CN110862400A - Preparation process of camptothecin-hydroxyacetic acid intermediate - Google Patents
Preparation process of camptothecin-hydroxyacetic acid intermediate Download PDFInfo
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- CN110862400A CN110862400A CN201810980932.5A CN201810980932A CN110862400A CN 110862400 A CN110862400 A CN 110862400A CN 201810980932 A CN201810980932 A CN 201810980932A CN 110862400 A CN110862400 A CN 110862400A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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Abstract
A process for preparing camptothecin-hydroxyacetic acid intermediate. The invention provides a preparation process of 1, camptothecin-glycolic acid III, which comprises the following steps: 1) reacting camptothecin with benzyloxyacetic acid to obtain a compound II, 2) carrying out a reduction reaction of the compound II in Pd/C and hydrogen at a suitable temperature in a suitable solvent, and purifying the product by suitable aftertreatment to obtain camptothecin-glycolic acid III:
Description
Technical Field
The invention belongs to the field of chemical drugs, and particularly relates to a novel preparation process of a medical synthetic intermediate camptothecin-glycolic acid.
Background
Camptothecin is an anticancer quinoline alkaloid discovered by Monroe Ewald and Mansukh Canal in 1958, has wide anticancer activity, and is mainly used for treating various cancers such as colon cancer, ovarian cancer, liver cancer, bone cancer, leukemia and the like. Camptothecin is bound to DNA topoisomerase I through its lactone structure to achieve antitumor effect. Norcantharidin (NCTD) is a compound obtained by removing 2, 3-methyl in cantharidin, and is a novel anti-cancer drug which is synthesized artificially preferentially in China. Has low toxicity and also has leukocyte increasing effect. Studies have shown that NCTD can protect liver cells from damage caused by Lipopolysaccharide (LPS); protection of renal tubular fibrosis; also has good immunoregulation function for human body. Therefore, the structural modification using norcantharidin as a primer is the research direction of the subject. With the increasing mortality and morbidity of cancer, it has become one of the most important problems in our country. Camptothecin is used as a synthetic raw material, glycolic acid is used as a binding intermediate III, camptothecin and norcantharidin derivatives are linked, and the camptothecin-20 site ester derivative with a novel anti-tumor effect is developed and subjected to activity determination and screening. Therefore, the purpose that one medicine treats multiple diseases and one medicine has multiple effects is achieved, the camptothecin has good anti-tumor efficacy, the effects of increasing the leucocytes and improving the immunity are achieved, and the development prospect and the application approach are good.
Camptothecin-glycolic acid is a key intermediate for synthesizing the novel medicine, and the literature is not much about the synthesis method and the preparation process of the intermediate. In the method disclosed in US5840900, camptothecin is reacted with benzyloxyacetic acid to give compound II, which is reduced with cyclohexene over Pd/C to give camptothecin-hydroxyacetic acid III. In the reduction reaction in the step 2, a reflux reaction is needed, the reaction temperature is high, and great potential safety hazards are brought to operation technicians.
Literature preparation method 1
The invention aims to improve the preparation process and provides a novel preparation process of camptothecin-glycolic acid, which is convenient and safe to operate.
Disclosure of Invention
The invention provides a novel preparation process of camptothecin-glycolic acid III, which comprises the following steps: 1) reacting camptothecin with benzyloxyacetic acid to obtain a compound II, 2) carrying out reduction reaction on the compound II in a proper solvent at a proper temperature by Pd/C and hydrogen, purifying the product by proper post-treatment to obtain camptothecin-glycolic acid III,
preferably, the camptothecin-glycolic acid III preparation process provided by the invention, step 2) of the reduction reaction is preferably a catalytic hydrogenation reaction, wherein the catalyst used for catalytic hydrogenation is selected from Pd/C, Pd (OH)2(ii) or Pt/C; Pd/C is more preferred.
Preferably, in the process for preparing camptothecin-glycolic acid III provided by the invention, the appropriate solvent in step 2) is selected from methanol, ethanol or propanol, and methanol is more preferred.
Preferably, in the preparation process of camptothecin-glycolic acid III provided by the invention, the proper temperature in the step 2) is 25-50 ℃; more preferably from 25 ℃ to 35 ℃ at room temperature.
The invention has the advantages that: the method for preparing the camptothecin-glycolic acid III has the advantages of easily obtained raw materials, low cost, easy separation and purification of a target product of the synthetic reaction and high yield; is easy to prepare.
Detailed Description
The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. Without departing from the inventive concept, a person skilled in the art may make modifications or combinations of the parameters or conditions of the claims, which modifications or combinations shall also be considered as the protective scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims. The solvent and reagent used in the present invention are from Shanghai reagent company, national drug group. The reagents used are all chemically pure, unless otherwise specified.
EXAMPLE 1 preparation of Compound II
Camptothecin (1g,3.45mmol) and CH2Cl2(35mL) were put in a round bottom flask and stirred at room temperature to give a yellow suspension, DMAP (500mg,4.1mmol,1.2eq), benzyloxyacetic acid (1mL,6.02mmol,1.74eq) and DIPC (5mL,39.68mmol,13eq) were slowly added in this order, and the mixture was stirred at room temperature further for reaction. Follow the TLC plate and observe the developing reagent (CH2Cl2: CH3OH ═ 97:3) under UV lamp 254 nm. After 12h of reaction, the reaction was stopped, filtered and the filter cake was dried to give the desired product II (1.08g, 100% yield) as a yellow solid, Rf=0.6(CH2Cl2:CH3OH 97: 3). The product was directly taken to the next reaction without further purification.
EXAMPLE 2 preparation of camptothecin-glycolic acid III
Putting the reactant II (200mg,0.4mmol) into a round-bottomed bottle, adding CH3OH 10ml, and then adding 10% Pd/C (50mg,0.5 mmol); after evacuation of the reaction flask, H2 was passed through and the reaction 24 was stirred at 30 ℃ at room temperature, the TLC plates were spotted and the developing reagent (CH2Cl2: CH3OH ═ 97:3) was observed under an ultraviolet lamp at 254 nm. The reaction was stopped, the catalyst was removed by filtration, the filtrate was spin-dried and the crude product was purified by column chromatography using an eluent (CH2Cl2: CH3OH ═ 97:3) to give product III as a yellow solid (116mg, 72% yield). M.p.159-160 ℃ C, Rf=0.3(DCM:CH3OH=97:3).1HNMR(400MHz,DMSO-d6)δ=8.69(s,1H),8.14(dd,J=8Hz,8Hz,2H),7.85(t,J=8Hz,1H),7.70(t,J=8Hz,1H),7.08(s,1H),5.49(s,1H),5.29(s,1H),4.33(d,J=16Hz,1H),4.16(d,J=16Hz,1H),3.42(q,J=8Hz,2H),2.07-2.17(m,2H),0.95(dt,J=8Hz,8Hz,3H).13C NMR(100MHz,DMSO-d6)δ=172.17,167.69,157.19,156.98,152.77,148.29,146.41,145.81,132.06,130.89,130.27,129.33,128.99,128.77,128.76,128.43,128.25,128.24,128.21,128.17,119.26,95.43,76.29,66.65,59.78,50.70,30.56,23.73,7.99.
COMPARATIVE EXAMPLE preparation of camptothecin-Hydroxyacetic acid III under different reaction conditions
Comparative example 1.
Putting the reactant II (500mg,1mmol) into a round-bottomed bottle, adding 10ml of EtOH, and then adding 10% Pd/C (250 mg); the air in the reaction flask was removed by passing nitrogen and 2.5ml of cyclohexene was added. After refluxing the reaction for 20 hours, the reaction was stopped. TLC plates were spotted and the developing reagent (CH2Cl2: CH3OH ═ 97:3) was viewed under UV lamp 254 nm. And stopping the reaction, filtering to remove the catalyst, and spin-drying the filtrate to obtain a residue. The residue was recrystallized from acetonitrile and dried to give product III201mg as a yellow solid in 50% yield.
Comparative example 2.
Putting the reactant II (200mg,0.4mmol) into a round-bottomed bottle, adding 5ml of MeOH, and then adding 10% Pd/C (50 mg); after evacuation of the reaction flask, HCOONH4(200mg,3.2mmol) was added and the reaction stirred at 30 ℃ for 24 hours at room temperature. TLC plates were spotted and the developing reagent (CH2Cl2: CH3OH ═ 97:3) was viewed under UV lamp 254 nm. And stopping the reaction, filtering to remove the catalyst, and spin-drying the filtrate to obtain a residue. The crude product was purified by column chromatography using eluent (CH2Cl2: CH3OH ═ 97:3) to give product III (50mg, 30% yield) as a yellow solid.
Comparative example 3.
Putting the reactant II (200mg,0.4m mol) into a round-bottomed bottle, adding CH3OH 10ml, and then adding 10% Pd/C (50mg,0.5 mmol); after evacuation of the reaction flask, H2 was passed through and the reaction 24 was stirred at 30 ℃ at room temperature, the TLC plates were spotted and the developing reagent (CH2Cl2: CH3OH ═ 97:3) was observed under an ultraviolet lamp at 254 nm. The reaction was stopped, the catalyst was removed by filtration, the filtrate was spin-dried and the crude product was purified by column chromatography using an eluent (CH2Cl2: CH3OH ═ 97:3) to give product III as a yellow solid (116mg, 72% yield).
TABLE 1 purification and product yield for different reduction conditions
Discussion of the results: the reaction conditions of 10% Pd/C and cyclohexene were applied during the experiment, yield: 50 percent. The reaction yield is not high, the byproducts are difficult to separate, and the reaction conditions are further optimized and screened. Hydrogenation was carried out with 10% Pd/C/ammonium formate and 10% Pd/C. The yields for these two reaction conditions were 30% and 72% in this order. The 10 percent Pd/C hydrogenation reaction condition has few byproducts and is easy to separate. 10% Pd/C/ammonium formate, the yield was also low and the by-products were also high. In consideration of the smooth progress of the experiment, the invention selects the reaction condition of 10 percent Pd/C hydrogenation to synthesize the intermediate.
Claims (8)
1. The preparation process of camptothecin-glycolic acid III comprises the following steps: 1) reacting camptothecin with benzyloxyacetic acid to obtain a compound II, 2) carrying out a reduction reaction of the compound II in Pd/C and hydrogen at a suitable temperature in a suitable solvent, and purifying the product by suitable aftertreatment to obtain camptothecin-glycolic acid III:
2. the process for preparing camptothecin-hydroxyacetate III according to claim 1, characterized in that said reduction reaction of step 2) is preferably a catalytic hydrogenation reaction.
3. The process of claim 2, wherein the catalyst used in the step 2) is selected from Pd/C, Pd (OH)2and/C or Pt/C.
4. The process of claim 3, wherein the catalyst used in the catalytic hydrogenation of step 2) is Pd/C.
5. The process for the preparation of camptothecin-hydroxyacetate III according to any one of claims 1 to 4, wherein the suitable solvent of step 2) is selected from methanol, ethanol or propanol.
6. The process of claim 5, wherein the suitable solvent of step 2) is methanol.
7. The process for the preparation of camptothecin-hydroxyacetic acid III according to any one of claims 1 to 4, wherein said suitable temperature of step 2) is comprised between 25 ℃ and 50 ℃.
8. The process of claim 7, wherein the suitable temperature in step 2) is 25-35 ℃ at room temperature.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5840900A (en) * | 1993-10-20 | 1998-11-24 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
CN105399757A (en) * | 2015-12-29 | 2016-03-16 | 遵义医学院 | Acid-sensitive camptothecin-site 20 norcantharidate derivative and antineoplastic application thereof |
CN105636592A (en) * | 2013-07-11 | 2016-06-01 | 伊万斯彻有限公司 | Pro-drug forming compounds |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5840900A (en) * | 1993-10-20 | 1998-11-24 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
CN105636592A (en) * | 2013-07-11 | 2016-06-01 | 伊万斯彻有限公司 | Pro-drug forming compounds |
CN105399757A (en) * | 2015-12-29 | 2016-03-16 | 遵义医学院 | Acid-sensitive camptothecin-site 20 norcantharidate derivative and antineoplastic application thereof |
Non-Patent Citations (2)
Title |
---|
XIAN H. WANG ET AL.: "Design, synthesis, and biological activity evaluation of campthothecin-HAA-Norcantharidin conjugates as antitumor agents in vitro", 《CHEM BIOL DRUG DES.》 * |
郭伟航等: "2((S)-羟基乙酸喜树碱酯中间体的制备", 《遵义医科大学学报》 * |
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