Bilobalide B hydrolyzed derivatives and application thereof

Abstract

The invention discloses two bilobalide B hydrolyzed derivatives of which the structural formulae are disclosed in the specification, and also discloses application thereof as impurity reference substances in inspection of related substances of methylsulfonyl 10-O-(dimethylaminoethyl)bilobalide B raw materials and preparations. The methylsulfonyl 10-O-(dimethylaminoethyl)bilobalide B preparations are methylsulfonyl 10-O-(dimethylaminoethyl)bilobalide B water injection, methylsulfonyl 10-O-(dimethylaminoethyl)bilobalide B freeze-dried powder injection, methylsulfonyl 10-O-(dimethylaminoethyl)bilobalide B high-capacity injection and methylsulfonyl 10-O-(dimethylaminoethyl)bilobalide B solid oral liquid. The invention effectively controls the related substances of the methylsulfonyl 10-O-(dimethylaminoethyl)bilobalide B raw materials and preparations, thereby ensuring the safety and effectiveness of the methylsulfonyl 10-O-(dimethylaminoethyl)bilobalide B preparations in clinical use.

Description

technical field

[0001] The present invention relates to the use of a class of ginkgolide B hydrolyzed derivatives, especially its application as an impurity reference substance in the inspection of related substances of 10-O-(dimethylaminoethyl) ginkgolide methanesulfonate B and preparations , belonging to the field of medical technology. Background technique

[0002] Ginkgolide B (Ginkgolide B, GB) is a diterpene compound with a hexacyclic cage structure extracted from Ginkgo biloba. It is the strongest platelet activating factor (PAF) antagonist found so far. , can stimulate coronary arteries and cerebral arteries, causing their contraction, spasm, resulting in myocardial and brain tissue ischemia.

[0003] 10-O-(dimethylaminoethyl) ginkgolide B (structural formula shown in formula III) is a derivative of ginkgolide B, reported by Qin Yinlin and others in the patent (publication number CN 1749257A) the compound

[0004]

[0005] 10-O-(dimethylaminoethyl) ginkgolide B...

Examples

Embodiment 1

[0018] Example 1 Separation and Preparation of Ginkgolide B Hydrolyzed Derivatives

[0019] Take an appropriate amount of 10-O-(dimethylaminoethyl) ginkgolide B methanesulfonate, add methanol to dissolve, separate with TLC, and use CHCl 3 / CH 3 OH (6 / 1) was developed repeatedly to obtain two spots with lower Rf value than the raw material, which were separated on a preparative plate, and the two products obtained were further separated by HPLC preparative column to obtain two compounds (A and B).

Embodiment 2

[0020] Example 2 Synthesis of Ginkgolide B Hydrolyzed Derivatives

[0021] Take about 5.0 g of 10-O-(dimethylaminoethyl) ginkgolide B methanesulfonate, dissolve it in water, add about 1.0 g of sodium carbonate powder, stir at 50°C for 6 hours, filter, and wash the filtrate with ethyl acetate for two Once, the aqueous layer was evaporated to dryness to obtain a white powder, which was separated by column chromatography, CHCl 3 / CH 3 OH (6 / 1) was eluted, and the desired eluent was collected, evaporated to dryness, and dried to obtain two compounds (C and D).

Embodiment 3

[0022] Example 3 Structure Confirmation

[0023] After analysis and identification, the compound C obtained in Example 2 is the same as the compound A obtained in Example 1, and the molecular structure is shown in Formula 1. MS(m / z): 514[M+H] +1 ; 1 H-NMR (CDCl 3 ): δ7.95(d, 1H), 7.62(d, 1H), 7.15(s, 1H), 6.34(s, 1H), 6.12(s, 1H), 5.31(s, 1H), 5.12(s, 1H), 4.54(s, H), 4.38(dt, 1H), 4.07(dd, H), 3.56(dt, H), 2.84(q, H), 2.61(s, H), 2.30(s, H ), 2.18(s,H), 2.13(s,H), 1.88(s,H), 1.73(s,H), 1.10(s,H), 1.04(s,H).

[0024] The compound D obtained in Example 2 is the same as the compound B obtained in Example 1, and its molecular structure is shown in Formula 2. MS(m / z): 514[M+H] +1 ; 1 H-NMR (CDCl 3 ): δ7.88(d, 1H), 7.60(d, 1H), 7.42(d, 1H), 7.12(s, 1H), 6.74(s, 1H), 6.04(s, 1H), 5.27(s, 1H), 5.04(s, 1H), 4.51(s, H), 4.29(dt, 1H), 4.11(dd, H), 3.48(dt, H), 2.71(s, H), 2.26(s, H ), 2.12(s,H), 2.01(s,H), 1.87(s,H), 1.76(s,H), 1.13(s,H), 1.02(s,H).

technical field

[0001] The present invention relates to the use of a class of ginkgolide B hydrolyzed derivatives, especially its application as an impurity reference substance in the inspection of related substances of 10-O-(dimethylaminoethyl) ginkgolide methanesulfonate B and preparations , belonging to the field of medical technology. Background technique

[0002] Ginkgolide B (Ginkgolide B, GB) is a diterpene compound with a hexacyclic cage structure extracted from Ginkgo biloba. It is the strongest platelet activating factor (PAF) antagonist found so far. , can stimulate coronary arteries and cerebral arteries, causing their contraction, spasm, resulting in myocardial and brain tissue ischemia.

[0003] 10-O-(dimethylaminoethyl) ginkgolide B (structural formula shown in formula III) is a derivative of ginkgolide B, reported by Qin Yinlin and others in the patent (publication number CN 1749257A) the compound

[0004]

[0005] 10-O-(dimethylaminoethyl) ginkgolide B...

Examples

Embodiment 1

[0018] Example 1 Separation and Preparation of Ginkgolide B Hydrolyzed Derivatives

[0019] Take an appropriate amount of 10-O-(dimethylaminoethyl) ginkgolide B methanesulfonate, add methanol to dissolve, separate with TLC, and use CHCl 3 / CH 3 OH (6 / 1) was developed repeatedly to obtain two spots with lower Rf value than the raw material, which were separated on a preparative plate, and the two products obtained were further separated by HPLC preparative column to obtain two compounds (A and B).

Embodiment 2

[0020] Example 2 Synthesis of Ginkgolide B Hydrolyzed Derivatives

[0021] Take about 5.0 g of 10-O-(dimethylaminoethyl) ginkgolide B methanesulfonate, dissolve it in water, add about 1.0 g of sodium carbonate powder, stir at 50°C for 6 hours, filter, and wash the filtrate with ethyl acetate for two Once, the aqueous layer was evaporated to dryness to obtain a white powder, which was separated by column chromatography, CHCl 3 / CH 3 OH (6 / 1) was eluted, and the desired eluent was collected, evaporated to dryness, and dried to obtain two compounds (C and D).

Embodiment 3

[0022] Example 3 Structure Confirmation

[0023] After analysis and identification, the compound C obtained in Example 2 is the same as the compound A obtained in Example 1, and the molecular structure is shown in Formula 1. MS(m / z): 514[M+H] +1 ; 1 H-NMR (CDCl 3 ): δ7.95(d, 1H), 7.62(d, 1H), 7.15(s, 1H), 6.34(s, 1H), 6.12(s, 1H), 5.31(s, 1H), 5.12(s, 1H), 4.54(s, H), 4.38(dt, 1H), 4.07(dd, H), 3.56(dt, H), 2.84(q, H), 2.61(s, H), 2.30(s, H ), 2.18(s,H), 2.13(s,H), 1.88(s,H), 1.73(s,H), 1.10(s,H), 1.04(s,H).

[0024] The compound D obtained in Example 2 is the same as the compound B obtained in Example 1, and its molecular structure is shown in Formula 2. MS(m / z): 514[M+H] +1 ; 1 H-NMR (CDCl 3 ): δ7.88(d, 1H), 7.60(d, 1H), 7.42(d, 1H), 7.12(s, 1H), 6.74(s, 1H), 6.04(s, 1H), 5.27(s, 1H), 5.04(s, 1H), 4.51(s, H), 4.29(dt, 1H), 4.11(dd, H), 3.48(dt, H), 2.71(s, H), 2.26(s, H ), 2.12(s,H), 2.01(s,H), 1.87(s,H), 1.76(s,H), 1.13(s,H), 1.02(s,H).

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