CN-122010885-A - Oraglycone intermediate, preparation method thereof and method for preparing key intermediate of Oraglycone

CN122010885ACN 122010885 ACN122010885 ACN 122010885ACN-122010885-A

Abstract

The invention provides an Oraglycone intermediate, a preparation method thereof and a method for preparing an Oraglycone key intermediate, and relates to the technical field of organic chemistry. The Oraglycone intermediate provided by the invention has a structure shown in a formula VIII, is easy to obtain, can be conveniently prepared by taking benzaldehyde as a starting raw material, does not need to use a chiral chromatographic column for preparation, has a key chiral center which is formed by catalyzing an asymmetric Knoevenagel-Michael addition reaction by an inexpensive chiral amine catalyst, and is easy to realize industrial production of the Oraglycone key intermediate (the structure shown in a formula I) and reduces the production cost. The invention provides a method for preparing an Oraglycone key intermediate (structure shown in formula I), which is prepared by nitroreduction reaction, japp-KLINGEMANN reaction and indole synthesis reaction of the Oraglycone intermediate, and is suitable for industrial production. The catalyst of formula VIII, Formula I.

Inventors

HU CHEN
LIU SIZHOU
ZHAO XUEFENG
WANG PENG
XU JINGLIN
ZOU YONG

Assignees

江西同和药业股份有限公司

Dates

Publication Date: 20260512
Application Date: 20260128

Claims (15)

1. An oxgliflozin intermediate having a structure according to formula VIII: Formula VIII.
2. A process for the preparation of an intermediate of oglitazone as claimed in claim 1, comprising the steps of: Mixing benzaldehyde, malonate, acetone, a first catalyst and a first organic solvent for Knoevenagel-Michael addition reaction to obtain a compound III, wherein the first catalyst comprises one or more of D-aspartic acid, D-glutamic acid, D-pipecolic acid, D-proline, (R) -diphenylprolyl trimethyl silyl ether and (8 a,9 s) -6 '-methoxy cinchonine-9-amine, the malonate has a structure shown in a formula a or a formula a', R in the structure shown in the formula a or the formula a 'is alkyl, substituted alkyl, aryl or substituted aryl, when the malonate has the structure shown in the formula a, the compound III has the structure shown in the formula III-a', and when the malonate has the structure shown in the formula a ', the compound III has the structure shown in the formula III-a'; A, a step of, A', The compound of the formula III-a, Formula III-a'; Mixing the compound III, water and a second organic solvent, or mixing the compound III and acid, and performing decarboxylation reaction to obtain a compound IV, wherein the compound IV has a structure shown in a formula IV: A formula IV; mixing the compound IV with an alcohol reagent for esterification reaction to obtain a compound V, wherein the alcohol reagent has a structure shown in a formula b, R' in the structure shown in the formula b is alkyl or substituted alkyl, and the compound V has a structure shown in a formula V: B, the step of, A formula V; Mixing the compound V, a methyl Grignard reagent and a third organic solvent for methylation reaction to obtain a compound VI, wherein the compound VI has a structure shown in a formula VI; formula VI; Mixing the compound VI, a reducing agent and a fourth organic solvent to perform a lactone reduction reaction to obtain a compound VII, wherein the compound VII has a structure shown in a formula VII; Formula VII; And mixing the compound VII, the nitrating reagent and the fifth organic solvent for nitration reaction to obtain the Oraglycone intermediate with the structure shown in the formula VIII.
3. The preparation method of the composition according to claim 2, wherein the mass ratio of the substances of the benzaldehyde, the malonate and the acetone is 1 (1.0-1.2): 4.0-6.0, the mass ratio of the benzaldehyde to the first catalyst is 1 (0.01-0.03), and the temperature of the Knoevenagel-Michael addition reaction is 20-30 ℃ and the time is 12-24 hours.
4. The preparation method according to claim 2, wherein the decarboxylation reaction is carried out at a temperature of 60-100 ℃ for a time of 6-12 hours.
5. The preparation method according to claim 2, wherein the alcohol reagent is a liquid alcohol or a solid alcohol, the ratio of the mass of the compound IV to the volume of the alcohol reagent is 1g (3-5) mL when the alcohol reagent is a liquid alcohol, the ratio of the mass of the compound IV to the volume of the alcohol reagent is 1 (1-5) when the alcohol reagent is a solid alcohol, and the esterification reaction temperature is 70-110 ℃ for 6-72 h.
6. The preparation method of the methyl Grignard reagent according to claim 2, wherein the methyl Grignard reagent comprises methyl magnesium chloride and/or methyl magnesium bromide, the mass ratio of the compound V to the methyl Grignard reagent is1 (1.5-2.0), the temperature of the methylation reaction is-20 to-10 ℃, and the time is 12-18 h.
7. The preparation method of the lactone reducing agent is characterized in that the reducing agent comprises one or more of triethylsilane, boron trifluoride diethyl ether, borane tetrahydrofuran, lithium aluminum hydride, sodium borohydride and diisobutyl aluminum hydride, the ratio of the compound VI to the reducing agent is 1 (1.5-3.0), the temperature of the lactone reducing reaction is 0-10 ℃, and the time is 4-8 hours.
8. The preparation method of the catalyst according to claim 2, wherein the nitrating agent comprises nitric acid, the mass ratio of the compound VII to the nitric acid is 1 (1.0-3.0), the temperature of the nitration reaction is-20 to-10 ℃ and the time is 2-4 hours.
9. A process for preparing an octulom key intermediate having a structure represented by formula IX comprising the steps of: Mixing the Oraglycone intermediate with the structure shown in the formula VIII, a reducing agent and a sixth organic solvent for nitroreduction reaction to obtain the Oraglycone key intermediate with the structure shown in the formula IX; Formula IX.
10. The method of claim 9, wherein the reducing agent comprises one or more of hydrogen, hydrazine hydrate, iron powder, zinc powder, tin powder, sodium hydrosulfite, sodium sulfite, sodium sulfide, stannous chloride, titanium trichloride and tetrahydroxy diborane, and the temperature of the nitroreduction reaction is 20-100 ℃ for 8-12 h.
11. The method of claim 9 or 10, wherein mixing the oxglibenclamide intermediate having the structure of formula VIII, the reducing agent, and the sixth organic solvent further comprises adding a second catalyst comprising one or more of palladium on carbon, raney nickel, and platinum dioxide.
12. A method for preparing an ogestrone key intermediate, wherein the ogestrone key intermediate has a structure shown in a formula X, and the method is characterized by comprising the following steps of; Mixing the Oraglycone intermediate with the structure shown in the formula VIII, a reducing agent and a sixth organic solvent for nitroreduction reaction to obtain the Oraglycone key intermediate with the structure shown in the formula IX; Formula IX; Diazotizing the key intermediate of the Orglisten with the structure shown in the formula IX and a nitrous reagent under an acidic condition, mixing the obtained reaction liquid with 2-methyl acetoacetate and an alkaline compound, and carrying out Japp-KLINGEMANN reaction to obtain the key intermediate of the Orglisten with the structure shown in the formula X, wherein the 2-methyl acetoacetate has the structure shown in the formula c, and R '' in the structure shown in the formula c is alkyl or substituted alkyl; C, the step of obtaining the product, Formula X.
13. The method of claim 12, wherein the nitrous acid reagent comprises one or more of nitrous acid, sodium nitrite, potassium nitrite, tert-butyl nitrite, nitrous acid sulfate and isoamyl nitrite, the diazotization reaction is carried out at a temperature of 0-5 ℃ for 1-6 hours, and the Japp-KLINGEMANN reaction is carried out at a temperature of-20-10 ℃ for 2-18 hours.
14. A method for preparing an ogestrone key intermediate, wherein the ogestrone key intermediate has a structure shown in a formula I, and is characterized by comprising the following steps of; Mixing the Oraglycone intermediate with the structure shown in the formula VIII, a reducing agent and a sixth organic solvent for nitroreduction reaction to obtain the Oraglycone key intermediate with the structure shown in the formula IX; Formula IX; Diazotizing the key intermediate of the Orglisten with the structure shown in the formula IX and a nitrous reagent under an acidic condition, mixing the obtained reaction liquid with 2-methyl acetoacetate and an alkaline compound, and carrying out Japp-KLINGEMANN reaction to obtain the key intermediate of the Orglisten with the structure shown in the formula X, wherein the 2-methyl acetoacetate has the structure shown in the formula c, and R '' in the structure shown in the formula c is alkyl or substituted alkyl; C, the step of obtaining the product, A formula X; Mixing the key intermediate of the Oraglycone with the structure shown in the formula X with acid to perform Fischer indole synthesis reaction to obtain the key intermediate of the Oraglycone with the structure shown in the formula I; Formula I.
15. The method of claim 14, wherein the temperature of the Fischer-tropsch indole synthesis reaction is 40-100 ℃ for 4-12 hours.

Description

Oraglycone intermediate, preparation method thereof and method for preparing key intermediate of Oraglycone Technical Field The invention relates to the technical field of organic chemistry, in particular to an Oglibenclamide intermediate, a preparation method thereof and a method for preparing an Oglibenclamide key intermediate. Background Glucagon-like peptide-1 receptor agonists, GLP-1 receptor agonists, are a class of drugs for the treatment of type 2 diabetes. The medicine can play the role of incretin to produce the effect of reducing blood sugar by exciting glucagon-like peptide-1 receptor, has the characteristics of promoting insulin secretion by glucose dependence, inhibiting glucagon secretion, delaying gastric emptying, reducing ingestion and improving blood lipid level. In addition to the hypoglycemic effect, GLP-1 receptor agonists have potential anti-inflammatory and anti-atherosclerosis effects of reducing body weight, intimal thickening and smooth muscle proliferation following vascular injury, and the drugs norand profitability have been shown to regulate appetite by activating GLP-1 receptors, while having therapeutic and weight management effects on diabetes. GLP-1 receptor agonists are injection type medicaments represented by semaglutin (Semaglutide) and telipopeptide (Tirzepatide), and have great success in the market due to the excellent hypoglycemic and weight-reducing effects. However, the manner in which the injection is administered presents challenges in terms of convenience and patient compliance. The advent of the ogestrone (Orforglipron) breaks through this bottleneck. Month 2025, it created a history of oral small molecule GLP-1 receptor agonists that were the first to successfully complete phase 3 clinical trials. This means that the patient can eventually go through daily injections, once daily without food and water restrictions. The structural formula of the Ogliflozin is as follows: 。 The success of the Oglibenclamide is derived from the breakthrough design of non-peptide small molecules, and compared with the traditional polypeptide GLP-1 drugs, the Oglibenclamide has remarkable advantages. The small molecule has stable structure and property, and can resist degradation of digestive enzyme, thereby realizing oral administration. The difficulty in the synthesis of the oxglibenclamide is that the chiral construction on the 5-pyran indole ring and the synthesis of the key intermediate of the oxglibenclamide containing the chiral 5-pyran indole ring become important research subjects. The related art discloses a method for constructing a racemized 5-pyran indole compound 31c by utilizing a Negishi coupling reaction, and separating the racemized 5-pyran indole compound by using a chiral chromatographic column to obtain a chiral compound shown in a formula I-2 (the preparation route is shown in a scheme 1). The problems with this route are 1) the expensive metallic palladium and ligand used in the Negishi coupling reaction, resulting in high costs, 2) the difficult availability of the starting material, ethyl 5-bromoindole-2-carboxylate, and 3) the need for separation with chiral chromatographic columns, which are difficult to use in commercial processes. Route 1. At present, a method for preparing an octreotide key intermediate containing chiral 5-pyran indole ring at low cost is needed to be developed, so that the method is more beneficial to industrial production. Disclosure of Invention In view of the above, the present invention aims to provide an oxgliflozin intermediate, a preparation method thereof and a method for preparing the oxgliflozin key intermediate. The Oraglycone intermediate provided by the invention is easy to obtain, can be conveniently prepared by taking benzaldehyde as a starting material, does not need to use a chiral chromatographic column for preparation, has a key chiral center which is catalyzed and constructed by a cheap chiral amine catalyst, is easy to realize industrial production of the Oraglycone key intermediate, and reduces production cost. In order to achieve the above object, the present invention provides the following technical solutions: the invention provides an Oraglycone intermediate, which has a structure shown in a formula VIII: Formula VIII. The invention provides a preparation method of the Oraglycone intermediate in the technical scheme, which comprises the following steps: Mixing benzaldehyde, malonate, acetone, a first catalyst and a first organic solvent for Knoevenagel-Michael addition reaction to obtain a compound III, wherein the first catalyst comprises one or more of D-aspartic acid, D-glutamic acid, D-pipecolic acid, D-proline, (R) -diphenylprolyl trimethyl silyl ether and (8 a,9 s) -6 '-methoxy cinchonine-9-amine, the malonate has a structure shown in a formula a or a formula a', R in the structure shown in the formula a or the formula a 'is alkyl, substituted alkyl, aryl or substituted aryl, when the malonate has the