US-12623992-B2 - Key intermediate for synthesis of prostaglandin compound and preparation method thereof

US12623992B2US 12623992 B2US12623992 B2US 12623992B2US-12623992-B2

Abstract

The present invention relates to the technical field of organic chemical engineering, and in particular to a key intermediate for synthesizing prostaglandin compounds and a preparation method therefor. When applied to the synthesis of prostaglandin compounds, the process flow is simplified, the yield and product purity are improved, the production costs are reduced, and the industrial application is easy.

Inventors

Xiaobing DING
Qiwei LANG
Wei Su
Shuang Gao

Assignees

SHENZHEN CATALYS TECHNOLOGY CO., LTD

Dates

Publication Date: 20260512
Application Date: 20220225
Priority Date: 20200916

Claims (12)

1 . A key intermediate for synthesis of a prostaglandin compound, having a structure shown below: wherein denotes a single bond or double bond, and if it is a double bond, R 1 is absent; and wherein R 1 and R 2 are each H or protecting groups; R 3 and R 4 are the same or different alkyl or aryl, or R 3 and R 4 form a ring.
2 . The key intermediate for the synthesis of the prostaglandin compound according to claim 1 , having a structure shown below: wherein R 1 , R 2 , R 3 , and R 4 are as defined above.
3 . The key intermediate for the synthesis of the prostaglandin compound according to claim 1 , which is wherein R 1 , R 2 , R 3 , and R 4 are as defined above.
4 . The key intermediate for the synthesis of the prostaglandin compound according to claim 1 , which is wherein R 1 and R 2 are as defined above, and n is an integer from 1 to 3.
5 . The key intermediate for the synthesis of the prostaglandin compound according to claim 1 , wherein the intermediate is
6 . The key intermediate for the synthesis of the prostaglandin compound according to claim 1 , wherein the protecting group is selected from an ether protecting group, an acyl protecting group, a silyl ether protecting group, an acetal protecting group.
7 . The key intermediate for the synthesis of the prostaglandin compound according to claim 1 , wherein the intermediate is selected from:
8 . A method for preparing the key intermediate for the synthesis of the prostaglandin compound according to claim 1 , comprising steps of: a) asymmetrically reducing compound S1 to obtain chiral alcohol compound S2, and then protecting hydroxyl group of the chiral alcohol compound S2 with silane to obtain Weinreb amide compound S3; b) subjecting the Weinreb amide compound S3 to an addition reaction with an alkyne reagent to obtain enyne compound S4; c) subjecting the enyne compound S4 to a Zhang enyne cycloisomerization to obtain five-membered ring S5; d) conjugating the five-membered ring S5 to reduce double bond thereof to obtain compound S6, and further reducing ketone of the compound S6 to obtain compound S7; and e) deprotecting the compound S7 by removing TIPS thereof to obtain compound S8; referring to the following reaction route:
9 . The key intermediate for the synthesis of the prostaglandin compound according to claim 1 , having a structure shown below: wherein R 1 , R 2 , R 3 , and R 4 are as defined above.
10 . The key intermediate for the synthesis of the prostaglandin compound according to claim 1 , which is wherein R 1 , R 2 , R 3 , and R 4 are as defined above.
11 . The key intermediate for the synthesis of the prostaglandin compound according to claim 1 , which is wherein R 1 and R 2 are as defined above, and n is an integer from 1 to 3.
12 . The key intermediate for the synthesis of the prostaglandin compound according to claim 1 , wherein the intermediate is selected from: wherein P is a protecting group.

Description

TECHNICAL FIELD The present invention relates to the technical field of organic chemical engineering, and particularly to a key intermediate for the synthesis of a prostaglandin compound and a preparation method thereof. BACKGROUND Prostaglandins are a class of important endogenous products with a variety of physiological activities, and many derivatives obtained therefrom by modifying their structures also have important physiological activities. At present, a number of compounds are available in the market for the treatment of glaucoma, ulcer, early pregnancy, constipation and high blood pressure and the like. The prostaglandin compounds include, but are not limited to, The synthetic routes for preparing the aforementioned compounds in the prior art mainly include: Although many molecules of the prostaglandin family can be obtained from Corey lactone, a key intermediate in the Corey's route through subsequent conversion, the synthesis procedure of this intermediate is complicated, which include nine steps of reactions starting from cyclopentadiene, and the subsequent conversion from the intermediate to the final product also requires nearly ten steps or even more than ten steps of reactions. The synthesis procedure of Aggarwal's route is simple. However, the yield of the first-step reaction is very low, and only 14%, causing it difficult to be scaled up for use. The conversion of the key intermediate to the final product is also difficult, and the chemical selectivity of the reaction is poor, with a low yield. The Shi's route refers to a racemic reaction, and a further resolution is required to obtain the prostaglandin compound. The Stork's route involves a key intermediate cyclopentenone. The synthesis of this intermediate is difficult, and generally realized by an enzymatic resolution reaction, which is adverse to atomic economy. Moreover, the conversion steps from this intermediate to the final product are troublesome, in which an organocopper lithium reagent that is sensitive to water and air is used, causing difficulty in operation. The Noyori's route also involves the difficult-to-be-synthesized cyclopentenone intermediate, and the organocopper lithium reagent that is sensitive to water and air, as well as a highly toxic organotin reagent, causing great harm to the humans and environment. When used for the synthesis of prostaglandin compounds, the aforementioned procedures are complex, and the yield and product purity need to be further improved. The present invention aims to provide a key intermediate for the synthesis of a prostaglandin compound and a preparation method thereof, for use in the synthesis of a prostaglandin. The present invention has the advantages of simple reaction operation, good functional group tolerance, no highly toxic chemicals involved in the synthetic route, being green and environmentally friendly, high yield and purity of the product, and more conducive to industrial application. SUMMARY In view of the problems existing in the prior art, the present invention provides a key intermediate for the synthesis of a prostaglandin compound and a preparation method thereof. Particularly, the present invention is accomplished through the following technical solutions. A key intermediate for the synthesis of a prostaglandin compound has a structure shown below: wherein denotes a single bond or double bond, and if it is a double bond, R1 is absent; and wherein R1 and R2 are each H or protecting groups; R3 and R4 are the same or different alkyl or aryl, or R3 and R4 form a ring; and R5 and R6 are the same or different H, alkyl, or aryl. The alkyl refers to a linear or branched alkyl group, including, but not limited to, For example, a C1-6 alkyl group or a C3-7 monocyclic cycloalkyl group. The C1-6 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, s-pentyl, t-pentyl, n-hexyl, isohexyl, neohexyl, s-hexyl, and t-hexyl. The C3-7 monocyclic cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The aryl refers to an aromatic ring structure containing a single ring or a fused polycyclic ring, including, but not limited to, naphthyl and the like. Further, the aryl group can be substituted with one or more halogens or alkyl groups. R3 and R4 form a ring by connecting the carbon chains, wherein one or more carbon atoms in the carbon chains can be replaced by a heteroatom selected from O, N and S. In a preferred embodiment of the present invention, the key intermediate for the synthesis of a prostaglandin compound has a structure shown below: wherein R1, R2, R3, and R4 are as defined above. In a preferred embodiment of the present invention, the key intermediate for the synthesis of a prostaglandin compound has a structure shown below: wherein R1, R2, R3, and R4 are as defined above. In a preferred embodiment of the present invention, the key intermediate for the