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QUẢNG CÁO
 
Truy cập
Đang online: 3
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CHI TIẾT
Nghiên cứu tổng hợp (S)-(−)-atenolol bằng xúc tác enzym
Enzyme-catalyzed synthesis of (S)-(−)-atenolol
Phạm Ngọc Tuấn Anh, Đinh Hữu Thành, Vũ Thanh Thảo, Trần Cát Đông
Số: 15 - Tháng 2/2021 - Trang 16-19

Atenolol thuộc nhóm thuốc chẹn beta có tác động chủ vận chọn lọc trên thụ thể β1 được sử dụng phổ biến trong điều trị các bệnh tim mạch như cao huyết áp, đau thắt ngực, nhồi máu cơ tim cấp. Các nghiên cứu đã chứng minh chỉ dạng đồng phân (S)-()-atenolol mới có tác dụng ức chế thụ thể β1 và dạng đồng phân (S)-()-atenolol đơn trị liệu có tác dụng dược lý như dạng hỗn hợp racemic. Việc sử dụng đồng phân (S)-()-atenolol sẽ cho tác dụng chọn lọc trên tim, giúp tránh được một số tác dụng phụ gây ra của dạng đồng phân (R)-(+)-atenolol. Với những ưu điểm trên, việc nghiên cứu tổng hợp (S)-()-atenolol dược dụng ứng dụng trong bào chế thuốc đang ngày càng được chú ý. Trong nghiên cứu này, (S)-()-atenolol được nghiên cứu tổng hợp ở quy mô phòng thí nghiệm trong điều kiện Việt Nam. Đây cũng là tiền đề cho việc xây dựng quy trình công nghệ tổng hợp (S)-()-atenolol dược dụng phù hợp với định hướng phát triển nền công nghiệp hóa dược Việt Nam.

Nguyên liệu

Các nguyên liệu sử dụng trong nghiên cứu được mua từ các hãng hóa chất như Acros Organics (Geel, Bỉ), TCI Chemicals (Tokyo, Nhật) và Merck (Darmstadt, Đức).

Phương pháp nghiên cứu

(S)-()-atenolol (5) được tổng hợp từ 4-hydroxyphenylacetamid (1) và epiclorohydrin tạo dẫn chất O-ether (2) dựa trên phản ứng Williamson. Dẫn chất O-ether (2) tham gia vào phản ứng mở vòng oxiran với tác nhân acetyl clorid tạo dẫn chất clorohydrin (3), theo sau bằng phản ứng ester hóa với tác nhân anhydrid acetic tạo dẫn chất (RS)-ester acetat (4).  Hỗn hợp racemic dẫn chất 4 được thủy phân chọn lọc bằng enzym Amano lipase từ chủng Pseudomonas fluorescens thu được (R)-ester acetat (R)-4. Dẫn chất (R)-4 được thủy phân ester trong môi trường kiềm theo sau được cho phản ứng với isopropyl amin thu được (S)-()-atenolol (5) (Sơ đồ 1). Các sản phẩm tổng hợp được kiểm tra độ tinh khiết bằng sắc ký lớp mỏng (SKLM), nhiệt độ nóng chảy và xác định cấu trúc bằng phổ MS, NMR, xác định độ tinh khiết quang học bằng đo góc quay cực.

Kết luận

Nghiên cứu đã tổng hợp thành công đồng phân (S)-()-atenolol theo quy trình tổng hợp 5 bước trong đó có sử dụng xúc tác lipase từ Pseudomonas fluorescens. Sản phẩm tổng hợp được có độ tinh khiết quang học cao, tuy nhiên hiệu suất toàn quy trình còn thấp. Từ kết quả này, những nghiên cứu tiếp theo sẽ hướng tới tối ưu hóa quy trình tổng hợp nhằm nâng cao hiệu suất và đồng thời nghiên cứu nâng cấp quy mô phản ứng, xây dựng quy trình công nghệ tổng hợp (S)-()-atenolol dược dụng phù hợp với điều kiện Việt Nam nhằm có thể ứng dụng đưa vào sản xuất nguyên liệu dược phẩm.   

The present study describes an efficient chemoenzymatic synthesis of enantiopure (S)-()-atenolol, a selective β1-adrenergic receptor blocker, via 5-step procedure. The chiral key intermediate, (R)-1-(4-(2-amino-2-oxoethyl)phenoxy)-3-chloropropane-2-yl acetate, was obtained by using the Amano lipase from Pseudomonas fluorescens. The (R)-enantiomer intermediate was then hydrolyzed and the resulting product was reacted with isopropylamine to afford (S)-()-atenolol with the high enantiomeric excess.

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