Omariglonide intermediate, preparation method thereof and method for preparing key intermediate of Omariglonide

Abstract

The invention provides an omariglitazone intermediate, a preparation method thereof and a method for preparing an omariglitazone key intermediate, and relates to the technical field of organic chemistry. The omarignelone intermediate provided by the invention has a structure as shown in a formula VIII; the omariglitazone intermediate is easy to obtain and can be conveniently prepared by taking benzaldehyde as a starting raw material, a chiral chromatographic column does not need to be used for preparation of the omariglitazone intermediate, a key chiral center of the omariglitazone intermediate is constructed by catalyzing a cheap chiral amine catalyst through an asymmetric Knoevenagel-Michael addition reaction, and the preparation method is simple and convenient. According to the omariglitazone intermediate, industrial production of the omariglitazone key intermediate (the structure as shown in the formula I) is easy to realize, and the production cost is reduced. The invention provides a method for preparing an omariglone key intermediate (a structure shown in a formula I), the omariglone key intermediate can be prepared from the omariglone intermediate through a nitro reduction reaction, a Jappp-Klingemann reaction and an indole synthesis reaction, and the method is suitable for industrial production. A formula VIII and a formula I are shown in the description.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, and in particular to an ogliflozin intermediate, its preparation method, and a method for preparing a key ogliflozin intermediate. Background Technology

[0002] Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of drugs used to treat type 2 diabetes. These drugs lower blood sugar by activating GLP-1 receptors, exerting an incretin-like effect. They exhibit glucose-dependent insulin secretion promotion and glucagon inhibition, while also delaying gastric emptying, reducing food intake, and improving blood lipid levels. In addition to their blood sugar-lowering effects, GLP-1 receptor agonists have potential anti-inflammatory and anti-atherosclerotic effects, including reducing weight, decreasing intimal thickening after vascular injury, and reducing smooth muscle proliferation. The drug NovoMix has been shown to regulate appetite by activating GLP-1 receptors, thus exhibiting both diabetes treatment and weight management effects.

[0003] GLP-1 receptor agonists, represented by injectable drugs such as semaglutide and tirzepatide, have achieved great market success due to their excellent blood sugar lowering and weight loss effects. However, the injection method of administration presents challenges in terms of convenience and patient compliance. Orforglipron has overcome this bottleneck. In April 2025, it made history—becoming the first oral small-molecule GLP-1 receptor agonist to successfully complete a Phase 3 clinical trial. This means that patients can finally say goodbye to the pain of daily injections and can take it once a day without food and water restrictions. The structural formula of orforglipron is as follows: .

[0004] The success of omaglione stems from its groundbreaking non-peptide small molecule design, which offers significant advantages over traditional peptide GLP-1 drugs. Its small molecule structure is stable and resistant to digestive enzyme degradation, thus enabling oral administration.

[0005] The synthesis of oxaliplatinone is challenging due to the chiral construction of the 5-pyranindole ring. The synthesis of key intermediates containing chiral 5-pyranindole rings has become an important research topic. Related techniques disclose the construction of racemic 5-pyranindole compounds 31c using the Negishi coupling reaction, followed by separation using a chiral column to obtain the chiral compound shown in Formula I-2 (preparation route is shown in Route 1). The problems with this route are: 1) the Negishi coupling reaction uses expensive palladium and ligands, resulting in high costs; 2) the starting material ethyl 5-bromoindole-2-carboxylate is not readily available; and 3) the need for chiral column separation makes it difficult to use for industrial production.

[0006] Route 1.

[0007] Currently, there is an urgent need to develop a low-cost method for preparing key intermediates of omaglione containing chiral 5-pyranindole rings, making them more suitable for industrial production. Summary of the Invention

[0008] In view of this, the purpose of this invention is to provide an oxaliplatin intermediate, a method for preparing the same, and a method for preparing a key oxaliplatin intermediate. The oxaliplatin intermediate provided by this invention is readily available and can be easily prepared from benzaldehyde as a starting material. Its preparation does not require the use of a chiral chromatographic column, and its key chiral center is constructed by catalysis using an inexpensive chiral amine catalyst. The oxaliplatin intermediate facilitates the industrial-scale production of key oxaliplatin intermediates, reducing production costs.

[0009] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides an oxaliplatin intermediate having the structure shown in Formula VIII: Formula VIII.

[0010] This invention provides a method for preparing the oxaliplatin intermediate described in the above technical solution, comprising the following steps: Benzaldehyde, malonic acid ester, acetone, a first catalyst, and a first organic solvent are mixed and subjected to a Knoevenagel-Michael addition reaction to yield compound III. The first catalyst comprises one or more of D-aspartic acid, D-glutamic acid, D-piperidinic acid, D-proline, (R)-diphenylprolyl trimethylsilyl ether, and (8a,9s)-6'-methoxycinnamine-9-amine. The malonic acid ester has the structure shown in formula a or formula a', where R is an alkyl, substituted alkyl, aryl, or substituted aryl group. When the malonic acid ester has the structure shown in formula a, compound III has the structure shown in formula III-a; when the malonic acid ester has the structure shown in formula a', compound III has the structure shown in formula III-a'. Formula a, Formula a' Formula III-a, Formula III-a'; Compound III is mixed with water and a second organic solvent, or compound III is mixed with an acid, and subjected to a decarboxylation reaction to obtain compound IV; compound IV has the structure shown in formula IV: Formula IV; Compound IV was mixed with an alcohol reagent and subjected to an esterification reaction to obtain compound V; the alcohol reagent had the structure shown in formula b, where R' was an alkyl or substituted alkyl group; compound V had the structure shown in formula V. Formula b, Formula V; The compound V, a methyl Grignard reagent, and a third organic solvent are mixed and subjected to a methylation reaction to obtain compound VI, which has the structure shown in formula VI. Formula VI; Compound VI, a reducing agent, and a fourth organic solvent are mixed to carry out a lactone reduction reaction to obtain compound VII, which has the structure shown in formula VII; Equation VII; The compound VII, the nitrifying agent, and the fifth organic solvent were mixed and subjected to a nitration reaction to obtain an oxaliron intermediate having the structure shown in Formula VIII.

[0011] Preferably, the molar ratio of benzaldehyde, malonic acid ester and acetone is 1:(1.0~1.2):(4.0~6.0), and the mass ratio of benzaldehyde to the first catalyst is 1:(0.01~0.03); the Knoevenagel-Michael addition reaction is carried out at a temperature of 20~30℃ for 12~24h.

[0012] Preferably, the decarboxylation reaction is carried out at a temperature of 60-100°C for a time of 6-12 hours.

[0013] Preferably, the alcohol reagent is a liquid alcohol or a solid alcohol. When the alcohol reagent is a liquid alcohol, the mass ratio of compound IV to the volume of the alcohol reagent is 1 g:(3~5) mL. When the alcohol reagent is a solid alcohol, the molar ratio of compound IV to the alcohol reagent is 1:(1~5). The esterification reaction is carried out at a temperature of 70~110℃ for 6~72 h.

[0014] Preferably, the methyl Grignard reagent comprises methyl magnesium chloride and / or methyl magnesium bromide; the molar ratio of compound V to the methyl Grignard reagent is 1:(1.5~2.0); the methylation reaction is carried out at a temperature of -20~-10℃ for 12~18h.

[0015] Preferably, the reducing agent includes one or more of triethylsilane, boron trifluoride ether, borane tetrahydrofuran, lithium aluminum hydride, sodium borohydride, and diisobutylaluminum hydride; the molar ratio of compound VI to the reducing agent is 1:(1.5~3.0); the temperature of the lactone reduction reaction is 0~10℃, and the time is 4~8h.

[0016] Preferably, the nitrifying agent includes nitric acid, and the molar ratio of compound VII to nitric acid is 1:(1.0~3.0); the nitration reaction is carried out at a temperature of -20~-10℃ for 2~4 hours.

[0017] This invention provides a method for preparing a key intermediate of oxaliplatin, the key intermediate of oxaliplatin having the structure shown in Formula IX, comprising the following steps; An algileron intermediate having the structure shown in Formula VIII, a reducing agent, and a sixth organic solvent are mixed and subjected to a nitro reduction reaction to obtain an algileron key intermediate having the structure shown in Formula IX. Formula IX.

[0018] Preferably, the reducing agent includes one or more of hydrogen, hydrazine hydrate, iron powder, zinc powder, tin powder, sodium dithionite, sodium sulfite, sodium sulfide, stannous chloride, titanium trichloride, and tetrahydroxyborane; the nitro reduction reaction is carried out at a temperature of 20~100℃ for 8~12h.

[0019] Preferably, the mixture of the oglioneron intermediate having the structure shown in Formula VIII, the reducing agent, and the sixth organic solvent further includes the addition of a second catalyst, the second catalyst comprising one or more of palladium on carbon, Raney nickel, and platinum dioxide.

[0020] This invention provides a method for preparing a key intermediate of oxaliplatin, the key intermediate of oxaliplatin having the structure shown in Formula X, comprising the following steps; An algileron intermediate having the structure shown in Formula VIII, a reducing agent, and a sixth organic solvent are mixed and subjected to a nitro reduction reaction to obtain an algileron key intermediate having the structure shown in Formula IX. Formula IX; The key intermediate of oxaliplatin with the structure shown in Formula IX and a nitrite reagent are subjected to a diazotization reaction under acidic conditions. The resulting reaction solution is then mixed with 2-methylacetoacetate and a basic compound to undergo a Japp-Klingemann reaction to obtain the key intermediate of oxaliplatin with the structure shown in Formula X. The 2-methylacetoacetate has the structure shown in Formula C, where R'' is an alkyl or substituted alkyl group. Equation c, Formula X.

[0021] Preferably, the nitrite reagent includes one or more of nitrite, sodium nitrite, potassium nitrite, tert-butyl nitrite, nitrite sulfate, and isoamyl nitrite; the diazotization reaction is carried out at a temperature of 0-5°C for 1-6 hours; and the Japp-Klingemann reaction is carried out at a temperature of -20-10°C for 2-18 hours.

[0022] This invention provides a method for preparing a key intermediate of oxaliplatin, the key intermediate of oxaliplatin having the structure shown in Formula I, comprising the following steps; An algileron intermediate having the structure shown in Formula VIII, a reducing agent, and a sixth organic solvent are mixed and subjected to a nitro reduction reaction to obtain an algileron key intermediate having the structure shown in Formula IX. Formula IX; The key intermediate of oxaliplatin with the structure shown in Formula IX and a nitrite reagent are subjected to a diazotization reaction under acidic conditions. The resulting reaction solution is then mixed with 2-methylacetoacetate and a basic compound to undergo a Japp-Klingemann reaction to obtain the key intermediate of oxaliplatin with the structure shown in Formula X. The 2-methylacetoacetate has the structure shown in Formula C, where R'' is an alkyl or substituted alkyl group. Equation c, Formula X; The key intermediate of omega-100 having the structure shown in Formula X was mixed with an acid and subjected to a Fischer indole synthesis reaction to obtain the key intermediate of omega-100 having the structure shown in Formula I. Formula I.

[0023] Preferably, the Fischer indole synthesis reaction is carried out at a temperature of 40-100°C for 4-12 hours.

[0024] This invention provides an oxaliplatin intermediate having the structure shown in Formula VIII. The oxaliplatin intermediate provided by this invention is readily available and can be easily prepared from benzaldehyde as a starting material. Its preparation does not require a chiral chromatographic column; its key chiral center is constructed by an asymmetric Knoevenagel-Michael addition reaction using inexpensive chiral amine catalysts (D-aspartic acid, D-glutamic acid, D-piperidinic acid, D-proline, (R)-diphenylprolyl trimethylsilyl ether, (8a,9s)-6'-methoxycinnamine-9-amine). The oxaliplatin intermediate with the structure shown in Formula VIII provided by this invention facilitates the industrial production of the key oxaliplatin intermediate (structure shown in Formula I), reducing production costs.

[0025] This invention provides a method for preparing a key intermediate of oxaliplatin (structure shown in Formula I). ​​The oxaliplatin intermediate of Formula VIII can be prepared via nitro reduction, Japp-Klingemann reaction, and indole synthesis. The process is simple and easy to operate, and does not require a chiral chromatographic column. The obtained oxaliplatin key intermediate exhibits high chiral purity. The preparation method provided by this invention is suitable for industrial production. Attached Figure Description

[0026] Figure 1 The proton nuclear magnetic resonance spectrum of the compound of formula III-a'-1 prepared for the example; Figure 2 Carbon nuclear magnetic resonance spectra of the compound of formula III-a'-1 prepared for the example; Figure 3 The proton nuclear magnetic resonance spectrum of the compound of formula V-1 prepared for the example; Figure 4 Carbon nuclear magnetic resonance spectra of the compound of formula V-1 prepared for the example; Figure 5 The proton nuclear magnetic resonance spectra of the compound of formula VI prepared for the example; Figure 6 Carbon NMR spectra of compounds of formula VI prepared for the example; Figure 7 The proton nuclear magnetic resonance spectrum of the compound of formula VII prepared for the example; Figure 8 Carbon nuclear magnetic resonance spectra of compounds of formula VII prepared for examples; Figure 9 The proton nuclear magnetic resonance spectra of the compound of formula I-2 prepared for the example; Figure 10 Carbon nuclear magnetic resonance spectra of the compound of formula I-2 prepared for the example. Detailed Implementation

[0027] This invention provides an oxaliplatin intermediate having the structure shown in Formula VIII: Formula VIII.

[0028] This invention provides a method for preparing the oxaliplatin intermediate described in the above technical solution, comprising the following steps: Benzaldehyde, malonic acid ester, acetone, a first catalyst, and a first organic solvent are mixed and subjected to a Knoevenagel-Michael addition reaction to yield compound III. The first catalyst comprises one or more of D-aspartic acid, D-glutamic acid, D-piperidinic acid, D-proline, (R)-diphenylprolyl trimethylsilyl ether, and (8a,9s)-6'-methoxycinnamine-9-amine. The malonic acid ester has the structure shown in formula a or formula a', where R is an alkyl, substituted alkyl, aryl, or substituted aryl group. When the malonic acid ester has the structure shown in formula a, compound III has the structure shown in formula III-a; when the malonic acid ester has the structure shown in formula a', compound III has the structure shown in formula III-a'. Formula a, Formula a' Formula III-a, Formula III-a'; Compound III is mixed with water and a second organic solvent, or compound III is mixed with an acid, and subjected to a decarboxylation reaction to obtain compound IV; compound IV has the structure shown in formula IV: Formula IV; Compound IV was mixed with an alcohol reagent and subjected to an esterification reaction to obtain compound V; the alcohol reagent had the structure shown in formula b, where R' was an alkyl or substituted alkyl group; compound V had the structure shown in formula V. Formula b, Formula V; The compound V, a methyl Grignard reagent, and a third organic solvent are mixed and subjected to a methylation reaction to obtain compound VI, which has the structure shown in formula VI. Formula VI; Compound VI, a reducing agent, and a fourth organic solvent are mixed to carry out a lactone reduction reaction to obtain compound VII, which has the structure shown in formula VII; Equation VII; The compound VII, the nitrifying agent, and the fifth organic solvent were mixed and subjected to a nitration reaction to obtain an oxaliron intermediate having the structure shown in Formula VIII.

[0029] Unless otherwise specified, all raw materials involved in this invention are commercially available products well known in the art.

[0030] In this invention, benzaldehyde, malonic acid ester, acetone, a first catalyst, and a first organic solvent are mixed and subjected to a Knoevenagel-Michael addition reaction to obtain compound III.

[0031] In this invention, the benzaldehyde has the structure shown in Formula II: Formula II.

[0032] In this invention, the malonic ester has the structure shown in formula a or formula a', where R in formula a or formula a' is an alkyl, substituted alkyl, aryl, or substituted aryl. In this invention, when R in the structure shown in formula a or formula a' is an alkyl or substituted alkyl, the alkyl group preferably has 1 to 6 carbon atoms, more preferably a straight-chain alkyl group, such as methyl or ethyl; the substituent of the substituted alkyl group is preferably an aryl or substituted aryl group, such as phenyl; the substituent of the substituted aryl group is preferably an alkyl group (preferably with 1 to 6 carbon atoms), a halogen group, or a methoxy group. This invention does not have particular requirements regarding the position of the substituent of the substituted aryl group, and it can be ortho, meta, para, or multiple substituted positions. In the embodiments of this invention, the substituted alkyl group is benzyl. In this invention, when R is an aryl or substituted aryl in the structure shown in formula a or formula a', the aryl can be phenyl, and the substituent of the substituted aryl is preferably an alkyl group (preferably with 1 to 6 carbon atoms), a halogen group, or a methoxy group. This invention does not have any particular requirements on the position of the substituent of the substituted aryl, and it can be ortho, meta, para, or multiple substituted. In the embodiments of this invention, the substituted aryl is chlorophenyl.

[0033] In this invention, the first catalyst (chiral catalyst) comprises one or more of D-aspartic acid, D-glutamic acid, D-piperidinic acid, D-proline, (R)-diphenylprolyl trimethylsilyl ether, and (8a,9s)-6'-methoxycinnamine-9-amine. This invention utilizes inexpensive chiral amine catalysts to catalyze the construction of key chiral centers via asymmetric Knoevenagel-Michael addition reactions.

[0034] In this invention, the first organic solvent preferably includes one or more of chloroform, ethyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, toluene, N,N-dimethylformamide, dimethyl sulfoxide, and methyl tert-butyl ether.

[0035] In this invention, the preferred molar ratio of benzaldehyde, malonic acid ester, and acetone is 1:(1.0~1.2):(4.0~6.0), which can be 1:(1.0~1.1):(5.0~5.5); the preferred mass ratio of benzaldehyde to the first catalyst is 1:(0.01~0.03), which can be 1:(0.02~0.03). This invention does not have specific requirements regarding the amount of the first organic solvent, as long as the dissolution of the raw materials and the smooth progress of the reaction are ensured.

[0036] The present invention preferably involves sequentially adding malonic acid ester, a first organic solvent, benzaldehyde, acetone, and a first catalyst into a reaction vessel.

[0037] In this invention, the temperature of the Knoevenagel-Michael addition reaction is preferably 20~30℃, or 20~25℃, and the time is preferably 12~24h, or 12, 18 or 24h; the Knoevenagel-Michael addition reaction is preferably carried out under stirring conditions.

[0038] After the Knoevenagel-Michael addition reaction is completed, the present invention preferably performs post-treatment on the resulting reaction solution. The preferred post-treatment method is as follows: the reaction solution obtained from the Knoevenagel-Michael addition reaction is concentrated to recover the first organic solvent and acetone; the resulting residue is dissolved in ethyl acetate and extracted three times with sodium bicarbonate aqueous solution; the liquids are separated and the aqueous layers are combined; the pH of the resulting aqueous layer is adjusted to 4 with dilute hydrochloric acid, and then extracted three times with ethyl acetate; the organic layers are combined; the resulting organic layer is concentrated to dryness to obtain compound III.

[0039] In this invention, when the malonic acid ester has the structure shown in formula a, compound III has the structure shown in formula III-a, and the R in the structure shown in formula III-a is consistent with the R in the structure shown in formula a; when the malonic acid ester has the structure shown in formula a', compound III has the structure shown in formula III-a', and the R in the structure shown in formula III-a' is consistent with the R in the structure shown in formula a'.

[0040] After obtaining compound III, the present invention mixes compound III with water and a second organic solvent, or mixes compound III with an acid, to carry out a decarboxylation reaction to obtain compound IV.

[0041] In this invention, the second organic solvent preferably includes one or more of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and N,N-dimethylacetamide; the volume ratio of water to the second organic solvent is preferably 1:(1~5), and can be 1:(2~3.5). This invention does not have specific requirements on the amount of water and organic solvent added, as long as the reaction proceeds smoothly.

[0042] In this invention, the acid preferably includes one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and p-toluenesulfonic acid; the molar ratio of compound III to the acid is preferably 1:(5~10), and can be 1:(5~8). In this invention, mixing compound III and the acid preferably also includes adding water, and the volume ratio of water to acid is preferably 1:(1~5).

[0043] In this invention, the temperature of the decarboxylation reaction is preferably 60-100°C, but can be 80, 90, or 100°C, and the time is preferably 6-12 hours. Preferably, in this invention, compound III, a second organic solvent (or acid), and water are added sequentially to a reaction vessel, stirred until homogeneous, and then the resulting system is heated to 60-100°C to carry out the decarboxylation reaction.

[0044] After the decarboxylation reaction is completed, the present invention preferably performs post-treatment on the obtained reaction solution. The preferred post-treatment method is as follows: cooling the reaction solution obtained from the decarboxylation reaction to room temperature, extracting with ethyl acetate, separating the liquids, concentrating the organic layer to dryness, and obtaining compound IV.

[0045] In this invention, compound IV has the structure shown in formula IV.

[0046] After obtaining compound IV, the present invention mixes compound IV with an alcohol reagent to carry out an esterification reaction to obtain compound V.

[0047] In this invention, the alcohol reagent can be a liquid alcohol or a solid alcohol. When the alcohol reagent is a solid alcohol, an additional solvent needs to be added. The solvent is preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide. This invention does not have any special requirements on the amount of solvent used, as long as the raw materials are dissolved and the reaction proceeds smoothly.

[0048] In this invention, the alcohol reagent has the structure shown in Formula b, where R' is an alkyl or substituted alkyl group, and the alkyl group preferably has 1 to 16 carbon atoms. The substituent in the substituted alkyl group is preferably an aryl or substituted aryl group, the aryl group is preferably phenyl, and the substituent in the substituted aryl group is preferably an alkyl group, a halogen group, or a methoxy group. This invention does not have particular requirements regarding the position of the substituent in the substituted aryl group; it can be ortho, meta, para, or multiple-substituted. In this invention, the alcohol reagent is a liquid alcohol or a solid alcohol. In the embodiments of this invention, the alcohol reagent is specifically methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, n-hexanol, benzyl alcohol, or hexadecyl alcohol.

[0049] In this invention, when the alcohol reagent is a liquid alcohol, the mass ratio of compound IV to the volume of the alcohol reagent is preferably 1 g:(3~5) mL, or 1 g:(3.2~4) mL; when the alcohol reagent is a solid alcohol, the molar ratio of compound IV to the alcohol reagent is preferably 1:(1~5), or 1:(2~3).

[0050] In this invention, a catalyst may be added to the mixture of compound IV and the alcohol reagent. The catalyst preferably comprises one or more of sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, dicyclohexylcarbodiimide, oxalyl chloride, acetic anhydride, and 1-hydroxybenzotriazole. In this invention, the molar ratio of compound IV to the catalyst is preferably 1:(0.5~1.5), where sulfuric acid is calculated as H₂SO₄ and hydrochloric acid as HCl. In this invention, when no catalyst is added to the mixture of compound IV and the alcohol reagent, an aqueous solvent is preferably added. The aqueous solvent is preferably one or more of benzene, toluene, cyclohexane, chloroform, carbon tetrachloride, ethyl acetate, and 1,2-dichloroethane.

[0051] In this invention, when a catalyst is added to the mixture of compound IV and alcohol reagent, it is preferable to add compound IV and alcohol reagent (and solvent if the alcohol reagent is a solid alcohol) to a reaction vessel, stir until dissolved, and then add the catalyst.

[0052] In this invention, the temperature of the esterification reaction is preferably 70~110℃, which can be 70, 80, 83, 90, 100 or 110℃, and the time is preferably 6~72h, which can be 6, 8, 12, 24 or 72h.

[0053] After the esterification reaction is completed, the present invention preferably performs post-treatment on the obtained reaction solution. The preferred post-treatment method is as follows: the reaction solution obtained from the esterification reaction is rotary evaporated to recover most of the alcohol, the pH of the obtained residue is adjusted to 8 with saturated sodium bicarbonate, and then extracted three times with ethyl acetate, and the organic layers are combined; the obtained organic layer is concentrated to dryness to obtain compound V.

[0054] In this invention, the compound V has the structure shown in Formula V, and R' in the structure shown in Formula V is consistent with R' in the structure shown in Formula b.

[0055] After obtaining compound V, the present invention mixes compound V, a methyl Grignard reagent, and a third organic solvent to carry out a methylation reaction to obtain compound VI.

[0056] In this invention, the methyl Grignard reagent preferably includes methyl magnesium chloride and / or methyl magnesium bromide. In this invention, the third organic solvent preferably includes one or more of chloroform, dichloromethane, tetrahydrofuran, n-hexane, and methyl tert-butyl ether.

[0057] In this invention, the preferred molar ratio of compound V to the methyl Grignard reagent is 1:(1.5~2.0), which can be 1:1.5, 1:1.8, or 1:2.0. This invention does not have specific requirements regarding the amount of the third organic solvent, as long as it ensures the dissolution of the raw materials and the smooth progress of the reaction.

[0058] In this invention, the preferred temperature for the methylation reaction is -20 to -10°C, which can be -20, -15, or -10°C, and the preferred time is 12 to 18 hours, which can be 14, 15, or 18 hours. The methylation reaction is preferably carried out under stirring. Preferably, compound V is dissolved in a third organic solvent, the resulting system is cooled to -20 to -10°C, and then a methyl Grignard reagent is added. The methyl Grignard reagent is preferably added dropwise in the form of a methyl Grignard reagent solution, and the solvent of the methyl Grignard reagent solution is preferably the same as the third organic solvent. In this invention, the methylation reaction time is calculated from the point when the methyl Grignard reagent is completely added.

[0059] After the methylation reaction is completed, the present invention preferably performs post-treatment on the obtained reaction solution. The preferred post-treatment method is as follows: the pH of the reaction solution obtained from the methylation reaction is adjusted to neutral with dilute hydrochloric acid, the layers are separated, the aqueous layer is extracted three times with ethyl acetate, and the organic layers are combined; the obtained organic layer is dried with anhydrous sodium sulfate and concentrated to dryness to obtain compound VI.

[0060] In this invention, compound VI has the structure shown in formula VI.

[0061] After obtaining compound VI, the present invention mixes compound VI, a reducing agent and a fourth organic solvent to carry out a lactone reduction reaction to obtain compound VII.

[0062] In this invention, the reducing agent preferably includes one or more of triethylsilane, boron trifluoride ethyl ether, boran tetrahydrofuran, lithium aluminum hydride, sodium borohydride, and diisobutylaluminum hydride; the fourth organic solvent preferably includes one or more of chloroform, dichloromethane, tetrahydrofuran, n-hexane, and methyl tert-butyl ether.

[0063] In this invention, the molar ratio of compound VI to reducing agent is preferably 1:(1.5~3.0), or can be 1:(1.5~2); this invention does not have special requirements for the amount of the fourth organic solvent, as long as the raw materials are dissolved and the reaction proceeds smoothly.

[0064] In this invention, the temperature of the lactone reduction reaction is preferably 0-10°C, which can be 0, 5, or 10°C, and the time is preferably 4-8 hours; the lactone reduction reaction is preferably carried out under stirring. Preferably, in this invention, under a nitrogen atmosphere, compound VI is dispersed in a fourth organic solvent, the resulting system is cooled to 0-10°C, and then a reducing agent is added to carry out the lactone reduction reaction.

[0065] After the lactone reduction reaction is completed, the present invention preferably performs post-treatment on the obtained reaction solution. The preferred post-treatment method is as follows: quench the reaction solution obtained from the lactone reduction reaction with dilute hydrochloric acid, separate the layers, extract the aqueous layer twice with ethyl acetate, and combine the organic layers; wash the obtained organic layer with saturated sodium chloride, dry it with anhydrous sodium sulfate, and concentrate it to dryness to obtain compound VII.

[0066] In this invention, compound VII has the structure shown in formula VII.

[0067] After obtaining compound VII, the present invention mixes compound VII, a nitrifying agent and a fifth organic solvent to carry out a nitration reaction to obtain an oxaliron intermediate having the structure shown in formula VIII.

[0068] In this invention, the nitrifying agent preferably includes nitric acid, and the molar ratio of compound VII to the nitrifying agent is preferably 1:(1.0~3.0), or can be 1:(1.0~2.0). In this invention, the nitric acid is also preferably combined with a dehydrating agent, which preferably includes one or more of sulfuric acid, acetic anhydride, and hydrochloric acid. The molar ratio of the dehydrating agent to the nitric acid is preferably (3.0~5.0):(1.0~3.0), or can be (3.0~4.0):(1.0~2.0). The nitric acid is calculated as HNO3, the sulfuric acid as H2SO4, and the hydrochloric acid as HCl.

[0069] In this invention, the fifth organic solvent preferably includes one or more of chloroform, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and methyl tert-butyl ether. This invention does not have special requirements on the amount of the fifth organic solvent used, as long as the raw materials are dissolved and the reaction proceeds smoothly.

[0070] In this invention, the preferred temperature for the nitration reaction is -20 to -10°C, which can be -20, -15, or -10°C, and the preferred time is 2 to 4 hours; the nitration reaction is preferably carried out under stirring. Preferably, the compound VII is dissolved in a fifth organic solvent, the resulting system is cooled to -20 to -10°C, and then a nitrating agent is added dropwise to it to carry out the nitration reaction.

[0071] After the nitration reaction is completed, the present invention preferably performs post-treatment on the obtained reaction solution. The preferred post-treatment method is as follows: pour the reaction solution obtained from the nitration reaction into ice water, separate the liquid and liquid phases, extract the aqueous phase with dichloromethane, wash the organic layer with saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, and concentrate to dryness to obtain an oxaliplatin intermediate having the structure shown in Formula VIII.

[0072] The method for preparing the ogliflozin intermediate provided by this invention uses benzaldehyde as the starting material. The raw material is readily available, the preparation process is simple and easy to operate, the cost is low, and it is suitable for industrial production.

[0073] This invention provides a method for preparing a key intermediate of oxaliplatin, the key intermediate of oxaliplatin having the structure shown in Formula IX, comprising the following steps; An algileron intermediate having the structure shown in Formula VIII, a reducing agent, and a sixth organic solvent are mixed and subjected to a nitro reduction reaction to obtain an algileron key intermediate having the structure shown in Formula IX. Formula IX.

[0074] In this invention, the reducing agent preferably includes one or more of hydrogen, hydrazine hydrate, iron powder, zinc powder, tin powder, sodium dithionite, sodium sulfite, sodium sulfide, stannous chloride (which requires the presence of an acid, such as hydrochloric acid), titanium trichloride, and tetrahydroxyborane. In this invention, when the reducing agent includes one or more of hydrazine hydrate, iron powder, zinc powder, tin powder, sodium dithionite, sodium sulfite, sodium sulfide, stannous chloride, titanium trichloride, and tetrahydroxyborane, the molar ratio of the oglionene intermediate having the structure shown in Formula VIII to the reducing agent is preferably 1:(1~5), and can be 1:(3~4); when the reducing agent includes hydrogen, the hydrogen is introduced into the reaction system under pressure, and the pressure of the hydrogen is preferably 1~3 MPa, and can be 1, 1.5, 2, or 3 MPa.

[0075] In this invention, the mixing of the oglione intermediate having the structure shown in Formula VIII, the reducing agent, and the sixth organic solvent preferably further includes the addition of a second catalyst. Specifically, when the reducing agent includes hydrogen and / or hydrazine hydrate, the second catalyst is added. In this invention, the second catalyst preferably includes one or more of palladium on carbon, Raney nickel, and platinum dioxide; the mass ratio of the oglione intermediate having the structure shown in Formula VIII to the second catalyst is preferably 1:(0.05~0.1), and can be 1:(0.05~0.08).

[0076] In this invention, the sixth organic solvent preferably includes one or more of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, 1,4-dioxane, and n-hexane. This invention does not have any special requirements on the amount of the sixth organic solvent used, as long as the dissolution of the raw materials and the reaction proceed smoothly.

[0077] In this invention, the temperature of the nitro reduction reaction is preferably 20~100℃, but can be 30, 50 or 80℃, and the time is preferably 8~12h, but can be 8, 10 or 12h. The nitro reduction reaction is preferably carried out under stirring. Preferably, this invention involves adding an augerilon intermediate having the structure shown in Formula VIII, a reducing agent, and a sixth organic solvent (which may also include a second catalyst) to a reaction vessel, adjusting the system temperature to 20~100℃, and carrying out the nitro reduction reaction.

[0078] After the nitro reduction reaction is completed, the present invention preferably performs post-treatment on the resulting reaction solution. The preferred post-treatment method is as follows: filter the reaction solution obtained from the nitro reduction reaction, pass hydrogen chloride gas into the filtrate to precipitate a solid, filter, and dry the filter cake to obtain an oxalidomide key intermediate (hydrochloride form) with the structure shown in Formula IX; or, the preferred post-treatment method is as follows: slowly pour the reaction solution obtained from the nitro reduction reaction into ice water, adjust the pH to 7-8 with saturated sodium bicarbonate to precipitate a large amount of solid; filter, extract the filtrate with ethyl acetate, separate the layers, pass hydrogen chloride gas into the ethyl acetate layer to precipitate a solid, filter, and dry the filter cake to obtain an oxalidomide key intermediate (hydrochloride form) with the structure shown in Formula IX.

[0079] This invention provides a method for preparing a key intermediate of oxaliplatin, the key intermediate of oxaliplatin having the structure shown in Formula X, comprising the following steps; An algileron intermediate having the structure shown in Formula VIII, a reducing agent, and a sixth organic solvent are mixed and subjected to a nitro reduction reaction to obtain an algileron key intermediate having the structure shown in Formula IX. Formula IX; The key intermediate of oxaliplatin with the structure shown in Formula IX and a nitrite reagent are subjected to a diazotization reaction under acidic conditions. The resulting reaction solution is then mixed with 2-methylacetoacetate and a basic compound to undergo a Japp-Klingemann reaction to obtain the key intermediate of oxaliplatin with the structure shown in Formula X. The 2-methylacetoacetate has the structure shown in Formula C, where R'' is an alkyl or substituted alkyl group. Equation c, Formula X.

[0080] In this invention, the conditions for the nitro reduction reaction are the same as those in the above-described technical solution, and will not be repeated here.

[0081] In this invention, the nitrite reagent preferably includes one or more of nitrous acid, sodium nitrite, potassium nitrite, tert-butyl nitrite, nitrite sulfate, and isoamyl nitrite; the acidic condition is provided by an acid reagent, which preferably includes one or more of hydrochloric acid, sulfuric acid, trifluoroacetic acid, and p-toluenesulfonic acid. In this invention, the mixture of the ogliterol key intermediate having the structure shown in Formula IX, the nitrite reagent, and the acid reagent preferably also includes a solvent; when the nitrite reagent is one or more of nitrous acid, sodium nitrite, and potassium nitrite, the solvent is preferably water, and the acid reagent is preferably an inorganic acid; when the nitrite reagent is one or more of tert-butyl nitrite, nitrite sulfate, and isoamyl nitrite, the solvent is preferably an organic solvent, such as acetonitrile, THF, dichloromethane, etc., and the acid reagent is preferably an organic acid. In this invention, the preferred ratio of the ogliterol key intermediate having the structure shown in Formula IX to the solvent is 1 g: 1 mL.

[0082] In this invention, the 2-methylacetoacetate has the structure shown in Formula c, where R'' is an alkyl or substituted alkyl group. The alkyl group preferably has 1 to 6 carbon atoms, more preferably a straight-chain alkyl group, such as methyl or ethyl. The substituent of the substituted alkyl group is preferably aryl or substituted aryl, and the aryl group is preferably phenyl. In the embodiments of this invention, the substituted alkyl group is benzyl. The substituent of the substituted aryl group is preferably an alkyl group, a halogen group, or a methoxy group. This invention does not have any particular requirements on the position of the substituent of the substituted aryl group, and it can be ortho, meta, para, or multiple substituted positions.

[0083] In this invention, the alkaline compound preferably includes one or more of sodium hydroxide, potassium hydroxide, sodium acetate, and potassium acetate.

[0084] In this invention, the preferred molar ratio of compound IX, acid reagent, nitrite reagent, basic compound and 2-methylacetoacetate is 1:(4.0~6.0):(1.0~1.1):(5.0~7.0):(1.0~1.2), and can be 1:(5.0~6.0):(1.0~1.1):6.0:(1.0~1.2).

[0085] In this invention, the preferred temperature for the diazotization reaction is 0-5°C, and the preferred time is 1-6 hours. Preferably, the compound IX and an acid reagent (which may also include a solvent) are added to a reaction vessel, stirred in an ice bath, and then nitrite reagents are added in batches. The diazotization reaction is carried out at 0-5°C to obtain a reaction solution (i.e., a diazonium salt solution).

[0086] In this invention, the preferred temperature for the Japp-Klingemann reaction is -20 to 10°C, which can be -10 or 5°C, and the preferred time is 2 to 18 hours. The Japp-Klingemann reaction is preferably carried out under stirring conditions. Preferably, 2-methylacetoacetate is dissolved in an organic solvent (such as ethanol), cooled to -20 to 10°C, and a basic compound is added to it. The mixture is stirred until homogeneous to obtain a solution. Under heat preservation, the diazonium salt solution is added dropwise to the mixture to carry out the Japp-Klingemann reaction.

[0087] After the Japp-Klingemann reaction is completed, the present invention preferably performs post-treatment on the obtained reaction solution. The preferred post-treatment method is as follows: extract the reaction solution obtained from the Japp-Klingemann reaction three times with toluene, and combine the organic layers; wash the obtained organic layer with saturated sodium chloride and dry it with anhydrous sodium sulfate to obtain an oxalidomide key intermediate having the structure shown in Formula X.

[0088] In this invention, R'' in the structure shown in formula X is consistent with R'' in the structure shown in formula c.

[0089] This invention provides a method for preparing a key intermediate of oxaliplatin, the key intermediate of oxaliplatin having the structure shown in Formula I, comprising the following steps; An algileron intermediate having the structure shown in Formula VIII, a reducing agent, and a sixth organic solvent are mixed and subjected to a nitro reduction reaction to obtain an algileron key intermediate having the structure shown in Formula IX. Formula IX; The key intermediate of oxaliplatin with the structure shown in Formula IX and a nitrite reagent are subjected to a diazotization reaction under acidic conditions. The resulting reaction solution is then mixed with 2-methylacetoacetate and a basic compound to undergo a Japp-Klingemann reaction to obtain the key intermediate of oxaliplatin with the structure shown in Formula X. The 2-methylacetoacetate has the structure shown in Formula C, where R'' is an alkyl or substituted alkyl group. Equation c, Formula X; The key intermediate of omega-100 having the structure shown in Formula X was mixed with an acid and subjected to a Fischer indole synthesis reaction to obtain the key intermediate of omega-100 having the structure shown in Formula I. Formula I.

[0090] In this invention, the conditions for the nitro reduction reaction, diazotization reaction and Japp-Klingemann reaction are the same as those described in the above technical solution, and will not be repeated here.

[0091] In this invention, the acid preferably includes one or more of polyphosphoric acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, trifluoroacetic acid, acetic acid, zinc chloride, boron trifluoride ether, ferric chloride, and aluminum trichloride, wherein zinc chloride, boron trifluoride ether, ferric chloride, and aluminum trichloride are Lewis acids. In this invention, the molar ratio of compound X to acid is preferably 1:(20~40), and can be 1:(35~40), wherein the hydrochloric acid is calculated as HCl and the sulfuric acid as H2SO4.

[0092] In this invention, when the acid is a solid acid, the mixing of compound X and the acid further includes the addition of an organic solvent (referred to as the seventh organic solvent). In this invention, the seventh organic solvent preferably includes one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, toluene, dichloromethane, and 1,2-dichloroethane. This invention does not have specific requirements regarding the amount of the seventh organic solvent used, as long as it ensures the dissolution of the raw materials and the smooth progress of the reaction.

[0093] In this invention, the temperature of the Fischer indole synthesis reaction is preferably 40~100℃, but can be 60, 90 or 100℃, and the time is preferably 4~12h; the Fischer indole synthesis reaction is preferably carried out under stirring conditions.

[0094] After the Fischer indole synthesis reaction is completed, the present invention preferably performs post-treatment on the obtained reaction solution. The preferred post-treatment method is as follows: the reaction solution obtained from the indole synthesis reaction is adjusted to neutral pH with sodium hydroxide aqueous solution, extracted three times with ethyl acetate, and the organic layers are combined; the obtained organic layer is washed with saturated sodium chloride, dried with anhydrous sodium sulfate, concentrated to dryness, and the obtained solid is recrystallized with n-hexane or methyl tert-butyl ether to obtain an oxaliplatin key intermediate having the structure shown in Formula I.

[0095] In this invention, R'' in the structure shown in Formula I is consistent with R'' in the structure shown in Formula X.

[0096] To further illustrate the present invention, the following detailed description, in conjunction with examples, of the oglione intermediates provided by the present invention, their preparation methods, and the methods for preparing key oglione intermediates, should not be construed as limiting the scope of protection of the present invention.

[0097] Example 1: Preparation of compounds with structural formula III-a'-1 100 g of Michaelis-Menten acid (0.69 mol), 500 mL of dichloromethane, 73.7 g of benzaldehyde (0.69 mol), 201.5 g of acetone (3.47 mol), and 2.13 g of (8a,9s)-6'-methoxycincinine-9-amine (6.5 mmol) were added sequentially to a reaction flask, and the mixture was stirred at room temperature for 18 h. The reaction solution was concentrated to recover dichloromethane and acetone. The residue was dissolved in ethyl acetate and extracted three times with an aqueous sodium bicarbonate solution. The aqueous layers were separated, and the pH was adjusted to 4 with dilute hydrochloric acid. The mixture was then extracted three times with ethyl acetate, and the organic layers were combined and concentrated to dryness to give the compound shown in Formula III-a'-1 (168 g, yield 83.8%).

[0098] 1 H-NMR (400M, CDCl3): δ 7.19-7.32 (m, 5H), 4.18-4.27 (m, 2H), 3.64-3.73 (dd, 1H), 2.98-3.06 (dd, 1H), 2.18 (s, 3H), 1.64 (s, 3H), 1.30 (s, 3H); 13 C-NMR (101M, CDCl3): δ 208.05, 165.54, 165.27, 139.80, 128.90, 128.85,127.88, 105.38, 49.05, 45.49, 39.68, 30.47, 28.19, 27.97. Figure 1 and Figure 2The images show the hydrogen nuclear magnetic resonance (NMR) spectrum and carbon nuclear magnetic resonance (NMR) spectrum of the prepared compound of formula III-a'-1, respectively.

[0099] Example 2: Preparation of compounds with structural formula III-a-1 100 g of dimethyl malonate (0.76 mol), 500 mL of chloroform, 73.7 g of benzaldehyde (0.69 mol), 221.6 g of acetone (3.82 mol), and 1.63 g of (R)-diphenylprolyl trimethylsilyl ether (5 mmol) were added sequentially to a reaction flask, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated to recover chloroform and acetone. The residue was dissolved in ethyl acetate and extracted three times with an aqueous sodium bicarbonate solution. The aqueous layers were separated, and the pH was adjusted to 4 with dilute hydrochloric acid. The mixture was then extracted three times with ethyl acetate, and the organic layers were combined and concentrated to dryness to give the compound shown in Formula III-a-1 (172 g, yield 89.5%).

[0100] Example 3: Preparation of compounds with structural formula III-a-2 205.8 g of dibenzyl malonate (0.72 mol), 500 mL of tetrahydrofuran, 73.7 g of benzaldehyde (0.69 mol), 161.2 g of acetone (2.77 mol), and 2.3 g of D-proline (20 mmol) were added sequentially to a reaction flask, and the mixture was stirred at room temperature for 24 h. The reaction solution was concentrated to recover tetrahydrofuran and acetone. The residue was dissolved in ethyl acetate and extracted three times with an aqueous sodium bicarbonate solution. The aqueous layers were separated, and the pH was adjusted to 4 with dilute hydrochloric acid. The mixture was then extracted three times with ethyl acetate, and the organic layers were combined and concentrated to dryness to give the compound shown in Formula III-a-2 (240 g, yield 80.8%).

[0101] Example 4: Preparation of compounds with structural formula III-a-3 234.1 g of bis-(4-chlorophenyl)malonate (0.72 mol), 500 mL of dichloromethane, 73.7 g of benzaldehyde (0.69 mol), 221.6 g of acetone (3.82 mol), and 1.1 g of D-aspartic acid (8.3 mmol) were added sequentially to a reaction flask, and the mixture was stirred at room temperature for 18 h. The reaction solution was concentrated to recover dichloromethane and acetone. The residue was dissolved in ethyl acetate and extracted three times with an aqueous sodium bicarbonate solution. The aqueous layers were separated, and the pH was adjusted to 4 with dilute hydrochloric acid. The mixture was then extracted three times with ethyl acetate, and the organic layers were combined and concentrated to dryness to give the compound shown in formula III-a-3 (245 g, yield 75.3%).

[0102] Example 5: Preparation of compounds with structure IV 168 g of the compound shown in formula III-a'-1 (0.58 mol), 500 mL of N,N-dimethylformamide, and 170 mL of water were added sequentially to the reaction flask. After stirring until homogeneous, the system was heated to 90 °C and the reaction was continued at this temperature until the starting material was completely reacted. The reaction solution was cooled to room temperature and extracted with ethyl acetate. The mixture was separated, and the organic layer was concentrated to dryness to obtain the crude product of the compound shown in formula IV (125 g, yield >100%), which can be used directly in the next reaction without purification.

[0103] Example 6: Preparation of compounds with structure IV 172 g of the compound shown in formula III-a-1 (0.62 mol), 550 mL of 2-methyltetrahydrofuran, and 200 mL of water were added sequentially to the reaction flask. After stirring until homogeneous, the system was heated to 80 °C and the reaction was continued at this temperature until the starting material was completely reacted. The reaction solution was cooled to room temperature and extracted with ethyl acetate. The mixture was separated, and the organic layer was concentrated to dryness to obtain the crude product of the compound shown in formula IV (132 g, yield >100%), which can be used directly in the next reaction without purification.

[0104] Example 7: Preparation of compounds with structure IV 240 g of the compound shown in formula III-a-2 (0.56 mol), 480 mL of dimethyl sulfoxide, and 150 mL of water were added sequentially to the reaction flask. After stirring until homogeneous, the system was heated to 100 °C and the reaction was continued at this temperature until the reactants were completely reacted. The reaction solution was cooled to room temperature and extracted with ethyl acetate. The mixture was separated, and the organic layer was concentrated to dryness to obtain the crude product of the compound shown in formula IV (123 g, yield >100%), which can be used directly in the next reaction without purification.

[0105] Example 8: Preparation of compounds with structure IV 245 g of the compound shown in formula III-a-3 (0.52 mol), 421 mL of concentrated hydrochloric acid (4.16 mol), and 150 mL of water were added sequentially to the reaction flask. After stirring until homogeneous, the system was heated to 80 °C and the reaction was continued at this temperature until the reactants were completely reacted. The reaction solution was cooled to room temperature and extracted with ethyl acetate. The mixture was separated, and the organic layer was concentrated to dryness to obtain the crude product of the compound shown in formula IV (110 g, yield >100%), which can be used directly in the next reaction without purification.

[0106] Example 9: Preparation of the compound with structure V-1 The compound of formula IV obtained in Example 5 (i.e., all of the compound of formula IV obtained in Example 5) and 400 mL of methanol were added sequentially to the reaction flask. After stirring until dissolved, 25.6 mL of concentrated sulfuric acid (98 wt%) was added, and the mixture was heated to 70 °C and reacted for 6 h. Most of the methanol was recovered by rotary evaporation. The pH of the residue was adjusted to 8 with saturated sodium bicarbonate, and then extracted three times with ethyl acetate. The organic layers were combined and concentrated to dryness to obtain the compound of formula V-1 (108 g, yield 84.5%).

[0107] 1 H-NMR (400M, CDCl3): δ 7.14-7.30 (m, 5H), 3.61-3.70 (m, 1H), 3.55(s,3H), 2.72-2.87 (td, 2H), 2.54-2.70(ddd, 2H), 2.03(s, 3H); 13 C-NMR (101M, CDCl3): δ 206.90, 172.29, 143.13, 128.72, 127.30, 126.94, 51.66, 49.42, 40.66, 37.31, 30.48. Figure 3 and Figure 4 The images show the hydrogen nuclear magnetic resonance (NMR) spectrum and carbon nuclear magnetic resonance (NMR) spectrum of the compound shown in V-1, respectively.

[0108] Example 10: Preparation of compounds with structural formula V-2 The compound of formula IV obtained in Example 6 and 420 mL of tert-butanol were added sequentially to the reaction flask. After stirring until dissolved, 71.1 mL of concentrated hydrochloric acid (36 wt%) was added, and the mixture was heated to 83 °C and refluxed for 8 h. Most of the tert-butanol was recovered by rotary evaporation. The pH of the residue was adjusted to 8 with saturated sodium bicarbonate, and then extracted three times with ethyl acetate. The organic layers were combined and concentrated to dryness to obtain the compound of formula V-2 (147.6 g, yield 90.7%).

[0109] Example 11 Preparation of compounds with structural formula V-3 The compound of formula IV obtained in Example 7 and 500 mL of benzyl alcohol were added sequentially to the reaction flask. After stirring until dissolved, 25.6 mL of concentrated sulfuric acid (98 wt%) was added, and the mixture was heated to 100 °C and refluxed for 12 h. Most of the benzyl alcohol was recovered by rotary evaporation. The pH of the residue was adjusted to 8 with saturated sodium bicarbonate, and then extracted three times with ethyl acetate. The organic layers were combined and concentrated to dryness to obtain the compound of formula V-3 (137.1 g, yield 82.6%).

[0110] Example 12 Preparation of compounds with structural formula V-4 55 g of the compound of formula IV obtained in Example 8, 126 g of cetyl alcohol (0.52 mol), and 225 mL of N,N-dimethylformamide were added sequentially to a reaction flask. After stirring until dissolved, 12.8 mL of concentrated sulfuric acid (98 wt%) was added, and the mixture was heated to 100 °C and refluxed for 10 h. Most of the solvent was recovered by rotary evaporation. The pH of the residue was adjusted to 8 with saturated sodium bicarbonate, and then extracted three times with ethyl acetate. The organic layers were combined and concentrated to dryness to obtain the compound of formula V-4 (105 g, yield 93.8%).

[0111] Example 13 Preparation of compounds with structural formula V-5 A water separator was installed on the reaction flask, and then 55 g of the compound of formula IV obtained in Example 8, 57.8 g of n-butanol (0.78 mol), and 250 mL of toluene were added sequentially. After stirring until dissolved, the mixture was heated to 110 °C and refluxed for 72 h to remove water. After the reaction was completed, the reaction solution was directly concentrated to dryness by rotary evaporation to obtain the compound of formula V-5 (68.2 g, 100% yield).

[0112] Example 14 Preparation of compounds with structure VI 96.2 g (0.43 mol) of the compound shown in formula V-1 was dissolved in 480 mL of tetrahydrofuran, and the system was cooled to -20 °C and stirred until homogeneous. Then, 262.1 mL of a 3M tetrahydrofuran solution of methylmagnesium chloride was added dropwise. After complete addition, the reaction system was stirred for 15 h. The pH of the reaction system was then adjusted to neutral with dilute hydrochloric acid. The mixture was separated, and the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solution was concentrated to dryness to obtain the crude product of the compound shown in formula VI (120 g, yield >100%), which can be used directly in the next reaction without purification.

[0113] 1 H-NMR (400M, CDCl3): δ 7.31-7.38 (m, 2H), 7.18-7.27 (m, 3H), 3.21-3.32(m, 1H), 2.81-2.89 (ddd, 1H), 2.41-2.51(dd, 1H), 1.99-2.07 (ddd, 1H), 1.86-1.96(m, 1H), 1.49(s, 3H), 1.48(s, 3H); 13C-NMR (101M, CDCl3): δ 170.88, 142.61, 129.05, 127.32, 126.65, 82.03, 41.92, 37.25, 34.90, 30.91, 27.68. Figure 5 and Figure 6 The images show the hydrogen nuclear magnetic resonance (NMR) spectrum and carbon nuclear magnetic resonance (NMR) spectrum of the prepared compound of formula VI, respectively.

[0114] Example 15 Preparation of compounds with structure VI 112.8 g (0.43 mol) of the compound shown in formula V-2 was dissolved in 480 mL of chloroform, and the system was cooled to -15 °C and stirred until homogeneous. Then, 216 mL of a 3M tetrahydrofuran solution of methyl magnesium bromide was added dropwise. After complete addition, the reaction system was stirred for 18 h. The pH of the reaction system was then adjusted to neutral with dilute hydrochloric acid. The mixture was separated, and the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solution was concentrated to dryness to obtain the crude product of the compound shown in formula VI (116 g, yield >100%), which can be used directly in the next reaction without purification.

[0115] Example 16 Preparation of compounds with structure VI 127.4 g (0.43 mol) of the compound shown in formula V-3 was dissolved in 480 mL of methyl tert-butyl ether, and the system was cooled to -10 °C and stirred until homogeneous. Then, 286 mL of a 3M methyl magnesium chloride tetrahydrofuran solution was added dropwise. After complete addition, the reaction system was stirred for 14 h. The pH of the reaction system was then adjusted to neutral with dilute hydrochloric acid. The mixture was separated, and the aqueous layer was extracted three times with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solution was concentrated to dryness to obtain the crude product of the compound shown in formula VI (109 g, yield >100%), which can be used directly in the next reaction without purification.

[0116] Example 17 Preparation of compounds with structure VII Under a nitrogen atmosphere, the crude compound of formula VI obtained in Example 14 was dispersed in 550 mL of anhydrous tetrahydrofuran. The system was cooled to 0 °C, and then 29.72 g of sodium borohydride (0.78 mol) was added. The mixture was stirred until the reaction was complete. The reaction was quenched with dilute hydrochloric acid, and the mixture was separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the compound of formula VII (63.6 g, yield 77.7%).

[0117] 1 H-NMR (400M, CDCl3): δ 7.29-7.35 (m, 2H), 7.19-7.25 (m, 3H), 3.76-3.91(m, 2H), 2.88-3.00 (m, 1H), 1.60-1.76(m, 4H), 1.33(s, 3H), 1.28(s, 3H); 13 C-NMR (101M, CDCl3): δ 146.07, 128.60, 126.90, 126.37, 71.96, 61.88, 44.43, 37.66, 33.50, 31.86, 21.87. Figure 7 and Figure 8 The images show the hydrogen nuclear magnetic resonance (NMR) spectrum and carbon nuclear magnetic resonance (NMR) spectrum of the prepared compound VII, respectively.

[0118] Example 18 Preparation of compounds with structure VII Under a nitrogen atmosphere, the crude compound of formula VI obtained in Example 15 was dispersed in 550 mL of anhydrous dichloromethane. The system was cooled to 5 °C, and then 32.63 g of lithium aluminum hydride (0.86 mol) was added. The mixture was stirred until the reaction was complete. The reaction was quenched with dilute hydrochloric acid, and the mixture was separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the compound of formula VII (60.1 g, yield 73.4%).

[0119] Example 19 Preparation of compounds with structure VII Under a nitrogen atmosphere, the crude compound of formula VI obtained in Example 16 was dispersed in 550 mL of anhydrous tetrahydrofuran. The system was cooled to 10 °C, and then 55.86 g of borane tetrahydrofuran (0.65 mol) was added. The mixture was stirred until the reaction was complete. The reaction was quenched with dilute hydrochloric acid, and the mixture was separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the compound of formula VII (66.7 g, yield 81.5%).

[0120] Example 20 Preparation of compounds with structural formula VIII 35 g of the compound shown in formula VII (0.18 mol) was dissolved in 175 mL of dichloromethane. The system was cooled to -10 °C, and 55.49 g of concentrated sulfuric acid (0.55 mol) was added dropwise. After the addition was complete, 18.85 g of 60% concentrated nitric acid (0.18 mol) was added dropwise, and stirring was continued until the reactants reacted completely. The reaction solution was poured into 500 mL of ice water, and the mixture was separated. The aqueous phase was extracted with dichloromethane, and the organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the crude product of the compound shown in formula VIII (43.87 g, yield >100%).

[0121] Example 21 Preparation of compounds with structural formula VIII 35 g of the compound shown in formula VII (0.18 mol) was dissolved in 150 mL of chloroform. The system was cooled to -20 °C, and 73.98 g of concentrated sulfuric acid (0.73 mol) was added dropwise. After the addition was complete, 24.23 g of 60% concentrated nitric acid (0.23 mol) was added dropwise, and stirring was continued until the reactants reacted completely. The reaction solution was poured into 500 mL of ice water, and the mixture was separated. The aqueous phase was extracted with dichloromethane, and the organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the crude product of the compound shown in formula VIII (41.07 g, yield 97%).

[0122] Example 22 Preparation of compounds with structural formula VIII 35 g (0.18 mol) of the compound shown in formula VII was dissolved in 175 mL of methyl tert-butyl ether. The system was cooled to -15 °C, and 90 g (0.9 mol) of concentrated sulfuric acid was added dropwise. After the addition was complete, 46.72 g (0.44 mol) of 60% concentrated nitric acid was added dropwise, and stirring was continued until the reactants reacted completely. The reaction solution was poured into 500 mL of ice water, and the mixture was separated. The aqueous phase was extracted with dichloromethane, and the organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the crude product of the compound shown in formula VIII (44.15 g, yield >100%).

[0123] Example 23 Preparation of compounds with structural formula IX The crude compound of formula VIII obtained in Example 20, 220 mL of methanol, and 2.2 g of palladium on carbon (containing 10 wt% palladium) were added to a 500 mL autoclave. The air was replaced with hydrogen, and the hydrogen pressure was increased to 1 MPa. The mixture was stirred, and the system was heated to 50 °C and stirred for 10 h. The mixture was filtered, and hydrogen chloride gas was passed through the filtrate to precipitate a solid. The solid was filtered again, and the filter cake was dried to obtain the hydrochloride form of the compound of structural formula IX (36.3 g, yield 83.4%).

[0124] Example 24 Preparation of compounds with structure formula IX The crude compound of formula VIII obtained in Example 21, 200 mL of tetrahydrofuran, and 4 g of Raney nickel were added to a 500 mL autoclave. The air was replaced with hydrogen, and the hydrogen pressure was increased to 3 MPa. The mixture was stirred, and the system was heated to 30 °C and stirred for another 8 h. The mixture was filtered, and hydrogen chloride gas was passed through the filtrate to precipitate a solid. The solid was then filtered again, and the filter cake was dried to obtain the hydrochloride form of the compound of structural formula IX (37.4 g, yield 85.9%).

[0125] Example 25 Preparation of compounds with structure formula IX The crude compound of formula VIII obtained in Example 22 was added to a 500 mL reaction flask and dissolved in 230 mL of ethanol. 121.8 g of stannous chloride dihydrate (0.54 mol) was added in portions at room temperature, and the mixture was stirred until homogeneous. Then, 90 mL of concentrated hydrochloric acid (36 wt%) was added dropwise, and the temperature was controlled below 30 °C. After the addition was complete, the reaction system was heated to 80 °C and stirred for 8 h. The reaction solution was cooled to room temperature and slowly poured into ice water. The pH was then adjusted to 7-8 with saturated sodium bicarbonate, resulting in the precipitation of a large amount of solid. The mixture was filtered, and the filtrate was extracted with ethyl acetate. The layers were separated, and hydrogen chloride gas was passed through the ethyl acetate layer, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was dried to obtain the hydrochloride form of the compound of formula IX (35.1 g, yield 80.6%).

[0126] Example 26 Preparation of compounds with structural formula X-1 9.3 g of the compound shown in Formula IX (45 mmol), 23.3 g of concentrated hydrochloric acid (225 mmol), and 93 mL of water were added sequentially to a reaction flask and stirred in an ice bath. Then, 3.45 g of sodium nitrite (49.5 mmol) was added in portions. The mixture was heated to 5 °C and stirred until the reactants were completely reacted to obtain a diazonium salt solution. 7.03 g of methyl 2-methylacetoacetate (54 mmol) was dissolved in 60 mL of ethanol, cooled to -10 °C, and 22.14 g of sodium acetate (270 mmol) was added. The mixture was stirred until homogeneous, and the diazonium salt solution was added dropwise while maintaining the temperature. Stirring continued until the reactants were completely reacted. The reaction solution was extracted three times with toluene. The combined organic layers were washed with saturated sodium chloride and dried over anhydrous sodium sulfate to obtain the crude compound shown in Formula X-1 (14.5 g, yield >100%), which can be used directly in the next reaction without further purification.

[0127] Example 27 Preparation of compounds with structural formula X-2 9.3 g of the compound shown in Formula IX (45 mmol), 28 g of concentrated hydrochloric acid (270 mmol), and 93 mL of water were added sequentially to a reaction flask and stirred in an ice bath. Then, 3.3 g of sodium nitrite (47 mmol) was added in portions. The mixture was heated to 5 °C and stirred until the reactants were completely reacted to obtain a diazonium salt solution. 6.5 g of ethyl 2-methylacetoacetate (45 mmol) was dissolved in 60 mL of ethanol, cooled to -10 °C, and 15.3 g of potassium hydroxide (270 mmol) was added. The mixture was stirred until homogeneous, and the diazonium salt solution was added dropwise while maintaining the temperature. Stirring continued until the reactants were completely reacted. The reaction solution was extracted three times with toluene. The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the crude compound shown in Formula X-2 (15.1 g, yield >100%), which can be used directly in the next reaction without further purification.

[0128] Example 28 Preparation of compounds with structural formula X-3 9.3 g of the compound shown in Formula IX (45 mmol), 23.3 g of concentrated hydrochloric acid (225 mmol), and 93 mL of water were added sequentially to a reaction flask and stirred in an ice bath. Then, 4.2 g of potassium nitrite (49.5 mmol) was added in portions. The mixture was heated to 5 °C and stirred until the reactants were completely reacted to obtain a diazonium salt solution. 11.13 g of 2-methylacetoacetate benzyl ester (54 mmol) was dissolved in 60 mL of ethanol, cooled to -10 °C, and 10.8 g of sodium hydroxide (270 mmol) was added. The mixture was stirred until homogeneous, and the diazonium salt solution was added dropwise while maintaining the temperature. Stirring continued until the reactants were completely reacted. The reaction solution was extracted three times with toluene. The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the crude product of the compound shown in Formula X-3 (17.5 g, yield >100%), which can be used directly in the next reaction without further purification.

[0129] Example 29 Preparation of compounds with structural formula I-1 The crude compound of formula X-1 obtained in Example 26 was dispersed in 100 mL of acetic acid, heated to 90 °C, and stirred until the reactants reacted completely. The reaction solution was concentrated to recover most of the acetic acid, water was added to the residue, and the pH was adjusted to neutral with an aqueous sodium hydroxide solution. The mixture was extracted three times with ethyl acetate, the combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness. The resulting solid was recrystallized from n-hexane to give the compound of formula I-1 (11.33 g, yield 87.6%).

[0130] Example 30 Preparation of compounds with structural formula I-2 The crude compound of formula X-2 obtained in Example 27 was dispersed in 100 mL of concentrated hydrochloric acid (36 wt%), heated to 60 °C, and stirred until the reactants reacted completely. The pH of the reaction solution was adjusted to neutral with an aqueous sodium hydroxide solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness. The resulting solid was recrystallized from n-hexane to obtain the compound of formula I-2 (12.88 g, yield 94.9%, >99% ee).

[0131] 1 H-NMR (400M, DMSO-d6): δ 11.77(s, 1H), 7.05-7.50(m, 4H), 4.28-4.36(q,2H), 3.66-3.73(m, 2H), 2.92-3.02(m, 1H), 1.44-1.71(m, 4H), 1.30-1.35(t, 3H),1.25(s, 3H), 1.17(s, 3H); 13 C-NMR (101M, DMSO-d6): δ 161.38, 137.95, 136.23,127.39, 126.90, 124.59, 118.98, 112.48, 107.55, 71.31, 60.85, 60.38, 44.50,36.66, 33.77, 31.65, 21.69, 14.34. Figure 9 and Figure 10 The hydrogen nuclear magnetic resonance (NMR) spectra and carbon NMR spectra of the compounds of formula I-2, respectively.

[0132] Example 31 Preparation of compounds with structural formula I-3 The crude compound of formula X-3 obtained in Example 28 was dispersed in 100 mL of polyphosphoric acid, heated to 100 °C, and stirred until the reactants reacted completely. The pH of the reaction solution was adjusted to neutral with an aqueous sodium hydroxide solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness. The resulting solid was recrystallized from methyl tert-butyl ether to obtain the compound of formula I-3 (14.06 g, yield 85.9%).

[0133] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. An oxaliplatin intermediate, characterized in that, It has the structure shown in Equation VIII: Formula VIII.

2. The method for preparing the oligomerone intermediate according to claim 1, characterized in that, Includes the following steps: Benzaldehyde, malonic acid ester, acetone, a first catalyst, and a first organic solvent are mixed and subjected to a Knoevenagel-Michael addition reaction to yield compound III. The first catalyst comprises one or more of D-aspartic acid, D-glutamic acid, D-piperidinic acid, D-proline, (R)-diphenylprolyl trimethylsilyl ether, and (8a,9s)-6'-methoxycinnamine-9-amine. The malonic acid ester has the structure shown in formula a or formula a', where R is an alkyl, substituted alkyl, aryl, or substituted aryl group. When the malonic acid ester has the structure shown in formula a, compound III has the structure shown in formula III-a; when the malonic acid ester has the structure shown in formula a', compound III has the structure shown in formula III-a'. Formula a, Formula a' Formula III-a, Formula III-a'; Compound III is mixed with water and a second organic solvent, or compound III is mixed with an acid, and subjected to a decarboxylation reaction to obtain compound IV; compound IV has the structure shown in formula IV: Formula IV; Compound IV was mixed with an alcohol reagent and subjected to an esterification reaction to obtain compound V; the alcohol reagent had the structure shown in formula b, where R' was an alkyl or substituted alkyl group; compound V had the structure shown in formula V. Formula b, Formula V; The compound V, a methyl Grignard reagent, and a third organic solvent are mixed and subjected to a methylation reaction to obtain compound VI, which has the structure shown in formula VI. Formula VI; Compound VI, a reducing agent, and a fourth organic solvent are mixed to carry out a lactone reduction reaction to obtain compound VII, which has the structure shown in formula VII; Equation VII; The compound VII, the nitrifying agent, and the fifth organic solvent were mixed and subjected to a nitration reaction to obtain an oxaliron intermediate having the structure shown in Formula VIII.

3. The preparation method according to claim 2, characterized in that, The molar ratio of benzaldehyde, malonic acid ester and acetone is 1:(1.0~1.2):(4.0~6.0), and the mass ratio of benzaldehyde to the first catalyst is 1:(0.01~0.03); the temperature of the Knoevenagel-Michael addition reaction is 20~30℃, and the time is 12~24h.

4. The preparation method according to claim 2, characterized in that, The decarboxylation reaction is carried out at a temperature of 60~100℃ for a time of 6~12h.

5. The preparation method according to claim 2, characterized in that, The alcohol reagent is a liquid alcohol or a solid alcohol. When the alcohol reagent is a liquid alcohol, the mass ratio of compound IV to the volume of the alcohol reagent is 1 g:(3~5) mL. When the alcohol reagent is a solid alcohol, the molar ratio of compound IV to the alcohol reagent is 1:(1~5). The esterification reaction is carried out at a temperature of 70~110℃ for 6~72 h.

6. The preparation method according to claim 2, characterized in that, The methyl Grignard reagent includes methyl magnesium chloride and / or methyl magnesium bromide; the molar ratio of compound V to the methyl Grignard reagent is 1:(1.5~2.0); the methylation reaction is carried out at a temperature of -20~-10℃ for 12~18h.

7. The preparation method according to claim 2, characterized in that, The reducing agent includes one or more of triethylsilane, boron trifluoride ether, borane tetrahydrofuran, lithium aluminum hydride, sodium borohydride, and diisobutylaluminum hydride; the molar ratio of compound VI to the reducing agent is 1:(1.5~3.0); the temperature of the lactone reduction reaction is 0~10℃, and the time is 4~8h.

8. The preparation method according to claim 2, characterized in that, The nitrifying agent includes nitric acid, and the molar ratio of compound VII to nitric acid is 1:(1.0~3.0); the nitration reaction is carried out at a temperature of -20~-10℃ for 2~4 hours.

9. A method for preparing a key intermediate of oxaliplatin, said key intermediate having the structure shown in Formula IX, characterized in that, Includes the following steps: An algileron intermediate having the structure shown in Formula VIII, a reducing agent, and a sixth organic solvent are mixed and subjected to a nitro reduction reaction to obtain an algileron key intermediate having the structure shown in Formula IX. Formula IX.

10. The method according to claim 9, characterized in that, The reducing agent includes one or more of hydrogen, hydrazine hydrate, iron powder, zinc powder, tin powder, sodium dithionite, sodium sulfite, sodium sulfide, stannous chloride, titanium trichloride, and tetrahydroxyborane; the nitro reduction reaction is carried out at a temperature of 20~100℃ for 8~12h.

11. The method according to claim 9 or 10, characterized in that, The mixture of the oglioneron intermediate having the structure shown in Formula VIII, the reducing agent, and the sixth organic solvent further includes the addition of a second catalyst, which comprises one or more of palladium on carbon, Raney nickel, and platinum dioxide.

12. A method for preparing a key intermediate of oxaliplatin, said key intermediate having the structure shown in Formula X, characterized in that, Includes the following steps; An algileron intermediate having the structure shown in Formula VIII, a reducing agent, and a sixth organic solvent are mixed and subjected to a nitro reduction reaction to obtain an algileron key intermediate having the structure shown in Formula IX. Formula IX; The key intermediate of oxaliplatin with the structure shown in Formula IX and a nitrite reagent are subjected to a diazotization reaction under acidic conditions. The resulting reaction solution is then mixed with 2-methylacetoacetate and a basic compound to undergo a Japp-Klingemann reaction to obtain the key intermediate of oxaliplatin with the structure shown in Formula X. The 2-methylacetoacetate has the structure shown in Formula C, where R'' is an alkyl or substituted alkyl group. Equation c, Formula X.

13. The method according to claim 12, characterized in that, The nitrite reagents include one or more of nitrite, sodium nitrite, potassium nitrite, tert-butyl nitrite, nitrite sulfate, and isoamyl nitrite; the diazotization reaction is carried out at a temperature of 0-5°C for 1-6 hours; the Japp-Klingemann reaction is carried out at a temperature of -20-10°C for 2-18 hours.

14. A method for preparing a key intermediate of oxaliplatin, said key intermediate having the structure shown in Formula I, characterized in that, Includes the following steps; An algileron intermediate having the structure shown in Formula VIII, a reducing agent, and a sixth organic solvent are mixed and subjected to a nitro reduction reaction to obtain an algileron key intermediate having the structure shown in Formula IX. Formula IX; The key intermediate of oxaliplatin with the structure shown in Formula IX and a nitrite reagent are subjected to a diazotization reaction under acidic conditions. The resulting reaction solution is then mixed with 2-methylacetoacetate and a basic compound to undergo a Japp-Klingemann reaction to obtain the key intermediate of oxaliplatin with the structure shown in Formula X. The 2-methylacetoacetate has the structure shown in Formula C, where R'' is an alkyl or substituted alkyl group. Equation c, Formula X; The key intermediate of omega-100 having the structure shown in Formula X was mixed with an acid and subjected to a Fischer indole synthesis reaction to obtain the key intermediate of omega-100 having the structure shown in Formula I. Equation I.

15. The method according to claim 14, characterized in that, The Fischer indole synthesis reaction was carried out at a temperature of 40–100 °C for 4–12 h.

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