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Preparation method of 5'-((5-methoxyl-2-phenyl indole-1-yl) methylene)-2'-oxo-3'-tetrahydrofurfuryl

A technology of methylenetetrahydrofuran and methoxymethoxyindole is applied in the directions of organic chemistry, drug combination, antitumor drugs, etc., and can solve the problems of difficult large-scale preparation, complicated steps, low yield and the like

Inactive Publication Date: 2009-11-11
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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Problems solved by technology

[0004] However, the previously reported synthetic method (Huasheng Ding: Bioorganic & Medicinal Chemistry Letters, 15 (21), 4799-4802) has cumbersome steps, and the overall yield is relatively low, and a lot of highly toxic and dangerous reagents will be used again. Difficulties with large-scale preparation

Method used

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  • Preparation method of 5'-((5-methoxyl-2-phenyl indole-1-yl) methylene)-2'-oxo-3'-tetrahydrofurfuryl
  • Preparation method of 5'-((5-methoxyl-2-phenyl indole-1-yl) methylene)-2'-oxo-3'-tetrahydrofurfuryl
  • Preparation method of 5'-((5-methoxyl-2-phenyl indole-1-yl) methylene)-2'-oxo-3'-tetrahydrofurfuryl

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Embodiment 1

[0031] The preparation of embodiment 1 intermediate compound 9 (route B)

[0032] (1) Preparation of N-hydroxyethylamino-3-phenyl ethyl acrylate (compound 11)

[0033] 19.2g of ethyl benzoyl acetate 1 (0.1mol) and 6.71g of aminoethanol 10 (0.11mol) were mixed and dissolved in 80ml of benzene, 5 drops of concentrated hydrochloric acid were added dropwise, split flow dehydration for 13h, concentration, separation on a silica gel column (petroleum ether : ethyl acetate=3:1, volume ratio), to obtain 12.1 g of green oil, yield 51%. 1 H 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).

[0034] (2) Preparation of ethyl 5-hydroxy-1-(2-hydroxyethyl)-2-phenyl-1H-indole-3-carboxylate (compound 12)

[0035] 2.664g of p-quinone and 2.7g of anhydrous zinc chloride were mixed in 74ml of dichloromethane, heated to boiling, then added 5.452g of the previous step product compound 11 in 25ml of dichloromethane sol...

Embodiment 2

[0038] The preparation of embodiment 2 intermediate compound 9 (route first):

[0039] 1, the preparation of 2-phenyl-5-oxindole (compound 5)

[0040] Compound 2 was obtained as described in the literature (J.Chem.Soc., Perkin Trans.1, 2002, 1663-1671), and then compound 2 and p-benzoquinone were prepared according to the operation of Example 1 to prepare compounds 12 and 9, to obtain Compound 5. The total yield of the above 3 steps is 38%. Melting point: 243-245°C. 1 H NMR (acetone-d 6 ): δ9.72 (s, 1H), 7.82-6.70 (m, 8H), 6.68 (s, 1H).

[0041] 2, Preparation of 2-phenyl-5-methoxymethoxyindole (compound 6)

[0042] 209 mg of compound 5 was dissolved in 15 ml of dry DMF, 45 mg of NaH was added, and reacted at room temperature for 5 min, then 0.1 ml of chloromethyl methyl ether was added, and stirring was continued at room temperature for 2 h. Add 30ml of cold water, extract with ether, dry the organic phase, and separate by column (petroleum ether:ethyl acetate=10:1, vol...

Embodiment 3

[0048] Example 3 5'-((5-methoxymethoxy-2-phenylindol-1-yl)methylene)-2'-oxo-3'-methylenetetrahydrofuran (S-10) preparation of

[0049] 1, Preparation of 2-(2-phenyl-5-methoxymethoxyindol-1-yl)ethanol (compound 13)

[0050] Dissolve 1.9 g of compound 9 in 30 ml of DMF, add 300 mg of NaH, stir at room temperature for 5 min, add 0.6 ml of chloromethyl methyl ether, and react at room temperature for 6 h. Terminate the reaction, add water and ethyl acetate, separate liquid extraction, wash the organic phase with water, dry, concentrate, silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1, volume ratio) to give 950mg yellow oil 13, yield 80%. 1 H 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).

[0051] 2. Preparation of 2-(2-phenyl-5-methoxyindol-1-yl)acetaldehyde (14)

[0052] 215mg of compound 13 was dissolved in 20ml of DMSO, added 304mg of IBX, stirred at room temperature until clea...

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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 [0001] The present invention relates to the antineoplastic compound 5'-((5-methoxymethoxy-2-phenylindol-1-yl)methylene)-2'-oxo-3'-methylenetetrahydrofuran (hereinafter Abbreviated as S-10) preparation method. Background technique [0002] S-10, whose chemical name is 5'-((5-methoxymethoxy-2-phenylindol-1-yl)methylene)-2'-oxo-3'-methylenetetrahydrofuran , is a molecular structure containing an α-methylene-γ-butyrolactone skeleton on the 1-position nitrogen of indole, has good cytotoxicity and antitumor activity, and it can be used as an alkylating agent and a biological nucleophile ( Such as L-cysteine, glutathione) or thiol-rich enzymes (such as phosphofructokinase, glycogen synthase, deoxyribonucleic acid polymerase, etc.) undergo a rapid irreversible Michael addition reaction. [0003] [0004] However, the previously reported synthetic method (Huasheng Ding: Bioorganic & Medicinal Chemistry Letters, 15 (21), 4799-4802) has cumbersome steps, and the ov...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/06A61P35/00
Inventor 吴茂江杨春皓谢毓元
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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