CN108752361A - A kind of preparation method of hydroxycamptothecin - Google Patents

A kind of preparation method of hydroxycamptothecin Download PDF

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Publication number
CN108752361A
CN108752361A CN201810959306.8A CN201810959306A CN108752361A CN 108752361 A CN108752361 A CN 108752361A CN 201810959306 A CN201810959306 A CN 201810959306A CN 108752361 A CN108752361 A CN 108752361A
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China
Prior art keywords
hydroxycamptothecin
preparation method
added
water
camptothecine
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CN201810959306.8A
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Chinese (zh)
Inventor
蒲祥
胡月
高湖川
张利
邹平
黄乾明
罗应刚
张程瑞
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四川农业大学
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Priority to CN201810959306.8A priority Critical patent/CN108752361A/en
Publication of CN108752361A publication Critical patent/CN108752361A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

Abstract

The invention belongs to synthetic drug technical fields, more particularly to a kind of preparation method of hydroxycamptothecin, sour solvent dissolves camptothecine and oxidant sodium perborate is added, and is concentrated under reduced pressure reaction solution after isothermal reaction, be added ice water after crystal is precipitated completely, be filtered, washed, dry to obtain 1- oxygen camptothecines；1- oxygen camptothecines are added dioxane, acetonitrile, water and concentrated sulfuric acid dissolution and stir, with ultraviolet lamp and high pressure mercury, ice water condensation reflux；Be concentrated under reduced pressure, be added ice water after crystal is precipitated completely, be filtered, washed, dry to obtain crude product；Purifying crude.Easy to operate, safety economy of the invention, environmentally protective, gross production rate is high.

Description

A kind of preparation method of hydroxycamptothecin

Technical field

The invention belongs to synthetic drug technical fields, and in particular to a kind of preparation method of hydroxycamptothecin.

Background technology

10-hydroxycamptothecine (HCPT) be from the fruit of Nyssaceae plant camptotheca acuminata (Camptotheca acuminata) with Ten hydroxylation derivants of camptothecine that preparation is detached in leaf are the synthesis camptothecins anticarcinogens such as topotecan and Irinotecan Important intermediate, therefore the preparation method for finding and developing HCPT is one of the important directions of camptothecin cancer drug development. Currently, preparing there are four types of the methods of HCPT：Direct extraction method, biotransformation method, chemical complete synthesizing process, molecular design method. The ultrasonic-microwave such as Cen Ye in 2017 cooperates with HCPT in extraction Common Camptotheca Fruit, average recoveries 4.61%.Method consumption is a large amount of Solvent, extraction process is complicated, and yield is relatively low, and a large amount of HCPT that extract can damage camplotheca acuminata resource.The utilizations such as Wang Lei in 2014 Camptothecin conversion is that HCPT, conversion ratio 7.37%, but strain culturing and screening technique require high, fermentation by camptotheca acuminate endophytic fungi Product design is low in liquid, and separation and Extraction complex steps, post processing extraction solvent consumption is big, and technology is still immature.Liu et al. passes through within 2008 Michael additions, intramolecular aldol condensation, the reaction of oxidation aromatization, intramolecular Diels-Alder cycloaddition and Sharpless The serial reactions such as asymmetric dihydroxylation are successfully prepared HCPT, yield 14%, but since reaction step is more, synthesize Gross production rate is low, and consumption of organic solvent is big, and environmental pollution is serious, and final product must split D/L type isomers, can not measure at present Production.

Camptothecine content in natural camplotheca acuminata plant is about 10 times or so of HCPT, in addition camptothecine extraction process more at It is ripe, advantage of lower cost, thus using camptothecine as the semi-synthetic preparation HCPT economical rationality of raw material.Existing molecular design method is main There are two types of, the first is quinoline ring reduction method：It uses precious metal by camptothecine catalytic hydrogenation first, is reduced into 1,2,6,7- tetra- After hydrogen camptothecine, then it is oxidized and prepares HCPT；Second is quinoline epoxidation process：Camptothecine is first oxidized to 1- with oxidant Oxygen camptothecine, then with high voltage mercury lamp radiation, photochemical rearrangement occurs, generate HCPT.Precious metal is urged used in quinoline ring reduction method Agent is of high cost, and hydrogenation safety coefficient is relatively low, and reaction condition is not easy to control.And quinoline epoxidation process is than quinoline ring reduction method With certain advantage, still, complicated for operation, time-consuming.

Invention content

The purpose of the present invention is the quinoline epoxidation process to molecular design hydroxycamptothecin to be improved, and solves existing skill The problem that time-consuming for art, safety coefficient is low, operation is inconvenient establishes a kind of convenient, efficient, environmentally protective new method.

A kind of preparation method of hydroxycamptothecin, includes the following steps：

(1) N- oxidation reactions

Sour solvent, stirring and dissolving camptothecine is added at 30-45 DEG C in camptothecine heating water bath；At the uniform velocity it is warming up to 60-70 DEG C, oxidant sodium perborate is added, continues stirring and condensing reflux；Sustained response stops heating to the end of reaction, naturally cold But to room temperature；

Reaction solution is concentrated under reduced pressure, ice water is added into concentrate, stands still for crystals；It after crystal is precipitated completely, filters, distillation Water washing, it is dry to get 1- oxygen camptothecines；

Wherein sour solvent is glacial acetic acid, formic acid, preferably glacial acetic acid；The ratio between camptothecine quality and glacial acetic acid volume are 1:50- 1:200, preferably 1:100；The ratio between amount of substance of camptothecine and sodium perborate is 1:10-1:70, preferably 1:45；Reaction temperature is 70-120 DEG C, preferably 90 DEG C；Reaction time is 30-100min, preferably 50min.

(2) photochemical rearrangement

Dioxane, acetonitrile, water and concentrated sulfuric acid dissolution is added in 1- oxygen camptothecine made from above-mentioned steps and is stirred, with purple Outer lamp and high pressure mercury, ice water condensation reflux；

To the end of reaction, stop illumination, cooled to room temperature；It is concentrated under reduced pressure, a large amount of ice water is added into reaction solution, it is quiet Set crystallization；After crystal is precipitated completely, water washing is distilled in filtering, dry to get HCPT crude products；

Wherein the ratio between volume of dioxane, acetonitrile and water is 5:3:1, water is distilled water, the concentrated sulfuric acid and distilled water volume it Than being 1:70-1:120, preferably 1:100,1- oxygen camptothecines are 1 with distilled water mass ratio:50-1:150 preferably 1:100, it is ultraviolet High-pressure sodium lamp power is 400-700W, preferably 500W, light application time 40-80min, preferably 60min.Reaction equation：

(3) purifying crude

Normal pressure glass chromatography column, with silicone filler.Chromatographic column height is 150~200mm, column diameter 250mm, sample The mass ratio of product and silica gel is 1:50-1:100, preferably 1:100.It, then will be above-mentioned with ethyl alcohol using chloroform wet method dress post HCPT crude products dissolving prepared by step, admixes a small amount of silica gel dry method loading.Methanol：Chloroform volume ratio is 1:30-1:70, It is preferred that 1:49 are used as mobile phase isocratic elution, are collected and are numbered using test tube, and TLC monitors product purity, merges after detection similar Fraction, be more than 98.5% amalgamation liquid by HCPT contents, product obtained after being evaporated under reduced pressure, being dried in vacuo；This is will be less than to contain The amalgamation liquid of amount has solid precipitation through being concentrated under reduced pressure into just, and concentrate, which is put into refrigerator, to be stood overnight, filtering, by solid vacuum 98.5% or more sterling, gross production rate 86.42% are obtained after drying.

The technique effect of the present invention：

(1) present invention prepares 1- oxygen camptothecines using sodium perborate as oxidant, shortens oxidation time, improves Oxidation reaction yield.

(2) present invention is with 1,4 ,-dioxane, acetonitrile, water volume ratio 5:3:1 mixed solvent is photochemical solvent, is carried High photochemical reaction conversion ratio.

(3) experimental implementation of the present invention is simple, and safety economy is environmentally protective, and gross production rate is high, reaches 86.42%.

Description of the drawings

Fig. 1 is the product 1- oxygen camptothecine mass spectrograms of embodiment；

Fig. 2 is the product 10-hydroxycamptothecine of embodiment1H-NMR；

Fig. 3 is the product 10-hydroxycamptothecine of embodiment13C-NMR。

Specific implementation mode

It is described in conjunction with the embodiments the specific technical solution of the present invention.

The preparation method of hydroxycamptothecin, includes the following steps：

(1) N- oxidation reactions

Accurately weighed appropriate camptothecine, places it in round-bottomed flask.It is molten that acid is added at 30-45 DEG C in heating water bath 10min is stirred in agent, dissolves camptothecine.It is at the uniform velocity warming up to 60-70 DEG C, oxidant sodium perborate is added, continues to stir and be condensed back to Stream.Heat up sustained response.To the end of reaction, stop heating, cooled to room temperature.Reaction solution is concentrated under reduced pressure, into concentrate A large amount of ice water are added, stand still for crystals.After crystal is precipitated completely, water washing is distilled in filtering on a small quantity, dry to get 1- oxygen camplotheca acuminatas Alkali, yield 96.46%.

Wherein sour solvent is glacial acetic acid；The ratio between camptothecine quality and glacial acetic acid volume are 1:100；Camptothecine and sodium perborate The ratio between the amount of substance be 1:45；Reaction temperature is 90 DEG C；Reaction time is 50min.

(2) photochemical rearrangement

1- oxygen camptothecine made from above-mentioned steps is placed in 1000mL photochemical reaction bottles, add dioxane, acetonitrile, Water and concentrated sulfuric acid dissolution simultaneously stir, with ultraviolet lamp and high pressure mercury, ice water condensation reflux.To the end of reaction, stop illumination, from So it is cooled to room temperature.It is concentrated under reduced pressure, a large amount of ice water is added into reaction solution, stand still for crystals.After crystal is precipitated completely, filtering, A small amount of distillation water washing, it is dry to get HCPT crude products.Wherein the ratio between volume of dioxane, acetonitrile and water is 5:3:1, the concentrated sulfuric acid It is 1 with the ratio between distilled water volume:100,1- oxygen camptothecines are 1 with distilled water mass ratio:100, ultraviolet high-pressure sodium lamp power is 500W, light application time 60min.

(3) column chromatography purifies

Normal pressure glass chromatography column, with silicone filler.Chromatographic column height is 150~200mm, column diameter 250mm, sample The mass ratio of product and silica gel is 1:100.Using chloroform wet method dress post, the HCPT for then being prepared above-mentioned steps with ethyl alcohol is thick Product dissolves, and admixes a small amount of silica gel dry method loading.Methanol：Chloroform volume ratio is 1:49 are used as mobile phase isocratic elution, make It is collected and is numbered with test tube, TLC monitors product purity, and similar fraction is merged after detection, is more than 98.5% by HCPT contents Amalgamation liquid obtains product after being evaporated under reduced pressure, being dried in vacuo；The amalgamation liquid that will be less than the content has admittedly through being concentrated under reduced pressure into just Body is precipitated, and concentrate is put into refrigerator and is stood overnight, and filtering obtains 98.5% or more sterling after being dried in vacuo solid, always Yield is 86.42%.

Product obtained as above is differentiated：

(1) N- oxidation reaction products：

1- oxygen camptothecines are yellow solid, are differentiated using LC-MS, such as Fig. 1.Chromatographic condition：Agilent 1290 is efficient Liquid-phase chromatographic column (ACQUITY UPLC BEH C18, 2.1 × 100mm, 1.7 μm) and separation, 30 DEG C of column temperature, flow velocity 0.3mL/min； 0.1 μ l of sample size；Flow phase composition A：+ 0.1% formic acid of water, B：Acetonitrile；Gradient elution program：1-18min, 5-50% (B), 18-25min, 50-80% (B), 25-28min, 80-98% (B), 28-33min, 98-98% (B).Detection wavelength 373nm.1- Oxygen camptothecine, which differentiates, uses Waters Xevo G2-XS QTOF, ESI positive ion modes, mass scan range m/z:50- 1000。HRMS m/z365.1814[M+H]+(calcd for C20H16N2O5,364.3510)。

(2) photorearrangement product：

10-hydroxycamptothecine, faint yellow solid, mp：264.4-265.6℃.Nuclear magnetic resonance spectroscopy such as Fig. 2, nuclear magnetic resonance Carbon composes number such as Fig. 3；240(15272),250(10706),255(15008),260 (16376),267(24885),273(21642),281(4977),286(5957),292(5478),297(5635),316 (7999),332(10171),370(20037),385(23260)；IR(KBr):3520,3095,2897,1722,1653, 1594,1553,1505,1336,1262,1173,1049,836,746,669cm-1；1H-NMR (400MHz, DMSO-d6):δ 0.88 (t, J=8Hz, 3H), 1.85-1.88 (t, 2H), 5.23 (s, 2H), 5.41 (s, 2H), 6.48 (s, 1H), 7.26 (s, 1H), 7.28 (d, J=4Hz, 1H), 7.41-7.44 (dd, J1=4Hz, J2=8Hz, 1H), 8.03 (d, J=8Hz, 1H), 8.45 (s,1H),10.32(s,1H)；13C-NMR (400MHz, DMSO-d6):δ8.20,30.68,50.56,65.67,72.83, 96.26,109.23,118.56,123.46,129.71,130.10,130.35,131.08,143.65,146.34,149.85, 150.48,157.09,157.28,172.94；HRMS m/z365.1814[M+H]+(calcd for C20H16N2O5, 364.3510)。

Claims (7)

1. a kind of preparation method of hydroxycamptothecin, which is characterized in that include the following steps：
(1) N- oxidation reactions
Sour solvent, stirring and dissolving camptothecine is added at 30-45 DEG C in camptothecine heating water bath；It is at the uniform velocity warming up to 60-70 DEG C, is added Enter oxidant sodium perborate, continues stirring and condensing reflux；Sustained response stops heating, naturally cools to room to the end of reaction Temperature；
Reaction solution is concentrated under reduced pressure, ice water is added into concentrate, stands still for crystals；After crystal is precipitated completely, filtering, distillation washing It washs, it is dry to get 1- oxygen camptothecines；
(2) photochemical rearrangement
Dioxane, acetonitrile, water and concentrated sulfuric acid dissolution is added in 1- oxygen camptothecine made from above-mentioned steps and is stirred, with ultraviolet height Pressure mercury lamp illumination, ice water condensation reflux；
To the end of reaction, stop illumination, cooled to room temperature；It is concentrated under reduced pressure, a large amount of ice water is added into reaction solution, stand knot It is brilliant；After crystal is precipitated completely, water washing is distilled in filtering, dry to get HCPT crude products；
(3) purifying crude
Purifying crude is obtained into sterling with column chromatography methods.
2. a kind of preparation method of hydroxycamptothecin according to claim 1, which is characterized in that the acid described in step (1) Solvent is glacial acetic acid, formic acid.
3. a kind of preparation method of hydroxycamptothecin according to claim 1, which is characterized in that in step (1), camptothecine The ratio between quality and sour solvent volume are 1:50-1:200；The ratio between amount of substance of camptothecine and sodium perborate is 1:10-1:70.
4. a kind of preparation method of hydroxycamptothecin according to claim 1, which is characterized in that described in step (1) Sustained response, reaction temperature are 70-120 DEG C, reaction time 30-100min.
5. a kind of preparation method of hydroxycamptothecin according to claim 1, which is characterized in that , bis- Evil in step (2) The ratio between volume of alkane, acetonitrile and water is 5:3:1, the ratio between the concentrated sulfuric acid and water volume are 1:70-1:120,1- oxygen camptothecines and water quality The ratio between amount is 1:50-1:150.
6. a kind of preparation method of hydroxycamptothecin according to claim 1, which is characterized in that in step (2), ultraviolet height Pressure mercury lamp power is 400-700W, light application time 40-80min.
7. a kind of preparation method of hydroxycamptothecin according to claim 1, which is characterized in that the column described in step (3) Chromatogram purification includes the following steps：Normal pressure glass chromatography column, with silicone filler；Using chloroform wet method dress post, second is then used Alcohol dissolves HCPT crude products, admixes silica gel dry method loading, methanol：Chloroform volume ratio is 1:30-1:70, as mobile phase Isocratic elution is collected and is numbered using test tube, and TLC monitors product purity, and similar fraction is merged after detection, HCPT contents are surpassed The amalgamation liquid for crossing 98.5% obtains product after being evaporated under reduced pressure, being dried in vacuo；The amalgamation liquid of the content be will be less than through being concentrated under reduced pressure To there is solid precipitation, concentrate is put into refrigerator and is stood overnight, filtering, solid is dried in vacuo after obtain 98.5% or more it is pure Product.
CN201810959306.8A 2018-08-22 2018-08-22 A kind of preparation method of hydroxycamptothecin CN108752361A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0074256A1 (en) * 1981-09-04 1983-03-16 Kabushiki Kaisha Yakult Honsha Camptothecin derivatives, processes for preparing same, formulations containing such derivatives and their use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0074256A1 (en) * 1981-09-04 1983-03-16 Kabushiki Kaisha Yakult Honsha Camptothecin derivatives, processes for preparing same, formulations containing such derivatives and their use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
战佩英等: "N-氧化吡啶合成新方法的探索", 《通化师范学院学报》 *

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