CN108947942A - A kind of preparation method of docetaxel impurity - Google Patents
A kind of preparation method of docetaxel impurity Download PDFInfo
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- CN108947942A CN108947942A CN201811043320.XA CN201811043320A CN108947942A CN 108947942 A CN108947942 A CN 108947942A CN 201811043320 A CN201811043320 A CN 201811043320A CN 108947942 A CN108947942 A CN 108947942A
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- 0 CC(C)(C)OC(NC(*C(*=C)=O)c1ccccc1)=O Chemical compound CC(C)(C)OC(NC(*C(*=C)=O)c1ccccc1)=O 0.000 description 2
- ZDXIOIDDAPSCJQ-UHFFFAOYSA-N C=C(NCC(Cl)Cl)O Chemical compound C=C(NCC(Cl)Cl)O ZDXIOIDDAPSCJQ-UHFFFAOYSA-N 0.000 description 1
- KMMVXFBRSFBBNH-FFDAWYENSA-N CC(C)(C)OC(N1C(c(cc2)ccc2[U]C)SC[C@@H]1c1ccccc1)=O Chemical compound CC(C)(C)OC(N1C(c(cc2)ccc2[U]C)SC[C@@H]1c1ccccc1)=O KMMVXFBRSFBBNH-FFDAWYENSA-N 0.000 description 1
- HTBWSCRZTSTTKF-UHFFFAOYSA-N O=C(CCC(Cl)Cl)Cl Chemical compound O=C(CCC(Cl)Cl)Cl HTBWSCRZTSTTKF-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
Abstract
The present invention provides a kind of docetaxel impurity: the preparation method of the bis- chloroethene oxygen carbonyl docetaxels of 10-; the following steps are included: (1) is using 7- triethyl group silicon substrate -10- deacetylate baccatin III as raw material; it is reacted with chloro-carbonic acid -2,2- dichloro ethyl ester, obtains product I；(2) under the action of condensing agent, reaction generates product II for product I and Duo Xi side-chain acid；(3) product III obtains the bis- chloroethene oxygen carbonyl docetaxels of 10- under the action of hydrochloric acid.This method is easy to operate, high income, good product purity, and products therefrom is significant to docetaxel quality research.
Description
Technical field
The present invention relates to field of medicine preparing technology, more particularly, to a kind of bis- chloroethene oxygen carbonyls of docetaxel impurity 10-
The preparation method of docetaxel.
Background technique
Docetaxel is Taxane family, its pharmacological action is to pray for pipe by promoting micro-pipe dimer to be assembled into, simultaneously
Make to pray for pipe and preventing polymerisation process to stablize, blocks cellular in G2 the and M phase, thus inhibit cancer cell mitosis and
Proliferation.With the development of technology, USP41 has updated several docetaxel impurity, 6-Dichloroethoxy carbonyl
Docetaxel (the bis- chloroethene oxygen carbonyl docetaxels of 10- i.e. of the present invention) is one of them.In order to preferably be connect with the world
Rail is also required to further investigate the impurity in the quality research of docetaxel, therefore it is necessary to prepares high-purity
The bis- chloroethene oxygen carbonyl docetaxels of 10-.Do not check in the pertinent literature report for synthesizing the impurity temporarily.
Summary of the invention
For the Research Requirements of docetaxel, the applicant provides a kind of preparation method of docetaxel impurity, we
Method is easy to operate, high income, good product purity, and products therefrom is significant to docetaxel quality research.
The docetaxel impurity: shown in the bis- chloroethene oxygen carbonyl docetaxel structures of 10- such as formula (1):
The preparation method of docetaxel impurity of the present invention the following steps are included:
(1) 7- triethyl group silicon substrate -10- deacetylate baccatin III is dissolved with solvent, and bis- chloroethene of chloro-carbonic acid -2,2- is added
Ester is reacted, and reaction solution adds water quenching to go out after fully reacting, and acid adding is neutralized to the aobvious acidity of water phase, is collected organic phase and is concentrated under reduced pressure
It is steamed to solvent-free, toluene is added, continued to be concentrated to a large amount of solids precipitations, filter, be dried to obtain product I；
(2) product I is dissolved with solvent, is reacted with how western side-chain acid and condensing agent, filters reaction solution, filtrate through dilute hydrochloric acid and
It is concentrated into after saturated sodium bicarbonate washing thick；Concentrate is added dropwise to the normal heptane in stirring, solid is precipitated, is filtered, is done
It is dry to obtain product II；
(3) product II is dissolved in methanol, and hydrochloric acid is added dropwise and is reacted, and after reaction, methylene chloride is added, then with saturation
Sodium bicarbonate is neutralized to water phase and shows alkalescent；Organic phase concentration is collected, concentrate obtains more shown in formula (1) through column chromatographic purifying
The bis- chloroethene oxygen carbonyl docetaxels of Xi Tasai impurity, i.e. 10-.
Preferably, the solvent of step (1) reaction is methylene chloride and pyridine, wherein pyridine dosage and raw material 7- triethyl group silicon
The ratio of base -10- deacetylate baccatin III is 2~10 (V/W), chloro-carbonic acid -2,2- dichloro ethyl ester and tri- second of raw material 7-
The ratio of base silicon substrate -10- deacetylate baccatin III is 1.2~2.4 (W/W).
Preferably, the reaction temperature of step (1) is 0~10 DEG C, 15~60min of reaction time.
Preferably, step (2) reaction dissolvent is toluene or methylene chloride.
Preferably, the ratio of step (2) the how western side-chain acid and product I are 0.5~2 (W/W).
Preferably, step (2) condensing agent is that carbodiimide class condensing agent and 4-dimethylaminopyridine are combined, wherein carbon
The molar ratio of diimine class condensing agent and product I are 1.5~2:1.
Preferably, the carbodiimide class condensing agent includes N, N- dicyclohexylcarbodiimide, N, N- diisopropyl carbon two
Imines or 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride.
Preferably, step (2) reaction temperature is 15~25 DEG C, and the reaction time is 1~2h.
Preferably, the equivalent of step (3) hydrochloric acid and product II are 2~10.
Preferably, step (3) reaction temperature is 15~25 DEG C, and the reaction time is 2~4h.
The reaction route that above-mentioned preparation process occurs is as follows:
The present invention is beneficial to be had the technical effect that
Preparation route of the invention makes to walk by selecting suitable starting material and step (1) reaction condition appropriate
Suddenly the product of (1) is relatively single, does not generate too many by-product (13 substitution products of generation are less)；Step (2) choosing
The how western side-chain acid selected can be sloughed by HCl, dexterously identical with Tes (triethyl group silicon substrate) condition is sloughed, and be subtracted to greatest extent
Reaction step is lacked.Of the invention this route steps that prepare are few, and each reaction yield is high, and condition is simple, respectively reacts newly-generated production
Object is easy discrimination, reduces the difficulty for preparing the bis- chloroethene oxygen carbonyl docetaxels of 10-.
Specific embodiment
Below with reference to embodiment, the present invention is specifically described.
Embodiment 1
(1) 7- triethyl group silicon substrate -10- deacetylate baccatin III (6.5g) is dissolved in 32.5ml methylene chloride and 65ml
It in pyridine, is placed in low temperature bath and stirs, be added dropwise chloro-carbonic acid -2,2- dichloro ethyl ester (7.8g), continue to react at 0 DEG C after dripping off
60min.10ml water quenching reaction is added in reaction solution, and hydrochloric acid is added to be neutralized to the aobvious acidity of water phase, collects organic phase and depressurizes in 45 DEG C
Be concentrated into it is solvent-free steam, 30ml toluene is added, continues to be concentrated to a large amount of solids and is precipitated, filter, dry product I (7.5g),
Yield is 95.0%.
(2) product I (7.5g) is dissolved in 75ml toluene, 4-dimethylaminopyridine (0.7g), how western side-chain acid is added
(4.5g) and N, N- Dicyclohexylcarbodiimide (3.3g, 1.7 equivalents), in 15 DEG C of reaction 2h.Reaction solution is filtered, filtrate is through dilute salt
It is concentrated into after acid and saturated sodium bicarbonate washing thick.Concentrate is added dropwise to the normal heptane (150ml) in stirring, is had a large amount of
Solid is precipitated, and filters, dry product II (10.3g), yield 93.0%.
(3) product II (10.3g) is dissolved in 100ml methanol, stirs lower dropwise addition 1mol/L hydrochloric acid (17.5ml, 2 equivalents),
In 25 DEG C of reaction 4h.After reaction, 100ml methylene chloride is added, then water phase is neutralized to saturated sodium bicarbonate and shows alkalescent,
Collect organic phase concentration.Concentrate obtains the bis- chloroethene oxygen carbonyl docetaxels (7.2g) of 10- through column chromatographic purifying, and yield is
87.0%.
Embodiment 2
(1) 7- triethyl group silicon substrate -10- deacetylate baccatin III (6.5g) is dissolved in 32.5ml methylene chloride and 13ml
It in pyridine, is placed in low temperature bath and stirs, be added dropwise chloro-carbonic acid -2,2- dichloro ethyl ester (15.6g), continue to react at 0 DEG C after dripping off
15min.10ml water quenching reaction is added in reaction solution, and hydrochloric acid is added to be neutralized to the aobvious acidity of water phase, collects organic phase and depressurizes in 45 DEG C
Be concentrated into it is solvent-free steam, 30ml toluene is added, continues to be concentrated to a large amount of solids and is precipitated, filter, dry product I (7.8g),
Yield is 98.9%.
(2) product I (7.8g) is dissolved in 78ml methylene chloride, 4-dimethylaminopyridine (0.7g), more west side chains is added
Sour (3.9g) and N, N- diisopropylcarbodiimide (1.8g, 1.5 equivalents), in 25 DEG C of reaction 1.5h.Filter reaction solution, filtrate warp
It is concentrated into after dilute hydrochloric acid and saturated sodium bicarbonate washing thick.Concentrate is added dropwise to the normal heptane (150ml) in stirring, is had
A large amount of solids are precipitated, and filter, dry product II (10.5g), yield 91.2%.
(3) product II (10.5g) is dissolved in 100ml methanol, stirs lower dropwise addition 1mol/L hydrochloric acid (89ml, 10 equivalents),
In 15 DEG C of reaction 2h.After reaction, 100ml methylene chloride is added, then water phase is neutralized to saturated sodium bicarbonate and shows alkalescent,
Collect organic phase concentration.Concentrate obtains the bis- chloroethene oxygen carbonyl docetaxels (6.8g) of 10- through column chromatographic purifying, and yield is
80.6%.
Embodiment 3
(1) 7- triethyl group silicon substrate -10- deacetylate baccatin III (6.5g) is dissolved in 32.5ml methylene chloride and 30ml
It in pyridine, is placed in low temperature bath and stirs, be added dropwise chloro-carbonic acid -2,2- dichloro ethyl ester (12.5g), continue to react at 0 DEG C after dripping off
15min.10ml water quenching reaction is added in reaction solution, and hydrochloric acid is added to be neutralized to the aobvious acidity of water phase, collects organic phase and depressurizes in 45 DEG C
Be concentrated into it is solvent-free steam, 30ml toluene is added, continues to be concentrated to a large amount of solids and is precipitated, filter, dry product I (7.3g),
Yield is 92.5%.
(2) product I (7.3g) is dissolved in 73ml toluene, 4-dimethylaminopyridine (0.7g), how western side-chain acid is added
(14.6g) and 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (3.5g, 2 equivalents), in 20 DEG C of reaction 1h.It takes out
Reaction solution is filtered, filtrate is concentrated into thick after dilute hydrochloric acid and saturated sodium bicarbonate washing.Concentrate is added dropwise in stirring
Normal heptane (150ml) has a large amount of solids to be precipitated, and filters, dry product II (10.0g), yield 92.8%.
(3) product II (10.0g) is dissolved in 100ml methanol, stirs lower dropwise addition 1mol/L hydrochloric acid (42ml, 5 equivalents), in
20 DEG C of reaction 3h.After reaction, 100ml methylene chloride is added, then water phase is neutralized to saturated sodium bicarbonate and shows alkalescent, receives
Collect organic phase concentration.Concentrate obtains the bis- chloroethene oxygen carbonyl docetaxels (6.7g) of 10-, yield 83.4% through column chromatographic purifying.
The invention is not limited to above-mentioned method detaileds, that is, do not mean that the present invention must rely on above-mentioned method detailed ability
Implement.It should be clear to those skilled in the art, any improvement in the present invention, to each raw material of product of the present invention etc.
Effect replacement and addition, the selection of concrete mode of auxiliary element etc., all of which fall within the scope of protection and disclosure of the present invention.
Claims (10)
1. a kind of preparation method of docetaxel impurity, shown in the docetaxel impurity structure such as formula (1):
It is characterized in that, preparation method the following steps are included:
(1) 7- triethyl group silicon substrate -10- deacetylate baccatin III is dissolved with solvent, be added chloro-carbonic acid -2,2- dichloro ethyl ester into
Row reaction, after fully reacting, reaction solution adds water quenching to go out, and acid adding is neutralized to the aobvious acidity of water phase, collects organic phase and is concentrated under reduced pressure into
It is solvent-free to steam, toluene is added, continues to be concentrated to a large amount of solids precipitations, filters, be dried to obtain product I；
(2) product I is dissolved with solvent, is reacted with how western side-chain acid and condensing agent, filters reaction solution, filtrate is through dilute hydrochloric acid and saturation
It is concentrated into after sodium bicarbonate washing thick；Concentrate is added dropwise to the normal heptane in stirring, solid is precipitated, is filtered, dry
To product II；
(3) product II is dissolved in methanol, and hydrochloric acid is added dropwise and is reacted, and after reaction, methylene chloride is added, then with unsaturated carbonate
Hydrogen sodium is neutralized to water phase and shows alkalescent；Collect organic phase concentration, concentrate through column chromatographic purifying obtain shown in formula (1) more west he
Match impurity, the i.e. bis- chloroethene oxygen carbonyl docetaxels of 10-.
2. the method according to claim 1, wherein the solvent of step (1) described reaction is methylene chloride and pyrrole
Pyridine, wherein pyridine dosage and the ratio of raw material 7- triethyl group silicon substrate -10- deacetylate baccatin III are 2~10 (V/W)；It is described
The ratio of chloro-carbonic acid -2,2- dichloro ethyl ester and raw material 7- triethyl group silicon substrate -10- deacetylate baccatin III is 1.2~2.4 (W/
W)。
3. being reacted the method according to claim 1, wherein the temperature of step (1) described reaction is 0~10 DEG C
15~60min of time.
4. the method according to claim 1, wherein step (2) solvent is toluene or methylene chloride.
5. the method according to claim 1, wherein the ratio of step (2) the how western side-chain acid and product I are
0.5~2 (W/W).
6. the method according to claim 1, wherein step (2) condensing agent is carbodiimide class condensing agent
It is combined with 4-dimethylaminopyridine, wherein the molar ratio of carbodiimide class condensing agent and product I are 1.5~2:1.
7. according to the method described in claim 5, it is characterized in that, the carbodiimide class condensing agent includes N, N- dicyclohexyl
Carbodiimide, N, N- diisopropylcarbodiimide or 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride.
8. according to the method described in claim 1, it is characterized by: the temperature of step (2) described reaction be 15~25 DEG C, reaction
Time is 1~2h.
9. according to the method described in claim 1, it is characterized by: the equivalent of step (3) hydrochloric acid and product II be 2~
10。
10. according to the method described in claim 1, it is characterized by: the temperature of step (3) described reaction is 15~25 DEG C, instead
It is 2~4h between seasonable.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115650882A (en) * | 2022-11-14 | 2023-01-31 | 肇庆学院 | Docetaxel impurity and preparation method thereof |
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| CN107141272A (en) * | 2017-06-30 | 2017-09-08 | 重庆市碚圣医药科技股份有限公司 | A kind of semi-synthetic docetaxel method and its intermediate |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107141272A (en) * | 2017-06-30 | 2017-09-08 | 重庆市碚圣医药科技股份有限公司 | A kind of semi-synthetic docetaxel method and its intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115650882A (en) * | 2022-11-14 | 2023-01-31 | 肇庆学院 | Docetaxel impurity and preparation method thereof |
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Address after: No.111, Qinxin Road, Donggang Town, Xishan District, Wuxi City, Jiangsu Province Applicant after: Wuxi Yeshan Pharmaceutical Co.,Ltd. Address before: 214199 red bean Industrial Park, Donggang Town, Xishan District, Jiangsu, Wuxi Applicant before: JIANGSU YEW PHARMACEUTICAL Co.,Ltd. |
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