A process for the preparation of 2,5-disubstituted amino caproic acid esters and a process for the preparation of litaciclib using the same

Abstract

The present application relates to a preparation method of 2,5-disubstituted amino hexanoate and a method for preparing letaxibatin using the same. The method comprises the following steps: reacting compound I with a methyl metal reagent to obtain compound II, and subjecting compound II to reductive amination with compound III to obtain 2,5-disubstituted amino hexanoate of formula V. The 2,5-disubstituted amino hexanoate of formula V can be used to synthesize letaxibatin through the following two synthetic routes, route 1: the compound of formula V is subjected to cyclization, reduction, deprotection, substitution, removal of the substituent and reaction with acryloyl chloride; route 2: the compound of formula V is subjected to hydrogenation to remove the substituent and simultaneously cyclize, deprotection, substitution, reduction and reaction with acryloyl chloride. The method of the present application uses an asymmetric synthesis method to construct a chiral center, and does not need to perform salt formation resolution to obtain a single configuration, and the reaction steps are simple and the conditions are mild.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for preparing and using 2,5-disubstituted aminohexanoate. Background Technology

[0002] Litexitinib is a kinase inhibitor that irreversibly inhibits Janus kinase 3 (JAK3) and the tyrosine kinase (TEC) family expressed in hepatocellular carcinoma by blocking the adenosine triphosphate (ATP) binding site. It received marketing approval from the U.S. Food and Drug Administration (FDA) on June 23, 2023, and from the China National Medical Products Administration (NMPA) on October 18, 2023, for the treatment of severe alopecia areata in adolescents aged 12 years and older and adults.

[0003] Existing patents report methods for preparing litexitinib:

[0004] Method 1 of CN106061973B uses chiral column chromatography for separation, which is costly.

[0005] Method 1:

[0006]

[0007] Method 2 of CN112888691B requires the separation of the reduced intermediate, followed by chiral column chromatography, which is costly.

[0008] Method 2:

[0009]

[0010] Pfizer reported that using (R)-(-)-N-(3,5-dinitrobenzoyl)-α-phenylglycine or N-acetyl-L-leucine to separate the hydrogenated intermediate resulted in significant losses; see Method 3 of CN112888691B.

[0011] Method 3:

[0012]

[0013] Method 4 in CN112430208A and CN112430235A uses Boc-D-pyroglutamic acid ethyl ester as a raw material to prepare litexitinib, and the reaction involves the separation of intermediates.

[0014] Method 4:

[0015]

[0016] Therefore, there is a need to develop a new method for the preparation of litexitinib and its intermediates, which involves simple reaction steps, mild conditions, is suitable for industrial production, and does not involve the resolution of intermediates or require chiral column chromatography separation. Summary of the Invention

[0017] In order to overcome the shortcomings of existing production methods and processes, one of the technical objectives of this invention is to provide a method for preparing 2,5-disubstituted aminohexanoate, a litecxitinib intermediate represented by Formula V.

[0018] Another technical object of the present invention is to provide a method for preparing litexitinib using compounds of the above formula V.

[0019] Another technical objective of this invention is to provide the various intermediates used in the above-described methods.

[0020] To achieve the above objectives, the present invention adopts the following technical solution:

[0021] In a first aspect, the present invention provides a method for preparing the 2,5-disubstituted aminohexanoate of Formula V.

[0022]

[0023] The method includes the following steps:

[0024] (1) Compound I reacts with a methyl metal reagent in solvent 1 to give compound II;

[0025] (2) With or without a catalyst, compound II and compound III undergo a reductive amination reaction in solvent 2 to give compound V;

[0026] Wherein, R is selected from C1-C6 alkyl or benzyl groups;

[0027] It can be (R) configuration, (S) configuration, or racemic;

[0028] R1 is selected from substituted or unsubstituted phenyl groups, wherein “substituted” means that the phenyl group may have 1 to 5 substituents selected from C1-C6 alkoxy, halogen, cyano or C1-C6 alkyl groups;

[0029] R2 is selected from H or C1-C6 alkyl groups.

[0030] In a specific embodiment, R is a C1-C4 alkyl group; R1 is a phenyl group selected from substituted or unsubstituted phenyl groups, wherein "substituted" means that the phenyl group may have 1-4 substituents selected from C1-C6 alkoxy, halogen, cyano or C1-C6 alkyl groups; and R2 is H, methyl or ethyl.

[0031] In a specific embodiment, R is selected from methyl, ethyl, isopropyl, propyl; R1 is selected from p-methoxyphenyl, phenyl, p-methylphenyl; and R2 is H or methyl.

[0032] In a specific embodiment, in step (1), the methyl metal reagent is selected from one or more of methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, lithium dimethyl copper, methyl lithium, and lithium methyl bromide complex; the solvent 1 is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane; the molar ratio of compound I to the methyl metal reagent is 1:1.1 to 1.5; the reaction temperature is -30 to 10°C; and the reaction time is 1 to 5 hours.

[0033] In step (2), when compounds II and III react, the mixture is stirred for a period of time, with or without catalyst 1, to form an imine intermediate. Then, a reducing agent is added to carry out a reduction reaction to obtain compound V.

[0034] Wherein, catalyst 1 is selected from one or more of tetraisopropyl titanate, tetraethyl titanate, p-toluenesulfonic acid, and titanium tetrachloride; the reducing agent is selected from one or more of sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride, hydrogen, Raney nickel, palladium on carbon, rhodium on carbon, RuCl2[(R)-(DM-BINAP)][(R)-DAIPEN], and RuCl2[(S)-(DM-BINAP)][(S)-DAIPEN].

[0035] Solvent 2 is selected from one or more of ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl acetate, dioxane, methanol, ethanol, and isopropanol; the molar ratio of compound II, compound III, and catalyst 1 is 1:1.0-1.3:1.0-1.5.

[0036] The weight ratio of the reducing agent to compound II is 1:1 to 50; the reaction temperature is 10 to 70°C; and the reaction time is 6 to 40 hours.

[0037] In a specific embodiment, in step (1), the methyl metal reagent is selected from one or two of methyl magnesium bromide and methyl magnesium chloride; the solvent 1 is tetrahydrofuran or 2-methyltetrahydrofuran; the molar ratio of compound I to the methyl metal reagent is 1:1.1; the reaction temperature is -20 to 0°C; and the reaction time is 2 to 3 hours.

[0038] In step (2), catalyst 1 is selected from one or two of tetraisopropyl titanate and tetraethyl titanate; reducing agent is selected from one or more of sodium borohydride, sodium triacetoxyborohydride, Raney nickel, and RuCl2[(S)-(DM-BINAP)][(S)-DAIPEN]; the molar ratio of compound II, compound III, and catalyst 1 is 1:1.0-1.2:1.0-1.3; the weight ratio of reducing agent to compound II is 1:3-46; the reaction temperature is 15-70℃; and the reaction time is 6-16h.

[0039] In a specific embodiment, the preparation method employs the following specific steps:

[0040] (1) Mix compound I with solvent 1, add methyl metal reagent dropwise, react under controlled temperature, quench after reaction, separate, extract, concentrate, and purify by column chromatography to obtain compound II;

[0041] (2) Mix compound II, compound III and solvent 2, react under controlled temperature, react with or without catalyst 1 for 4-8 hours, react with reducing agent, quench after reaction, separate, extract, concentrate, and column chromatography to obtain compound V.

[0042] Secondly, the present invention provides a method for preparing litexitinib using a compound of formula V:

[0043]

[0044] As shown in the reaction formula above, the method includes the following steps:

[0045] (1) Compound V undergoes a cyclization reaction to give compound VI, with or without solvent 1'.

[0046] (2) In the presence of solvent 2', compound VI undergoes a reduction reaction under the action of a reducing agent to give compound VII;

[0047] (3) Compound VII was deprotected from the Boc protecting group in the presence of solvent 3' to give compound VIII;

[0048] (4) In the presence of solvent 4' and base, compound VIII and compound IX undergo a substitution reaction to give compound X;

[0049] (5) In the presence of solvent 5', with or without additives, compound X is desubstituented to obtain compound XI;

[0050] (6) In the presence of solvent 6' and base, compound XI reacts with acryloyl chloride to give compound rituximab;

[0051] The definitions of R, R1, and R2 are the same as those defined in the first aspect above.

[0052] In a specific embodiment, in step (1), the catalyst 2 for the cyclization reaction is a base or an acid. The base is one or more of potassium carbonate, sodium carbonate, potassium tert-butoxide, potassium acetate, sodium ethoxide, triethylamine, and N,N-diisopropylethylamine. The acid is one or more of acetic acid, formic acid, and propionic acid. The solvent 1' is selected from one or more of methanol, ethanol, toluene, tetrahydrofuran, acetonitrile, N-methylpyrrolidone (NMP), and N,N-dimethylacetamide (DMAc). The molar ratio of compound V to catalyst 2 is 1:0.1 to 6.0, the reaction temperature is 50 to 150°C, and the reaction time is 6 to 40 hours.

[0053] In step (2), the reducing agent is selected from one or more of borane dimethyl sulfide, borane tetrahydrofuran, sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium dihydrobis(2-methoxyethoxy)aluminate (red aluminum), and diisobutylaluminum hydride; the solvent 2' is selected from one or more of ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl acetate, dioxane, and toluene; the molar ratio of compound VI to the reducing agent is 1:1.0 to 4.0; the reaction temperature is -20 to 50°C; and the reaction time is 2 to 20 h.

[0054] In step (3), an acid is used to remove the Boc protecting group. The acid is selected from one or more of trifluoroacetic acid, ethyl acetate hydrochloride, dioxane hydrochloride, methanol hydrochloride, concentrated hydrochloric acid, and dilute hydrochloric acid. The solvent 3' is selected from one or more of dichloromethane, tetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, and dioxane. The molar ratio of compound VII to acid is 1:4 to 30. The reaction temperature is 10 to 50°C, and the reaction time is 1 to 12 hours.

[0055] In step (4), the substitution reaction is carried out in a base and solvent 4', wherein the base is one or more of potassium carbonate, sodium carbonate, sodium ethoxide, triethylamine, and N,N-diisopropylethylamine; the solvent 4' is selected from one or more of water, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, toluene, and methyl isobutyl ketone; the molar ratio of compound IX, compound VIII, and base is 1:1.0-1.3:1.5-3; the reaction temperature is 80-120℃, and the reaction time is 10-24h.

[0056] In step (5), the removal of substituents is carried out in a metal catalyst and solvent 5', wherein the metal catalyst is one or more of palladium on carbon, palladium hydroxide on carbon, rhodium on carbon, and Raney nickel; the solvent 5' is selected from one or more of water, methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, and 2-methyltetrahydrofuran; the additive is one or more of acetic acid, formic acid, and dilute hydrochloric acid; the mass ratio of compound X to metal catalyst is 1:0.02-0.2; the molar ratio of compound X to acid is 1:1.0-2.0; the reaction temperature is 40-100℃, and the reaction time is 4-24h; and

[0057] In step (6), the reaction with acryloyl chloride is carried out in an alkali and a solvent 6', wherein the alkali is one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, and N,N-diisopropylethylamine; the solvent 6' is selected from one or more of water, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, toluene, dioxane, and ethyl acetate; the molar ratio of compound XI, acryloyl chloride, and alkali is 1:1.0 to 1.4:1.2 to 2; the reaction temperature is -10 to 40°C, and the reaction time is 1 to 10 h.

[0058] In a specific embodiment, in step (1), the alkali is selected from one or two of potassium carbonate and sodium carbonate; the acid is acetic acid; the solvent 1' is one or two of methanol and toluene; the molar ratio of compound V to catalyst 2 is 1:0.1 to 6.0; the reaction temperature is 50 to 120°C; and the reaction time is 6 to 10 hours.

[0059] In step (2), the reducing agent is selected from one or two of boranetetrahydrofuran and sodium dihydrobis(2-methoxyethoxy)aluminate; solvent 2' is tetrahydrofuran; the molar ratio of compound VI to the reducing agent is 1:1.0 to 4.0; the reaction temperature is 0 to 50°C; and the reaction time is 2 to 10 h.

[0060] In step (3), the acid is ethyl hydrochloride; solvent 3' is one or both of dioxane and ethyl acetate; the molar ratio of compound VII to acid is 1:4 to 10; the reaction temperature is 20 to 30°C; and the reaction time is 2 to 6 hours.

[0061] In step (4), the base is selected from one or two of potassium carbonate and triethylamine; solvent 4' is methyl isobutyl ketone; the molar ratio of compound IX, compound VIII and base is 1:1.0 to 1.1:2 to 3; the reaction temperature is 80 to 100°C; and the reaction time is 16 to 23 h.

[0062] In step (5), the metal catalyst is palladium on carbon; the additive is acetic acid; the solvent 5' is ethanol; the mass ratio of compound X to the metal catalyst is 1:0.05–0.1; the molar ratio of compound X to the acid is 1:1.0–1.5; the reaction temperature is 50–70℃; the reaction time is 6–16 h; and

[0063] In step (6), the alkali is selected from one or two of sodium bicarbonate, sodium carbonate, and triethylamine; solvent 6' is tetrahydrofuran; the molar ratio of compound XI, acryloyl chloride, and alkali is 1:1.1-1.3:1.2-1.5; the reaction temperature is 0-30℃; and the reaction time is 1-5h.

[0064] In a specific implementation, the method includes the following steps:

[0065] (1) Mix compound V with or without solvent 1' and catalyst 2, react under controlled temperature, filter after reaction, concentrate, and purify by column chromatography to obtain compound VI;

[0066] (2) Compound VI and solvent 2' were mixed, a reducing agent was added to react, the reaction was quenched after the reaction was completed, extracted, separated, concentrated and purified by column chromatography to obtain compound VII;

[0067] (3) Mix compound VII and solvent 3', add acid to react, concentrate after the reaction is complete to obtain compound VIII;

[0068] (4) Mix compound VIII, compound IX, solvent 4' and base, heat and react, cool after the reaction is complete, extract, combine organic phases, wash, dry, filter, concentrate, and purify by pulping to obtain compound X.

[0069] (5) Mix compound X, with or without additives, with solvent 5', add a metal catalyst to carry out hydrogenation reaction, filter after the reaction is completed, concentrate to obtain compound XI;

[0070] (6) Compound XI, solvent 6', acryloyl chloride and base were mixed and reacted. After the reaction was completed, the mixture was extracted, the organic phases were combined, washed, dried, filtered, concentrated and purified by column chromatography to obtain rituximab.

[0071] Thirdly, the present invention provides another method for preparing litexitinib using compounds of formula V:

[0072]

[0073] As shown in the reaction formula above, the method includes the following steps:

[0074] (1) In the presence of solvent 1”, with or without additives, compound V was hydrogenated to remove substituents and simultaneously cyclized to obtain compound XII;

[0075] (2) In the presence of solvent 2”, compound XII was deprotected by the Boc protecting group to obtain compound XIII;

[0076] (3) In the presence of solvent 3” and base, compound XIII and compound IX undergo a substitution reaction to give compound XIV;

[0077] (4) In the presence of solvent 4”, compound XIV undergoes a reduction reaction under the action of a reducing agent to give compound XI;

[0078] (5) In the presence of solvent 5” and base, compound XI reacts with acryloyl chloride to give compound rituxitinib;

[0079] The definitions of R, R1, and R2 are the same as those defined in the first aspect above.

[0080] In a specific embodiment, in step (1), the removal of substituents is carried out in a metal catalyst and solvent 1”, wherein the metal catalyst is one or more of palladium on carbon, palladium hydroxide on carbon, rhodium on carbon, and Raney nickel; the additive is one or more of acetic acid, formic acid, and dilute hydrochloric acid; the mass ratio of compound V to metal catalyst is 1:0.02-0.2; the molar ratio of compound V to acid is 1:1.0-2.0; the reaction temperature is 40-100℃; and the reaction time is 4-24h.

[0081] In step (2), an acid is used to remove the Boc protecting group. The acid is selected from one or more of trifluoroacetic acid, ethyl acetate hydrochloride, dioxane hydrochloride, methanol hydrochloride, and hydrochloric acid. The molar ratio of compound XII to acid is 1:4 to 30. The reaction temperature is 10 to 50°C. The reaction time is 1 to 12 hours.

[0082] In step (3), the substitution reaction is carried out in a base and solvent 3”, wherein the base is an organic base or an inorganic base, the organic base is selected from one or more of sodium ethoxide, triethylamine, and N,N-diisopropylethylamine; the inorganic base is selected from one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, and sodium hydroxide; the molar ratio of compound IX, compound XIII, and base is 1:1.0-1.3:1.5-3; the reaction temperature is 80-120℃; and the reaction time is 10-24h.

[0083] In step (4), the reducing agent is selected from one or more of borane dimethyl sulfide, borane tetrahydrofuran, sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium dihydrobis(2-methoxyethoxy)aluminate, and diisobutylaluminum hydride; the molar ratio of compound XIV to the reducing agent is 1:1.0 to 4.0; the reaction temperature is -20 to 70°C; the reaction time is 2 to 20 h; and

[0084] In step (5), the reaction with acryloyl chloride is carried out in an alkali and solvent 5”, wherein the alkali is one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, and N,N-diisopropylethylamine; the molar ratio of compound XI, acryloyl chloride, and alkali is 1:1.0~1.4:1.2~2; the reaction temperature is -10~40℃; and the reaction time is 1~10h.

[0085] In a specific embodiment, in step (1), the metal catalyst is palladium on carbon or palladium hydroxide on carbon; the additive is acetic acid; the solvent 1” is ethanol; the mass ratio of compound V to metal catalyst is 1:0.05~0.1; the molar ratio of compound V to acetic acid is 1:1.0~1.5; the reaction temperature is 50~70℃; and the reaction time is 6~16h.

[0086] In step (2), the acid is one or both of hydrochloric acid and ethyl acetate hydrochloride; solvent 2” is dioxane; the molar ratio of compound XII to acid is 1:4 to 10; the reaction temperature is 20 to 30°C; and the reaction time is 2 to 6 hours.

[0087] In step (3), the base is selected from one or two of potassium carbonate and triethylamine; solvent 3” is one or two of water and methyl isobutyl ketone; the molar ratio of compound IX, compound XIII and base is 1:1.0~1.1:2~3; the reaction temperature is 80~100℃; the reaction time is 16~23h;

[0088] In step (4), the reducing agent is selected from one or both of boranetetrahydrofuran and sodium dihydrobis(2-methoxyethoxy)aluminate; solvent 4” is tetrahydrofuran; the molar ratio of compound XIV to the reducing agent is 1:1.1–4.0; the reaction temperature is 0–70℃; the reaction time is 2–10 h; and

[0089] In step (5), the alkali is selected from one or two of sodium bicarbonate, sodium carbonate, and triethylamine; solvent 5” is tetrahydrofuran; the molar ratio of compound XI, acryloyl chloride, and alkali is 1:1.1~1.3:1.2~1.5; the reaction temperature is 0~30℃; and the reaction time is 1~5h.

[0090] In a specific implementation, the method includes the following steps:

[0091] (1) Mix compound V with or without additives with solvent 1”, add a metal catalyst to carry out hydrogenation reaction, filter after the reaction is completed, concentrate to obtain compound XII;

[0092] (2) Mix compound XII with solvent 2”, add acid to react, concentrate after the reaction is complete, and obtain compound XIII;

[0093] (3) Mix compound XIII, compound IX, solvent 3” and base, heat and react, cool after the reaction is complete, extract, combine organic phases, wash, dry, filter, concentrate, and purify by pulping to obtain compound XIV.

[0094] (4) Mix compound XIV with solvent 4”, add reducing agent to react, quench after reaction, extract, separate, concentrate, and purify by column chromatography to obtain compound XI;

[0095] (5) Compound XI, solvent 5”, acryloyl chloride and base were mixed and reacted. After the reaction was completed, the mixture was extracted, the organic phases were combined, washed, dried, filtered, concentrated and purified by column chromatography to obtain rituximab.

[0096] In a specific embodiment, solvent 1” is selected from one or more of methanol, ethanol, toluene, tetrahydrofuran, N-methylpyrrolidone (NMP), and N,N-dimethylacetamide (DMAc);

[0097] The solvent 2” is selected from one or more of dichloromethane, tetrahydrofuran, methanol, ethanol, ethyl acetate, and dioxane;

[0098] The solvent 3” is selected from one or more of water, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, toluene, and methyl isobutyl ketone;

[0099] The solvent 4” is selected from one or more of ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl acetate, dioxane, and toluene;

[0100] The solvent 5” is selected from one or more of water, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, toluene, dioxane, and ethyl acetate.

[0101] Fourthly, the present invention provides compounds represented by formulas V, VI, VII, VIII, and X, and their salts.

[0102]

[0103]

[0104] In the above equations, R, R1, and R2 are defined as in the first aspect.

[0105] Fifthly, the present invention provides compounds represented by formulas XII, XIII, and XIV, and their salts.

[0106]

[0107] Beneficial effects

[0108] This invention provides a novel method for synthesizing litexitinib and its intermediates. This method can construct chiral centers using asymmetric synthesis, without the need for salt-forming resolution to obtain a single configuration. The reaction steps are simple, the conditions are mild, and it is suitable for industrial production.

[0109] The present invention also provides a series of novel intermediates for the preparation of litexitinib. Detailed Implementation

[0110] The present invention will be further described below with reference to the embodiments. It should be noted that the following embodiments are provided for illustrative purposes only and do not constitute a limitation on the scope of protection of the present invention.

[0111] Unless otherwise specified, the raw materials, reagents, and methods used in the embodiments are all conventional raw materials, reagents, and methods in the art.

[0112] the term

[0113] The numbers or symbols used after certain features in this article, such as solvent 1, solvent 2, solvent 1', solvent 2', solvent 1”, solvent 2”, base 1, base 2, etc., are used only to distinguish one feature from another feature of the same class, and have no other additional meaning.

[0114] The following reaction formula illustrates the synthetic route of litexitinib intermediate and litexitinib in this application.

[0115]

[0116] In the following examples 1-8, each step in the above reaction formula will be described in detail.

[0117] Example 1

[0118] (1) Preparation of compound II

[0119] Under nitrogen protection, compound I (25.7 g, 100 mmol) and 260 mL of anhydrous THF were added to a reaction flask and stirred until dissolved. After cooling to -10 °C, methyl magnesium bromide (110 mL, 110 mmol) was slowly added dropwise. After the addition was complete, stirring was continued at this temperature for 2 h. After the reaction was completed, 50 mL of saturated NH4Cl solution was added to quench the reaction. The mixture was filtered, and the filtrate was diluted with 150 mL of ethyl acetate and 150 mL of water. The mixture was extracted with ethyl acetate (200 mL x 2), and the organic phases were combined. The organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:1 to 5:1) to give 20.6 g of compound II, with a yield of 75%. 1H NMR (400MHz, CDCl3) δ: 5.16 (d, J = 8.0Hz, 2H), 4.20 (q, J = 7.2Hz, 2H), 2.41-2.61 (m, 2H), 2.16(s,3H),2.06-2.16(m,1H),1.83-1.92(m,1H),1.44(s,9H),1.28(d,J=7.2Hz,3H).

[0120] Example 2

[0121] (2) Preparation of compound V-1

[0122] Under nitrogen protection, compound II (20.6 g, 75.4 mmol) and compound III-1 (10.0 g, 82.9 mmol) were added to tetrahydrofuran (200 mL), followed by the dropwise addition of tetraisopropyl titanate (26.8 g, 94.2 mmol), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was directly transferred to a 500 mL hydrogenation vessel, and Raney nickel (6.3 g, 30 wt%, washed successively with ethanol and tetrahydrofuran) was added for hydrogenation (8 bar, 35 °C). After the reaction was completed, sodium hydroxide solution (1.0 M, 113 mL, 113 mmol) was added, and the mixture was stirred at room temperature for 4 h. The mixture was filtered, washed with ethyl acetate, and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give 24.1 g of compound V-1, with a yield of 85%. 1 H NMR(400MHz, CDCl3)δ:7.23-7.37(m,5H),5.54(d,J=8.0Hz,1H),4.15-4.24(m,3H),3.96(q,J=6.8Hz,1H),2.60-2. 67(m,1H),1.67-1.79(m,2H),1.52-1.64(m,1H),1.36-1.49(m,13H),1.28(t,J=7.2Hz,3H),1.04(d,J=4.0Hz,3H).

[0123] Example 3

[0124] (3) Preparation of compound VI-1

[0125] Compound V-1 (22.7 g, 60 mmol) was added to methanol (200 mL), followed by potassium carbonate (24.8 g, 180 mmol). The reaction was stirred at 50 °C for 6 hours. After the reaction was complete, the mixture was filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1 to 1:2) to give 18.2 g of compound VI-1, in 91% yield. 1 H NMR(400MHz, CDCl3)δ:7.22-7.37(m,5H),5.64(d,J=8.0Hz,1H),4.97(q,J=6.8Hz,1H),3.99(t,J=6.8Hz,1H),3.36-3.47( m,1H),2.49-2.62(m,1H),1.75-1.92(m,2H),1.57-1.65(m,1H),1.47(d,J=8.0Hz,3H),1.42(s,9H),1.26(d,J=9.2Hz,3H).

[0126] Example 4

[0127] (4) Preparation of compound VII-1

[0128] Under nitrogen protection, compound VI-1 (18.2 g, 54.8 mmol) and 180 mL of anhydrous THF were added to a reaction flask and stirred until dissolved. The flask was placed in an ice-water bath, and boranetetrahydrofuran (60 mL, 60 mmol) was slowly added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 2 h. After the reaction was completed, 10 mL of methanol was slowly added to quench the reaction. The mixture was diluted with water and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give 16.6 g of compound VII-1, with a yield of 95%. 1 H NMR (400MHz, CDCl3) δ: 7.22-7.34 (m, 5H), 4.45 (d, J = 8.0Hz, 1H), 3.87-3.95 (m, 1H), 3.55 (q, J = 5.2Hz, 1H), 3.27 (dd, J = 10.0Hz, J = 5.6Hz, 1H), 2.54-2. 66(m,1H),2.53(dd,J=10.0Hz,J=5.6Hz,1H),1.99-2.08(m,1H),1.57-1.6 7(m,2H),1.36-1.47(m,10H),1.27(d,J=5.2Hz,3H),1.06(d,J=5.2Hz,3H).

[0129] Example 5

[0130] (5) Preparation of compound VIII-1

[0131] 100 mL of dioxane was added to a reaction flask containing VII-1 (16.6 g, 52.1 mmol), followed by the addition of 60 mL of ethyl hydrochloride solution (240 mmol, 4 mol / L). The mixture was stirred at room temperature for 3 h. After the reaction was complete, the solution was concentrated to give 15.1 g of compound VIII-1, with a yield of 99%. 1 H NMR (400MHz, DMSO-d6) δ: 13.8 (s, 1H), 7.22-7.34 (m, 5H), 4.30 (q, J = 12.0Hz, 1H), 4.24 (s,3H),3.45-3.71(m,4H),1.75-2.10(m,6H),1.42-1.55(m,1H),1.1(d,J=5.2Hz,3H).

[0132] Example 6

[0133] (6) Preparation of compound X-1

[0134] At room temperature, 100 mL of water, 30 mL of methyl isobutyl ketone, compound IX (7.7 g, 50 mmol), and K₂CO₃ (17.9 g, 130 mmol) were added sequentially to a reaction flask containing compound VIII-1 (15.1 g, 52.0 mmol). The mixture was heated to 90 °C and stirred at that temperature for 22 h. After the reaction was complete, the mixture was cooled to room temperature and diluted with 100 mL of ethyl acetate. The mixture was separated, and the aqueous phase was extracted once with 100 mL of ethyl acetate. The organic phases were combined, washed with 100 mL of saturated brine, dried, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by slurrying with 50 mL of methanol to give 14.8 g of compound X-1, with a yield of 88%. 1 H NMR(400MHz,MeOD)δ:8.08(d,J=10.0Hz,1H),7.39(d,J=8.0Hz,2H),7.22-7.36( m,6H),3.65(q,J=5.2Hz,1H),3.52(dd,J=10.0Hz,J=5.6Hz,1H),2.91-2.98(m,1 H),2.67-2.85(m,1H),2.66(dd,J=10.0Hz,J=5.6Hz,1H),1.99-2.08(m,1H),1.5 7-1.67(m,2H),1.36-1.52(m,1H),1.29(d,J=5.2Hz,3H),1.07(d,J=5.2Hz,3H).

[0135] Example 7

[0136] (7) Preparation of compound XI

[0137] At room temperature, 150 mL of ethanol, 2.6 g of acetic acid (44 mmol), and 1.3 g of wet palladium on carbon (10 wt%) were added sequentially to a reaction flask containing compound X-1 (13.4 g, 40 mmol). The reaction mixture was purged with hydrogen, hydrogenated at atmospheric pressure, and heated to 60 °C with stirring for 10 hours. After the reaction was complete, the mixture was filtered, the filter cake was washed with ethanol, and the filtrate was concentrated to give 8.8 g of compound XI, with a yield of 95%. 1 H NMR(400MHz, DMSO-d6)δ:11.42(brs,1H), 8.12(s,1H), 7.08(s,1H), 6.85(d ,J=8.0Hz, 1H), 6.64(s, 1H), 4.11-4.22(m, 1H), 2.96(d,J=12.0H, 1H), 2.82( d,J=12.0Hz,1H), 2.61-2.72(m,1H), 2.04(brs,1H), 1.87-1.96(m,1H), 1.5 7-1.67(m,1H),1.36-1.52(m,1H),1.27-1.33(m,1H),1.03(d,J=6.0Hz,3H).

[0138] Example 8

[0139] (8) Preparation of 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (litexitinib)

[0140] At room temperature, NaHCO3 (4.25 g, 51 mmol), 85 mL of water, and 90 mL of THF were added to a 250 mL single-necked flask containing compound XI (8.1 g, 35 mmol). The reaction solution was cooled to 0 °C, and acryloyl chloride (3.8 g, 42 mmol) was slowly added dropwise. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate (80 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give 8.7 g of litexitinib, in 88% yield.

[0141] 1H NMR(400MHz, DMSO-d6)δ:11.53(s,1H),8.14(d,J=11.2Hz,1H),7.27-7.52(m,1H),7.08(d,J=3 0.9,17.3Hz,1H),6.80(d,J=30.9,17.3Hz,1H),6.58(s,1H),5.95-6.12(m,1H),5.67(dd,J=10. 5,1.9Hz,1H),4.79(s,0.5H),4.54(d,J=13.2Hz,0.5H),4.37(s,0.5H),4.21-3.94(m,1.5H),3. 07-2.89(m,0.5H),2.64(dd,J=20.0,12.0Hz,0.5H),1.52-1.91(m,4H),1.24(d,J=10.0Hz,3H).

[0142] The following reaction formula illustrates a second synthetic route for the litexitinib intermediate and litexitinib in this application.

[0143]

[0144] In the following examples 9-13, each step in the above reaction formula will be described in detail.

[0145] Example 9

[0146] (1) Preparation of compound XII

[0147] At room temperature, 150 mL of ethanol, 2.6 g of acetic acid, and 1.3 g of wet palladium on carbon (10 wt%) were added sequentially to a reaction flask containing compound V-1 (15.1 g, 40 mmol). The reaction mixture was purged with hydrogen, subjected to high pressure hydrogenation (4 MPa), and heated to 70 °C for 8 hours. After the reaction was completed, the mixture was filtered, the filter cake was washed with ethanol, and the filtrate was concentrated to give 8.6 g of compound XII, with a yield of 94%. 1 H NMR (400MHz, DMSO-d6) δ: 7.46 (s, 1H), 6.80 (d, J = 4.0Hz, 1H), 3.67-3.82 (m, 1H), 3.25- 3.41(m,1H),1.62-1.92(m,3H),1.38(s,9H),1.22-1.37(m,1H),1.05(d,J=4.0Hz,3H).

[0148] Example 10

[0149] (2) Preparation of compound XIII

[0150] 100 mL of dioxane was added to a reaction flask containing XII-1 (11.8 g, 52 mmol), followed by the addition of 60 mL of ethyl acetate hydrochloride solution (240 mmol, 4 mol / L). The mixture was stirred at room temperature for 3 h. After the reaction was complete, the solution was concentrated to give 8.5 g of compound XIII, with a yield of 99%. 1 H NMR (400MHz, DMSO-d6) δ: 7.29 (s, 1H), 4.36 (s, 3H), 3.61 (t, J = 4.0Hz, 1H), 3.25-3.41 (m, 1H), 2.42- 2.48(m,1H),2.07-2.14(m,1H),1.62-1.72(m,1H),1.47-1.55(m,1H),1.26(d,J=4.0Hz,3H).[M+H] + =129.1.

[0151] Example 11

[0152] (3) Preparation of compound XIV

[0153] At room temperature, 100 mL of water, 30 mL of methyl isobutyl ketone, compound IX (7.7 g, 50 mmol), and K₂CO₃ (17.9 g, 130 mmol) were added sequentially to a reaction flask containing compound XIII (8.5 g, 52.0 mmol). The mixture was heated to 100 °C and stirred at that temperature for 22 h. After the reaction was complete, the mixture was cooled to room temperature and diluted with 100 mL of ethyl acetate. The mixture was separated, and the aqueous phase was extracted once with 100 mL of ethyl acetate. The organic phases were combined, washed with 100 mL of saturated brine, dried, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by slurrying with 50 mL of methanol to obtain 10.5 g of compound XIV, with a yield of 86%. 1 H NMR(400MHz, DMSO-d6)δ:11.62(s,1H),8.05(s,1H),7.64-7.81(m,2H),7.11(s,1H),6.60(d,J=24.0Hz, 1H),4.61-4.79(m,1H),3.03-3.12(m,1H),1.76-2.03(m,3H),1.42-1.66(m,1H),1.13(d,J=8.0Hz,3H).

[0154] Example 12

[0155] (4) Preparation of compound XI

[0156] Under nitrogen protection, compound XIV (13.4 g, 54.8 mmol) and 180 mL of anhydrous THF were added to a reaction flask and stirred until dissolved. The flask was placed in an ice-water bath, and sodium dihydrobis(2-methoxyethoxy)aluminate (22.2 g, 110 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to 70 °C and stirred for 2 h. After the reaction was complete, 10 mL of methanol was slowly added to quench the reaction. The mixture was diluted with water and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give 10.4 g of compound XI, in 82% yield. [M+H] + =232.0.

[0157] Example 13

[0158] (5) Preparation of 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (litexitinib)

[0159] At room temperature, NaHCO3 (4.25 g, 51 mmol), 85 mL of water, and 90 mL of THF were added to a 250 mL single-necked flask containing compound XI (8.1 g, 35 mmol). The reaction solution was cooled to 0 °C, and acryloyl chloride (3.8 g, 42 mmol) was slowly added dropwise.

[0160] After the addition was complete, the mixture was slowly heated to room temperature and stirred for 2 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (80 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give 8.7 g of litexitinib, in 88% yield. [M+H] + =286.1.

[0161] The following provides another method for synthesizing litexitinib, and the steps therein are described in detail in Examples 14-20.

[0162]

[0163] Example 14

[0164] (2) Preparation of compound V-2

[0165] Under nitrogen protection, compound II (20.6 g, 75.4 mmol) (the preparation of which is described in Example 1 above) and compound III-2 (8.5 g, 79.2 mmol) were added to tetrahydrofuran (200 mL), followed by the addition of tetraisopropyl titanate (26.8 g, 94.2 mmol). The mixture was stirred at room temperature for 6 hours. The reaction mixture was directly transferred to a 500 mL hydrogenation reactor, and RuCl2[(S)-(DM-BINAP)][(S)-DAIPEN] (451 mg, 0.37 mmol) was added for hydrogenation (40 bar, 50 °C). After the reaction, the mixture was neutralized to pH 9 with saturated sodium carbonate aqueous solution, filtered, washed with ethyl acetate, and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give 25.5 g of compound V-2, with a yield of 93%. [M+H] + =365.2.

[0166] Example 15

[0167] (3) Preparation of compound VI-2

[0168] Compound V-2 (21.9 g, 60 mmol) was added to toluene (200 mL), followed by acetic acid (600 mg, 10 mmol). The reaction was stirred at 80 °C for 6 hours. After the reaction was complete, the mixture was filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1–1:2) to give 18.3 g of compound VI-2, in 96% yield. [M+H] + =319.2.

[0169] Example 16

[0170] (4) Preparation of compound VII-2

[0171] Under nitrogen protection, compound VI-2 (17.4 g, 54.8 mmol) and 170 mL of anhydrous THF were added to a reaction flask and stirred until dissolved. The flask was placed in an ice-water bath, and a red aluminum solution (39.6 g, 137 mmol, 70%) was slowly added dropwise. After the addition was complete, the temperature was raised to 50 °C and stirred for 2 h. After the reaction was complete, 10 mL of methanol was slowly added to quench the reaction. The mixture was diluted with water and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give 15.6 g of compound VII-2, in 93% yield. [M+H] + =305.2.

[0172] Example 17

[0173] (5) Preparation of compound VIII-2

[0174] 100 mL of ethyl acetate was added to a reaction flask containing VII-2 (15.8 g, 52.1 mmol), followed by the addition of 60 mL of ethyl hydrochloride solution (240 mmol, 4 mol / L). The mixture was stirred at room temperature for 3 h. After the reaction was complete, the solution was concentrated to give 14.1 g of compound VIII-2, in 98% yield. [M+H] + =205.2.

[0175] Example 18

[0176] (6) Preparation of compound X-2

[0177] At room temperature, 100 mL of water, 30 mL of methyl isobutyl ketone, compound IX (7.7 g, 50 mmol), and K₂CO₃ (17.9 g, 130 mmol) were added sequentially to a reaction flask containing compound VIII-2 (14.4 g, 52.0 mmol). The mixture was heated to 90 °C and stirred at that temperature for 22 h. After the reaction was complete, the mixture was cooled to room temperature and diluted with 100 mL of ethyl acetate. The mixture was separated, and the aqueous phase was extracted once with 100 mL of ethyl acetate. The organic phases were combined, washed with 100 mL of saturated brine, dried, filtered, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by slurrying with 50 mL of methanol to give 14.6 g of compound X-2, with a yield of 91%. [M+H] + =322.2.

[0178] Example 19

[0179] (7) Preparation of compound XI

[0180] At room temperature, 150 mL of ethanol, 2.6 g of acetic acid (44 mmol), and 1.3 g of wet palladium on carbon (10 wt%) were added sequentially to a reaction flask containing compound X-2 (12.8 g, 40 mmol). The reaction mixture was purged with hydrogen, hydrogenated at atmospheric pressure, and heated to 50 °C with stirring for 10 hours. After the reaction was complete, the mixture was filtered, the filter cake was washed with ethanol, and the filtrate was concentrated to give 8.9 g of compound XI, with a yield of 96%. [M+H] + =232.2.

[0181] Example 20

[0182] (8) Preparation of 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (litexitinib)

[0183] At room temperature, NaHCO3 (4.25 g, 51 mmol), 85 mL of water, and 90 mL of THF were added to a 250 mL single-necked flask containing compound XI (8.1 g, 35 mmol). The reaction solution was cooled to 0 °C, and acryloyl chloride (3.8 g, 42 mmol) was slowly added dropwise.

[0184] After the addition was complete, the mixture was slowly brought to room temperature and stirred for 2 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (80 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain 8.7 g of litexitinib, with a yield of 88%. 1 H NMR(400MHz, DMSO-d6)δ:11.53(s,1H),8.14(d,J=11.2Hz,1H),7.27-7.52(m,1H),7.08(d,J=3 0.9,17.3Hz,1H),6.80(d,J=30.9,17.3Hz,1H),6.58(s,1H),5.95-6.12(m,1H),5.67(dd,J=10. 5,1.9Hz,1H),4.79(s,0.5H),4.54(d,J=13.2Hz,0.5H),4.37(s,0.5H),4.21-3.94(m,1.5H),3. 07-2.89(m,0.5H),2.64(dd,J=20.0,12.0Hz,0.5H),1.52-1.91(m,4H),1.24(d,J=10.0Hz,3H).

Claims

1. A method for preparing the 2,5-disubstituted aminohexanoate of formula V, The method includes the following steps: (1) Compound I reacts with a methyl metal reagent in solvent 1 to give compound II; (2) In the presence of catalyst 1, compound II and compound III form an imine intermediate in solvent 2, which is then reduced by catalyst 1' with hydrogen to give compound V. Wherein, R is selected from C1-C6 alkyl or benzyl groups; for( R Configuration, (S) Configuration or racemate; R1 is selected from substituted or unsubstituted phenyl groups, wherein "substituted" means that the phenyl group may have 1 to 5 substituents selected from C1-C6 alkoxy, halogen, cyano or C1-C6 alkyl groups; R2 is selected from H or C1-C6 alkyl groups. In step (1), the methyl metal reagent is selected from one or more of methyl magnesium bromide, methyl magnesium chloride, and methyl magnesium iodide; In step (2), catalyst 1 is selected from one or more of tetraisopropyl titanate, tetraethyl titanate, p-toluenesulfonic acid, and titanium tetrachloride; catalyst 1' is selected from one or more of Raney nickel, palladium on carbon, rhodium on carbon, and RuCl2[(S)-(DM-BINAP)][(S)-DAIPEN].

2. The method according to claim 1, wherein, R is methyl, ethyl, isopropyl, or propyl; R1 is a phenyl group selected from substituted or unsubstituted phenyl groups, wherein "substituted" means that the phenyl group may have 1 to 4 substituents selected from C1-C6 alkoxy, halogen, cyano, or C1-C6 alkyl groups; and R2 is H, methyl, or ethyl.

3. The method according to claim 1, wherein, In step (1), solvent 1 is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane; the molar ratio of compound I and methyl metal reagent is 1:1.1~1.5; the reaction temperature is -30~10℃; and the reaction time is 1~5h. In step (2), solvent 2 is selected from one or more of ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl acetate, dioxane, methanol, ethanol, and isopropanol; the molar ratio of compound II, compound III, and catalyst 1 is 1:1.0~1.3:1.0~1.5; the weight ratio of catalyst 1' to compound II is 1:1~50; the reaction temperature is 10~70℃, and the reaction time is 6~40h.

4. The method according to claim 1, wherein the method comprises the following steps: (1) Mix compound I with solvent 1, add methyl metal reagent dropwise, control the temperature for reaction, quench the reaction after it is completed, separate the liquid, extract, concentrate, and purify by column chromatography to obtain compound II; (2) Mix compound II, compound III and solvent 2, react under controlled temperature, add catalyst 1 and react for 4-8 hours, add catalyst 1' and react with hydrogen to carry out reduction reaction, quench after reaction, separate, extract, concentrate, and column chromatography to obtain compound V.

5. A method for preparing litexitinib using a compound of formula V: As shown in the reaction formula above, the method includes the following steps: (1) In the presence of solvent 1' and catalyst 2, compound V undergoes a cyclization reaction to give compound VI; (2) In the presence of solvent 2', compound VI undergoes a reduction reaction under the action of a reducing agent to give compound VII; (3) In the presence of solvent 3', compound VII was deprotected by the Boc protecting group to give compound VIII; (4) In the presence of solvent 4' and base, compound VIII and compound IX undergo a substitution reaction to give compound X; (5) In the presence of solvent 5', additives and metal catalyst, compound X is desubstituented to obtain compound XI; (6) In the presence of solvent 6' and a base, compound XI reacts with acryloyl chloride to give compound rituximab. Wherein, the definitions of R, R1, and R2 are the same as those defined in claim 1, wherein, In step (1), the catalyst 2 for the cyclization reaction is a base or an acid. The base is one or more of potassium carbonate, sodium carbonate, potassium tert-butoxide, potassium acetate, sodium ethoxide, triethylamine, and N,N-diisopropylethylamine. The acid is one or more of acetic acid, formic acid, and propionic acid. The solvent 1' is selected from one or more of methanol, ethanol, toluene, tetrahydrofuran, acetonitrile, N-methylpyrrolidone (NMP), and N,N-dimethylacetamide (DMAc). The molar ratio of compound V to catalyst 2 is 1:0.1~6.0, the reaction temperature is 50~150℃, and the reaction time is 6~40h. In step (2), the reducing agent is selected from one or more of borane dimethyl sulfide, borane tetrahydrofuran, sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium dihydrobis(2-methoxyethoxy)aluminate, and diisobutylaluminum hydride; the solvent 2' is selected from one or more of ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl acetate, dioxane, and toluene; the molar ratio of compound VI to the reducing agent is 1:1.0~4.0; the reaction temperature is -20~50℃; and the reaction time is 2~20h. In step (3), an acid is used to remove the Boc protecting group. The acid is selected from one or more of trifluoroacetic acid, ethyl acetate hydrochloride, dioxane hydrochloride, methanol hydrochloride, concentrated hydrochloric acid, and dilute hydrochloric acid. The solvent 3' is selected from one or more of dichloromethane, tetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, and dioxane. The molar ratio of compound VII to acid is 1:4~30. The reaction temperature is 10~50℃ and the reaction time is 1~12h. In step (4), the substitution reaction is carried out in a base and solvent 4', wherein the base is one or more of potassium carbonate, sodium carbonate, sodium ethoxide, triethylamine, and N,N-diisopropylethylamine; the solvent 4' is selected from one or more of water, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, toluene, and methyl isobutyl ketone; the molar ratio of compound IX, compound VIII, and base is 1:1.0~1.3:1.5~3; the reaction temperature is 80~120℃, and the reaction time is 10~24h; In step (5), the metal catalyst is one or more of palladium on carbon, palladium hydroxide on carbon, rhodium on carbon, and Raney nickel; the solvent 5' is selected from one or more of water, methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, and 2-methyltetrahydrofuran; the additive is one or more of acetic acid, formic acid, and dilute hydrochloric acid; the mass ratio of compound X to the metal catalyst is 1:0.02~0.2; the molar ratio of compound X to the additive is 1:1.0~2.0; the reaction temperature is 40~100℃, and the reaction time is 4~24h; and In step (6), the alkali is one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, and N,N-diisopropylethylamine; the solvent 6' is selected from one or more of water, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, toluene, dioxane, and ethyl acetate; the molar ratio of compound XI, acryloyl chloride, and alkali is 1:1.0~1.4:1.2~2; the reaction temperature is -10~40℃, and the reaction time is 1~10h.

6. The method according to claim 5, wherein, In step (1), the base is selected from one or two of potassium carbonate and sodium carbonate; the acid is acetic acid; the solvent 1' is one or two of methanol and toluene; the molar ratio of compound V to catalyst 2 is 1:0.1~6.0; the reaction temperature is 50~120℃; and the reaction time is 6~10h. In step (2), the reducing agent is selected from one or two of boranetetrahydrofuran and sodium dihydrobis(2-methoxyethoxy)aluminate; solvent 2' is tetrahydrofuran; the molar ratio of compound VI to the reducing agent is 1:1.0~4.0; the reaction temperature is 0~50℃; and the reaction time is 2~10h. In step (3), the acid is ethyl hydrochloride; solvent 3' is one or both of dioxane and ethyl acetate; the molar ratio of compound VII to acid is 1:4~10; the reaction temperature is 20~30℃; and the reaction time is 2~6h. In step (4), the base is selected from one or two of potassium carbonate and triethylamine; solvent 4' is methyl isobutyl ketone; the molar ratio of compound IX, compound VIII and base is 1:1.0~1.1:2~3; the reaction temperature is 80~100℃; the reaction time is 16~23h; In step (5), solvent 5' is ethanol; the mass ratio of compound X to metal catalyst is 1:0.05~0.1; the molar ratio of compound X to additive is 1:1.0~1.5; the reaction temperature is 50~70℃; the reaction time is 6~16h; and In step (6), the alkali is selected from one or two of sodium bicarbonate, sodium carbonate, and triethylamine; solvent 6' is tetrahydrofuran; the molar ratio of compound XI, acryloyl chloride, and alkali is 1:1.1~1.3:1.2~1.5; the reaction temperature is 0~30℃; and the reaction time is 1~5h.

7. The method according to claim 5, wherein, The method includes the following steps: (1) Compound V, solvent 1' and catalyst 2 were mixed and reacted under controlled temperature. After the reaction was completed, the mixture was filtered, concentrated, and purified by column chromatography to obtain compound VI. (2) Mix compound VI and solvent 2', add reducing agent to react, quench after reaction, extract, separate, concentrate, and purify by column chromatography to obtain compound VII; (3) Mix compound VII and solvent 3', add acid to react, concentrate after the reaction is complete to obtain compound VIII; (4) Mix compound VIII, compound IX, solvent 4' and base, heat and react, cool after the reaction is complete, extract, combine organic phases, wash, dry, filter, concentrate, and purify by pulping to obtain compound X; (5) Mix compound X, additive and solvent 5', add metal catalyst to carry out hydrogenation reaction, filter after reaction, concentrate to obtain compound XI; (6) Compound XI, solvent 6', acryloyl chloride and base were mixed and reacted. After the reaction was completed, the mixture was extracted, the organic phases were combined, washed, dried, filtered, concentrated and purified by column chromatography to obtain rituximab.

8. A method for preparing litexitinib using a compound of formula V: As shown in the reaction formula above, the method includes the following steps: (1) In the presence of solvent 1'' and with additives, compound V was hydrogenated to remove substituents and simultaneously cyclized to obtain compound XII; (2) In the presence of solvent 2'', compound XII was deprotected by the Boc protecting group to give compound XIII; (3) In the presence of solvent 3'' and base, compound XIII and compound IX undergo a substitution reaction to give compound XIV; (4) In the presence of solvent 4'', compound XIV undergoes a reduction reaction under the action of a reducing agent to give compound XI; (5) In the presence of solvent 5'' and base, compound XI reacts with acryloyl chloride to give compound rituximab; Wherein, R, R1, and R2 are defined as in claim 1, in, In step (1), the removal of substituents is carried out in a metal catalyst and solvent 1'', wherein the metal catalyst is one or more of palladium on carbon, palladium hydroxide on carbon, rhodium on carbon, and Raney nickel; the additive is one or more of acetic acid, formic acid, and dilute hydrochloric acid; the mass ratio of compound V to metal catalyst is 1:0.02~0.2; the molar ratio of compound V to additive is 1:1.0~2.0; the reaction temperature is 40~100℃; the reaction time is 4~24h; and the solvent 1'' is selected from one or more of methanol, ethanol, toluene, tetrahydrofuran, N-methylpyrrolidone (NMP), and N,N-dimethylacetamide (DMAc). In step (2), an acid is used to remove the Boc protecting group. The acid is selected from one or more of trifluoroacetic acid, ethyl acetate hydrochloride, dioxane hydrochloride, methanol hydrochloride, and hydrochloric acid. The molar ratio of compound XII to acid is 1:4~30. The reaction temperature is 10~50℃. The reaction time is 1~12h. The solvent 2'' is selected from one or more of dichloromethane, tetrahydrofuran, methanol, ethanol, ethyl acetate, and dioxane. In step (3), the substitution reaction is carried out in a base and solvent 3'', wherein the base is an organic base or an inorganic base, the organic base being selected from one or more of sodium ethoxide, triethylamine, and N,N-diisopropylethylamine; the inorganic base being selected from one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, and sodium hydroxide; the molar ratio of compound IX, compound XIII, and base is 1:1.0~1.3:1.5~3; the reaction temperature is 80~120℃; the reaction time is 10~24h; and the solvent 3'' is selected from one or more of water, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, toluene, and methyl isobutyl ketone. In step (4), the reducing agent is selected from one or more of borane dimethyl sulfide, borane tetrahydrofuran, sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium dihydrobis(2-methoxyethoxy)aluminate, and diisobutylaluminum hydride; the molar ratio of compound XIV to the reducing agent is 1:1.0~4.0; the reaction temperature is -20~70℃; the reaction time is 2~20h; the solvent 4'' is selected from one or more of ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl acetate, dioxane, and toluene; and In step (5), the alkali is one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, and N,N-diisopropylethylamine; the molar ratio of compound XI, acryloyl chloride, and alkali is 1:1.0~1.4:1.2~2; the reaction temperature is -10~40℃; the reaction time is 1~10h; and the solvent 5'' is selected from one or more of water, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, toluene, dioxane, and ethyl acetate.

9. The method according to claim 8, wherein, In step (1), the metal catalyst is palladium on carbon or palladium hydroxide on carbon; the additive is acetic acid; the solvent 1'' is ethanol; the mass ratio of compound V to metal catalyst is 1:0.05~0.1; the molar ratio of compound V to acetic acid is 1:1.0~1.5; the reaction temperature is 50~70℃; and the reaction time is 6~16h. In step (2), the acid is one or both of hydrochloric acid and ethyl acetate hydrochloride; solvent 2'' is dioxane; the molar ratio of compound XII to acid is 1:4~10; the reaction temperature is 20~30℃; and the reaction time is 2~6h. In step (3), the alkali is selected from one or two of potassium carbonate and triethylamine; the solvent 3'' is one or two of water and methyl isobutyl ketone; the molar ratio of compound IX, compound XIII and alkali is 1:1.0~1.1:2~3; the reaction temperature is 80~100℃; and the reaction time is 16~23h. In step (4), the reducing agent is selected from one or both of boranetetrahydrofuran and sodium dihydrobis(2-methoxyethoxy)aluminate; solvent 4'' is tetrahydrofuran; the molar ratio of compound XIV to the reducing agent is 1:1.1~4.0; the reaction temperature is 0~70℃; the reaction time is 2~10h; and In step (5), the alkali is selected from one or two of sodium bicarbonate, sodium carbonate, and triethylamine; the solvent 5'' is tetrahydrofuran; the molar ratio of compound XI, acryloyl chloride, and alkali is 1:1.1~1.3:1.2~1.5; the reaction temperature is 0~30℃; and the reaction time is 1~5h.

10. The method according to claim 8, wherein, The method includes the following steps: (1) Mix compound V, additive and solvent 1'', add metal catalyst to carry out hydrogenation reaction, filter after reaction, concentrate to obtain compound XII; (2) Mix compound XII with solvent 2'', add acid to react, concentrate after the reaction is complete to obtain compound XIII; (3) Mix compound XIII, compound IX, solvent 3'' and base, heat and react, cool after the reaction is complete, extract, combine organic phases, wash, dry, filter, concentrate, and purify by pulping to obtain compound XIV; (4) Mix compound XIV and solvent 4'', add reducing agent to react, quench after reaction, extract, separate, concentrate, and purify by column chromatography to obtain compound XI; (5) Compound XI, solvent 5'', acryloyl chloride and base were mixed and reacted. After the reaction was completed, the mixture was extracted, the organic phases were combined, washed, dried, filtered, concentrated and purified by column chromatography to obtain rituximab.

11. A compound represented by formula V and its salt, In formula V, R, R1, and R2 are defined as in claim 1.

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