Palladium/silver co-catalyzed tandem reactions synthesis of phenylacetophenone derivatives by oxabenzonorbornadienes with terminal alkynes and their anti-tumor or anti-cancer activities

Patent metadata

Field	Value
Publication number	US-9783519-B2
Application number	US-201514743209-A
Country	US
Kind code	B2
Filing date	Jun 18, 2015
Priority date	Jun 18, 2015
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

This invention relates to the quick and efficient synthesis of anti-tumor or anti-cancer compounds. More particularly, it relates to the quick and efficient synthesis of anti-tumor or anti-cancer compounds comprising phenylacetophenone derivatives using oxabenzonorbornadienes with terminal alkynes.

First claim

What we claim:

1. A method of synthesizing a compound having a structure of formula (I) or formula (II):

wherein each of R 1 , R 2 , R 3 , R 4 is selected from a group consisting of H, OH, OCH 2 CH 2 O, OCH 2 O, OCF 3 , CF 3 , CH 2 CH 2 OH, aryl, aryloxyl, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, amine and nitro groups, among them one of OCH 2 CH 2 O and OCH 2 O is substituted between R 1 and R 2 , or R 2 and R 3 , or R 3 and R 4 , and
wherein each of R 5 , R 6 , R 7 , R 8 , R 9 is selected from a group consisting of H, OH, OCH 2 CH 2 O, OCH 2 O, OCF 3 , CF 3 , CH 2 CH 2 OH, aryl, aryloxyl, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, amine, nitro, nitrile, alkylthio, alkyl sulfonyl, and aryl sulfonyl groups, among them one of OCH 2 CH 2 O and OCH 2 O is substituted between R 1 and R 2 , or R 2 and R 3 , or R 3 and R 4 ,
comprising steps of:
adding a Pd complex, a ligand and a first solvent in a first noble gas atmosphere to form a first mixture;
stirring the first mixture at a first given temperature for a first given time duration;
adding CF 3 SO 3 Ag to the stirred first mixture to form a second mixture;
stirring the second mixture for a second given time duration;
adding an oxobenzonorbornadiene derivative and a second solvent to the stirred second mixture to form a third mixture;
stirring the third mixture for a third given time duration;
adding a terminal alkyne to the third mixture to form a fourth mixture;
stirring the fourth mixture in a second noble gas atmosphere at a second given temperature until the complete consumption of the oxobenzonorbornadiene derivative;
evaporating the solvents in the stirred fourth mixture to obtain residue; and
purifying the residue to obtain the compound;
wherein the oxobenzonorbornadiene derivative is of a structure of formula (III):

wherein R 1 is selected from a group consisting of H, OMe, Me, OCH 2 CH 2 O, OCH 2 O, Ph, and OPh; R 2 is selected from a group consisting of H, Me, Br, Cl, F, OCH 2 , OMe, OCH 2 CH 2 O, OCH 2 O, Ph, and OPh; R 3 is selected from a group consisting of H, Me, Br, Cl, F, CH 2 O, O, OMe, OCH 2 CH 2 O, OCH 2 O, Ph, and OPh; and R 4 is selected from a group consisting of H, OMe, Me, OCH 2 CH 2 O, OCH 2 O, Ph, and OPh; and
wherein the terminal alkyne is of a structure of formula (IV):
R 1 —≡—R 2   (IV),

wherein R 1 is selected from a group consisting of H and D; and R 2 is selected from a group consisting of Ph, 3-MeOC 6 H 4 3,5-diMeOC 6 H 3 , 4-FC 6 H 4 4-PhOC 6 H 4 , 4-CF 3 OC 6 H 4 , 4-BrC 6 H 4 , 4-MeC 6 H 4 , 4-OHCH 2 C 6 H 4 , 4-CF 3 C 6 H 4 , and 4-CNC 6 H 4 .

2. The method of claim 1 , wherein said compound comprises:
1-(3,5-dimethoxyphenyl)-2-(naphthalen-2-yl) ethanone;
1-(4-fluorophenyl)-2-(naphthalen-2-yl) ethanone;
2-(naphthalen-2-yl)-1-(4-(trifluoromethoxy) phenyl) ethanone;
1-(4-bromophenyl)-2-(naphthalen-2-yl) ethanone;
2-(naphthalen-2-yl)-1-(4-phenoxyphenyl) ethanone;
2-(naphthalen-2-yl)-1-(4-(trifluoromethyl) phenyl) ethanone;
4-(2-(naphthalen-2-yl) acetyl) benzonitrile;
2-(naphthalen-2-yl)-1-phenylethanone-2-D;
2-(5,8-dimethoxynaphthalen-2-yl)-1-phenylethanone;
2-(5,8-dimethylnaphthalen-2-yl)-1-phenylethanone;
2-(6,7-dimethylnaphthalen-2-yl)-1-phenylethanone;
2-(6,7-dibromonaphthalen-2-yl)-1-phenylethanone;
7-(phenylethynyl)-2,3-dihydronaphtho [2,3-b][1,4] dioxine; and
6-(phenylethynyl) naphtho [2,3-d][1,3] dioxole.

3. The method according to claim 1 wherein the Pd complex comprises Pd(OAc) 2 , C 10 H 14 O 4 Pd, PdBr 2 , Pd(CF 3 COO) 2 , Pd(C 6 HF 6 O 2 ) 2 , PdCl 2 ; PdI 2 , and C 6 H 10 Pd 2 Cl 2 .

4. The method according to claim 1 wherein the ligand comprises (±)-Binap, Xantphos, DPEphos, Dppf, Dppb, and PPh 3 .

5. The method according to claim 1 wherein the first solvent comprises 1,2-dichloroethane, dichloromethane, dimethoxyethane, tetraphdrofuran and toluene.

6. The method according to claim 1 wherein the second solvent comprises 1,2-dichloroethane, dichloromethane, dimethoxyethane, tetraphdrofuran and toluene.

7. The method according to claim 1 wherein the first noble gas and/or second noble gas comprises argon gas.

8. The method according to claim 1 wherein the first and/or second given temperature ranges between 34° C. to 76° C.

9. The method according to claim 1 wherein the first and/or second given temperature is room temperature.

10. The method according to claim 1 wherein the first and/or second and/or third given time duration is at least 10 minutes.

11. The method according to claim 1 wherein the evaporation method comprises vacuum evaporation.

12. The method according to claim 1 wherein the purification method comprises silica gel column chromatography.

13. A method of treating esophageal carcinoma in a subject by administering a compound having a structure of formula (I) or formula (II) to the subject,

wherein each of R 1 , R 2 , R 3 , R 4 is selected from a group consisting of H, OH, OCH 2 CH 2 O, OCH 2 O, OCF 3 , CF 3 , CH 2 CH 2 OH, aryl, aryloxyl, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, amine and nitro groups, among them one of OCH 2 CH 2 O and OCH 2 O is substituted between R 1 and R 2 , or R 2 and R 3 , or R 3 and R 4 ; and
wherein each of R 5 , R 6 , R 7 , R 8 , R 9 is selected from a group consisting of H, OH, OCH 2 CH 2 O, OCH 2 O, OCF 3 , CF 3 , CH 2 CH 2 OH, aryl, aryloxyl, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, amine, nitro, nitrile, alkylthio, alkyl sulfonyl, and aryl sulfonyl groups, among them one of OCH 2 CH 2 O and OCH 2 O is substituted between R 1 and R 2 , or R 2 and R 3 , or R 3 and R 4 .

14. The method according to claim 13 , wherein the compound is selected from a group consisting of: 2-(naphthalen-2-yl)-1-phenylethanone, 1-(4-methoxyphenyl)-2-(naphthalen-2-yl) ethanone, 1-(2-methoxyphenyl)-2-(naphthalen-2-yl) ethanone, 1-(3-methoxyphenyl)-2-(naphthalen-2-yl) ethanone, 1-(3,5-dimethoxyphenyl)-2-(naphthalen-2-yl) ethanone, 1-(4-fluorophenyl)-2-(naphthalen-2-yl) ethanone, 2-(naphthalen-2-yl)-1-(4-(trifluoromethoxy) phenyl) ethanone, 1-(4-bromophenyl)-2-(naphthalen-2-yl) ethanone, 2-(naphthalen-2-yl)-1-(p-tolyl) ethanone, 2-(naphthalen-2-yl)-1-(4-phenoxyphenyl) ethanone, 1-(4-(hydroxymethyl)phenyl)-2-(naphthalen-2-yl) ethanone, 2-(naphthalen-2-yl)-1-(4-(trifluoromethyl) phenyl) ethanone, 4-(2-(naphthalen-2-yl) acetyl) benzonitrile, 2-(naphthalen-2-yl)-1-phenylethanone-2-D, 2-(5,8-dimethoxynaphthalen-2-yl)-1-phenylethanone, 2-(5,8-dimethylnaphthalen-2-yl)-1-phenylethanone, 2-(6,7-dimethylnaphthalen-2-yl)-1-phenylethanone, 2-(6,7-dibromonaphthalen-2-yl)-1-phenylethanone, 7-(phenylethynyl)-2,3-dihydronaphtho [2,3-b][1,4] dioxine, and 6-(phenylethynyl) naphtho [2,3-d][1,3] dioxole.

Assignees

• Univ Hong Kong Baptist Univ
• Univ Yunnan Minzu

Inventors

• Bian Zhaoxiang
• Lin Chengyuan
• Mu Huaixue
• Fan Baomin
• Zhou Yongyun
• Chen Jingchao
• Lu Aiping
• Chan Albert Sun-Chi

Classifications

• A61K31/12 Primary

  Ketones · CPC title

• C07D317/70

  condensed with ring systems containing two or more relevant rings · CPC title

• C07D319/22 Primary

  condensed with one naphthalene or hydrogenated naphthalene ring system · CPC title

• A61K31/36

  Compounds containing methylenedioxyphenyl groups, e.g. sesamin · CPC title

• A61K31/357

  having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel · CPC title