AU5364700A - One pot processes for preparation of caffeic acid ester derivatives - Google Patents

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: 9 9 Name of Applicant: Medicam Chemical Pharmaceutical Co., Ltd.

Actual Inventor(s): YEAN-JANG LEE Address for Service: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: ONE POT PROCESSES FOR PREPARATION OF CAFFEIC ACID ESTER DERIVATIVES Our Ref 624267 POF Code: 97273/453767 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1q US-1847 ONE POT PROCESSES FOR PREPARATION OF CAFFEIC ACID ESTER DERIVATIVES Field of the Invention The present invention relates to one pot processes for the preparation of caffeic acid ester derivatives.

Background of the Invention Caffeic acid ester derivatives caffeic acid phenylethyl ester (CAPE)), which are present in propolis, can be extracted by general known methods or synthesized by known chemical methods. For instance, Nakanishiet et al, (Experientia, 44:230-232, 1988) use methanesulfonic acid as a catalyst and heat caffeic acid and phenylethyl alcohol in benzene to reflux for 4 S. days to obtain a 40 yield of the desired CAPE. Rao et al, (Chem. Biol.

Interact., 84:277-290, 1992) use hexamethylphosphoric triamide (HMPA) 15 as a solvent, 25% sodium hydroxide as a catalyst and replace (2-phenylethyl)benzene with phenylethyl alcohol to synthesize CAPE.

The synthesis reaction is performed at room temperature for 2 days.

Furthermore, Chen et al., (Cancer Lett, 108:211-214, 1996) use dicyclohexyl carbodiimide (DCC) as a catalyst to synthesize CAPE. The synthesis reaction is performed at room temperature for 2 days. In addition, the hydroxy on the phenyl ring of caffeic acid can be protected by a protecting group biphenyl dichloromethane). The protected acid is P:\CCK\US2694SP.DOC US-1847 -2esterified and deprotected by appropriate acids acetic acid) to obtain CAPE. Alternatively, caffeic acid is reacted with a halogenating reagent SOC12) and then the resultant product is reacted with phenylethyl alcohol to synthesize CAPE.

However, the above known methods have disadvantages including lower yields, longer reaction time, greater reactant amounts, more complex steps and undesired products. There is no way to fully satisfy the commercial production for caffeic acid esters.

Summary of the Invention It is an object of the present invention to provide a one pot process for the preparation of caffeic acid ester derivatives of the formula I: Ar-A-C-O- (CH 2 )m -B I 15 wherein Ar is aryl, which is unsubstituted or substituted with halogen, hydroxy, C i-6 alkyl or C 1-6 alkoxy, A is C1-6 alkylene, C2- 6 alkenylene or C2- 6 alkynylene, m is a number from 0 to 6; and 20 B is C-.6 alkyl or aryl, which is unsubstituted or substituted with Shalogen, hydroxy, C 16 alkyl or C 1 .6 alkoxy, -4 which process comprises reacting in a suitable solvent for esterification of carboxylic acid derivatives of the formula II: Ar-A-C-OH II P:\CCK\US2694SP.DOC US-1847 -3 wherein Ar is aryl, which is, unsubstituted or substituted with halogen, hydroxy, Ci.

6 alkyl or C 1-6 alkoxy, -A is C 16 alkylene, C2- 6 alkenylene or C2- 6 alkynylene, with a halogenating reagent and an alcohol of the formula III:

HO-(CH

2 )m-B III wherein m is a number from 0 to 6; and B is C 1 6 alkyl or aryl, which is unsubstituted or substituted with halogen, hydroxy, C1-6 alkyl or C1- 6 alkoxy.

Detailed Description of the Invention The term "halogen", as used herein, refers to fluorine, chlorine, bromine or iodine.

15 The term "aryl", as used herein, refers to aromatic, mono- to tri-nuclear 'cyclic system with 6-14 membranes such as phenyl, naphthyl and anthryl.

The preferred aryl is phenyl unsubstituted or substituted with one or more substituents selected from the groups consisting of hydroxy, C 16 alkyl, Ci-6 alkoxy and halogen. The most preferred aryl is 3, 4-dihydroxyphenyl.

20 The term "halogenating reagent", as used herein, refers to the reagents halogenating carboxylic acid to acid haloride. The preferred reagents are thionyl chloride (SOC 2 oxalyl chloride (C1COCOC1), phosphoric chloride and phosphorous chloride.

The term "suitable esterifying solvent", as used herein, refers to the solvents facilitating the esterification between the reactants in the processes of the invention. For instance, an aprotic solvent such as methyl chloride or benzene; or a protic solvent such as trichloromethane, acetone, acetonitrile, nitrobenzene, THF, ether, dioxane, DMF and DMSO can be P:\CCK\US2694SP.DOC US-1847 applied. The polar solvent is preferred. The most preferred solvent is nitrobenzene.

The present invention relates to a one pot processes for the preparation of caffeic acid ester derivatives of formula I wherein the reaction steps are as follows: halogenating reagent Ar-A-C-OH +HO(CH2)m-B >Ar-A-C-O-O-(CH2-B II suitable esterifying solvant (wherein Ar, A, m and B are as defined as above).

The above reaction can be accomplished at room temperature or by heating to quickly obtain the final ester.

Surprisingly, the preparation processes of the invention can be performed in one pot. The alcohol amounts essential for the processes are less than those of the known processes. Furthermore, the reaction time of the inventive processes is reduced to 2 hours and the yield of the inventive processes is more than 50%. Therefore, the processes of the invention solve the disadvantages of the known processes of preparing caffeic acid ester derivatives. In addition, the inventive processes are cheaper in cost.

than the known processes.

20 To facilitate the understanding of purpose, methods, characteristics and principles of the invention, the following examples illustrate various aspects of the present invention but do not limit the claims in any manner whatsoever.

Examples Example 1 P: CCK\US2694SP.DOC US-1847 A solution of caffeic acid (1.05 g, 5.8 mmol), SOCl 2 (0.43 ml, 5.8 mmol), and phenylethyl alcohol (0.70 ml, 5.8 mmol) in nitrobenzene (20 ml) was heated for 2 hours. The resulting solution was subjected to column chromatography (Silica, ether hexane 1 1) to give the desired CAPE (1.42 g, yield :60 mp 127-128 oC.

'H NMR (400 MHz, CDCl 3 0 3.02 (2 H, t, J= 7.2 Hz), 4.42 (2 H, t, J=7.2 Hz), 5.98 and 6.14 (2 H, brs), 6.25 (1 H, d, J= 16 Hz), 6.87 (1 H, d, J= 8 Hz), 6.99 (1 H, dd, J= 8, 2 Hz), 7.09 (1 H, d, J= 2 Hz), 7.23-7.34 (5 H, 0o 7.57 (1 H, d, J= 16.0 Hz).

13C NMR (100 MHz, CDCl 3 135.3, 65.2, 114.3, 115.2, 115.4, 122.4, 126.5, 127.3, 128.4, 128.8, 137.6, 143.7, 145.1, 146.3, 167.6.

EIMS m/z (rel. int): 284 [M] 180(100), 163(44).

HRMS: Calc.'for C1 7

HI

6 0 4 284.1048. Found: 284.1047. Anal. Calcd for C1 7

HI

6 0 4 C, 71.82; H, 5.67; 0, 22.51. Found: C, 71.55; H, 5.60; 0, 22.75.

Example 2: Comparison between the processes of the invention and the conventional processes Comparative Example A According to the results of Nakanishiet et al, (Experientia, 44:230-232, 1988), the use of methanesulfonic acid as a catalyst; caffeic acid and phenylethyl alcohol in benzene were heated to reflux for 4 days to obtain yield of CAPE.

Comparative Example B The caffeic acid (0.5 g, 2.7 mmole) and dicyclohexyl carbodiimide (DCC) (0.372 g, 3.0 mmol) were placed together with dimethylaminopyridine (DMAP) (0.459 g, 2.2 mmol) into a 25 ml reaction bottle. 10 ml P: CCKI US2694SP. DOC US-1847

DMF/CH

2 CI2 solution was added to the mixture. Phenylethyl alcohol (1 ml, 8.3 mmol) was slowly added to the reaction bottle. The reaction mixture was stirred at room temperature. The precipitate was produced. The reaction liquid was filtrated, taken and chromatographed by TLC (diethyl ether hexane 2: The products were separated through a silica column and then were eluted with diethyl ether hexane 2 1. The residue was concentrated to obtain a 46 yield of CAPE.

Comparative Example C Caffeic acid (0.50 g, 2.8 mmol) was placed together with to dichlorodiphenylmethane (0.54 ml, 2.8 mmol, 1.0 equiv.) into a 25 ml, two-necked, round-bottomed flask under a nitrogen atmosphere. The mixture was then heated to 170-180 C (oil bath temperature) while being stirred under nitrogen reflux and was maintained at that temperature for minutes. The flask was removed from the oil bath and allowed to cool to 5s ambient temperature. The dark brown residue was dissolved in dichloromethane, applied to a 3x30 cm SiO 2 column, and eluted with diethyl ether/petroleum ether The crude product was recrystallized from cyclohexane as a white solid (0.53 The purified acid was added to excess SOC12, used as solvant, and was heated to reflux for 2 hours.

20 The residue was concentrated by a reducing pressure machine and SOCI 2 was removed. The concentrated acid chloride in dichloromethane was slowly added to phenylethyl alcohol (183 il, 15.40 mmole) and pyridine (121 pl, 15.40 mmole) and then was stirred at room temperature for 2 hours.

The reaction liquid was taken and chromatographed by TLC (diethyl ether 25 hexane 2: The products were separated through a silica column and then were eluted with diethyl ether hexane 2 1. The residue was concentrated to a white solid, which was reacted with acetic acid to obtain a 12% yield of CAPE.

Comparative Example D P: \CCK\US2694SP.DOC US-1847 -7- The caffeic acid (500 mg, 2.77 mmole) in excess SOC12 was heated to reflux for 2 hours. SOC12 was removed and the residue was concentrated in a vacuum. The concentrated acid chloride in 10 ml nitrobenzene was slowly added to phenylethyl alcohol (1.65 ml, 13.8 mmole) and then was heated at 50 °C for 2 hours. The reaction liquid was taken and chromatographed by TLC (diethyl ether dichloromethane hexane 2: 2 to identify the formation of the products, which were separated through a silica column. Dichloromethane was firstly used as eluant to remove nitrobenzene and then, the products was collected by eluting with diethyl ether dichloromethane hexane 2 2 1. The residue was concentrated to a white solid, which was recrystalized dichloromethane/hexane to obtain a 50% yield of CAPE.

SW

0000 Su 0004 4 5*

S

*4 S .0 65' S 0 S. S 0*

S.

The comparative results are as follows: Examples alcohol amounts reaction time cost/g CAPE yield Comparative 5- equivalent 3 days larger than 0-40% Example A NT$328 Comparative 1 equivalent 2 days NT$350 46% Example B Comparative 1 equivalent 8 hours larger than 12% Example C NT$1000 Comparative 5 equivalent 4 hours NT$500 Example D Example 1 1 equivalent 2 hours NT$250 In view of the above table, the processes of the invention are superior in alcohol amounts, reaction time, cost and CAPE yield than the known processes.

P: \CCK\ US2694SP. DOC US-1847 -8- The examples provided above are not meant to be exclusive. Many other variations and modifications of the above described embodiments of the present invention would be carried out without departing from the spirit and scope of this invention.

.o.o e P:\CCKIUS2694SP.DOC

Claims (12)

1. A one pot process for preparing caffeic acid ester derivatives of the formula I: Ar-A-C-O- (CH 2 )m -B I wherein Ar is aryl, which is unsubstituted or substituted with halogen, hydroxy, C 1 -6 alkyl or C.-6 alkoxy, A is C1-6 alkylene, C 2 6 alkenylene or C 2 6 alkynylene, m is a number from 0 to 6; and B is C 1 6 alkyl or aryl, which is unsubstituted or substituted with halogen, hydroxy, C 1 6 alkyl or C 1 6 alkoxy; which process comprises reacting in a suitable solvent for esterification df carboxylic acid derivatives of the formula II: •Ar-A-C-OH wherein 20 Ar is aryl, which is unsubstituted or substituted with halogen, hydroxy, C.-6 alkyl or C1- 6 alkoxy; A is C 16 alkylene, C 2 6 alkenylene or C 2 6 alkynylene, with a halogenating reagent and alcohol of the formula III: HO-(CH 2 III wherein m is a number from 0 to 6; and B is C1- 6 alkyl or aryl, which is unsubstituted or substituted with halogen, hydroxy, C1-6 alkyl or C 1 -6 alkoxy. P: CCK\US2694SP.DOC US-1847

2. The process according to Claim 1, wherein the halogenating reagent halogenating carboxylic acid to acid haloride.

3. The process according to Claim 2, wherein the halogenating s reagent is thionyl chloride or oxalyl chloride.

4. The process according to Claim 1, wherein the reaction is performed under a heating condition. to 5. The process according to Claim 1, wherein the suitable esterifying solvent facilitates the esterification between the reactants in the Sprocess.

6. The process according to Claim 5, wherein the suitable 15 esterifying solvent is an aprotic solvent.

7. The process according to Claim 6, wherein the aprotic solvent is methyl chloride or benzene. 20 8. The process according to Claim 1, wherein the suitable esterifying solvent is a protic solvent.

9. The process according to Claim 8, wherein the protic solvent is selected from the group consisting of trichloromethane, acetone, acetonitrile, nitrobenzene, THF, ether, dioxane, DMF and DMSO. The process according to Claim 9, wherein the protic solvent is nitrobenzene.

11. The process according to Claim 1, wherein Ar is aromatic, mono- to trinuclear cyclic system with 6-14 membranes. P:\CCKlUS2694SP.DOC US-1847 -11

12. The process according to Claim 11, wherein Ar is selected from a group consisting of phenyl, naphthyl and anthryl.

13. The process according to Claim 12, wherein Ar is phenyl substituted by hydroxy.

14. The process according to Claim 13, wherein Ar is 3,4-dihydroxyphenyl, A is C 2 alkenylene, m is 2 and B is phenyl. The process according .to Claim 12, where Ar is phenyl substituted by Ci-6 alkoxy.

16. The process according to Claim 15, wherein Ar is 15 3,4-dimethoxyphenyl. DATED: 24th August, 2000 PHILLIPS ORMONDE FITZPATRICK Attorneys for: MEDICAM CHEMICAL PHARMACEUTICAL CO., LTD. P:1CCKAUS2694SP.DOC