High-efficiency high-stereoselectivity semisynthesis method of harringtonine and allied alkaloids

A technology of triceps fir and alkaloids, which is applied in chemical instruments and methods, active ingredients of silicon compounds, active ingredients of heterocyclic compounds, etc., can solve the problems of long synthesis lines, is not easy to be applied to industrial production, etc., and achieves short synthesis steps. , easy operation, high chemical yield and high diastereoselectivity

Active Publication Date: 2012-01-04
NANKAI UNIV
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  • Description
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Problems solved by technology

Utilizing this method and using similar side chains, in 2008, Jin reported the synthesis of optically pure homoharringtonine, dehydroharringtonine and harringtonine analogues and carried out physiological activity tests (Chem .Eur.J.2008,14,4293-4306). The harringtonine obtained by this method has a high purity, but optically pure raw materials are used, and the synthetic route is long, so it is not easy to apply to industrial production

Method used

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  • High-efficiency high-stereoselectivity semisynthesis method of harringtonine and allied alkaloids
  • High-efficiency high-stereoselectivity semisynthesis method of harringtonine and allied alkaloids
  • High-efficiency high-stereoselectivity semisynthesis method of harringtonine and allied alkaloids

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] The preparation of embodiment 1α-ketoacyl harringtonine (16)

[0049]

[0050] To 205mg keto acid (21) (0.75mmol, 1.5mmol) in 3mL CH 2 Cl 2 2,4,6-trichlorobenzoyl chloride (0.26mL, 2mmol) was added dropwise into the solution, then harringtonine (158mg, 0.5mmol), pyridine (0.16mL, 2mmol) in CH 2 Cl 2 (5 mL) solution. After the reaction, extract with 10 mL ether and 10 mL pH=5 buffer solution, and separate the layers. The organic phase was washed again with buffer solution. Combine the aqueous phases and add NaHCO 3 (s) to pH=7, extract with ether, combine the organic phases, wash with saturated NaCl, anhydrous NaCl 2 SO 4 dry. After filtration, it was spin-dried, and the residual solvent and pyridine were removed in vacuum. 171mg of yellow solid was obtained, the yield was 60%.

[0051] Recrystallization gave pale yellow crystals, mp=180-181°C, [α] D =-22° (c 0.5, CHCl 3 , 20°C); 1 H NMR (400MHz, CDCl 3 )δ6.58(s, 1H), 6.56(s, 1H), 5.88(d, J=9.2Hz, 1H), 5...

Embodiment 2

[0052] Preparation of Example 2α-ketoacyl harringtonine (17)

[0053]

[0054] The harringtonine (1.6g, 4mmol), Et 3 A solution of N (triethylamine, 1.4 mL, 10 mmol) and 4-dimethylaminopyridine (DMAP 97 mg, 0.8 mmol) in 20 ml of dichloromethane was slowly added dropwise to ketoacid (22) (1.728 g, 6 mmol) and 2, 4,6-trichlorobenzoyl chloride in 25 mL of dichloromethane solution. After the reaction is complete, add 50ml of saturated sodium bicarbonate solution, separate the layers, extract the aqueous phase with 30mL ether three times, combine the organic phases, wash twice with 50mL of pH=5 buffer solution, and wash with 10% Na 2 CO 3 Wash twice with solution, once with saturated saline, and with anhydrous Na 2 SO 4 Dry, spin dry, dissolve in n-hexane, filter, and place in the refrigerator to precipitate a white solid to obtain a total of 1.75 g of white solid, with a yield of 75%. mp=114-115°C; [α] D =-113° (c 0.5, CHCl 3 , 20°C); 1 HNMR (400MHz, CDCl 3 )δ6.58(s, 1H...

Embodiment 3

[0055] Preparation of Example 3α-ketoacyl harringtonine (18)

[0056]

[0057] The same method as in Example 1, except that compound (18) was obtained from compound (23), and recrystallized to obtain 179 mg of light yellow solid, with a yield of 81%. mp=98-100°C; [α] D =-125.4° (c 1.0, CHCl 3 , 20°C); 1 H NMR (400MHz, CDCl 3 )δ6.56(s, 1H, ArH), 6.54(s, 1H, ArH), 5.86(d, J=9.2Hz, 1H, ArCHCH), 5.82(s, 2H, OCH 2 O), 5.09(s, 1H, vinyl H), 3.81(d, J=9.2Hz, 1H, ArCHCH), 3.68(s, 3H, OCH 3 ), 3.19 (td, J=11.6, 7.6Hz, 1H, CH 2 ), 3.04 (m, 1H, CH 2 ), 2.91 (m, 1H, CH 2 ), 2.57 (m, 2H, CH 2 ), 2.33 (m, 2H, CH 2 ), 2.22 (m, 1H, CH 2 ), 2.02 (dt, J=12.0, 9.6Hz, 1H, CH 2 ), 1.88 (m, 1H, CH 2), 1.72 (m, 2H, CH 2 ), 1.41 (septet, J=6.8Hz, 1H, (CH 3 ) 2 CH), 1.24(m, 2H, CH 2 ), 0.80 (d, J=6.8Hz, 6H, (CH 3 ) 2 CH)ppm; HRMS(EI)m / z calcd for C 25 h 32 NO 6 (M+H) + 442.2220 found 442.2224.

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Abstract

The invention relates to a high-efficiency high-stereoselectivity semisynthesis method of harringtonine and allied alkaloids, which uses optical pure cephalotaxin serving as a raw material to perform reactive synthesis with substituted silicon ketene in Lewis acid catalysis. The structural general formula of the compound is shown as (A), wherein the meaning of each group is shown as the specification. The method has the advantages of high chemical yield and diastereoselectivity of key reactions, convenient operation, short synthesis steps and the like. The method is a universal method for synthesizing the optical pure compound with the structural general formula shown as (A), and is suitable for massive preparation. The compound is widely applied to anti-tumor (malignant and non-malignant tumors), anti-parasitic, antifungal and antimicrobial chemotherapy medicaments.

Description

technical field [0001] The present invention relates to the synthesis of harringtonine alkaloids, in particular to a semi-synthetic method and application of harringtonine alkaloids with high efficiency and high stereoselectivity, specifically optically pure harringtonine A novel method for the efficient and highly stereoselective semi-synthesis of optically pure harringtonine alkaloids and their analogs from starting materials. Background technique [0002] In 1970, Paudler and Powell et al. (Tetrahedron Lett. 1970, 47, 815; Tetrahedron 1972, 28, 1995) isolated and identified four harringtonines from the genus Herringophytum, namely harringtonine 1 ( Harringtonine, HT), homoharringtonine 2 (Homoharringtonine, HHT), deoxyharringtonine 3 (Deoxyharringtonine, DHT) and isoharringtonine 4 (Isoharringtonine, IHT), and found to have significant anti- tumor activity. Wherein homoharringtonine 2 was loaded into Chinese Pharmacopoeia in 1990 for the clinical treatment of acute non-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/20C07F7/18A61K31/695A61K31/55A61P35/00A61P33/00A61P31/10A61P31/04
Inventor 陈莉李卫东
Owner NANKAI UNIV
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