CN101575331B - Preparation method of 5'-((5-MethoxyMethoxy-2- phenylindole-1-yl)methylene)-2'-oxo-3'- methylenetetrahydrofuran - Google Patents
Preparation method of 5'-((5-MethoxyMethoxy-2- phenylindole-1-yl)methylene)-2'-oxo-3'- methylenetetrahydrofuran Download PDFInfo
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Abstract
The invention discloses a preparation method of 5'-((5-methoxyl-2-phenyl indole-1-yl) methylene)-2'-oxo-3'-tetrahydrofurfuryl which is an antineoplastic compound. The method comprises the following steps: performing reformatsky reaction on 2-(2-phenyl-5-methoxyl indole-1-yl) acetaldehyde and Alpha-bromine ethyl methacrylate to obtain the compound. Ethyl benzoylacetate and aminoethanol are used as raw materials and are condensed to obtain N-hydroxyethyl amino-3-ethyl phenylacrylate which makes a synthetic reaction with benzoquinone by Nenitzescu indole to remove an ester group at 3-position, and 2-(2-phenyl-5-hydroxyl indole-1-yl) ethanol is obtained; then 2-(2-phenyl-5-hydroxyl indole-1-yl) ethanol and chloromethyl methyl ether react to obtain a product, and the product is oxidized to obtain 2-(2-phenyl-5-methoxyl indole-1-yl) acetaldehyde. The invention has short route, mild reaction condition, convenient aftertreatment, cheap and easily-obtained reagent and avoids using dangerous hypertoxic reagents, thereby not only lowering the cost, but also being suitable for industrial production.
Description
Technical field
The present invention relates to the preparation method of antineoplastic compound 5 '-((5-methoxy methoxy base-2-phenylindone-1-yl) methylene radical)-2 '-oxo-3 '-methylene radical tetrahydrofuran (THF) (hereinafter referred S-10).
Background technology
S-10, its chemical name is 5 '-((5-methoxy methoxy base-2-phenylindone-1-yl) methylene radical)-2 '-oxo-3 '-methylene radical tetrahydrofuran (THF), it is a kind of molecular structure that on 1 nitrogen of indoles, contains the alpha-methylene-gamma-butyrolactone skeleton, good cell toxicity and anti-tumor activity are arranged, and it can be used as alkanisation reagent and biological nucleophile (as L-halfcystine, Triptide) or is rich in the irreversible fast Michael reaction of enzyme (as phosphofructokinase, glycogen synthetase, deoxyribonucleic acid polymerase etc.) generation of sulfydryl.
But Bao Dao synthetic method (Huasheng Ding:Bioorganic ﹠amp in the past; MedicinalChemistry Letters, 15 (21), 4799-4802) step is comparatively loaded down with trivial details, and total yield is lower, uses a lot of severe toxicity and dangerous reagent again, and this brings difficulty to mass preparation.The inventor adopts Nenitzescu (southern Nietzsche Si storehouse) indole synthesis, just can realize the preparation of S-10 by simple several steps reaction, and avoid use some costlinesses, danger and reagent severe toxicity, save time, save cost, thereby bring possibility to suitability for industrialized production.
Summary of the invention
Therefore, the objective of the invention is to overcome the above-mentioned weak point of prior art, provide with benzoquinones, ethyl benzoylacetate these be simple and easy to raw material and avoid using danger, preparation method that poisonous reagent synthesizes S-10 ultimate aim product.
To achieve these goals, the invention provides the preparation method of antineoplastic compound S-10, this method comprises that 2-(2-phenyl-5-methoxy methoxy base indoles-1-yl) acetaldehyde (being compound 14) and α-brooethyl ethyl propenoate (being compound 15) are by Reformatsky (row formal thatch base) reaction, generate compound S-10
In above-mentioned Reformatsky reaction, compound 15 (α-brooethyl ethyl propenoate) can be bought and obtain, and perhaps obtains according to following document is synthetic: 1. P.Block Organic SynthesesCV 5,381-382; (the 2. acrylate.OrganicSyntheses CV 7 of K.Ramarajan Ethyl α-(bromomethyl), 210-212.
Described compound 14 can obtain by following reaction formula:
That is: in DMF or pure equal solvent, under the effect of alkali such as NaH or sodium alkoxide, 2-(2-phenyl-5-oxyindole-1-yl) ethanol (being compound 9) and chloromethyl methyl ether reaction make 2-(2-phenyl-5-methoxy methoxy base indoles-1-yl) ethanol (being compound 13); Then, in the presence of solvent (for example DMSO), under effects such as oxygenant 2-iodoxy phenylformic acid (IBX), pyridine chromium trioxide (PDC) or Pyridine chromate salt (PCC), compound 13 oxidations generate compound 14.
In the preparation process of compound 14, wherein compound 9 can synthesize by following two lines.
The reaction scheme first:
(1) in organic solvents such as benzene or toluene, add appropriate hydrochloric acid or sulfuric acid etc., raw material ethyl benzoylacetate (compound 1) and ammonium salt back flow reaction such as ammonium formiate or ammonium acetate 24～48 hours make compound 2;
(2) in solvent, compound 2 and benzoquinone (compound 3) obtain compound 4 by Nenitzescu indoles building-up reactions;
(3) in DMF or pure equal solvent, under the effect of alkali such as NaH or sodium alkoxide, compound 4 and chloromethyl methyl ether reaction obtain compound 7;
(4) compound 7 and bromoethyl acetate or ethyl chloroacetate reacted under the NaH/DMF condition 2～12 hours, and the crude product that obtains after conventional aftertreatment passes through reduction reaction with reductive agent (for example Lithium Aluminium Hydride) again, obtains compound 8;
(5) compound 8 refluxes under acidic conditions and sloughs 3 ester groups and 5 s' methoxymethyl, obtains compound 9, and wherein the acid of being adopted is the hydrochloric acid of 5-35wt% or sulfuric acid etc., and temperature is 25-150 ℃, and the reaction times is 1-48 hour; Perhaps compound 8 adopts basic hydrolysis to remove ethyl earlier, refluxes under acidic conditions and sloughs 3 carboxyls, obtains compound 9, and wherein the alkali that is adopted is NaOH, KOH or K
2CO
3Deng, the acid of being adopted is the hydrochloric acid of 5-35wt% or sulfuric acid etc.
Used boron tribromide when pass course first prepared in reaction compound 9, its operation can be avoided the demethylation of previous report.This reagent costs an arm and a leg, and toxicity is big, and high volatility is unfavorable for preserving.
In the reaction scheme first, wherein the compound 4 that obtains of step (2) refluxes under acidic conditions and sloughs 3 ester groups, obtains compound 5, and wherein the acid of being adopted is the hydrochloric acid of 5-35wt% or sulfuric acid etc., and temperature is 25-150 ℃, and the reaction times is 1-48 hour; Perhaps compound 4 adopts basic hydrolysis to remove ethyl earlier, refluxes under acidic conditions and sloughs 3 carboxyls, obtains compound 5, and wherein the alkali that is adopted is NaOH, KOH or K
2CO
3Deng, the acid of being adopted is the hydrochloric acid of 5-35wt% or sulfuric acid etc.; In DMF or pure equal solvent and under the effect of alkali such as NaH or sodium alkoxide, compound 5 and chloromethyl methyl ether reaction obtain compound 6; Reference literature (Huasheng Ding:Bioorganic ﹠amp then; Medicinal Chemistry Letters, 15 (21), preparation method 4799-4802) can make antineoplastic compound S-10.
Reaction scheme second:
Route second is to prepare the more easy method of compound, and concrete steps are as follows:
(1) ethyl benzoylacetate and monoethanolamine obtain N-hydroxyethylamino-3-ethyl phenylacrylate (compound 11) through dehydrating condensation; Wherein the solvent that is adopted in this reaction is benzene, toluene or dimethylbenzene etc., and catalyzer can adopt hydrochloric acid or sulfuric acid etc., reaction times 3-48 hour;
(2) compound 11 that obtains of step (1) and benzoquinone obtain 5-hydroxyl-1-(2-hydroxyethyl)-2-phenyl-1H-indole-3-carboxylic acid ethyl ester (compound 12) by Neniztescu indoles building-up reactions; Wherein the solvent that is adopted in this reaction is acetone, methylene dichloride or chloroform etc., and catalyzer can adopt Lewis acids such as zinc chloride or aluminum chloride;
(3) compound 12 refluxes under acidic conditions and sloughs 3 ester groups, obtains compound 9, and wherein the acid of being adopted is the hydrochloric acid of 5-35wt% or sulfuric acid etc., and temperature is 25-150 ℃, and the reaction times is 1-48 hour; Perhaps compound 12 adopts basic hydrolysis to remove ethyl earlier, refluxes under acidic conditions and sloughs 3 carboxyls, obtains compound 9, and wherein the alkali that is adopted is NaOH, KOH or K
2CO
3Deng, the acid of being adopted is the hydrochloric acid of 5-35wt% or sulfuric acid etc.
This route is simple and clear, and used step is few, has more saved cost, has avoided dangerous, expensive reagent such as picture boron tribromide, tetrahydrochysene lithium aluminium.Help scale operation.
Embodiment
Illustrate the present invention below, these embodiment only are used to illustrate the present invention, but do not limit the present invention in any way.
Agents useful for same of the present invention is commercially available, and nuclear magnetic resonance spectrum is measured by Varian Mercury-400 fourier transform NMR spectrometer, and mass spectrum is measured by MAT-95 type mass spectrograph, and the fusing point instrument adopts Buchi 510, and temperature is not proofreaied and correct.
The preparation of embodiment 1 midbody compound 9 (route second)
(1) preparation of N-hydroxyethylamino-3-ethyl phenylacrylate (compound 11)
19.2g ethyl benzoylacetate 1 (0.1mol) and 6.71g monoethanolamine 10 (0.11mol) mixing are dissolved in the 80ml benzene, and Dropwise 5 drips concentrated hydrochloric acid, shunting dehydration 13h, concentrate, silicagel column separates (sherwood oil: ethyl acetate=3: 1, volume ratio), obtain green oily matter 12.1g, yield 51%.
1H?NMR(CDCl
3)：δ8.63(s，1H)，7.38(m，5H)，4.67(s，1H)，4.15(q，2H，J＝7.2)，3.62(t，2H，J＝6)，3.24(m，2H)，1.28(t，3H，J＝7.2)。
(2) preparation of 5-hydroxyl-1-(2-hydroxyethyl)-2-phenyl-1H-indole-3-carboxylic acid ethyl ester (compound 12)
2.664g benzoquinone and 2.7g Zinc Chloride Anhydrous are mixed in the 74ml methylene dichloride, be heated to boiling, add 5.452g again and go up the 25ml dichloromethane solution that goes on foot product compound 11, back flow reaction 40min has solid to separate out, stir 2-3h in 0-5 ℃, filter, washed with dichloromethane twice, drying obtain 5.655g khaki color solid, yield 75%, fusing point 202-204 ℃.
1H?NMR(CDCl
3)：δ7.98(s，1H)，7.67(d，1H，J＝2.7)，7.48(s，5H)，7.41(d，1H，J＝6.6)，6.85(dd，1H，J＝2.7，J＝9)，4.09(t，2H，J＝6)，4.01(t，2H，J＝6.9)，3.73(q，2H，J＝6)，1.02(t，3H，J＝6.9)。
(3) preparation of 2-(2-phenyl-5-oxyindole-1-yl) ethanol (compound 9)
Compound of last step 12 product 1.21g are put in the 50ml 20wt% hydrochloric acid back flow reaction 3h.Cooling, ethyl acetate extraction is washed to neutrality, anhydrous magnesium sulfate, concentrating under reduced pressure, silicagel column separate (sherwood oil: ethyl acetate=3: 1, volume ratio) and obtain solid 622mg, yield 80%, Mp160-162 ℃.
1H NMR (acetone-d6): δ 7.71 (s, 1H), 7.37-7.65 (m, 5H), 7.43 (d, 1H, J=8.1), 6.98 (d, 1H, J=2.4Hz), 6.77 (dd, 1H, J=2.4, J=8.1), 6.33 (s, 1H), 4.24 (t, 2H, J=6.1), 3.97 (t, 1H, J=6.0), 3.80 (q, 2H, J=6.1).
The preparation of embodiment 2 midbody compounds 9 (route first):
1, the preparation of 2-phenyl-5-oxyindole (compound 5)
According to document (J.Chem.Soc., Perkin Trans.1,2002,1663-1671) describe and to make compound 2, then with compound 2 and benzoquinone successively according to the operation of embodiment 1 preparation compound 12 and 9, obtain compound 5.More than 3 the step total recoverys 38%.Fusing point: 243-245 ℃.
1H NMR (acetone-d
6): δ 9.72 (s, 1H), 7.82-6.70 (m, 8H), 6.68 (s, 1H).
2, the preparation of 2-phenyl-5-methoxy methoxy base indoles (compound 6)
The compound 5 of 209mg is dissolved among the 15ml exsiccant DMF, adds the NaH of 45mg, room temperature reaction 5min adds the chloromethyl methyl ether of 0.1ml again, and room temperature continues to stir 2h.Add 30ml cold water, use ether extraction, the organic phase drying, post separates (sherwood oil: ethyl acetate=10: 1, volume ratio) and obtains the 210mg white solid.Yield 83%.Fusing point: 114-115 ℃.
1H?NMR(CDCl
3)：δ8.28(s，1H)，7.67-6.94(m，8H)，6.76(s，1H)，5.22(s，2H)，3.55(s，3H)。
3,, make after the compound 6, according to document (Huasheng Ding:Bioorganic ﹠amp according to the work of drilling; Medicinal Chemistry Letters, 15 (21), report 4799-4802) promptly can prepare crucial intermediate 14.
4, the preparation of 2-phenyl-5 methoxy methoxy base indole-3-carboxylic acid ethyl ester (compound 7)
Compound 7 prepares compound 6 same method and operation stepss by compound 4 according to compound 5 and prepares.
5, the preparation of 2-(2-phenyl-5-oxyindole-1-yl) ethanol (compound 9)
The compound 7 of getting 325mg is dissolved among the dry DMF of 15ml, adds the NaH of 45mg, room temperature reaction 5min, the bromoethyl acetate that adds 200mg again, room temperature reaction 4-6h adds the cancellation of 35ml frozen water, ether extraction, anhydrous magnesium sulfate drying, concentrate,, directly be dissolved in the 30ml anhydrous tetrahydro furan without separation, add the 300mg Lithium Aluminium Hydride, room temperature reaction spends the night.The careful shrend on the rocks excessive Lithium Aluminium Hydride that goes out, ethyl acetate extraction, drying concentrates, and directly is dissolved in the hydrochloric acid soln of 30ml 20wt% reflux 5h.Cooling, ethyl acetate extraction, drying concentrates, and silicagel column separates (sherwood oil: ethyl acetate=3: 1, volume ratio) and obtains solid 137mg, yield 54%.
The preparation of embodiment 35 '-((5-methoxy methoxy base-2-phenylindone-1-yl) methylene radical)-2 '-oxo-3 '-methylene radical tetrahydrofuran (THF) (S-10)
1, the preparation of 2-(2-phenyl-5-methoxy methoxy base indoles-1-yl) ethanol (compound 13)
1.9g compound 9 is dissolved among the 30ml DMF, adds 300mgNaH, behind the stirring at room 5min, add the 0.6ml chloromethyl methyl ether, room temperature reaction 6h.Termination reaction adds entry and ethyl acetate, the separatory extraction, and the organic phase washing, drying concentrates, and silica gel column chromatography (sherwood oil: ethyl acetate=4: 1, volume ratio) gets 950mg yellow oil 13, yield 80%.
1H?NMR(CDCl
3)：δ7.54-6.97(m，8H)，6.47(s，1H)，5.21(s，2H)，4.31-4.28(t，J＝5.6Hz)，3.83-3.80(t，J＝5.6Hz)，3.53(s，3H)。
2, the preparation of 2-(2-phenyl-5-methoxy methoxy base indoles-1-yl) acetaldehyde (14)
215mg compound 13 is dissolved among the 20ml DMSO, adds 304mg IBX, and stirring at room is to clarification, reaction 45min under 50 ℃, termination reaction is with water and ethyl acetate separatory, extraction, washing, drying, concentrate, silicagel column separates, and is eluent with the ether, obtains off-white color solid 130mg, yield 60.8%, Mp110-112 ℃.
1H?NMR(CDCl
3)：δ9.65(s，1H)，7.46-6.98(m，8H)，6.59(s，1H)，5.22(s，2H)，4.80(m，2H)，3.53(s，3H)。
3, the preparation of 5 '-((5-methoxy methoxy base-2-phenylindone-1-yl) methylene radical)-2 '-oxo-3 '-methylene radical tetrahydrofuran (THF) (S-10)
Under the nitrogen protection, with the 58mg activated zinc powder, the tetrahydrofuran solution of the compound 14 (239mg) of 2mg Resorcinol and 5ml is added in the 5ml anhydrous tetrahydro furan successively, slowly adds the anhydrous tetrahydrofuran solution of compound 15 (172mg) then, 70 ℃ of reaction 3h.Termination reaction, cooling, with water and ethyl acetate separatory, extraction, washing, drying concentrates, column chromatography (sherwood oil: ethyl acetate=4: 1, volume ratio), receive colorless oil 191mg, yield 65%.
1H?NMR(CDCl
3)：δ7.50-6.98(m，8H)，6.50(s，1H)，6.09(t，J＝2.8Hz，1H)，5.40(t，J＝2.8Hz，1H)，5.22(s，2H，OCH
2)，4.70-4.64(m，1H)，4.50-4.29(m，2H)，3.53(s，3H)，2.72-2.28(m，2H)。
Claims (3)
1. the preparation method of antineoplastic compound 5 '-((5-methoxy methoxy base-2-phenylindone-1-yl) methylene radical)-2 '-oxo-3 '-methylene radical tetrahydrofuran (THF), it is characterized in that this method comprises that 2-(2-phenyl-5-methoxy methoxy base indoles-1-yl) acetaldehyde of compound 14 expressions obtains by following reaction formula:
That is: in DMF or alcoholic solvent, under the effect of NaH or sodium alkoxide, 2-(2-phenyl-5-oxyindole-1-yl) ethanol is compound 9 and chloromethyl methyl ether reaction, and making 2-(2-phenyl-5-methoxy methoxy base indoles-1-yl) ethanol is compound 13; Then, in the presence of solvent DMSO, under oxygenant 2-iodoxy phenylformic acid, pyridine chromium trioxide or Pyridine chromate salt action, compound 13 oxidations generate compound 14,
2-(2-phenyl-5-methoxy methoxy base indoles-1-yl) acetaldehyde and α-brooethyl ethyl propenoate react by Reformatsky then, generate compound S-10, and reaction formula is as follows:
Wherein, compound 15 expression α-brooethyl ethyl propenoates, S-10 represents 5 '-((5-methoxy methoxy base-2-phenylindone-1-yl) methylene radical)-2 '-oxo-3 '-methylene radical tetrahydrofuran (THF).
2. the preparation method of antineoplastic compound 5 ' according to claim 1-((5-methoxy methoxy base-2-phenylindone-1-yl) methylene radical)-2 '-oxo-3 '-methylene radical tetrahydrofuran (THF) is characterized in that described compound 9 prepares by the following method:
(1) in organic solvent-benzene or toluene, add appropriate hydrochloric acid or sulfuric acid, raw material ethyl benzoylacetate and ammonium salt ammonium formiate or ammonium acetate back flow reaction 24～48 hours make compound 2;
(2) in solvent, compound 2 and benzoquinone obtain compound 4 by Nenitzescu indoles building-up reactions;
(3) in DMF or alcoholic solvent, under the effect of NaH or sodium alkoxide, compound 4 and chloromethyl methyl ether reaction obtain compound 7;
(4) compound 7 and bromoethyl acetate or ethyl chloroacetate reacted under the NaH/DMF condition 2～12 hours, and the crude product that obtains after conventional aftertreatment passes through reduction reaction with the reductive agent Lithium Aluminium Hydride again, obtains compound 8;
(5) compound 8 refluxes under acidic conditions and sloughs 3 ester groups and 5 s' methoxymethyl, obtains compound 9, and wherein the acid of being adopted is hydrochloric acid or the sulfuric acid of 5-35wt%, and temperature is 25-150 ℃, and the reaction times is 1-48 hour; Perhaps compound 8 adopts basic hydrolysis to remove ethyl earlier, refluxes under acidic conditions and sloughs 3 carboxyls, obtains compound 9, and wherein the alkali that is adopted is NaOH, KOH or K
2CO
3, the acid of being adopted is hydrochloric acid or the sulfuric acid of 5-35wt%, reaction formula is as follows:
3. the preparation method of antineoplastic compound 5 ' according to claim 1-((5-methoxy methoxy base-2-phenylindone-1-yl) methylene radical)-2 '-oxo-3 '-methylene radical tetrahydrofuran (THF) is characterized in that described compound 9 prepares by the following method:
(1) to obtain N-hydroxyethylamino-3-ethyl phenylacrylate be compound 11 through dehydrating condensation for ethyl benzoylacetate and monoethanolamine; Wherein the solvent that is adopted in this reaction is benzene, toluene or dimethylbenzene, and catalyzer adopts hydrochloric acid or sulfuric acid, reaction times 3-48 hour;
(2) compound 11 that obtains of step (1) and benzoquinone are by Neniztescu indoles building-up reactions, and obtaining 5-hydroxyl-1-(2-hydroxyethyl)-2-phenyl-1H-indole-3-carboxylic acid ethyl ester is compound 12; Wherein the solvent that is adopted in this reaction is acetone, methylene dichloride or chloroform, and catalyzer adopts zinc chloride or aluminum chloride;
(3) compound 12 refluxes under acidic conditions and sloughs 3 ester groups, obtains compound 9, and wherein the acid of being adopted is hydrochloric acid or the sulfuric acid of 5-35wt%, and temperature is 25-150 ℃, and the reaction times is 1-48 hour; Perhaps compound 12 adopts basic hydrolysis to remove ethyl earlier, refluxes under acidic conditions and sloughs 3 carboxyls, obtains compound 9, and wherein the alkali that is adopted is NaOH, KOH or K
2CO
3, the acid of being adopted is hydrochloric acid or the sulfuric acid of 5-35wt%, reaction formula is as follows:
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| CN1872851A (en) * | 2005-06-01 | 2006-12-06 | 中国科学院上海药物研究所 | Compound of alpha - methylene - gamma - butyrolactone, preparation method, and method |
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| Title |
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| Huasheng Ding et al..Novel indole а-methylene-γ-lactones as potent inhibitors for AKT-mTOR signaling pathway kinases.《Bioorganic & Medicinal Chemisty Letters》.2005,第15卷4799-4802. * |
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