embodiments, the acid is hydrochloric acid or sulfuric acid;

[0055] In some embodiments, the organic solvent is an ether solvent, preferably tetrahydrofuran or dioxane.

[0056] In some embodiments, the deamination protection reaction described in step (F) is carried out in a mercaptoacetic acid, a base, and an alcohol solvent;

[0057] In some embodiments, the alkali is potassium carbonate, sodium carbonate, or lithium carbonate;

[0058] In some embodiments, the alcohol solvent is methanol or ethanol.

[0059] In some embodiments, the hydrolysis reaction described in step (G) is carried out in an alkali, hydrogen peroxide, and an organic solvent;

[0060] In some embodiments, the alkali is potassium hydroxide, sodium hydroxide, or lithium hydroxide;

[0061] In some embodiments, the organic solvent is DMSO or DMF.

[0062] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0063] 1. This invention employs a highly efficient chiral source introduction method, which involves converting D-alanine into a chiral aziridine derivative and reacting it with an indoline fragment to prepare a 5-substituted indoline chiral amine. This avoids the optical resolution step, resulting in a compound with a high ee value and improved yield.

[0064] 2. Based on this, 5-substituted indoline chiral amines were further reacted to obtain celodoxine with a high ee value. This preparation method has the advantages of readily available raw materials, simple process, convenient operation, high yield and low cost, and has potential industrialization value, which is in line with the development direction of green chemistry. Detailed Implementation

[0065] This invention describes in detail a 5-substituted indoline chiral amine and its preparation method, as well as a method for preparing serodoline.

[0066] In this invention, optical purity is characterized by the ee value. The calculation method for the ee (enantiomeric excess) value is: ee = ([R] - [S]) / ([R] + [S]) * 100%, where R represents the content of R configuration product and S represents the content of S configuration product.

[0067] Example 1: Preparation of (R)-2-methyl-1-tert-butoxycarbonylaziridine

[0068] Step 1: 18g of D-alanine was added to 100mL of methanol. 20mL of thionyl chloride was slowly added dropwise to the reaction flask at 0℃, followed by reflux for 1 hour. After the reaction was complete, the solvent was removed under reduced pressure. 150mL of ethyl acetate was added to the residue, and the mixture was stirred at -10℃. A large amount of white solid precipitated. The precipitate was filtered and dried to obtain 27.63g of white solid D-alanine methyl ester hydrochloride, with a yield of 98.6%.

[0069] Step 2: Dissolve 27.63 g of D-alanine methyl ester hydrochloride in 70 mL of methanol, add 150 mL of tetrahydrofuran, and then add 50 g of sodium bicarbonate to the reaction solution. Stir the reaction mixture in an ice-water bath. Dissolve 43.6 g of di-tert-butyl dicarbonate in 70 mL of tetrahydrofuran and slowly add it dropwise to the reaction solution. After the addition is complete, move the reaction solution to room temperature and stir for 3 hours. After the reaction is complete, add 200 mL of water to the reaction solution. After separation, extract the aqueous phase twice with 50 mL of ethyl acetate. Combine the organic phases, wash twice with saturated brine, and concentrate to obtain 40 g of Boc-D-alanine methyl ester, with a yield of 99%.

[0070] Step 3: Dissolve 40g of Boc-D-alanine methyl ester in 200mL of tetrahydrofuran, add 11.34g of sodium borohydride, and stir the reaction at room temperature. Slowly add 160mL of methanol dropwise to the reaction mixture, controlling the dropping rate to maintain a gentle boil. After the addition is complete, incubate the reaction mixture at 65℃ for 1 hour. After the reaction is complete, add 200mL of water to the reaction mixture. After separation, extract the aqueous phase twice with 50mL of ethyl acetate. Combine the organic phases, wash twice with saturated brine, and concentrate. Add 100mL of petroleum ether to the concentrate and stir at -10℃. A large amount of white solid precipitates out. Filter to obtain 31.5g of white solid Boc-D-aminopropanol, yield 91.3%.

[0071] Step 4: Dissolve 17.5 g of Boc-D-aminopropanol in 200 mL of tetrahydrofuran, add 22.4 g of freshly ground potassium hydroxide powder, and stir the reaction mixture in an ice-water bath. Dissolve 30 g of p-toluenesulfonyl chloride in 100 mL of tetrahydrofuran and slowly add it dropwise to the reaction mixture. After the addition is complete, transfer the reaction mixture to 70 °C and stir overnight. After the reaction is complete, remove the tetrahydrofuran under reduced pressure, then add 200 mL of water to the residue, extract twice with 100 mL of dichloromethane, combine the organic phases, wash with saturated brine, and concentrate. Distill the residue under reduced pressure at 20 Torr, and collect the fraction at 70 °C to give 11.3 g of (R)-2-methylaziridine-1-carboxylic acid tert-butyl ester, yield 71.9%.

[0072] Compound spectral data: 1H NMR (400MHz, Chloroform-d) δ2.53-2.38 (m, 1H), 2.25 (d, J = 5.7Hz, 1H), 1.89 (d, J = 3.3Hz, 1H), 1.47 (s, 9H), 1.28 (d, J = 5.4Hz, 3H). 13 C NMR(101MHz,Chloroform-d)δ80.96,33.62,32.53,27.98,17.44.

[0073] Example 2: Preparation of (R)-2-methyl-1-p-toluenesulfonylaziridine

[0074] Replacing ditert-butyl dicarbonate in Example 1 with p-toluenesulfonyl chloride yields (R)-2-methyl-1-p-toluenesulfonylaziridine.

[0075] Compound spectral data: 1 H NMR (400MHz, Chloroform-d) δ7.35(t,J=1.0Hz,1H),7.34-7.31(m,1H),2.61(d,J=7.0Hz,1H),2.45(s,3H),2.02(d,J=4.6Hz,1H),1.25(d,J=5.6Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ144.45,135.43,129.74,127.86,35.91,34.80,21.69,16.85.

[0076] Example 3: Preparation of N-(3-(benzyloxy)propyl)indoline

[0077] At room temperature, 10 g of 2,3-dihydro-1H-indole was dissolved in 30 mL of N,N-dimethylformamide, followed by the addition of 13 g of N,N-diisopropylethylamine and 8.6 g of sodium bromide, and then purged three times with argon gas. The reaction solution was heated to 85 °C, and 18.6 g of 1-benzyloxy-3-chloropropane was slowly injected into it, followed by stirring at 85 °C for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature, and 100 mL of water, 2.5 mL of concentrated hydrochloric acid, and then 100 mL of petroleum ether were added. After separation, the aqueous phase was extracted once with 50 mL of petroleum ether. The organic phases were combined, and 200 mL of water was added with stirring, followed by the addition of dilute hydrochloric acid to adjust the pH to ≤2.0, and stirring for 10 min. After standing and separating, sodium carbonate solution was added to the aqueous phase to adjust the pH to ≥ 8.0. Then, it was extracted twice with 100 mL of petroleum ether. The organic phases were combined, washed with saturated sodium chloride, dried with sodium sulfate, and concentrated to obtain 20 g of N-(3-(benzyloxy)propyl)indoline, with a yield of 89%.

[0078] Compound spectral data: 1 H NMR(400MHz,Chloroform-d)δ7.50-7.34(m,5H),7.12(t,J=7.7Hz,2H),6.70(t,J=7.3Hz,1H),6.55(d,J=7.7Hz, 1H), 4.59 (s, 2H), 3.66 (m, 2H), 3.40 (t, J = 8.3Hz, 2H), 3.25 (t, J = 7.0Hz, 2H), 3.01 (t, J = 8.3Hz, 2H), 1.98 (m, 2H). 13 C NMR(101MHz,Chloroform-d)δ152.73,138.57,129.99,128.48,127.77,127.6 7,127.39,124.43,117.41,106.96,73.14,68.11,53.27,46.33,28.67,27.90.

[0079] Example 4: Preparation of 5-bromo-1-(3-(benzyloxy)propyl)indoline

[0080] Under argon protection, 13.4 g of N-(3-(benzyloxy)propyl)indoline was dissolved in 100 mL of dichloromethane and stirred at -10 °C. 8.9 g of N-bromosuccinimide was dissolved in 20 mL of N,N-dimethylformamide and slowly added dropwise to the reaction solution. After the addition was complete, the reaction mixture was kept at -10 °C for 30 min. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate solution, washed with 1N sodium hydroxide solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give 16.9 g of 5-chloro-1-(3-(benzyloxy)propyl)indoline, with a yield of 97.5%.

[0081] Compound spectral data: 1 H NMR(400MHz,Chloroform-d)δ7.50-7.33(m,5H),7.17(d,J=7.4Hz,2H),6.37(d,J=8.2Hz,1H),4.56(s,2H),3. 62(t,J=5.9Hz,2H), 3.39(t,J=8.4Hz,2H), 3.21(t,J=7.1Hz,2H), 2.98(t,J=8.4Hz,2H), 1.94(t,J=6.7Hz,2H). 13C NMR(101MHz,Chloroform-d)δ151.81,138.47,132.28,129.91,128.49,127.7 6,127.71,127.33,108.69,107.99,73.15,67.87,53.15,46.04,28.38,27.67.

[0082] Example 5: Preparation of 5-substituted indolineamine I: R-5-(2-(p-toluenesulfonyl)amino)propyl-1-(3-(benzyloxy)propyl)indoline

[0083] Step 1: Place 0.36g of magnesium shavings and one grain of iodine in a dry two-necked flask, purge with argon gas three times, then add 10mL of anhydrous tetrahydrofuran. Dissolve 3.45g of 5-bromo-1-(3-(benzyloxy)propyl)indoline in 10mL of anhydrous tetrahydrofuran. Add 2mL of the 5-bromo-1-(3-(benzyloxy)propyl)indoline solution to the two-necked flask, gradually heat until the iodine decolorizes, then slowly add the remaining solution dropwise, maintaining a gentle boil throughout the reaction. After the addition is complete, reflux the reaction mixture for 2 hours before use.

[0084] Step 2: Place the above reaction solution in a -30℃ reaction bath and add 0.2g of cuprous dimethyl sulfide bromide. Then, dissolve 1.1g of (R)-2-methyl-1-p-toluenesulfonylaziridine in 5mL of anhydrous tetrahydrofuran and slowly add it dropwise to the reaction. After stirring at -30℃ for 30min, quench the reaction by injecting 5mL of saturated ammonium chloride solution. Add 50mL of water and 30mL of ethyl acetate to the reaction solution. After separation, extract the aqueous phase with 30mL of ethyl acetate, combine the organic phases, dry them with anhydrous sodium sulfate, concentrate, and column chromatography to obtain 1.8g of R-5-(2-(p-toluenesulfonyl)amino)propyl-1-(3-(benzyloxy)propyl)indoline, yield 75%, ee value 99.3%.

[0085] Compound spectral data: 1H NMR(400MHz,Chloroform-d)δ7.61(d,J=8.3Hz,2H),7.39-7.27(m,5H),7.22(d,J=7 .8Hz,2H),6.67(m,2H),6.33(d,J=8.4Hz,1H),4.53(s,2H),4.45(d,J=6.8Hz,1H),3 .60(t,J=6.2Hz,2H),3.44-3.38(m,1H),3.32(t,J=8.3Hz,2H),3.16(t,J=7.1Hz,2H ),2.85(m,2H),2.53(m,2H),2.40(s,2H),1.98-1.83(m,2H),1.11(d,J=6.5Hz,3H).

[0086] Example 6: Preparation of 5-substituted indolineamine I: R-5-(2-(tert-butoxycarbonyl)amino)propyl-1-(3-(benzyloxy)propyl)indoline

[0087] Step 1: Place 0.6g of magnesium shavings and one grain of iodine in a dry two-necked flask, purge with argon gas three times, then add 10mL of anhydrous tetrahydrofuran. Dissolve 5.2g of 5-bromo-1-(3-(benzyloxy)propyl)indoline in 15mL of anhydrous tetrahydrofuran. Add 2mL of the 5-bromo-1-(3-(benzyloxy)propyl)indoline solution to the two-necked flask, gradually heat until the iodine decolorizes, then slowly add the remaining solution dropwise, maintaining a gentle boil throughout the reaction. After the addition is complete, reflux the reaction mixture for 2 hours before use.

[0088] Step 2: Place the above reaction solution in a -30℃ reaction bath and add 0.3g of cuprous dimethyl sulfide bromide. Then, dissolve 1.57g of (R)-2-methyl-1-tert-butoxycarbonylaziridine in 10mL of anhydrous tetrahydrofuran and slowly add it dropwise to the reaction mixture. After stirring at -30℃ for 30min, quench the reaction by injecting 5mL of saturated ammonium chloride solution. Add 50mL of water and 30mL of ethyl acetate to the reaction solution. After separation, extract the aqueous phase with 30mL of ethyl acetate, combine the organic phases, dry them with anhydrous sodium sulfate, concentrate, and column chromatography to obtain 2.96g of R-5-(2-(tert-butoxycarbonyl)amino)propyl-1-(3-(benzyloxy)propyl)indoline, yield 72%.

[0089] Compound spectral data: 1H NMR(400MHz,Chloroform-d)δ7.38-7.27(m,5H),6.89(s,1H),6.84(d,J=7.9Hz,1H),6. 40(d,J=7.9Hz,1H),4.52(s,2H),4.46-4.25(m,1H),3.80(s,1H),3.59(t,J=6.2Hz,2H), 3.31(t,J=8.3Hz,2H),3.15(t,J=7.1Hz,2H),2.92(t,J=8.3Hz,2H),2.72(dd,J=13.4,5. 2Hz,1H),2.52(dd,J=13.5,7.5Hz,1H),1.91(m,2H),1.43(s,9H),1.07(d,J=6.6Hz,3H).

[0090] Example 7: Preparation of 5-substituted indolineamine I: R-5-(2-(p-nitrobenzenesulfonyl)amino)propyl-1-(3-(benzyloxy)propyl)indoline

[0091] Step 1: Place 0.6g of magnesium shavings and one grain of iodine in a dry two-necked flask, purge with argon gas three times, then add 10mL of anhydrous tetrahydrofuran. Dissolve 5.2g of 5-bromo-1-(3-(benzyloxy)propyl)indoline in 15mL of anhydrous tetrahydrofuran. Add 2mL of the 5-bromo-1-(3-(benzyloxy)propyl)indoline solution to the two-necked flask, gradually heat until the iodine decolorizes, then slowly add the remaining solution dropwise, keeping the reaction mixture at a gentle boil. After the addition is complete, reflux the reaction mixture for 2 hours before use.

[0092] Step 2: Place the above reaction solution in a -30℃ reaction bath and add 0.3g of cuprous dimethyl sulfide bromide. Then, dissolve 1.57g of (R)-2-methyl-1-tert-butoxycarbonylaziridine in 10mL of anhydrous tetrahydrofuran and slowly add it dropwise to the reaction. After stirring at -30℃ for 30min, quench the reaction by adding 5mL of saturated ammonium chloride solution. Add 50mL of water and 30mL of ethyl acetate to the reaction solution. After separation, extract the aqueous phase with 30mL of ethyl acetate, combine the organic phases, dry them with anhydrous sodium sulfate, and concentrate. Dissolve the concentrated solution in 20mL of methanol, add 30mL of 2M dilute hydrochloric acid, and stir the reaction at 60℃. After the reaction is complete, remove methanol from the reaction solution under reduced pressure, and adjust the pH to ≥8 by adding saturated sodium bicarbonate solution. Then extract twice with 30mL of ethyl acetate, combine the organic phases, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and concentrate for later use.

[0093] Step 3: Dissolve the concentrated solution from Step 2 in 30 mL of dichloromethane, add 1.5 mL of triethylamine, and slowly add 2.21 g of p-nitrobenzenesulfonyl chloride dissolved in 10 mL of dichloromethane to the reaction solution. Stir the reaction solution at room temperature for 30 min. After the reaction is complete, dilute the reaction solution with 30 mL of dichloromethane, then wash with 1N sodium hydroxide solution and saturated sodium chloride solution successively, dry with sodium sulfate, and concentrate. Add 50 mL of petroleum ether to the concentrated solution, stir at room temperature for 10 min, then let it stand at -30℃ for 10 min, then pour off the supernatant, and repeat this operation once more. Remove the solvent from the residue in the flask and let it stand to solidify. 3.05 g of a deep purple solid R-5-(2-(p-nitrobenzenesulfonyl)amino)propyl-1-(3-(benzyloxy)propyl)indoline is obtained, with a yield of 60%.

[0094] Compound spectral data: 1 H NMR(400MHz,Chloroform-d)δ8.14(d,J=8.4Hz,2H),7.70(d,J=8.4Hz,2H),7.44-7.28(m,5H),6.67-6.51(m,2H),6.22(d,J=7.8Hz,1H),4.62(d,J=7.3Hz ,1H),4.54(s,2H),3.60(t,J=6.1Hz,2H),3.42(m,1H),3.29(t,J=9.1Hz,2H) ,3.12(m,2H),2.73(m,3H),2.37(m,1H),1.90(m,2H),1.28(d,J=6.5Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ151.77,149.48,146.25,138.54,130.49,128.47,128.05,127.75,127.67, 125.50,125.11,123.93,123.39,106.59,73.10,68.04,53.04,52.70,46.17,42.79,28.39,27.69,22.87.

[0095] Example 8: Preparation of Compound IV: R-7-formyl-5-(2-(p-nitrobenzenesulfonyl)amino)propyl-1-(3-(benzyloxy)propyl)indoline

[0096] Under argon protection and in an ice-water bath, 2.3 g of phosphorus oxychloride was slowly added dropwise to 10 mL of N,N-dimethylformamide. After the addition was complete, the reaction mixture was moved to room temperature and stirred for 10 min. 2.55 g of R-5-(2-(p-nitrobenzenesulfonyl)5amino)propyl-1-(3-(benzyloxy)propyl)indoline was dissolved in 15 mL of N,N-dimethylformamide and slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was heated to 65 °C and stirred for 45 min. After the reaction was complete, the reaction mixture was poured into 100 mL of ice water, and the pH was adjusted to ≥8 with 1 N sodium hydroxide solution. The mixture was then extracted twice with 50 mL of ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate, and concentrated. The concentrate was added to 50 mL of petroleum ether, cooled and solidified, and filtered to obtain 2.47 g of red solid R-7-formyl-5-(2-(p-nitrobenzenesulfonyl)amino)propyl-1-(3-(benzyloxy)propyl)indoline, with a yield of 92%.

[0097] Compound spectral data: 1 H NMR(400MHz,Chloroform-d)δ9.94(s,1H),8.16(d,J=8.8Hz,2H),7.77(d,J=8.8Hz,2H),7.36-7.26(m,5H),7.08(s,1H),6.69(s,1H),4.64(d,J= 7.9Hz,1H),4.52(s,2H),3.58-3.49(m,7H),2.84(m,2H),2.62(m,1H),2.42(m,1H),1.92(t,J=7.2Hz,2H),1.26(d,J=6.4Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ188.92,152.34,149.49,146.60,138.28,134.08,129.93,129.29,128.48,128. 03,127.78,127.72,125.13,123.90,117.42,73.16,67.57,54.47,52.31,50.14,42.35,27.61,27.50,22.91.

[0098] Example 9: Preparation of compound V: R-7-cyano-5-(2-(p-nitrobenzenesulfonyl)amino)propyl-1-(3-(benzyloxy)propyl)indoline

[0099] Under argon protection, 2.69 g of R-7-formyl-5-(2-(p-nitrobenzenesulfonyl)amino)propyl-1-(3-(benzyloxy)propyl)indoline was dissolved in 30 mL of methanol, and 2 mL of 50% hydroxylamine aqueous solution was added. The reaction mixture was sealed in a tube at 50 °C for 3 h. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure, 50 mL of ethyl acetate was added, and the mixture was washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated for later use. The concentrated solution was diluted with 20 mL of dimethyl sulfoxide, and 2.1 g of anhydrous potassium carbonate was added, followed by the slow addition of 1 mL of acetic anhydride. After the addition was complete, the reaction mixture was heated to 100 °C and stirred for 1 h. After the reaction was complete, 100 mL of water was added to the reaction solution, and the mixture was extracted twice with 50 mL of ethyl acetate. The organic phases were combined. The organic phase was washed successively with water and saturated sodium chloride solution, dried over sodium sulfate, and concentrated. The residue was added to 50 mL of petroleum ether, cooled and solidified, and filtered to obtain 2.5 g of red solid R-7-cyano-5-(2-(p-nitrobenzenesulfonyl)amino)propyl-1-(3-(benzyloxy)propyl)indoline, with a yield of 93.6%.

[0100] Compound spectral data: 1 H NMR(400MHz,Chloroform-d)δ8.23(d,J=7.4Hz,2H),7.83(d,J=7.4Hz,2H),7.40-7.28(m,5H),6.69(d,J=12.2Hz,2H),4.69(d,J=8.6Hz,1H), 4.52(d,J=1.7Hz,2H),3.70-3.56(m,4H),3.51-3.46(m,3H),2.82-2.7 4(m,2H),2.56(m,1H),2.39(m,1H),1.94(m,2H),1.23(d,J=6.3Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ151.82,149.63,146.59,138.39,132.99,131.67,129.07,128.44,128.03,127 .78,127.66,125.18,124.01,119.15,87.17,73.16,67.69,52.98,52.27,44.99,42.23,27.80,27.17,22.68.

[0101] Example 10: Preparation of compound VI: (R)-N-(1-(1-(3-(benzyloxy)propyl)-7-cyanoindoline-5-yl)propyl-2-yl)-4-nitro-N-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)benzenesulfonamide

[0102] Under argon protection, 2.4 g of R-7-cyano-5-(2-(p-nitrobenzenesulfonyl)amino)propyl-1-(3-(benzyloxy)propyl)indoline was dissolved in 30 mL of acetonitrile, and 1.2 g of anhydrous potassium carbonate was added. The reaction mixture was heated to 85 °C with stirring. 2.0 g of 2-(2-trifluoroethoxyphenoxy)ethyl bromide was dissolved in 5 mL of acetonitrile and added to the reaction mixture at 85 °C. The reaction mixture was kept at this temperature and stirred for 12 h. After the reaction was complete, the mixture was cooled to room temperature, and 50 mL of water was added. The mixture was extracted twice with 50 mL of ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated. Petroleum ether was added to the residue, and the mixture was cooled to solidify. Filtration yielded 2.82 g of red solid, which was (R)-N-(1-(1-(3-(benzyloxy)propyl)-7-cyanoindoline-5-yl)propyl-2-yl)-4-nitro-N-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)benzenesulfonamide, with a yield of 85%.

[0103] Compound spectral data: 1 H NMR(400MHz,Chloroform-d)δ8.18(d,J=7.3Hz,2H),7.89(d,J=7.3Hz,2H),7.39-7.27(m, 5H),7.02(t,J=7.5Hz,1H),6.96-6.91(m,3H),6.82(d,J=7.5Hz,2H),4.51(s,2H),4.34(q ,J=7.8Hz,2H),4.22(t,J=5.2Hz,2H),4.09-4.04(m,1H),3.67-3.62(m,6H),3.53(t,J=8. 4Hz,2H),2.88-2.78(m,3H),2.56-2.51(m,1H),1.99-1.92(m,2H),1.16(d,J=6.4Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ151.88,149.62,148.38,147.01,146.58,143.51 ,138.40,133.02,131.52,129.14,128.43,128.03,127.78,127.65,126.01,12 4.12,123.70,121.84,120.88,119.30,115.49,113.84,102.72,100.47,87.32,73.17,68.00,67.73,56.74,53.14,45.10,42.85,40.80,27.89,27.26,18.53.

[0104] Example 11: Compound of Formula VII: (R)-N-(1-(1-(3-(hydroxy)propyl)-7-cyanoindoline-5-yl)propyl-2-yl)-4-nitro-N-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)benzenesulfonamide

[0105] 2.82 g of (R)-N-(1-(1-(3-(benzyloxy)propyl)-7-cyanoindoline-5-yl)propyl-2-yl)-4-nitro-N-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)benzenesulfonamide was dissolved in 15 mL of 1,4-dioxane, and 15 mL of 25% hydrochloric acid aqueous solution was added. The reaction was refluxed at 100 °C for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, and the pH was adjusted to ≥8 by adding saturated sodium bicarbonate solution. The mixture was extracted twice with 50 mL of ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated. Petroleum ether was added to the residue, and the mixture was cooled to solidify. Filtration yielded 2.2 g of red solid, which was (R)-N-(1-(1-(3-(hydroxypropyl)-7-cyanoindoline-5-yl)propyl-2-yl)-4-nitro-N-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)benzenesulfonamide, with a yield of 86%.

[0106] Compound spectral data: 1 H NMR(400MHz,Chloroform-d)δ8.18(d,J=8.2Hz,2H),7.89(d,J=8.2Hz,2H),7.02(t,J=7 .5Hz,1H),6.96-6.82(m,5H),4.35(q,J=8.1Hz,2H),4.21(t,J=5.4Hz,2H),4.07(q,J=6. 7Hz,1H),3.80(t,J=5.8Hz,2H),3.70–3.61(m,4H),3.57(t,J=8.6Hz,2H),2.89(t,J=8.6 Hz,2H),2.84-2.79(m,1H),2.57-2.52(m,1H),1.94-1.88(m,2H),1.17(d,J=6.6Hz,3H). 13C NMR(101MHz,Chloroform-d)δ149.62,148.35,146.99,132.96,129.31,128.03,126.32,124.12,121.84,119.65,1 15.45,113.82,87.41,67.99,67.10(q,J=35.0Hz),60.44,56.74,53.23,45.29,42.86,40.78,30.51,27.26,18.55.

[0107] Example 12: Preparation of compound VIII: (R)-1-(3-hydroxypropyl)-5-(2-((2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)amino)propyl)indoline-7-carboxynitrile

[0108] 2.2 g of (R)-N-(1-(1-(3-(hydroxypropyl)-7-cyanoindoline-5-yl)propyl-2-yl)-4-nitro-N-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)benzenesulfonamide was dissolved in 20 mL of methanol, and 0.9 g of anhydrous potassium carbonate was added. Then, 0.5 mL of mercaptoacetic acid was added with stirring. The reaction was carried out at room temperature for 12 h. After the reaction was complete, methanol was removed under reduced pressure, the residue was diluted with ethyl acetate, washed successively with 1 N sodium hydroxide aqueous solution and saturated sodium chloride solution, dried over sodium sulfate, and concentrated to give 1.42 g of (R)-1-(3-hydroxypropyl)-5-(2-((2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)amino)propyl)indoline-7-carboxynitrile, yield 91%.

[0109] Compound spectral data: 1 H NMR(400MHz,Chloroform-d)δ7.03(t,J=7.6Hz,1H),6.95-6.89(m,5H),4.31(q,J=8.1Hz,2H),4.09(q,J=4.8Hz,2H),3.79(t,J=5.6Hz,2H) ,3.65(t,J=7.0Hz,2H),3.56(t,J=8.5Hz,2H),3.14-2.77(m,5H),2.63-2.58(m,1H),2.45-2.40(m,1H),1.91(m,3H),1.05(d,J=5.8Hz,3H). 13C NMR(101MHz,Chloroform-d)δ151.98,149.73,147.46,132.78,131.42,129.73,127.83,124.30,121.57, 119.99,118.05,114.68,87.60,68.85,68.09(q,J=35.0Hz),60.36,54.31,53.40,46.30,45.57,42.34,30.59,27.36,19.97.

[0110] Example 13: Preparation of serodoxine

[0111] 1.42 g of (R)-1-(3-hydroxypropyl)-5-(2-((2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)amino)propyl)indoline-7-carboxynitrile was dissolved in 10 mL of dimethyl sulfoxide, and 1.5 mL of 20% sodium hydroxide aqueous solution was added. The reaction was stirred at room temperature. 0.75 mL of 30% hydrogen peroxide aqueous solution was slowly added dropwise to the reaction solution. After the addition was complete, the reaction was stirred overnight. After the reaction was completed, saturated sodium bisulfite solution was added to quench the reaction, followed by extraction twice with 30 mL of ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution, dried over sodium sulfate, and concentrated to give 1.39 g of celodorin, with a yield of 95% and an ee value of 99.5%.

[0112] Compound spectral data: 1 H NMR (500MHz, DMSO-d6) δ7.66 (s, 1H), 7.30 (s, 1H), 7.08 (d, J = 8.1Hz, 1H), 7.04-7.00 (m, 2H), 6.95-6.88 (m,2H),6.86(s,1H),4.68(q,J=9.0Hz,2H),4.38(t,J=4.9Hz,1H),4.03(t,J=5.5Hz,2H),3.43(q,J=5. 6Hz,2H),3.33(t,J=8.6Hz,2H),3.13(t,J=7.2Hz,2H),2.97-2.90(m,2H),2.87-2.79(dt,J=23.1,7.3H z,3H),2.64(dd,J=13.2,5.1Hz,1H),2.28(dd,J=13.2,7.8Hz,1H),1.63(m,2H),0.92(d,J=6.1Hz,3H). 13C NMR(101MHz,DMSO-d6)δ171.31,149.36,148.07,147.33,132.62,128.68,128.09,126.92,124.62(q,J=278.4Hz),123.96,121.54,119.29,117.10,115.14,69.26,66.74(q,J=33.7Hz),59.18,54.76,53.83,48.49,46.06,42.63,30.60,28.26,20.2

Claims

1. A method for preparing a 5-substituted indoline chiral amine of Formula I, characterized in that, Includes the following steps: (1) 2,3-Dihydro-1H-indole is reacted in one or more steps to give compound II. (2) The compound of formula II reacts with a halogenated reagent to give the compound of formula III. (3) Compound III first forms a Grignard reagent, and then reacts with an (R)-2-aminopropanol-derived aziridine derivative in the presence of a Cu(I) catalyst to give 5-substituted indoline chiral amine I. In equations (Ⅰ) to (Ⅲ), R 1 It is a hydroxyl protecting group; R 2 is an amino protecting group; X is a halogen.

2. The preparation method according to claim 1, characterized in that, The R 1 The group is ester, silyl, tetrahydropyranyl, methoxymethylene, benzyl, or benzyl, methyl, diphenylmethyl, triphenylmethyl, or allyl with substituents on the benzyl ring; wherein the substituent on the benzyl ring is a C1-C4 alkyl or C1-C4 alkoxy, halogen, nitro, amino, aminoacyl, cyano, C1-C4 alkamido, or hydroxyl group; the ester group is R. 3 CO-, where R 3 It is an alkyl group, preferably C1 to C2. 10 Alkyl; the silicon group is trialkyl. Silicon-based R 4 R 5 R 6 Si-, R 4 R 5 and R 6 It is an alkyl group, preferably C1 to C2. 10 Alkyl, more preferably C1-C6 alkyl, even more preferably C1-C4 alkyl, wherein R 4 R 5 and R 6 They can be the same or different; R 2 The group can be methanesulfonyl, substituted or unsubstituted benzylsulfonyl, tert-butoxycarbonyl, allyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, triphenylmethyl, trifluoroacetyl, acetyl, substituted or unsubstituted benzyl, wherein benzylsulfonyl and benzyloxycarbonyl can be unsubstituted, single-substituted or multi-substituted, and the substituent can be C1-C4 alkyl or C1-C4 alkoxy, halogen, nitro, amino, aminoacyl, cyano, C1-C4 alkamido, hydroxyl; X represents chlorine, bromine, or iodine.

3. The preparation method according to claim 1, characterized in that, The R mentioned 1 It is a benzyl group or a benzyl group with a substituent on the benzene ring, or a benzoyl group or a benzoyl group with a substituent on the benzene ring, wherein the substituent on the benzene ring is one or more of a C1-C4 alkyl or C1-C4 alkoxy group, F, Cl or Br; The R mentioned 2 It is a tert-butoxycarbonyl, substituted or unsubstituted benzenesulfonyl group, wherein the substituent is one or more of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br or nitro.

4. The preparation method according to claim 1, characterized in that, Step 1) involves the reaction of 2,3-dihydro-1H-indole with 1-benzyloxy-3-halopropane in the presence of an organic base, wherein the organic base is an organic amine, preferably triethylamine or N,N-diisopropylethylamine; and the reaction solvent is a polar solvent, preferably DMF or DMSO. The halogenating agent in step 2) is a halogen or NBS; The (R)-2-aminopropanol-derived aziridine derivatives in step 3) are (R)-2-methyl-1-tert-butoxycarbonylaziridine, (R)-2-methyl-1-benzenesulfonylaziridine, (R)-2-methyl-1-p-nitrobenzenesulfonylaziridine, or (R)-2-methyl-1-p-toluenesulfonylaziridine; The Cu(I) catalyst in step 3) includes cuprous iodide, cuprous bromide, cuprous chloride, cuprous bromide dimethyl sulfide, and tris(triphenylphosphine)cuprous bromide.

5. The preparation method according to claim 4, characterized in that, The 1-benzyloxy-3-halopropane in step 1) is 1-benzyloxy-3-chloropropane, 1-benzyloxy-3-bromopropane or 1-benzyloxy-3-iodopropane; Step 1) A bromide or iodide can be added as a catalyst, preferably sodium iodide or sodium bromide.

6. The preparation method according to claim 1, characterized in that, Includes the following steps: (1) 2,3-Dihydro-1H-indole reacts with 1-benzyloxy-3-halopropane to give compound II-1. (2) The reaction of compound II-1 with a halogenated reagent yields compound III-1. (3) Compound III-1 first forms a Grignard reagent, and then reacts with the (R)-2-aminopropanol-derived aziridine derivative in the presence of a Cu(I) catalyst to give 5-substituted indoline chiral amine I-1.

7. A 5-substituted indoline chiral amine compound, characterized in that, The structure is shown in Equation I: Among them, R 1 R is a hydroxyl protecting group. 2 It is an amino protecting group.

8. The compound according to claim 7, characterized in that, R 1 The group can be ester, silyl, tetrahydropyranyl, methoxymethylene, substituted or unsubstituted benzyl, methyl, diphenylmethyl, triphenylmethyl, or allyl, wherein the substituent on the benzyl ring is a C1-C4 alkyl or C1-C4 alkoxy, halogen, nitro, amino, aminoacyl, cyano, C1-C4 alkamido, or hydroxyl group; the ester group is R. 3 CO-, where R 3 It is an alkyl group, preferably C1 to C2. 10 Alkyl; the silicon group is a trialkylsilyl group R 4 R 5 R 6 Si-, R 4 R 5 and R 6 It is an alkyl group, preferably C1 to C2. 10 Alkyl, wherein R 4 R 5 and R 6 Can be the same They can also be different; R 2 The group can be methanesulfonyl, substituted or unsubstituted benzyl, tert-butoxycarbonyl, allyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl, triphenylmethyl, trifluoroacetyl, acetyl, substituted or unsubstituted benzyl, wherein benzyl and benzyloxycarbonyl can be unsubstituted, single-substituted or multi-substituted, and the substituent can be C1-C4 alkyl or C1-C4 alkoxy, halogen, nitro, amino, aminoacyl, cyano, C1-C4 alkamide, or hydroxyl.

9. The 5-substituted indoline chiral amine according to claim 8, characterized in that, The benzyl group or the benzyl group on the benzene ring has a substituent, and the benzyl group or the benzyl group on the benzene ring has a substituent that is one or more of C1-C4 alkyl or C1-C4 alkoxy, F, Cl or Br; R 2 It is a tert-butoxycarbonyl, substituted or unsubstituted benzenesulfonyl group; the substituent on the benzenesulfonyl group is one or more of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br or nitro.

10. The compound according to claim 7, characterized in that, The compound is shown in any of the following structural formulas:

11. A method for preparing celodoxine, characterized in that, Includes the following steps: (B) The 5-substituted indoline chiral amine I reacts in the presence of DMF / POCl3 to give compound IV. (C) Compound IV reacts first with hydroxylamine, and then reacts again with a dehydrating agent to obtain compound V. (D) The reaction of compound V with 2-(2-trifluoroethoxyphenoxy)ethyl bromide yields compound VI. (E) Compound VI is dehydroxylated to prepare compound VII. (F) The compound of formula VII is deamino protecting to obtain the compound of formula VIII. The hydrolysis of compound (G)VIII yields serodoxin; Among them, R 1 and R 2 The definition is as described in any one of claims 1 to 10.

12. The preparation method according to claim 11, characterized in that, In step C), the reaction of compound IV with hydroxylamine is carried out in an alcohol solvent, and the dehydration reaction is carried out in the presence of acetic anhydride and a base. The solvent for the dehydration reaction is DMSO or DMF. Step D) involves a reaction in a base and an organic solvent; The dehydroxylation protection reaction described in step E) is carried out in an acid and an organic solvent; The deamination protection reaction described in step F) is carried out in thioglycolic acid, a base, and an organic solvent; The hydrolysis reaction described in step G) is carried out in an alkali, hydrogen peroxide, and an organic solvent.

13. The preparation method according to claim 12, characterized in that, In step C), the alcohol solvent is methanol or ethanol; the base is an inorganic base, selected from one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate, preferably potassium carbonate; In step D), the alkali is selected from potassium carbonate, sodium carbonate, or lithium carbonate, and the organic solvent is acetonitrile. In step E), the acid is hydrochloric acid or sulfuric acid; the organic solvent is an ether solvent, preferably tetrahydrofuran or dioxane. In step F), the alkali is potassium carbonate, sodium carbonate, or lithium carbonate; the organic solvent is an alcohol solvent, preferably methanol or ethanol. In step G), the alkali is potassium hydroxide, sodium hydroxide, or lithium hydroxide; the organic solvent is DMSO or DMF.

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