The Synthesis Of Ifosfamide

Ifosfamide, brand name of which is Holoxan, is the isomer of Cyclophosphamide. It was first synthesized by Germany Asta corporation in the middle of 20th century 1960s. It went to clinic after the appearance of urinary tract Mesna till the 20th century 1980s. Now, it had used widely. Ifosfamid belongs to broad spectrum antitumor drug. It is the second generation alkylating agent. Its chemical name is 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide.Malignanc is currently has a strong impact on human health, is one of the principal disease threaten human life and world allied nations medical science region graveness research subject. Form three large cause of death alongside with heart cerebrovascular disease and contingency all over the world. Near twenty in the last years, the cause of death spectra in China changed a lot. Malignancy and some communicable disease became the main cause of death. Malignancy death had became the second place of the cause of death. The rose, clinically versus curative effect all the better, low poison subsidiary reaction in high demand of antitumor drug in company with global aging social advent as well as tumor morbidity. It is anticipated that, in the next few years the world antitumor drug market would continue"heating-up". Medication possess an important position and has the most development speed in cancerous three large therapeutics. Recently, tumor chemotherapy procure equivalent advancement, tumor sufferer survival time distinctly prolong, especially leukemia, malignant lymphoma, but versus imperil humanity life health most severe, occupy malignancy 90% foregoing entity neoplastic cure cannot reach satisfied. The curative effect, must from tumorigenesis extend mechanism embark, talent procure new breach gender headway into of the be both pharmacy home and oncologist increasingly deeper aware that, want advance oncotherapy. In recent years, the development of numerator oncology, molecular pharmacology lead tumor essence under gradually thrown a light upon; the invention and application of wholesale fast screening, combinatorial chemistry and genetic engineering accelerate the exploitation process of medicine. The study and development of antitumor drug enter a new era.Ifosfamide was a sort of newfashioned antitumor drug, its structural bear a resemblance to Cyclophosphamide alkylation's oxygen nitrogen phosphorus loops medicine. As the isomer of Cyclophosphamide, it possess high therapeutic index and low virulence. It was a sort of require in vivo myoneure pigment P450 mixed function oxidase system activation exert cell toxicant active pro-drug. Hydroxylation brought into existence four-hydroxyl-Ifosfamide, and aldehyde Ifosfamide spontaneity equilibria, aldehyde Ifosfamide cracking succeed primary alkylating agent Ifosfamide nitrogen mustard and urethra toxic material acrolein. The slowness of carbo-homocycle hydroxyl course, generate another metabolic pathway brought some kind of alkylation intermediate metabolites, namely dechlorinate ethyl cyclophosphamide, dechlorinate ethyl Ifosfamide and chloroacetaldehyde, the latter brings neurotoxicity substance. Both of metabolic pathway rest with medication (ingestion or intravenous injection), generate different resist tumor action and poison side effect. Its cytotoxic action is occur cross link with DNA, fight DNA's synthesis, also disturb DNA's function, genera cell cycle nonspecific agent. Take Ifosfamide, cell cycle G2+m proportionate increase, notify cell transit G2 delay. The antitumor drug have got cumulation, whereas virulence cut down where fractionation administration. Thus, fractionation administration scheme afterwards successfully apply to clinic, elevate against cancer curative effect and sufferer tolerance.In recent years, Ifosfamide is one of the important chemotherapy medicine among antitumor drug, possess favorable head and ears or local security and tolerance that. Via 17 years clinic demonstration from 1971.In 1988 Dec, it capture America FDA warrant, Ifosfamide/Mesna (I/M) came into the market, juxtaposition for supreme grade 1A level antitumor drug. Middle, low price product,belong to antitumor drug, go on sale in 1993 in our country. Its ingestion absorption all right, bioavailability approach 100%. The sale equal reside to antecedent of antitumor drug all over the world, wide market outlook and favorable extend posture. By comparison to foreign product, Ifosfamide raw material drug and preparation cost on the low side, possess distinct price predominance. Therefore, The medical came into the market certainly should alleviate the economic burden for tumor sufferer, it also create a certainty social advantage and economic interest.Text design with synthesis of Ifosfamide in two way. Way one with ethylenimine for raw material, through the medium of alkylation, cyclization, supersede three step reaction get object compound Ifosfamide, Total yield is 28.97%. Way two with phosphorus oxychloride for raw material, past cyclization, alkylation, acylate, reduction four step got antitumor drug Ifosfamide, Total yield is 30.1%. The structure of intermediate compound and ultimately compound get ascertainment by infrared spectrum, mass spectrum, nuclear magnetic resonance hydrogen spectra, carbon spectra and phosphorus spectra.The systhesis of second key intermediate 2-chlorotetrahydro-2H-1,3,2- oxazaphosphorine-2-oxide at way two, change the droplets order of raw material, the yield is 71.3%.Compared with literature reportorial, it has simple craft, low cost price and high yield.At way two, we adopt cheap and low-toxicity bulk drug phosphorus oxychloride instead of expensive and high-toxicity bulk drug ethylenimine at way one, cost low price and reduce operational risk.At the same time we optimize the after-treatment of way two, reducing reaction operation and react time.Way two we designed, with phosphorus oxychloride for raw material is the better. Decrease the use of virulent and expensive materal, reduce the risk of synthesis technical, shorten the lab proc, cost low price, rise the yield up. The reaction conditions is gentle, fit to industrialized production.The synthesis of the Ifosfamide provided optimized synthetic route and safe reliable quality criteria with industrial application of it. Therefore, the feasibility of industry of the medicine was ensured.The method we metioned provide less noxious and more simple Ifosfamide systhesis technology, moreover it decrease effectively the cost of the bulk drug. Thus it is possible of realization of serving for much more patients of cancer. Accordingly, the research and development of the Ifosfamide will bring about great economic returns and social benefit.