CN100430387C - 6,7-dihydroligustilide and alkylidene phthalide synthesis method - Google Patents
6,7-dihydroligustilide and alkylidene phthalide synthesis method Download PDFInfo
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- CN100430387C CN100430387C CNB2006100934030A CN200610093403A CN100430387C CN 100430387 C CN100430387 C CN 100430387C CN B2006100934030 A CNB2006100934030 A CN B2006100934030A CN 200610093403 A CN200610093403 A CN 200610093403A CN 100430387 C CN100430387 C CN 100430387C
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Abstract
The present invention discloses a novel method for synthesizing a plurality of perfumes and medicinal intermediate bodies, namely that 1-cyclohexene-1, 2-bianhydride is prepared from 4-cyclohexene-1, 2-bianhydride under the catalysis of a palladium catalyst under a heating condition, and phthalide compounds, namely 6, 7-dihydro-ligustilide and alkylidene phthalide, are prepared from a Grignard reagent of alkyl and 1-cyclohexene-1, 2-bianhydride or phthalic anhydride by reaction under cuprous catalysis. The method for synthesizing the phthalide compounds has the advantages of easy acquirement of raw materials, low synthesis cost and simple operating method and is suitable for industrial amplification. Compared with the prior art, the method of the present invention has much lower preparation cost and higher yield.
Description
Technical field:
The present invention relates to some spices and medicine intermediate synthetic novel method, definite say that what relate to is the synthetic method of some compounds of phthalide-type.
Background technology:
(3Z)-3-n-butene-4,5,6,7-tetrahydrochysene isobenzofuran-1-3 (hydrogen)-ketone (6, the 7-dihydro-homophthalic lactone), (3z)-n-butene base phthalide and 3-n-butylphthalide (Butylphthalide) etc. all have good smell to be added an amount of phthalide analog compound and can produce pleasant fragrance in soap and fruit juice.They become normal adopted spices already.In addition, this compounds also has good pharmacologically active effect, and for example n-butene base phthalide lactone has cholinolytic effect, it is the composition of Radix Angelicae Sinensis spasmolysis, have very strong inhibition uterine contraction effect, also can have significant relexation, so also have antiasthmatic effect the animal tracheal smooth muscle.With the butylidene phthalide normal-butyl phthalein lactone that further hydrogenation obtains under the catalysis of palladium carbon is Butylphthalide, equally also has good pharmacological action.
Usually the synthetic the easiest method of this compounds is that the metallic compound with carboxylic acid derivative and alkyl reacts and obtains, referring to S.B.Li et al, Syn.Commun., 23,2909, (1993).But two alkylates are difficult to avoid in this reaction.Mostly be carboxylic acid derivative is changed into acyl chlorides earlier or they are become lithium salts in order to obtain the monoalkylated product prior art, obtain with itself and other metal alkyl compound or with the lithium alkylide reaction again, the reaction process complexity, cost is higher.Especially synthetic 6, during the precursor raw material of 7-dihydro-homophthalic lactone, referring to S.B.Li et al, Syn.Commun., 23,2051, (1993), be to use the Brich reduction reaction, specifically be to use Tetra hydro Phthalic anhydride in liquefied ammonia, carry out at low temperatures, will use sodium Metal 99.5 in addition as reductive agent, operation is comparatively dangerous and difficult, especially when amplification quantity is synthetic, reaction is difficult to control, the not high and complicated operation of productive rate.And, used the higher butyllithium of cost with in the alkylated reaction of butyllithium, and under extremely low temperature, react again, need bigger refrigerating duty, consumes energy, the equipment complexity, and often to environment generation influence to a certain degree; In addition, the by product of dialkyl groupization is difficult to avoid, and has increased isolating difficulty again.
Summary of the invention:
The invention provides a kind of synthetic 1-tetrahydrobenzene-1 of reaction that utilizes double-bond isomerization, the method for 2-dicarboxylic anhydride; It is a kind of under cuprous halide catalysis that the present invention provides again, and Grignard reagent is to the selective alkylation method of acid anhydrides.These methods can overcome the deficiencies in the prior art, have simplified 1-tetrahydrobenzene-1 greatly, and 2-dicarboxylic anhydride synthetic step reacts simple to operate than prior art, and preparation cost is lower; Also simplified 1-tetrahydrobenzene-1, the alkylation of 2-dicarboxylic anhydride and Tetra hydro Phthalic anhydride has reduced synthetic difficulty, has reduced synthetic cost.
The present invention is with the 4-tetrahydrobenzene-1 that is easy to get, and the 2-dicarboxylic anhydride is under palladium catalyst catalysis, and heating makes two keys take place to reset and obtained 1-tetrahydrobenzene-1, the 2-dicarboxylic anhydride.
4-tetrahydrobenzene-1 of the present invention, in the 2-dicarboxylic anhydride double bond isomerization reaction, the palladium catalyst of usefulness is 3～10% palladium/carbon catalyst or 1～3% palladium/aluminium oxide catalyst.
4-tetrahydrobenzene-1 of the present invention, in the 2-dicarboxylic anhydride double bond isomerization reaction, the temperature of reaction is carried out under 80～250 ℃.The temperature of reaction is high more, and the time of reaction is just short more.
4-tetrahydrobenzene-1 of the present invention in the 2-dicarboxylic anhydride double bond isomerization reaction, is to add substrate in 5: 1～30: 1 by the amount of substrate and catalyzer.The amount of the catalyzer that adds is many more, and the time of reaction is just short more.
Grignard reagent of the present invention is to 1-tetrahydrobenzene-1, and the selective alkylation reaction of 2-dicarboxylic anhydride and Tetra hydro Phthalic anhydride is to react having under the cuprous halide catalytic condition.
To 1-tetrahydrobenzene-1, in the selective alkylation reaction of 2-dicarboxylic anhydride and Tetra hydro Phthalic anhydride, employed cuprous halide is best with the cuprous iodide effect at Grignard reagent of the present invention.
1-tetrahydrobenzene-1 of the present invention; in the selective alkylation reaction of 2-dicarboxylic anhydride and Tetra hydro Phthalic anhydride; earlier cuprous iodide is dissolved in the tetrahydrofuran (THF); again by substrate: catalyzer equals 10: 1～and 110: 1 amount adds it in substrate; add the reaction the Grignard reagent amount be 1～2 times of mole of amount of substrate; under protection of inert gas, add Grignard reagent gradually during reaction.
The moieties of Grignard reagent of the present invention is normal-butyl, n-propyl or ethyl, i.e. C
2H
5, C
3H
7Or C
4H
9Alkyl.Product is that the Grignard reagent with positive n-butyl bromide is the reactant definition.
With 1-tetrahydrobenzene-1, when the 2-dicarboxylic anhydride is the substrate of reaction, when Grignard reagent is 1 to 2 times of amount of substrate, can obtain higher reaction yield; During mole such as Grignard reagent and substrate, the reaction times long (shortening the reaction times) but improve temperature of reaction.Experiment shows, the Grignard reagent consumption that uses as the present invention can obtain the selectivity that higher reaction yield is become reconciled during as 2 times of molar weights of substrate.
When being the substrate of reaction, when Grignard reagent is 1 to 2 times of amount of substrate, can obtain higher reaction yield with the Tetra hydro Phthalic anhydride.Experiment shows, the Grignard reagent consumption that uses as the present invention can obtain the selectivity that higher reaction yield is become reconciled during as 2 times of molar weights of substrate.
Method of the present invention is operated easily, and reaction is to carry out at normal temperatures.Help removing of reaction heat and drip Grignard reagent lentamente, make reaction control easily.Method of the present invention is suitable for industry amplifies, and raw materials used being easy to get, and synthetic cost is also lower, adopts many that its cost of method of the present invention will be low than prior art.
Embodiment:
In the experiment of being carried out of the present invention, with 4-tetrahydrobenzene-1, the 2-dicarboxylic anhydride adds a certain amount of palladium catalyst, and 80～220 ℃ of reactions, when question response finished, filtering catalyst had obtained pure 1-tetrahydrobenzene-1,2-dicarboxylic anhydride.
The moieties of the Grignard reagent that is adopted in the experiment of being carried out of the present invention is normal-butyl or n-propyl.Substrate has used respectively and has comprised 1-tetrahydrobenzene-1 in each relevant experiment, and 2-dicarboxylic anhydride and Tetra hydro Phthalic anhydride are as substrate, and catalyzer has adopted cuprous bromide, cuprous chloride respectively, and cuprous iodide, all obtains the product envisioned, and the ideal yield is arranged.Most preferred embodiments more of the present invention below are provided:
Example one: 6,7-dihydro-homophthalic lactone synthetic
A:1-tetrahydrobenzene-1,2-dicarboxylic anhydride synthetic
The present invention promptly 10 restrains 4-tetrahydrobenzene-1 with 0.066 mole, the blended solid thing of the palladium carbon (3%) of 2-dicarboxylic anhydride and 0.5 gram is heated to 130 ℃ and stirred 12 hours, and product is dissolved with chloroform, removes by filter palladium carbon, steam solvent, obtain white wax tabular crystal 9.9 grams.
B: alkylated reaction
With 0.05 mole is the 1-tetrahydrobenzene-1 of 7.60 grams; 2-dicarboxylic anhydride and 0.1 gram cuprous iodide are dissolved in the anhydrous tetrahydro furan; argon shield; normal temperature; stir the alkyl Grignard reagent that drips 0.1 mole (solution of in the 60ml anhydrous diethyl ether, making with 2.4 bromination of n-butane that restrain MAGNESIUM METAL and 13.7g) down; the dropping Grignard reagent is half an hour approximately; reaction 5-6 hour adds dilute hydrochloric acid 2mol/L solution 40ml cancellation reaction, 25ml * 3 extracted with diethyl ether; the aqueous solution 25ml washing ether extraction liquid of saturated sodium bicarbonate 3-5 time; saturated common salt solution washing 1-2 time, anhydrous magnesium sulfate drying, steam desolventize crude product; crude product is dissolved in the benzene; added a little tosic acid reflux dewatering two hours, the saturated solution of cooling back salt of wormwood washs 2-3 time the solution washing of saturated sodium bicarbonate 3-5 time rapidly; the saturated common salt water washing; anhydrous magnesium sulfate drying, decompression steams solvent and obtains product (3Z)-3-butenyl 4,5; 6,7-tetrahydrochysene isobenzofuran-1-3 (hydrogen)-ketone 8.9 grams.Productive rate 93%.Carry out TCL and spectroscopic analysis and meet predetermined structure.
Example two: butylidene phthalide synthetic
With 0.05 mole is that the Tetra hydro Phthalic anhydrides of 7.4 grams and 0.1 gram (less than 2%) CuI of catalytic amount are dissolved in the 50ml anhydrous tetrahydro furan; argon shield; drip the alkyl Grignard reagent of 0.1 mole (solution of in the 60ml anhydrous diethyl ether, making with 2.4 bromination of n-butane that restrain MAGNESIUM METAL and 13.7g) under the stirring at normal temperature; the dropping Grignard reagent is half an hour approximately; reaction 12-15 hour; add dilute hydrochloric acid 2mol/L solution 20ml cancellation reaction; 25ml * 3 extracted with diethyl ether; the aqueous solution 25ml washing ether extraction liquid of saturated sodium bicarbonate 3-5 time; saturated common salt solution washing 1-2 time; anhydrous magnesium sulfate drying; steaming desolventize crude product, crude product is dissolved in the benzene, added a little tosic acid reflux dewatering two hours; the saturated solution of cooling back Anhydrous potassium carbonate washs 2-3 time rapidly; the solution washing of saturated sodium bicarbonate 3-5 time, saturated common salt water washing, anhydrous magnesium sulfate drying; remove solvent under reduced pressure and obtain product 3-butylene isobenzofuran-1-3 (hydrogen)-ketone 8.93 grams, productive rate is 95%.Carry out TCL and spectroscopic analysis and meet predetermined structure.
Example three: propenyl phthalide synthetic
With 0.05 mole is that the Tetra hydro Phthalic anhydrides of 7.4 grams and 0.1 gram (less than 2%) CuI of catalytic amount are dissolved in the 50ml anhydrous tetrahydro furan; argon shield; drip the alkyl Grignard reagent of 0.1 mole (solution of in the 60ml anhydrous diethyl ether, making with 2.4 n-propyl bromides that restrain MAGNESIUM METAL and 12.3g) under the stirring at normal temperature; the dropping Grignard reagent is half an hour approximately; reaction 12-14 hour; add dilute hydrochloric acid 2mol/L solution 20ml cancellation reaction; 25ml * 3 extracted with diethyl ether; the aqueous solution 25ml washing ether extraction liquid of saturated sodium bicarbonate 3-5 time; saturated common salt solution washing 1-2 time; anhydrous magnesium sulfate drying; steaming desolventize crude product, crude product is dissolved in the benzene, added a little tosic acid reflux dewatering two hours; the saturated solution of cooling back Anhydrous potassium carbonate washs 2-3 time rapidly; the solution washing of saturated sodium bicarbonate 3-5 time, saturated common salt water washing, anhydrous magnesium sulfate drying; remove solvent under reduced pressure and obtain product 3-propylene isobenzofuran-1-3 (hydrogen)-ketone 8.3 grams, productive rate is 95%.Carry out TCL and spectroscopic analysis and meet predetermined structure.
Claims (6)
1. one kind is synthesized 6, and the method for 7-dihydro-homophthalic lactone is characterized by: step 1 is with 4-tetrahydrobenzene-1, and the 2-dicarboxylic anhydride under the effect of palladium catalyst, utilizes heating to make the synthetic 1-tetrahydrobenzene-1,2-dicarboxylic anhydride of obtaining of reaction of double-bond isomerization; Step 2 is used 1-tetrahydrobenzene-1, and the Grignard reagent of 2-dicarboxylic anhydride and normal-butyl is under the cuprous iodide katalysis of catalytic amount, and optionally monoalkylation has obtained 6, the 7-dihydro-homophthalic lactone.
2. according to the method for claim 1, it is characterized by catalyzer in the step 1 and be 3～10% the palladium/carbon catalyst or the catalyzer of 1～3% palladium/aluminum oxide.
3. according to the method for claim 1, the temperature that it is characterized by heating in the step 1 is carried out at 80～250 ℃.
4. according to the method for claim 1, the amount that it is characterized by the catalyzer that adds in the step 1 is by substrate 4-tetrahydrobenzene-1, and the amount of 2-dicarboxylic anhydride and palladium/carbon catalyst is adding in 5: 1～30: 1.
5. according to the method for claim 1, the consumption that it is characterized by the Grignard reagent of normal-butyl in the step 2 is by 1-tetrahydrobenzene-1,1 to 2 times of amount of 2-dicarboxylic anhydride.
6. according to the method for claim 1, it is characterized by in the step 2 is by 1-tetrahydrobenzene-1, the 2-dicarboxylic anhydride: the amount of catalyzer cuprous iodide equals 10: 1～and 110: 1.
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| CN101284825B (en) * | 2008-06-03 | 2010-08-04 | 河南省科学院化学研究所有限公司 | Synthetic method of tetramethylene maleic anhydride |
| CN101962374A (en) * | 2010-10-21 | 2011-02-02 | 上海应用技术学院 | Preparation method of butylphthalide |
| CN111196794A (en) * | 2020-01-17 | 2020-05-26 | 韩城市宏达花椒香料有限公司 | Synthesis method of food additive butylidenephthalide and application of butylidenephthalide in seasoning aspect |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1084851A (en) * | 1992-09-30 | 1994-04-06 | 兰州大学 | The synthetic method of Z-ligustilide |
| CN1088324A (en) * | 1993-12-15 | 1994-06-22 | 项晟 | Diode array pen input device of computer |
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2006
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1084851A (en) * | 1992-09-30 | 1994-04-06 | 兰州大学 | The synthetic method of Z-ligustilide |
| CN1088324A (en) * | 1993-12-15 | 1994-06-22 | 项晟 | Diode array pen input device of computer |
Non-Patent Citations (2)
| Title |
|---|
| 苯酞和1，7二芳基庚烷类的天然产物的全合成及相应烷基化反应的研究. 吴莉，1－22，兰州大学. 2006 |
| 苯酞和1，7二芳基庚烷类的天然产物的全合成及相应烷基化反应的研究. 吴莉，1－22，兰州大学. 2006 * |
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