JP2001199933A - One-pot process for production of caffeic acid ester derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a one-pot process for the production of a caffeic acid ester derivative of formula I. SOLUTION: The present invention relates to a one-pot process for the production of a caffeic acid ester derivative of formula I. The process includes a step to react a carboxylic acid derivative of formula II with a halogenation reagent and an alcohol of formula HO-(CH2)m-B in a solvent suitable for ester- forming reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a one-pot process for the preparation of caffeic acid ester derivatives.

[0002]

2. Description of the Related Art Caffeic acid ester derivatives (for example,
Phenyl acid phenylethyl ester (CAPE)) (this
Are present in beeswax) according to common and known methods.
Or a known chemical method
Can be synthesized by For example, Nakanishie
(Expertientia, 44: 230-23)
2, 1988) uses methanesulfonic acid as a catalyst
And add caffeic acid and phenylethyl alcohol
Heat to reflux for 4 days in
% Yield. Rao et al. (Chem. Biol. In
teract. , 84: 277-290, 1992).
Uses hexamethylphosphoric triamide (HMP
A), using 25% sodium hydroxide as catalyst,
And (2-phenylethyl) benzene is converted to phenylethyl
Cape is synthesized by replacing alcohol. this
The synthesis reaction is performed at room temperature for 2 days. In addition, Chen et al.
(Cancer Lett, 108: 211-214,
1996) is dicyclohexylcarbodii as a catalyst.
CAPE is synthesized using mid (DCC). This combination
The reaction is carried out for 2 days at room temperature. In addition, caffeic acid
The hydroxy on the phenyl ring can be protected by a protecting group (eg, biphenyl).
Nyldichloromethane). This protection
The acid obtained is esterified and the appropriate acid (eg, vinegar)
Acid) to give CAPE. Alternatively,
The faic acid is converted to a halogenating reagent (eg, SOCl _Two) And anti
And then the resulting product is
Reacts with CAPE to synthesize CAPE.
The known method has disadvantages, including lower yields, more
Long reaction times, larger volumes of reactants, more complex processes,
And undesired products. Caffeic acid esthetic
There is no way to completely satisfy the commercial production of le.

[0003]

It is an object of the present invention to provide a one-pot process for preparing caffeic acid ester derivatives of the following formula I:

[0004]

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Wherein Ar is aryl, which may be unsubstituted or halogen, hydroxy,
Substituted with C _1-6 alkyl or C _1-6 alkoxy,
Is a C _1-6 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 halogen, hydroxy, C
Substituted with _1-6 alkyl or C _1-6 alkoxy.

[0006]

SUMMARY OF THE INVENTION The present invention is a one-pot process for preparing caffeic acid ester derivatives of formula I:

[0007]

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Wherein Ar is aryl, which may be unsubstituted or halogen, hydroxy,
Substituted with C _1-6 alkyl or C _1-6 alkoxy,
Is a C _1-6 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 halogen, hydroxy, C
Substituted with _1-6 alkyl or C _1-6 alkoxy; wherein the process comprises a carboxylic acid derivative of formula II:

[0009]

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Is reacted with a halogenating reagent and an alcohol of formula III: HO- (CH ₂ ) _m -B III in a suitable solvent to form an ester, wherein Ar Is aryl, which is unsubstituted or substituted by halogen, hydroxy, C _1-6 alkyl or C _1-6 alkoxy; A is C _1-6 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 halogen, hydroxy, C _{1 -6} is substituted by alkyl or C _1-6 alkoxy).

[0011] In one aspect, the halogenating reagent halogenates a carboxylic acid to an acid halide.

[0012] In one aspect, the halogenating reagent is thionyl chloride or oxalyl chloride.

In one aspect, the reaction is performed under heating conditions.

In one aspect, the suitable esterification solvent promotes esterification between the reactants in the process.

[0015] In one aspect, the suitable esterification solvent is an aprotic solvent.

[0016] In one aspect, the aprotic solvent is methyl chloride or benzene.

In one aspect, the suitable esterification solvent is a protic solvent.

[0018] In one aspect, the protic solvent is trichloromethane, acetone, acetonitrile, nitrobenzene, THF, ether, dioxane, DMF.
And DMSO.

[0019] In one aspect, the protic solvent is nitrobenzene.

In one aspect, the Ar is a 6-14 membered aromatic mononuclear to trinuclear cyclic system.

In one aspect, the Ar is selected from the group consisting of phenyl, naphthyl, and anthryl.

In one aspect, Ar is phenyl substituted by hydroxy.

In one aspect, the Ar is 3,4
- a dihydroxyphenyl, A is a C ₂ alkenylene, m is 2 and B is phenyl.

In one aspect, the Ar is C _1-6
Phenyl substituted with alkoxy.

In one aspect, Ar is 3,4
-Dimethoxyphenyl.

[0026]

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a one-pot process for preparing a caffeic acid ester derivative of Formula I, wherein the process comprises a carboxylic acid derivative of Formula II:

[0027]

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Reacting with a halogenating reagent and an alcohol of formula III: HO- (CH ₂ ) _m -B III in a suitable solvent for esterification, wherein Ar is , Aryl, which is unsubstituted or substituted by halogen, hydroxy, C _1-6 alkyl or C _1-6 alkoxy; A is C _1-6 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.

[0029] As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

As used herein, the term "aryl" refers to a 6-14 membered aromatic mono- to tri-nuclear cyclic system,
For example, phenyl, naphthyl and anthryl.
Preferred aryls are unsubstituted phenyl or phenyl substituted with one or more substituents selected from the group consisting of hydroxy, C _1-6 alkyl, C _1-6 alkoxy and halogen. The most preferred aryl is 3,
4-dihydroxyphenyl.

As used herein, the term "halogenating reagent" refers to a reagent that halogenates a carboxylic acid to an acid halide. Preferred reagents are thionyl chloride (SOCl ₂ ), oxalyl chloride (ClCOCOC)
l), phosphorus pentachloride and phosphorus trichloride.

As used herein, the term "suitable esterification solvent" refers to a solvent that promotes esterification between reactants in the process of the present invention. Aprotic solvents such as, for example, methyl chloride or benzene; or trichloromethane, acetone, acetonitrile,
Nitrobenzene, THF, ether, dioxane, DM
Protic solvents such as F and DMSO can be applied. Polar solvents are preferred. The most preferred solvent is nitrobenzene.

The present invention relates to a one-pot process for the preparation of a caffeic acid ester derivative of the formula I, wherein
The reaction steps are as follows:

[0034]

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(Where Ar, A, m and B are as defined above).

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

Surprisingly, the preparation process of the present invention can be performed in one pot. The amount of alcohol required for this process is less than that of known processes. Furthermore, the reaction time of the process of the present invention is reduced to 2 hours, and the yield of the process of the present invention is higher than 50%. Thus, the process of the present invention overcomes the shortcomings of known processes for preparing caffeic acid ester derivatives. Further, the process of the present invention is less costly than known processes.

To facilitate an understanding of the objects, methods, features and principles of the present invention, the following examples illustrate various aspects of the present invention, but in any event, It does not limit the scope of the claims.

[0039]

EXAMPLES (Example 1) Caffeic acid (1.05 g, 5.
8 mmol), SOCl ₂ (0.43 ml, 5.8 mm)
ol), and phenylethyl alcohol (0.70 m
l, 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 obtain the desired CAPE (1.42 g, yield: 60).
%).

Melting point 127-128 ° C.

¹ H NMR (400 MHz, CDC
l ₃ ): δ 3.02 (2H, t, J = 7.2 Hz),
4.42 (2H, t, J = 7.2 Hz), 5.98 and 6.14 (2H, brs), 6.25 (1H, d, J
= 16 Hz), 6.87 (1H, d, J = 8 Hz),
6.99 (1H, dd, J = 8.2 Hz), 7.09
(1H, d, J = 2 Hz), 7.23-7.34 (5
H, m), 7.57 (1H, d, J = 16.0 Hz).

¹³ C NMR (100 MHz, CDC
l ₃ ): δ 35.3, 65.2, 114.3, 11
5.2, 115.4, 122.4, 126.5, 12
7.3, 128.4, 128.8, 137.6, 14
3.7, 145.1, 146.3, 167.6.

EIMS m / z (relative intensity): 284
[M] ⁺ (21), 180 (100), 163 (4
4).

HRMS: Calculated for C ₁₇ H ₁₆ O ₄ :
284. 1048. Found: 284.1047. C ₁₇ H
Calcd for _{16 O 4: C, 71.82;} H, 5.
67; O, 22.51. Found: C, 71.55; H,
5.60; O, 22.75.

Example 2: Comparison between the process of the present invention and a conventional process Comparative Example A: Nakanishiet et al. (Experi)
entia, 44: 230-232, 1988), following the results of the use of methanesulfonic acid as a catalyst; caffeic acid and phenylethyl alcohol in benzene.
Heated to reflux for one day to give CAPE in 40% yield.

(Comparative Example B) Caffeic acid (0.5 g, 2.
7 mmol) and dicyclohexylcarbodiimide (DCC) (0.372 g, 3.0 mmol) in dimethylaminopyridine (DMAP) (0.459 g, 2.2).
mmol) in a 25 ml reaction bottle. 10m
1 of DMF / CH ₂ Cl ₂ (1: 1) 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. A precipitate formed. The reaction was filtered, removed, and TLC (diethyl ether:
Hexane = 2: 1). The product was separated through a silica column, then eluted with diethyl ether: hexane = 2: 1. The residue was concentrated to give CAPE in 46% yield.

Comparative Example C Caffeic acid (0.50 g,
2.8 mmol) with dichlorodiphenylmethane (0.5
4 ml, 2.8 mmol, 1.0 eq.) In a 25 ml two-necked round bottom flask under a nitrogen atmosphere. Then, the mixture was stirred for 170 to 1 under nitrogen reflux.
Heated to 80 ° C. (oil bath temperature) and maintained at that temperature for 15 minutes. The flask was removed from the oil bath and allowed to cool to ambient temperature. This dark brown residue was dissolved in dichloromethane and packed into a 3 × 30 cm SiO ₂ column,
And eluted with diethyl ether / petroleum ether (1: 1). The crude product was recrystallized from cyclohexane as a white solid (0.53 g). The purified acid is replaced with excess S
Added to OCl ₂ (used as solvent) and heated to reflux for 2 hours. The residue was concentrated by a vacuum device and the SOCl ₂ was removed. The concentrated acid chloride was slowly added to phenylethyl alcohol (183 μl, 15.40 mmol) and pyridine (121 μl, 15.40 mmol) in dichloromethane and then stirred for 2 hours at room temperature. The reaction was collected, and TLC (diethyl ether: hexane =
2: 1). The product was separated through a silica column and then eluted with diethyl ether: hexane = 2: 1. The residue is concentrated to a white solid, which solid is reacted with acetic acid to give C
APE was obtained in 12% yield.

Comparative Example D Caffeic acid (500 mg, 2.77 mmol) in excess SOCl ₂ was heated at reflux for 2 hours. SOCl ₂ was removed and the residue was concentrated under reduced pressure. This concentrated acid chloride was dissolved in phenylethyl alcohol (1.65 m) in 10 ml of nitrobenzene.
1, 13.8 mmol), and then
Heated at 50 ° C. for 2 hours. The reaction was collected and chromatographed by TLC (diethyl ether: dichloromethane: hexane = 2: 2: 1) to confirm product formation and the product was separated through a silica column. To remove the nitrobenzene, dichloromethane was first used as eluent, then the product was treated with diethyl ether: dichloromethane: hexane =
It was recovered by elution using 2: 2: 1. The residue was concentrated to a white solid, which was recrystallized from dichloromethane / hexane to give CAFE in 50% yield.

The comparison results are as follows:

[0050]

[Table 1]

In view of the above table, the process of the present invention shows that the amount of alcohol, reaction time, cost and CAPE
Is better than known processes.

The present invention relates to a one-pot process for preparing caffeic acid ester derivatives of formula I:

[0053]

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Where Ar is aryl, which may be unsubstituted or halogen, hydroxy,
Substituted with C _1-6 alkyl or C _1-6 alkoxy,
Is a C _1-6 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 halogen, hydroxy, C
Substituted with _1-6 alkyl or C _1-6 alkoxy, wherein the process comprises a carboxylic acid derivative of formula II:

[0055]

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Reacting with a halogenating reagent and an alcohol of formula III: HO- (CH ₂ ) _m -B III in a suitable solvent for esterification, wherein Ar is , Aryl, which is unsubstituted or substituted by halogen, hydroxy, C _1-6 alkyl or C _1-6 alkoxy; A is C _1-6 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.

The examples provided above are not intended to be limiting. Many other changes and modifications of the above-described embodiments of the invention can be made without departing from the spirit and scope of the invention.

[0058]

The present invention provides a one-pot process for preparing caffeic acid ester derivatives of Formula I.

 ──────────────────────────────────────────────────の Continuation of front page (71) Applicant 500468456 3-3rd Floor, No. 188, Sec. 5, Nanking East Road, Taipei, Taiwan, R.A. O. C. (72) Inventor Yen-Chang Lee Taiwan, Taichung, Sea Tun Road, Section 3, Lane 159, Array 96, Number 68, 10F F-term (reference) 4H006 AA02 AC48 BA52 BB11 BB12 BB15 BB16 BB18 BB21 BB25 BB41 BC10 BE51 BJ50 BN30 BP30 KA06 KA14

Claims (16)

[Claims] 1. A one-pot process for preparing a caffeic acid ester derivative of the formula I, comprising: Wherein Ar is aryl, which is unsubstituted or halogen, hydroxy, C _1-6 alkyl or C
_1-6 is substituted with alkoxy, A is, C _1-6 alkylene, C _2-6 alkenylene or C
_2-6 alkynylene, m is the number of 0-6; and B is a C _1-6 alkyl or aryl, which is unsubstituted or halogen, hydroxy, C _{1- 6} alkyl or C
Substituted with _1-6 alkoxy; wherein the process comprises:
Carboxylic acid derivative of formula II: The alcohol of a halogenating reagent and formula III: HO- using (CH _{2) m} -B III, comprising the step of reacting in a suitable solvent to form an ester, a process: here Ar is aryl, which is unsubstituted or halogen, hydroxy, C _1-6 alkyl or C
Substituted by _C1-6 alkoxy; A is, C _1-6 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 is halogen, hydroxy, C _1-6 alkyl or C _1-6 alkoxy. The process to be replaced. 2. The process of claim 1 wherein said halogenating reagent halogenates a carboxylic acid to an acid halide. 3. The process according to claim 2, wherein said halogenating reagent is thionyl chloride or oxalyl chloride. 4. The process according to claim 1, wherein said reaction is performed under heating conditions. 5. The process of claim 1, wherein said suitable esterification solvent promotes esterification between reactants in said process. 6. The process according to claim 5, wherein said suitable esterification solvent is an aprotic solvent. 7. The process according to claim 6, wherein said aprotic solvent is methyl chloride or benzene. 8. The process according to claim 1, wherein said suitable esterification solvent is a protic solvent. 9. The protic solvent comprises trichloromethane, acetone, acetonitrile, nitrobenzene, TH
9. The process according to claim 8, wherein the process is selected from the group consisting of F, ether, dioxane, DMF and DMSO. 10. The process according to claim 9, wherein said protic solvent is nitrobenzene. 11. The method according to claim 11, wherein said Ar is an aromatic 6 to 14-membered mononuclear compound.
2. The process of claim 1, wherein the process is a trinuclear cyclic system. 12. The process of claim 11, wherein said Ar is selected from the group consisting of phenyl, naphthyl, and anthryl. 13. The process according to claim 12, wherein said Ar is phenyl substituted by hydroxy. 14. The method according to claim 14, wherein said Ar is 3,4-dihydroxyphene.
Nil and A is C _TwoAlkenylene and m is 2
14. The process according to claim 13, wherein B is phenyl.
Roses. 15. The process of claim 12, wherein said Ar is phenyl substituted with C _1-6 alkoxy. 16. The process according to claim 15, wherein said Ar is 3,4-dimethoxyphenyl.