CN101607907B - Substituted benzoic acid derivative and synthesizing method thereof and application thereof - Google Patents

Substituted benzoic acid derivative and synthesizing method thereof and application thereof Download PDF

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CN101607907B
CN101607907B CN 200910023010 CN200910023010A CN101607907B CN 101607907 B CN101607907 B CN 101607907B CN 200910023010 CN200910023010 CN 200910023010 CN 200910023010 A CN200910023010 A CN 200910023010A CN 101607907 B CN101607907 B CN 101607907B
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borneol
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CN101607907A (en
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郑晓晖
南叶飞
赵新锋
王世祥
张群正
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Northwest University
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Abstract

The invention relates to a compound expressed by a general formula (I), wherein R2, R3, R4 are independently selected from H, OH, methoxy or ethoxy; R1 and R5 are independently selected from H, OH, F or C1; and R6 is selected from cycloalkyloxy. The invention also relates to a synthesizing method of the compound expressed by the general formula (I) and the application of the compound expressed by the general formula (I) used for preparing a drug for preventing and treating cardio-cerebrovascular diseases.

Description

The benzoic acid derivative and the preparation method and use thereof that replace
Technical field
The benzoic acid derivative that the present invention relates to replace, its synthetic method and for the preparation of the purposes of medicine of control cardiovascular and cerebrovascular diseases.
Background technology
Choerospondias axillaris is that the Mongolian medicine commonly uses and controls the worry medicinal material, anaesthetic control in the worry prescription most take fructus choerospondiatis as main ingredient or compatibility fructus choerospondiatis (adjuvant) is arranged, determined curative effect is reliable.The bibliographical information fructus choerospondiatis contains phenolic acids, flavonoid and sterols composition, and wherein liposoluble ingredient has gallic acid, Protocatechuic Acid, Whitfield's ointment and ellagic acid etc.Modern pharmacological research shows, the liposoluble ingredients such as gallic acid and Protocatechuic Acid have significantly anti-oxidant, to remove free radical, anticoagulant effect and anti-hypoxia active.But this type of phenol acid substance becomes the property of medicine not strong.The present invention's phenolic acid such as contained gallic acid, Protocatechuic Acid in the fructus choerospondiatis is transformed as precursor structure, and improved derivative verifies to have stronger pharmacologically active through pharmacological evaluation.
Summary of the invention
The object of the present invention is to provide a kind of benzoic acid derivative and synthetic method thereof, and with the purposes of benzoic acid derivative for the preparation of the medicine of prevention and treatment cardiovascular and cerebrovascular diseases.
Implementation procedure of the present invention is as follows:
The compound of general formula (I) expression:
Figure G2009100230106D00011
Wherein, R 2, R 3, R 4Be selected from independently of each other H, OH, methoxy or ethoxy; R 1, R 5Be selected from independently of each other H, OH, F or Cl; R 6Be cycloalkyloxy
Figure G2009100230106D00012
In one embodiment of the invention, R 1, R 5Be F or Cl simultaneously.
In another embodiment of the invention, R 1, R 5Be H simultaneously.
In the 3rd embodiment of the present invention, R 1, R 4, R 5Be H simultaneously.
In a preferred embodiment of the invention, R 1, R 5Be H simultaneously, R 2, R 3, R 4Be OH, R 6Be selected from cycloalkyloxy
Figure G2009100230106D00021
Namely suc as formula (IV) with the Gallic Acid norbornene ester (V) and Gallic Acid menthyl ester.
Figure G2009100230106D00022
In another preferred embodiment of the present invention, R 1, R 4, R 5Be H simultaneously, R 2, R 3Be OH, R 6Be selected from cycloalkyloxy Namely suc as formula (VI) with the PCA norbornene ester (VII) and PCA menthyl ester.
Figure G2009100230106D00024
The synthetic method of the described compound of above-mentioned general formula (I): synthetic take compound shown in general formula (II) and the general formula (III) as raw material,
R 6-H
(III)
R wherein 1, R 2, R 3, R 4, R 5And R 6The same general formula of meaning (I) described in.
The catalyzer that reaction relates in the synthetic route method is dense H 2SO 4, HCl (gas), DCC/DMAP (1,3-dicyclohexylcar-bodiimide, 1,3-dicyclohexyl carbodiimide/4-dimethylaminopyridine, DMAP), p-methyl benzenesulfonic acid or S 2O 8 2-/ ZrO 2, use DCC/DMAP, p-methyl benzenesulfonic acid or S 2O 8 2-/ ZrO 2Especially favourable.
Described reaction is carried out in solvent, and used solvent is selected from tetrahydrofuran (THF), acetone, toluene, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether and DMF.Preferably, used solvent is selected from tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane.
Temperature of reaction changes according to the difference of selected route, and it is favourable being controlled at 0 ℃～150 ℃.Preferably, temperature of reaction is 25 ℃～100 ℃.
Reaction times can be 2h～24h, preferred 5h～15h, more preferably 8h～12h, most preferably 8h.
In a specific embodiments of the present invention, the synthetic method of the compound of formula (II) comprising: Gallic Acid and borneol are reacted in the presence of catalyzer.Wherein said catalyzer is lewis acid catalyst, such as p-methyl benzenesulfonic acid or S 2O 8 2-/ ZrO 2The reaction mol ratio of wherein said Gallic Acid and borneol is 1: 1～1: 1.5, is preferably 1: 1.2～1: 1.5, more preferably 1: 1.5.Described reaction is carried out in solvent, and solvent is selected from tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or DMF, is preferably Isosorbide-5-Nitrae-dioxane.Temperature of reaction changes according to the difference of solvent for use, usually is controlled at 65 ℃～150 ℃, preferably is controlled at 105 ℃.Reaction times is 15～24h, is preferably 18h.
Using S 2O 8 2-/ ZrO 2In the situation as catalyzer, randomly can prepare by the following method S 2O 8 2-/ ZrO 2: under 0～10 ℃, ammoniacal liquor is added to ZrOCl 2In the solution, to pH value 9-12, ageing, washing precipitation is extremely without Cl -, oven dry, grinding are placed on (NH 4) 2S 2O 8Soak in the solution, filtration, dry, grinding make S in 500～700 ℃ of roast 2-5h 2O 8 2-/ ZrO 2
In a third aspect of the present invention, the purposes of compound of the present invention for the preparation of the medicine of prevention and treatment cardiovascular and cerebrovascular diseases is provided, especially with the medicine of Gallic Acid norbornene ester (compound of formula II) for the preparation of prevention and treatment cardiovascular and cerebrovascular diseases.
Embodiment
Below in conjunction with synthetic example and acceptor chromatogram and cytoactive test, the present invention is described in further detail.Should be appreciated that following examples only are used for describing the present invention, rather than restriction the present invention.
Embodiment 1:3,4,5-trihydroxybenzoic acid borneol ester synthesis one
(1) 3,4,5-triacetoxyl group is benzoic synthetic
Add 0.05mol gallic acid and 0.30mol diacetyl oxide in there-necked flask, stir, dissolving slowly adds several dense H fully 2SO 4, reinforced process cooling bath control temperature is below 60 ℃.Be warmed up to 90 ℃, reaction 1h.Stopped reaction, the adularescent crystal is separated out after the cooling, suction filtration, washing gets the white crystals thing, 50 ℃ of vacuum-dryings.
(2) 3,4,5-triacetoxyl group phenylformic acid borneol ester synthesis
With 0.01mol 3,4,5-triacetoxyl group phenylformic acid, 0.015mol borneol are inserted in the 100mL there-necked flask, then add the 36mL tetrahydrofuran (THF), stir, and dissolving adds 0.01g DMAP, 0.01mol DCC, room temperature reaction 24h again.After reaction finishes, suction filtration, reaction solvent is removed in underpressure distillation, adds the 20mL ethyl acetate in gained light tan oily matter, and gained solution is used saturated NaHCO successively 3, saturated NaCl washing.Anhydrous Na 2SO 4Drying, concentrating under reduced pressure gets glassy yellow oily matter, and column chromatography for separation gets white or light yellow solid, 60 ℃ of vacuum-drying powderings, this material is infrared and nuclear magnetic resonance data is as follows:
IR (KBr) v/cm -1: 3004.35 (Ar-H), 2942.60 (CH 3), 2886.96 (CH 2), 1781.92,1709.00 (C=O), 1594.37,1498.32,1425.79 (phenyl ring skeletons), 1369.22,1324.58 (CH (CH 3) 2), 1251.10,1188.14 (C-O);
1H-NMR(CDCl 3，400MHz)δ/ppm：7.784(s，Ar-H)，5.083-5.106(t，1H)，2.428-2.437(m，1H)，2.310-2.316(s，9H CH 3CO)，2.012-2.078(m，1H)，1.724-1.832(m，2H)，1.365-1.428(m，1H)，1.241-1.330(m，1H)，1.072-1.115(m，1H)，0.857-0.953(t，9H)。
(3) Gallic Acid borneol ester synthesis
With 0.26g 3,4,5-triacetoxyl group phenylformic acid norbornene ester places the there-necked flask that contains 15mL acetone, after the decorating film dissolving, adds the rare HCl of 5mL, backflow 3h, and stopped reaction is chilled to room temperature, adds the 30mL ethyl acetate again, saturated NaCl washing, anhydrous Na 2SO 4Drying, concentrating under reduced pressure gets light yellow oil, and column chromatography for separation gets white or light yellow solid, 60 ℃ of vacuum-dryings.Products therefrom is characterized by mass spectrum, infrared spectra, nuclear magnetic resonance spectrum, and concrete data are as follows:
ESI(-)-MS：m/z 305.0(M-1)；
IR (KBr) v/cm -1: 3470.85,3331.45 (OH), 3047.83 (Ar-H), 2954.77 (CH 3), 2878.64 (CH 2), 1678.43 (C=O), 1612.68,1536.05,1453.05 (phenyl ring skeletons), 1246.56 (C-O);
1HNMR(CD 3SOCD 3，400MHz)δ/ppm：9.252(s，OH)，8.912(s，OH)，6.977(s，Ar-H)，4.916-4.935(m，1H)，2.34-2.50(m，1H)，2.032-2.085(m，1H)，1.762(s，1H)，1.703(s，1H)，1.373-1.403(d，1H)，1.239-1.279(t，1H)，0.841-1.005(q，9H)。
13CNMR(CD 3SOCD 3，400MHz)δ/ppm：168.680，147.989，140.736，122.585，111.061，81.672，51.264，50.093，46.975，39.184，30.341，29.590，22.076，21.289，21.207，16.152，16.075。
Embodiment 2:3,4,5-trihydroxybenzoic acid borneol ester synthesis two
Add 0.012mol Gallic Acid and 0.018mol borneol in there-necked flask, then add 0.20g catalyzer p-methyl benzenesulfonic acid, the 25mL tetrahydrofuran (THF) is at 65 ℃ of lower reaction 18h.Column chromatography for separation was removed catalyzer, solvent and unreacted borneol after reaction finished, and got white or light yellow solid.The mass spectrum of products therefrom, infrared spectra, 1The H-NMR spectrum, 13CNMR spectrum data are identical with embodiment 1.
Embodiment 3:3,4,5-trihydroxybenzoic acid borneol ester synthesis three
Add 0.012mol Gallic Acid and 0.015mol borneol in there-necked flask, then add 0.20g catalyzer p-methyl benzenesulfonic acid, 25mL Isosorbide-5-Nitrae-dioxane is at 105 ℃ of lower reaction 18h.Reaction solvent was removed in underpressure distillation after reaction finished, and added 200mL ethyl acetate, the saturated NaHCO of gained solution in the gained solid matter 3Washing is to remove unreacted gallic acid and p-methyl benzenesulfonic acid, and concentrating under reduced pressure is got ethyl acetate layer, gets faint yellow solid, and column chromatography for separation gets white or light yellow solid.The mass spectrum of products therefrom, infrared spectra, 1The H-NMR spectrum, 13CNMR spectrum data are identical with embodiment 1.
Embodiment 4:3,4,5-trihydroxybenzoic acid borneol ester synthesis four
In there-necked flask, add 0.1mol Gallic Acid and 0.15mol borneol, then add the 1.33g catalyst S 2O 8 2-/ ZrO 2, the 5ml concentrated hydrochloric acid, 400ml Isosorbide-5-Nitrae-dioxane is in 105 ℃ of lower reaction 18h.Suction filtration was removed catalyst S after reaction finished 2O 8 2-/ ZrO 2, then underpressure distillation desolventizing gets pale red brown solid, adds 200mL ethyl acetate, the saturated NaHCO of gained solution in the gained solid matter 3, saturated NaCl washing is neutral, anhydrous Na 2SO 4Drying, concentrating under reduced pressure, column chromatography for separation gets white or light yellow solid.The mass spectrum of product, infrared spectra and nuclear magnetic resonance spectrum ( 1H-NMR and 13CNMR) data are identical with embodiment 1.
Catalyst S 2O 8 2-/ ZrO 2The preparation method as follows: get 0.025mol ZrOCl 28H 2O is mixed with 1molL -1ZrOCl 2Solution stirs in ice-water bath, slowly splashes into 6molL -1Ammoniacal liquor, until pH value to 10, ageing 12h, suction filtration is precipitated to without Cl with distilled water wash -Till (use 0.1molL -1AgNO 3Check).To be deposited in 110 ℃ of lower baking 10h, then porphyrize uses 0.5molL -1(NH 4) 2S 2O 8Solution soaking 12h, suction filtration, drying, porphyrize, 600 ℃ of lower roast 3h namely make S in retort furnace 2O 8 2-/ ZrO 2
Embodiment 5:3,4-resorcylic acid borneol ester synthesis
PCA borneol ester synthesis is similar to embodiment 1,2,3,4.To react take PCA and borneol as raw material in implementation.Products therefrom is white crystal.
ESI(-)-MS：m/z 289.0(M-1)；
IR (KBr) v/cm -1: 3445.94 (OH), 2965.57 (CH 3), 2877.59 (CH 2), 1680.30 (C=O), 1605.73,1524.91,1447.97 (phenyl ring skeletons), 1379.88,1307.01 (CH (CH 3) 2), 1235.45 (C-O);
1HNMR(CD 3SOCD 3，400MHz)δ/ppm：9.775(s，-OH)，9.395(s，-OH)，7.410-7.414(d，1H)，7.335-7.360(dd，1H)，6.829-6.850(d，1H)，4.948-4.971(m，1H)，2.34-2.50(m，1H)，2.036-2.068(m，1H)，1.759(s，1H)，1.702-1.728(t，1H)，1.244-1.404(2H)，0.922-1.077(1H)，0.690-0.883(q，9H)。
Embodiment 6:3,4,5-trihydroxybenzoic acid peppermint ester synthesis
Gallic Acid peppermint ester synthesis is similar to embodiment 1,2,3,4.To react take Gallic Acid and peppermint as raw material in implementation.Products therefrom is white crystal.
ESI(-)-MS：m/z 307.0(M-1)
IR (KBr) v/cm -1: 3372.01 (OH), 2956.96 (CH 3), 2927.73 (CH 2), 2869.73 (CH), 1678.03 (C=O), 1612.96,1535.47,1452.86 (phenyl ring skeletons), 1388,1313.01 (CH (CH 3) 2), 1250.78 (C-O);
1HNMR(CD 3SOCD 3，400MHz)δ/ppm：9.269(s，OH)，8.944(s，OH)，6.929(s，ArH)，4.688-4.752(m，1H)，1.922-1.951(1H)，1.818-1.888(1H)，1.666-1.692(2H)，1.446-1.502(2H)，1.163-1.199(3H)，0.727-0.909(9H)。
Embodiment 7:3,4-resorcylic acid peppermint ester synthesis
PCA peppermint ester synthesis is similar to embodiment 1,2,3,4.To react take PCA and peppermint as raw material in implementation.Products therefrom is white crystal.
ESI(-)-MS：m/z 291.0(M-1)；
IR (KBr) v/cm -1: 3281.33 (OH), 2957.33 (CH 3), 2927.73 (CH 2), 2869.58 (CH), 1676.42 (C=O), 1603.17,1524.25,1444.80 (phenyl ring skeletons), 1371,1296.02 (CH (CH 3) 2), 1229.40 (C-O);
1HNMR(CD 3SOCD 3，400MHz)δ/ppm：9.776(s，1H)，9.371(s，1H)，7.320-7.362(t，2H)，6.793-6.813(d，1H)，4.714-4.778(t，1H)，1.922-1.951(1H)，1.818-1.888(1H)，1.666-1.692(2H)1.446-1.502(2H)1.163-1.199(3H)0.677-0.905(9H)。
Embodiment 8:3,5-dimethoxy-4 ' hydroxy-benzoic acid borneol ester synthesis
3,5-dimethoxy-4 ' hydroxy-benzoic acid borneol ester synthesis is similar to embodiment 2,3,4.To be that raw material reacts with 3,5-dimethoxy-4 ' hydroxy-benzoic acid and borneol in implementation.Products therefrom is white crystal.
ESI(-)-MS：m/z 333.0(M-1)；
IR (KBr) v/cm -1: 3430.75 (OH), 2954.20 (CH 3), 2882.44 (CH 2), 2840.47 (CH), 1690.21 (C=O), 1613.08,1519.22,1461.74 (phenyl ring skeletons), 1376.42,1337.98 (CH (CH 3) 2), 1272.98,1236.60,1202.17 (C-O-C);
1HNMR(CD 3SOCD 3，400MHz)δ/ppm：9.372(s，1H)，7.223(s，2H)，4.973-4.996(d，1H)，3.819(s，6H)，2.367-2.376(d，1H)，2.051-2.068(t，1H)，1.704-1.770(2H)，1.297-1.389(t，2H)，1.030-1.072(q，1H)，0.864-0.931(t，9H)。
Embodiment 9:2,5-two fluoro-4 hydroxy-benzoic acid borneol ester synthesis
2,5-, two fluoro-, 4 hydroxy-benzoic acid borneol ester synthesis are similar to embodiment 2,3,4.To be that raw material reacts with 2,5-, two fluoro-, 4 hydroxy-benzoic acids and borneol in implementation.Products therefrom is white crystal.
ESI(-)-MS：m/z 309.3(M-1)；
IR (KBr) v/cm -1: 3320.23 (OH), 2968.14 (CH 3), 2876.36 (CH 2), 2845.69 (CH), 1688.30 (C=O), 1609.15,1522.19,1474.61 (phenyl ring skeletons), 1367.24,1334.48 (CH (CH 3) 2), 1268.56,1234.88,1198.11 (C-O-C);
1HNMR(CD 3SOCD 3，400MHz)δ/ppm：9.551(s，1H)，7.082(d，2H)，4.505-4.569(d，1H)，3.759(s，6H)，2.264-2.286(d，1H)，1.923-1.946(t，1H)，1.515-1.530(2H)，1.280-1.301(t，2H)，1.025-1.068(q，1H)，0.877-0.964(t，9H)。
Embodiment 10:3,4,5-trihydroxybenzoic acid norbornene ester treating cerebral ischemia
One, method
Get 60 of body weight 180-220g SD rats, male, be divided at random Sham-operated control group (2% poloxamer), model control group (2% poloxamer) and Gallic Acid norbornene ester group (5,10 and 20mg/kg).After the anesthesia, neck median incision exposes left common carotid (CCA), outwards draw biventer and nutator, free successively by CCA crotch head-end, ligation and all branches of cutting off external carotid artery (ECA) make its trunk free for subsequent use in the ligation of ECA far-end and cut-out; Then separate internal carotid artery (ICA), make a call to one with silk thread at the ECA root and release, folder closes CCA and ICA.With ready-made bolt line through ECA trunk otch, slowly entering the cranium direction to ICA advances, take the CCA crotch as mark, feel resistance when advancing the 20mm left and right sides, namely reached in the thinner arteria cerebri anterior, blocked all blood of MCA for the source, tightened the ECA root and release, unclamp the arteriole folder of CCA and ICA, skin suture.Sham operated rats is not except inserting the line bolt, and all the other steps are the same.Respectively at 23h tail vein injection administration after at once reaching modeling after the modeling respectively once.
1.Bederson behavior scoring
The clear-headed method by Bederson of postoperative anesthesia is carried out rank scores to the behavioral deficiency of animal, carries out system scoring in 5 minutes: 0 minute, and impassivity afunction symptom; 1 minute, can not full extension offside fore paw; 2 minutes, turn-taked on (left side) laterally; 3 minutes, topple over to offside; 4 minutes, can not walk voluntarily the loss of consciousness.Score value is higher, and behavior disorder is more serious, and each group model all is successful.
2. the impact of Range of Cerebral Infarction
Behind the MCAO 24h, the sacrificed by decapitation rat is taken out left brain, weighs behind removal olfactory bulb, cerebellum and the low brain stem.At optic chiasma and each 2mm place, front and back thereof, do crown section, brain section 37 ℃ of lucifuges in TTC solution are hatched 20min, healthy tissues is dyed rose, and infarction tissue is white in color, white organized carefully to dig down weigh, account for the per-cent of right side half brain weight as Range of Cerebral Infarction with blocking tissue's weight.
3.SOD, the impact of MDA content
The sacrificed by decapitation rat, sharp separation left side pallium is made homogenate with ice-cold homogenate medium in the ice pan, presses the test kit specification sheets, measures MDA, SOD, LA, the GSH equal size of respectively organizing cortex.
Two, result
1. on the impact of rat nervous symptoms
Table 13,4,5-trihydroxybenzoic acid norbornene ester is on the impact of MCAT rat nervous symptoms
Figure G2009100230106D00091
Compare * P＜0.05, * * P＜0.01 with model group
Experimental result shows that sham operated rats has no dystropy and changes, and cerebral ischemic model group rat is 6h after surgery, and hemiplegia sample symptom all appears in 24h, and main manifestations is receipts in the operation offside forelimb, the shoulder inward turning, and muscle of anterior limb tension force reduces, and the shoulder drag descends.Gallic Acid norbornene ester 20mg/kg dosage group is to rat postoperative 6h, and the nervous symptoms of 24h all has clear improvement.
2. on the impact of Range of Cerebral Infarction
Table 23,4,5-trihydroxybenzoic acid norbornene ester is on the impact of MCAT rat cerebral infarction scope
Figure G2009100230106D00101
Compare * P＜0.05, * * P＜0.01 with model group
Experimental result shows, postoperative 24h, and Gallic Acid norbornene ester 20mg/kg group rat infraction degree is compared with model group and is had clear improvement.
3. on the impact of SOD, MDA content
Table 33,4,5-trihydroxybenzoic acid norbornene ester is to the SOD of rat cerebral tissue vigor and MDA content influence
Compare P＜0.01, P＜0.05 with model group
Experimental result shows that Gallic Acid norbornene ester 10mg/kg and 20mg/kg rats with cerebral ischemia brain SOD vigor further obviously raise; Gallic Acid norbornene ester 20mg/kg can obviously suppress the content of MDA in the rats with cerebral ischemia cerebral tissue.

Claims (5)

1. the purposes of the compound of general formula (I) expression in preparation prevention and treatment cardiovascular and cerebrovascular diseases medicament,
（I）
Wherein, R 2, R 3, R 4Be selected from independently of each other H, OH, methoxy or ethoxy; R 1, R 5Be selected from independently of each other H or OH.
2. described purposes according to claim 1 is characterized in that: R 1, R 5Be H simultaneously.
3. described purposes according to claim 2 is characterized in that: R 2, R 3, R 4Be OH simultaneously.
4. described purposes according to claim 2 is characterized in that: R 2, R 3Be OH, R 4Be H.
5. described purposes according to claim 1 is characterized in that: R 1, R 4, R 5Be H simultaneously, R 2, R 3Be methoxyl group.
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