CN101182324A - Method for synthesizing spiro ketal by employing double organic zincons - Google Patents
Method for synthesizing spiro ketal by employing double organic zincons Download PDFInfo
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Abstract
The present invention discloses a method of synthesizing spiro ketal by dual-organic zinc reagent. The method is that the dual-organic zinc iodide with ketal is used to react with acyl chloride to produce the diketone with ketal to be deoxidized and synthesized as dihydroxy ketal by sodium borohydride, and then the spiro ketal is further synthesized under the catalysis of p-toluenesulfonic acid. The present invention shortens the synthesis route of the spiro ketal greatly and at the same time reduces the synthesis cost; the reaction yield is high, and the total yield is 24 percent to 38 percent; the reaction condition is gentle; the operation is simple; the present invention is easy for the industrialized production.
Description
Technical field
The invention belongs to technical field of organic synthesis, relate to a kind of synthetic method of spiro ketal, relate in particular to a kind of method that adopts the double-organic zinc reagent synthesizing spiro ketal.
Background technology
Natural product has very important significance with design is synthetic for the discovery of new drug, in fact in the medicine of having used, has 40% to be from natural product and derivative thereof, and ratio is especially up to 60% in the medicine of treatment cancer.Yet because some natural product is considerably less at the content of occurring in nature, and from the ecological protection angle, people can not obtain enough amounts from occurring in nature and be used for medicine.Therefore just has only the synthetic of passing through for the good natural product of some drug effects.
The spiro ketal structure extensively is present in the natural product, and particularly some that extract from marine organisms in recent years have in the natural product of antitumour activity, and spiro ketal is its basic structure.For example in the structure of spongistatin (1-9), Integramycin, halichondrins tautomycin didemnaketal etc., all contain the spiro ketal structure, at present in these natural products complete synthesis, the synthetic of spiro ketal structure is precursor with dihydroxyl ketone substantially all, and the dihydroxyl ketone of synthetic these chiralitys needs long linear synthesis step, thereby makes whole synthetic productive rate very low.With spongistatin is example, and the NCI of the U.S. thinks that spongistatin family is the best medicine of present antitumour activity, wherein active best with spongistatin 1.(productive rate: 0.00000034%), therefore the chemosynthesis to it seems very important because the content of occurring in nature is few.But in the synthetic method of finishing at present, there is not a kind of method that product more than 4 milligrams can be provided.Its major cause is that synthetic route is oversize, and generally more than 80 steps, setting up spiro ketal partly needs 60 multisteps, and wherein the longest linear step is more than 35 steps.Therefore searching quickly and easily, the method for synthesizing spiro ketal has certain meaning effectively.
Summary of the invention
The purpose of this invention is to provide that a kind of cost is low, productive rate is high, synthetic route is short, the method for simple and direct synthesizing spiro ketal effectively.
The method of synthesizing spiro ketal of the present invention is to make diketone with the two organic iodate zincon and the acyl chloride reaction of band ketal, synthesizes the dihydroxyl ketal through sodium borohydride reduction again, then further synthesizing spiro ketal under Catalyzed by p-Toluenesulfonic Acid.Its concrete building-up process is shown below:
R＝Ph，a-ClC
6H
4，a-BrC
6H
4，a-lC
6H
4，a-CH
3(CH
2)
nOC
6H
4，a-CH
3(CH
2)
nC
6H
4，
a-NO
2C
6H
4，a-CF
3C
6H
4，CH
3(CH
2)
n，Cl(CH
2)
n. a＝2～4；n＝0～12
The concrete grammar of synthesizing spiro ketal of the present invention comprises following processing step:
(1) preparation of the double-organic zinc reagent of band ketal
1. with 1,7-two chloro-dipropyl ketone (compound 1) and sodium iodide are dissolved in the acetone by 1: 3～1: 4 mol ratio, in 50～60 ℃ of back flow reaction 6～8 hours, cooling boils off and adds ether behind the acetone and make the reaction product dissolving, removes by filter NaCl and excessive N aI that reaction is produced then, promptly gets crude product after boiling off ether, get white crystal with recrystallizing methanol again---1,7-two iodo-dipropyl ketone (compound 2), fusing point is 41～42 ℃, productive rate is more than 99.
2. with 1, (ratio is 1: 2.1: 0.05～1: 2.2: 0.1 when alcohol is monohydroxy-alcohol in molar ratio for 7-two iodo-dipropyl ketone, alcohols, tosic acid; Ratio is 1: 1.2: 0.05～1: 1.2: 0.1 when alcohol is dibasic alcohol) be dissolved in benzene, in 80～90 ℃ of reflux, tell the water that generates in the reaction simultaneously, reacted 2～3 hours, add 1 after being cooled to room temperature, the salt of wormwood that 7-two iodo-dipropyl ketone molar weights are 2～3 times (be used for catalyst neutralisation tosic acid) stirring reaction 1～2 hour, normal pressure steams solvent benzol, use the mixture (volume ratio of the two is 5: 1) of sherwood oil and ethyl acetate to get compound 3 again for eluent carries out column chromatography---1,7-two iodo-dipropyl ketone condensed ethandiols, productive rate is more than 90%.
Alcohols of the present invention is methyl alcohol, ethanol, propyl alcohol, ethylene glycol, 1, ammediol and 1, any in the 4-butyleneglycol.
3. with the tetrahydrofuran (THF) solvent; two idohydrocarbons and the zinc powder mol ratio with 1: 2～1: 3 is joined in the reactor; the zinc powder activator that adds zinc powder quality 1%～5% more promptly got target product in 4～10 hours in 40 ℃～45 ℃ back flow reaction under protection of inert gas---the double-organic zinc reagent (compound 4) of band ketal.
The zinc powder activator that the present invention adopts is glycol dibromide and the trimethylchlorosilane mixture with 1: 1～1: 2 mixed in molar ratio.
Raw material 1 of the present invention, 7-two chloro-dipropyl ketone are got by following prepared:
With 1, the sodium Metal 99.5 piece that 4-butyrolactone molar weight is 0.5 times joins in the methyl alcohol of capacity in batches, treat to add 1 after sodium disappears, the 4-butyrolactone, in 70～80 ℃ of reflux 3～4 hours, boil off methyl alcohol after the cooling, under cooling and vigorous stirring, add 1, the concentrated hydrochloric acid that 4-butyrolactone molar weight is 10～15 times adds the back in 90～100 ℃ of reflux 0.5～1 hour, cooling back extracted with diethyl ether, the salt of wormwood drying, filter, boil off that the mixture with sherwood oil and ethyl acetate is that the eluent column chromatography gets target product behind the solvent, productive rate is more than 70%.
(2) cyclohexadione compounds (compound 5) is synthetic
Under protection of inert gas, cuprous cyanide and the lithium chloride mol ratio with 1: 2～1: 4 is dissolved in the tetrahydrofuran solvent, be cooled to-20 ℃～-50 ℃, the band that adds cuprous cyanide and lithium chloride total amount 50%～80% carbonyl double-organic zinc reagent that contracts, be warming up to 0 ℃～-10 ℃, stirring reaction 10～30 minutes; Be cooled to-20 ℃～-50 ℃ then, and add the acyl chlorides of double-organic zinc reagent 60%～100%, under agitation reacted 6～8 hours, obtain cyclohexadione compounds with ketal through extraction, drying, separation.Productive rate is 54～68%.
The acyl chlorides of described employing is any in aromatic series acyl chlorides and the aliphatics acyl chlorides.
(3) dihydroxyl ketal (compound 6) is synthetic
The diketone (compound 5) of band ketal is dissolved in the methylene dichloride, the sodium borohydride methanol solution that under agitation adds 2～4 times of diketone molar weights gradually, continue to stir 0.5～1 hour, boil off methyl alcohol, adding aqueous sodium carbonate and ethyl acetate extracts, anhydrous magnesium sulfate drying, boil off behind the solvent target product---compound 6, productive rate is more than 99%.
(4) spiro ketal (compound 7) is synthetic
With benzene is solvent, and dihydroxyl ketal (compound 6), tosic acid are joined in the reactor by 1: 0.05～1: 0.1 mol ratio, in 80 ℃～90 ℃ reflux 2～5 hours, is cooled to the K that adds 2～3 times of tosic acid molar weights after the room temperature
2CO
3(being used for the catalyst neutralisation tosic acid), stirred 1～2 hour, boil off that the mixture with sherwood oil and ethyl acetate is that eluent (the two volume ratio is 100: 1) column chromatography gets target product compound 7---spiro ketal behind the solvent, productive rate is 70～86%.
The spiro ketal compound of the present invention's preparation, warp
1HNMR, IR,
13CNMR detects, and its product is pure target compound.
The present invention compares in prior art and has the following advantages:
1, the synthetic method of spiro ketal of the present invention, be to make diketone with the two organic iodate zincon and the acyl chloride reaction of band ketal, again through the synthetic dihydroxyl ketal of sodium borohydride reduction, further synthesizing spiro ketal under Catalyzed by p-Toluenesulfonic Acid then, shortened synthetic route greatly, shorten whole synthesis cycle, effectively reduced synthetic cost simultaneously.
2, the reaction conditions gentleness is simple to operate, is easy to suitability for industrialized production.
3, productive rate height, total recovery reaches 24～38%.
4, raw material is cheap and easy to get, and cost reduces.
Embodiment
Embodiment 1, and reaction equation is as follows:
1, the preparation of the double-organic zinc reagent of band ketal
Add exsiccant NaI (0.6mol), exsiccant 100ml acetone and 1 in a single port bottle, 7-two chloro-dipropyl ketone (compound 1) (0.2mol) are installed reflux condensing tube backflow 8h again.Boil off acetone after the cooling, add the 100ml ether again and make product dissolving after-filtration fall NaCl and excessive N aI, promptly get crude product after boiling off solvent.Get white crystal (compound 2) (mp:41～42 ℃) with recrystallizing methanol at last.Productive rate is 99%.
Add 1 then in a single port bottle, 7-two iodo-dipropyl ketone (0.025mol), ethylene glycol (0.03mol), tosic acid (0.001mol) and 60ml benzene are installed water trap and reflux condensing tube again, fill with benzene in the water trap, reflux until telling about 0.5ml water, approximately needs 2h.Stop heating, be cooled to and add 0.3g salt of wormwood after the room temperature and stir 2h, normal pressure steams benzene, uses petrol ether/ethyl acetate=5: 1 column chromatographies again, compound 3---1,7-two iodo-dipropyl ketone condensed ethandiols.Productive rate is 90.7%.
2, dione compounds is synthetic
In a reactor, add zinc powder (0.11mol; 7.1g); use argon shield, add 10mlTHF, stir; add 1ml1 again; the 2-ethylene dibromide, heating makes it be back to foaming, is cooled to add 1ml trimethylchlorosilane (1 after the room temperature; 2-ethylene dibromide and trimethylchlorosilane are used for activated zinc powder), THF (80ml) solution of adding compound 3 (0.05mol) behind the stirring 15min.Heating makes it maintain the temperature at 35～40 ℃, and zinc powder disappearance behind about 3h makes the THF solution of compound 4, and it is standby to be cooled to room temperature.
In another reactor, add exsiccant CuCN (0.1mol) and exsiccant LiCl (0.2mol), use argon shield, add 80mlTHF; stir; treat that its dissolving postcooling to-30 ℃, slowly adds the made double-organic zinc reagent of previous step, be warming up to 0 ℃ after adding and stir 15min.And then be cooled to-30 ℃, and slowly add Benzoyl chloride (0.08mol), make it rise to room temperature naturally after dripping off.Add the 200ml saturated aqueous ammonium chloride, with extracted with diethyl ether three times (100ml * 3), anhydrous magnesium sulfate drying, filter, boil off that the mixture with sherwood oil and ethyl acetate is that eluent (the two volume ratio is 5: 1) column chromatography gets white crystal behind the solvent---compound 5, fusing point is 36-37 ℃, and productive rate is 68%.
The detection of dione compounds: above-mentioned synthetic dione compounds, warp
1HNMR, IR,
13CNMR detects, and its product is pure target compound.Its each performance index or characterization data are as follows:
IR(KBr)：3447，2955，2893，1681，1450，1268，1202，732，688cm
-1.
1HNMR(400MHz，CDCl
3，δppm)：7.97-7.95(m，4H)，7.57-7.53(m，2H)，7.48-7.44(m，4H)，3.95(s，4H)，3.02-2.99(m，4H)，1.87-1.81(m，4H)，1.76-1.72(m，4H).
13CNMR(100MHz，CDCl
3，TMS)：200.1，137.0，132.9，128.6，128.0，111.4，65.0，38.5，36.4，18.6。
3, dihydroxyl ketal compound 6 is synthetic
In a reactor, add compound 5 (0.02mol) and 100mlCH
2Cl
2, stir, drip NaBH then
4Methyl alcohol (0.044mol) (100ml) solution adds the back and continues to stir 0.5h.Boil off methyl alcohol, add aqueous sodium carbonate, with ethyl acetate extraction three times (100ml * 3), anhydrous magnesium sulfate drying, boil off behind the solvent product, productive rate is 99%.
4, spiro ketal compound 7 is synthetic
In a reactor, add compound 6 (0.02mol), tosic acid (0.002mmol) and 300ml benzene, in 80～90 ℃ of reflux 2h postcooling to room temperature after adding 2g K
2CO
3(be used for catalyst neutralisation tosic acid) stirs 1h, boils off that the mixture with sherwood oil and ethyl acetate is that eluent (the two volume ratio is 100: 1) column chromatography gets target product behind the solvent, and productive rate is 86%.
The detection of spiro ketal compound: above-mentioned synthetic spiro ketal compound, warp
1HNMR, IR,
13CNMR detects, and its product is pure target compound.Its each performance index or characterization data are as follows:
IR(KBr)：3442，2943，1493，1450，1379，1219，1049，977，751，697，530.
1HNMR(400MHz，CDCl
3，δppm)：7.41-7.24(m，10H)，4.73-4.70(m，2H，)，2.14-2.06(m，2H)，1.86-1.80(m，4H)，1.68-1.45(m，6H).
13CNMR(100MHz，CDCl
3，TMS)：143.6，128.2，127.0，126.0，97.1，70.9，35.3，33.0，19.3.
Embodiment 2, reaction equation are as follows:
1, the preparation of the double-organic zinc reagent of band ketal
The preparation method is with embodiment 1.
2, dione compounds 5 is synthetic
In a reactor, add zinc powder (0.11mol; 7.1g); use argon shield, add 10mlTHF, stir; add 1ml1 again; the 2-ethylene dibromide, heating makes it be back to foaming, is cooled to add 1ml trimethylchlorosilane (1 after the room temperature; 2-ethylene dibromide and trimethylchlorosilane are used for activated zinc powder), THF (80ml) solution of adding compound 3 (0.05mol) behind the stirring 15min.Heating makes it maintain the temperature at 35～40 ℃, and zinc powder disappearance behind about 3h makes the THF solution of compound 4, and it is standby to be cooled to room temperature.
In another reactor, add exsiccant CuCN (0.1mol) and exsiccant LiCl (0.2mol), use argon shield, add 80mlTHF; stir; treat that its dissolving postcooling to-30 ℃, slowly adds the made double-organic zinc reagent of previous step, be warming up to 0 ℃ after adding and stir 15min.And then be cooled to-30 ℃, and slowly add parachlorobenzoyl chloride (0.08mol), make it rise to room temperature naturally after dripping off.Add the 200ml saturated aqueous ammonium chloride, with extracted with diethyl ether three times (100ml * 3), anhydrous magnesium sulfate drying, filter, boil off that the mixture with sherwood oil and ethyl acetate is that eluent (the two volume ratio is 5: 1) column chromatography gets white crystal behind the solvent, fusing point is 88-89 ℃, and productive rate is 66%.
The detection of dione compounds: above-mentioned synthetic dione compounds, warp
1HNMR, IR,
13CNMR detects, and its product is pure target compound.Its each performance index or characterization data are as follows:
IR(KBr)：3442，2927，2893，1686，1589，1402，1364，1203，1089，1051，962，818，522.
1HNMR(400MHz，CDCl
3，δppm)：7.91-7.89(m，4H)，7.44-7.42(m，4H)，3.94(s，4H)，2.99-2.96(m，4H)，1.85-1.79(m，4H)，1.74-1.70(m，4H).
13CNMR(100MHz，CDCl
3，TMS)：198.8，139.3，135.2，129.4，128.8，111.2，64.9，38.4，36.2，18.4.
3, dihydroxyl ketal compound 6 is synthetic
In a reactor, add compound 5 (0.02mol) and 100mlCH
2Cl
2, stir, drip NaBH then
4Methyl alcohol (0.044mol) (100ml) solution adds the back and continues to stir 0.5h.Boil off methyl alcohol, add aqueous sodium carbonate, with ethyl acetate extraction three times (100ml * 3), anhydrous magnesium sulfate drying, boil off behind the solvent product, productive rate is 99%.
4, spiro ketal compound 7 is synthetic
In a reactor, add compound 6 (0.02mol), tosic acid (0.002mmol) and 300ml benzene, to room temperature, add 2gK in 80～90 ℃ of reflux 2h postcooling
2CO
3(be used for catalyst neutralisation tosic acid) stirs 1h, boils off that the mixture with sherwood oil and ethyl acetate is that eluent (the two volume ratio is 100: 1) column chromatography gets target product behind the solvent, and productive rate is 81%.
The detection of spiro ketal compounds: above-mentioned synthetic spiro ketal compounds, warp
1HNMR, IR,
13CNMR detects, and its product is pure target compound.Its each performance index or characterization data are as follows: IR (KBr): 3441,2937,2868,1489,1219,1088,980,802,689,529,434.
1HNMR (400MHz, CDCl
3, δ ppm): 7.34-7.25 (m, 8H), 4.64-4.61 (d, 2H, J=12Hz), 2.10-2.05 (m, 2H), 1.83-1.80 (m, 4H), 1.69-1.40 (m, 6H).
13CNMR (100MHz, CDCl
3, TMS): 141.9,132.7,128.3,127.2,97.2,70.4,35.1,33.0,19.1.
Claims (9)
1. the preparation method of a spiro ketal compounds comprises following processing step:
(1) preparation of the double-organic zinc reagent of band ketal
1. with 1,7-two chloro-dipropyl ketone and sodium iodide are dissolved in the acetone by 1: 3～1: 4 mol ratio, in 50～60 ℃ of back flow reaction 6～8 hours, cooling, separate compound 1,7-two iodo-dipropyl ketone;
2. with 1,7-two iodo-dipropyl ketone, alcohols, tosic acid are dissolved in benzene by 1: 1.2: 0.05～1: 2.2: 0.1 mol ratio, in 80～90 ℃ of reflux, tell the water that generates in the reaction simultaneously, reacted 2～3 hours, cool off, separate compound 1,7-two iodo-dipropyl ketone condensed ethandiols;
3. with the tetrahydrofuran (THF) solvent, two idohydrocarbons and the zinc powder mol ratio with 1: 2～1: 3 is joined in the reactor, the zinc powder activator that adds zinc powder quality 1%～5% more promptly got target product in 4～10 hours in 40 ℃～45 ℃ back flow reaction under protection of inert gas---the double-organic zinc reagent of band ketal;
(2) cyclohexadione compounds is synthetic
Under protection of inert gas, cuprous cyanide and the lithium chloride mol ratio with 1: 2～1: 4 is dissolved in the tetrahydrofuran solvent, be cooled to-20 ℃～-50 ℃, the double-organic zinc reagent that adds the band ketal of cuprous cyanide and lithium chloride total amount 50%～80%, be warming up to 0 ℃～-10 ℃, stirring reaction 10～30 minutes; Be cooled to-20 ℃～-50 ℃ then, and add the acyl chlorides of double-organic zinc reagent 60%～100%, under agitation reacted 6～8 hours, obtain cyclohexadione compounds with ketal through extraction, drying, separation;
(3) the dihydroxyl ketal is synthetic
The diketone of band ketal is dissolved in the methylene dichloride, under agitation adds the sodium borohydride methanol solution of 2～4 times of diketone molar weights gradually, continue to stir 0.5～1 hour,, be drying to obtain target product through extraction---the dihydroxyl ketal;
(4) spiro ketal is synthetic
With benzene is solvent, and dihydroxyl ketal, tosic acid are joined in the reactor by 1: 0.05～1: 0.1 mol ratio, in 80 ℃～90 ℃ reflux 2～5 hours, is cooled to the K that adds 2～3 times of tosic acid molar weights after the room temperature
2CO
3, stirred 1～2 hour, boil off that the mixture with sherwood oil and ethyl acetate is that the eluent column chromatography promptly gets target product behind the solvent.
2. the preparation method of spiro ketal compounds according to claim 1 is characterized in that: step (1) is 1. described 1, and 7-two chloro-dipropyl ketone are got by following prepared:
With 1, the sodium Metal 99.5 piece that 4-butyrolactone molar weight is 0.5 times joins in the methyl alcohol of capacity in batches, treat to add 1 after sodium disappears, the 4-butyrolactone in 70～80 ℃ of reflux 3～4 hours, boils off methyl alcohol after the cooling, under cooling and vigorous stirring, add 1, the concentrated hydrochloric acid that 4-butyrolactone molar weight is 10～15 times adds the back and promptly got raw material in 0.5～1 hour in 90～100 ℃ of reflux---and 1,7-two chloro-dipropyl ketone.
3. the preparation method of spiro ketal compounds according to claim 1, it is characterized in that: the 1. described separation of step (1) is to boil off in the reaction system to add ether behind the acetone and make the reaction product dissolving, remove by filter the NaCl and the excessive N aI of generation, boil off ether again and get crude product, get white crystal for making with extra care-1,7-two iodo-dipropyl ketone with recrystallizing methanol.
4. the preparation method of spiro ketal compounds according to claim 1, it is characterized in that: the 2. described separation of step (1) is to add 1 in reaction system, the salt of wormwood stirring reaction that 7-two iodo-dipropyl ketone molar weights are 2～3 times 1～2 hour, normal pressure steams solvent benzol, be that eluent carries out column chromatography and gets compound 1,7-two iodo-dipropyl ketone condensed ethandiols with the mixture of sherwood oil and ethyl acetate again; Described sherwood oil and ethyl acetate volume ratio be 5: 1.
5. the preparation method of spiro ketal compounds according to claim 1, it is characterized in that: the 2. described alcohols of step (1) is methyl alcohol, ethanol, propyl alcohol, ethylene glycol, 1, ammediol and 1, any in the 4-butyleneglycol.
6. the preparation method of spiro ketal compounds according to claim 1 is characterized in that: the 3. described zinc powder activator of step (1) is glycol dibromide and the trimethylchlorosilane mixture with 1: 1～1: 2 mixed in molar ratio.
7. the preparation method of spiro ketal compounds according to claim 1, it is characterized in that: the described extraction of step (2), drying, separating technology are for adding saturated aqueous ammonium chloride in reaction system, with extracted with diethyl ether three times, anhydrous magnesium sulfate drying, filter, boil off behind the solvent mixture with sherwood oil and ethyl acetate and be the eluent column chromatography and get white crystal promptly with the cyclohexadione compounds of ketal; Described sherwood oil and ethyl acetate volume ratio be 5: 1.
8. the preparation method of spiro ketal compounds according to claim 1 is characterized in that: the described acyl chlorides of step (2) is any in aromatic series acyl chlorides and the aliphatics acyl chlorides.
9. the preparation method of spiro ketal compounds according to claim 1, it is characterized in that: the described separation of step (3), drying are to boil off methyl alcohol earlier, add aqueous sodium carbonate and ethyl acetate and extract, anhydrous magnesium sulfate drying boils off solvent and promptly gets target product---the dihydroxyl ketal.
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