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Pemetrexed disodium key intermediate and its synthesis method, and method for synthesizing pemetrexed disodium from the said intermediate

A technology of pemetrexed disodium salt and metrexed disodium salt, which is applied in the field of pemetrexed disodium salt key intermediate and its synthesis, compound and its preparation, and can solve the problem of low yield

Inactive Publication Date: 2006-07-12
SHANGHAI GOLDEN PHARMATECH +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] 3. Eli Lilly has published another synthetic route, (US 6,262,262,2001; 6,090,168,2000; 6,013,828,2000), using methyl p-bromobenzoate as raw material, although methyl p-bromobenzoate is more effective than p-iodobenzoic acid Methyl ester is cheap, but the yield of Heck reaction is low, the yield of bromination and subsequent reaction with 2,6-diamino-4-(3H)oxopyrimidine is also relatively low, and the total yield to compound 5 is only 26.5 %, much lower than the 33% yield of Professor Taylor's synthetic route 2, the synthetic route is as follows:

Method used

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  • Pemetrexed disodium key intermediate and its synthesis method, and method for synthesizing pemetrexed disodium from the said intermediate
  • Pemetrexed disodium key intermediate and its synthesis method, and method for synthesizing pemetrexed disodium from the said intermediate
  • Pemetrexed disodium key intermediate and its synthesis method, and method for synthesizing pemetrexed disodium from the said intermediate

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Experimental program
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Embodiment 1

[0026] Embodiment 1: Synthesis of 1-nitro-2-(2,6-diamino-4-(3H) oxopyrimidin-5-yl)-4-(4-carboxyphenyl)-1-butane

[0027] Add 0.1 mole of 1-nitro-4-(4-carboxyphenyl)-1-butene (8) and 0.1 mole of 2,6-diamino-4(3H)oxopyrimidine into the reaction flask, then add NaOH aqueous solution , Insulate the reaction at 50-60°C until the raw materials disappear. Cool, add AcOH to adjust the pH=5-6, precipitate out, and the filter cake obtained by suction filtration is the desired product: 1-nitro-2-(2,6-diamino-4-(3H)oxopyrimidine- 5-yl)-4-(4-carboxyphenyl)-1-butane (9). Yield 80%, Bp=180°C (dec), 1 HNMR: 1.680-2.143 (2H, m, m), 2.501-2.682 (2H, m, m), 3.441 (H, m), 4.753-4.990 (2H, m, m), 6.490 (2H, s), 6.952 (2H, s), 6.948 (2H, d), 7.808 (2H, d).

Embodiment 2

[0028] Example 2: Synthesis of 4-[2-(2-amino-4-(3H)oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid

[0029] Add compound 9 obtained above into the reaction flask, then add sodium hydroxide solution and stir until the solid dissolves. The reaction was incubated at 50°C for 2 hours. Prepare 8N sulfuric acid and cool to below 0°C. Stir and control the reaction temperature below 0°C, add the above reaction solution dropwise into the acid, and then continue the reaction for 3 hours. The pH value of the reaction solution was adjusted to 8 with sodium oxide solution, and the reaction was continued for 1 hour. Glacial acetic acid was added dropwise to generate a precipitate, and the filtered solid was the desired product. 4-[2-(2-Amino-4-(3H)oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid. Yield 75%, 1 H NMR (DMSO-d 6 , 400MHz) δ: 2.83(t, 2H, Bz-CH 2 -), 2.96(t, 2H, Ph-CH 2 -), 6.08(s, 2H, NH 2 ), 6.31 (s, 1H, C=CH-), 7.28, 7.83 (AA'BB', d, d, 4H, C 6 h 4 ), 1...

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Abstract

The invention relates to a disodium salt key point intermediate 1-nitro -2-(2, 6-diamino -4-(3H) oxo-metadiazine -5-group)-4 - (4-carboxyl phenyl)-1-butagas in the field of chemistry and medicine. It also discloses a method for preparing for the compound and the method for using the intermediate to synthesize the disodium salt.

Description

technical field [0001] The invention belongs to the field of chemical industry and pharmacy, and relates to a compound and its preparation process. More specifically, the invention relates to a key intermediate of pemetrexed disodium salt and its synthesis method, and the synthesis of pemetrexed from the new intermediate The method of trecet disodium salt. Background technique [0002] Pemetrexed disodium salt (Alimta, pemetrexates disodium) is a new type of folic acid anti-tumor compound, multi-target anti-folate agent, it mainly acts on the DNA base synthetase system, by inhibiting a variety of DNA base synthetases (GARFT, DHFR, TS) to block the DNA synthesis of tumor cells, so as to achieve the purpose of inhibiting and eliminating tumor cells. Alimta effectively solves the problem of tumor resistance to anti-tumor drugs in clinical treatment, and is a representative new drug in current anti-tumor drug research. In clinical research, Alimta has shown strong inhibitory a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48C07D487/04
Inventor 毛振民刘增路朱高军彭敏
Owner SHANGHAI GOLDEN PHARMATECH
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