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QUẢNG CÁO
 
Truy cập
Đang online: 19
Tổng số: 402,317
CHI TIẾT
Tổng hợp dimesna (dinatri 2-(2-sulfonatoethyldisulfanyl)ethansulfonat) sử dụng hydroperoxid
Novel approach for synthesis of dimesna (disodium 2-(2-sulfonatoethyldisulfanyl)ethanesulfonate) using hydrogen peroxide
Nguyễn Văn Hải, Đào Nguyệt Sương Huyền
Số: 523 - Tháng 11/2019 - Trang 22-25, 31

Dimesna (dinatri 2-(2-sulfonatoethyldisulfanyl)ethansulfonat) là dẫn chất disulfid của mesna - thuốc được chỉ định bắt buộc trong giải độc hóa trị liệu ung thư nhóm oxazaphosphorin như cyclophosphamid và ifosfamid. Tác dụng giải độc này được đảm bảo nhờ cân bằng chuyển hóa dimesna/mesna trong cơ thể: tại huyết tương mesna (thiol) nhanh chóng bị oxy hóa thành dimesna (disulfid); ngược lại, ở ống thận dimesna bị khử thành mesna (nhờ hệ glutathion) để phản ứng với các chất gây độc thận như acrolein và 4-hydroxy-ifosfamid. Gần đây, các nghiên cứu lâm sàng đã chỉ ra, dimesna có tác dụng làm giảm độc tính của thuốc chống ung thư nhóm phức hợp bạch kim (cis-platin, carboplatin) và taxan (docetaxel, paclitaxel). Ngoài ra, dimesna cũng là tạp chất sinh ra trong quá trình tổng hợp, bào chế và bảo quản thuốc mesna. Việc nghiên cứu tổng hợp phân tử này đã được một số tác giả trên thế giới thực hiện, đi từ các nguồn nguyên liệu khác nhau như: acid 2-mercaptoethansulfonic, mesna, natri vinylsulfonat, natri 2-bromoethansulfonat, natri S-acetyl-2-mercaptoethansulfonat. Cơ sở của các phương pháp này là oxy hóa nhóm chức thiol (-SH) bằng các tác nhân oxy hóa để tạo liên kết disulfid (-S-S-). Hiện nay, chưa có công bố nào về phương pháp tổng hợp dimesna bằng phản ứng oxy hóa trực tiếp mesna sử dụng các tác nhân xanh như hydroperoxid và oxy không khí. Nghiên cứu này được thực hiện với mục tiêu: tổng hợp được dimesna đạt hàm lượng trên 98% ở quy mô 5,0 g/mẻ từ nguyên liệu mesna sử dụng tác nhân hydroperoxid.

Nguyên liệu

Mesna; hydroperoxid 30%, natri hydroxid, natri iodid, ethanol; ethyl acetat; nước cất, acid 2-(2-sulfonatoethyldisulfanyl)ethanesulfonic chuẩn.

Phương pháp nghiên cứu

Độ tinh khiết của sản phẩm được kiểm tra sơ bộ bằng sắc ký lớp mỏng (TLC) và đo nhiệt độ nóng chảy (t°nc). Tiến hành SKLM trên bản mỏng silicagel 60 F254 (Merck), dung môi hòa tan là hỗn hợp nước và ethanol, hệ dung môi khai triển n-butanol : acid acetic : nước (9,0 : 6,0 : 6,0), hiện vết bằng cách hơ trên ngọn lửa đèn cồn. Đo nc bằng máy EZ-Melt (Mỹ). Xác định cấu trúc bằng phân tích dữ liệu các phổ: phổ IR được ghi trên máy Shimadzu sử dụng kỹ thuật viên nén KBr trong vùng 4000-400 cm-1; phổ MS được ghi trên máy LTQ Orbitrap XLTM với chế độ đo ESI, dung môi MeOH; phổ NMR được ghi trên máy Bruker AscendTM 500, dung môi D2O. Các phổ đều được ghi tại Khoa Hóa học - Trường Đại học Khoa học Tự nhiên - Đại học Quốc gia Hà Nội. Định lượng theo phương pháp sắc kí lỏng hiệu năng cao (HPLC) tại Viện Kiểm nghiệm thuốc Trung ương.

Kết luận

Đã tổng hợp được dimesna ở quy mô 5,0 g/mẻ bằng phương pháp oxy hóa mesna sử dụng tác nhân dung dịch H2O2 30%, hiệu suất phản ứng đạt ổn định 74,02%. Quy trình phản ứng có khả năng phát triển ở quy mô lớn hơn, phù hợp với tiêu chí công nghệ xanh. Cấu trúc của dimesna được khẳng định bằng các phương pháp phân tích phổ: IR, NMRMS.

Dimesna (disodium 2-(2-sulfonatoethyldisulfanyl)ethanesulfonate), as a chemotherapeutic protective agent for mitigating the toxicity of antitumor drugs, was synthetised from mesna using hydrogen peroxide as oxidative agent. Some reaction conditions such as time, temperature, pH and solvent were investigated. The reaction yield was stable at 74.02% at the scale of 5.0 g/batch. The product was obtained in high purity and structurally confirmed by the IR, MS, NMR. The method proved well environment-friendly  and capable of enlarging the scale.

 

Quay trở lại

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