CN100560576C - The semisynthesis of taxol and Docetaxel - Google Patents
The semisynthesis of taxol and Docetaxel Download PDFInfo
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- CN100560576C CN100560576C CNB2007100364883A CN200710036488A CN100560576C CN 100560576 C CN100560576 C CN 100560576C CN B2007100364883 A CNB2007100364883 A CN B2007100364883A CN 200710036488 A CN200710036488 A CN 200710036488A CN 100560576 C CN100560576 C CN 100560576C
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Abstract
The invention discloses the semisynthesis of a kind of taxol and Docetaxel, this method is to carry out condensation prepared with the 10-deacetylate Tetraol 10-DAB of protection and the C-13 side chain of synthetic chirality to form.This method is simple, and the reaction conditions gentleness is suitable for suitability for industrialized production.
Description
Technical field
The present invention relates to the synthetic field of medicine, relate in particular to the semi-synthetic novel method of a kind of taxol and Docetaxel.
Background technology
Taxol and Docetaxel are the human up to now the most effective cancer therapy drugs of finding; from Chinese yew genus plants, extract; but this type of plant genus state guarantee plant and the content that extracts from plant are very low; so the chemical synthesis process of seeking taxol and Docetaxel just becomes the direction of a lot of scientist's researchs.
Patent PCT/CN2006/003150 has described a kind of semisynthesis of taxol: adopt different novel chiral side chain-2S, the 10-deacetylate Tetraol 10-DAB of 3S-phenylisoserine type and 2-epi taxol and Docetaxel C-13 side chain precursor and protection carries out condensation prepared taxol and Docetaxel.
It is long that but this method has synthetic route, the defective that yield is low.
Technology contents
Technical problem to be solved by this invention is to provide the semisynthesis of a kind of taxol and Docetaxel, to address the deficiencies of the prior art.
Principle of the present invention is: the present invention finds on the basis of patent PCT/CN2006/003150; the butt joint condition of 10-deacetylate Tetraol 10-DAB by improving novel chiral side chain and protection; the chirality of 2 ' of chiral side chain directly can be turned into correct configuration in the butt joint reaction; thereby need not after removing protection, to carry out 2 ' chirality upset according to the method for former patent; thereby shortened the synthetic route of original patent, improved yield greatly.
The semisynthesis of taxol provided by the present invention and Docetaxel specifically comprises the steps:
1. 10-deacetylate Tetraol 10-DAB (formula 1) and novel chiral side chain (formula 2) condensation reaction with protection makes the compound of formula 3;
2. finish the upset of 2 ' of side chain in condensation reaction, the protection that removes side chain then obtains the compound of formula 4;
3. the compound of formula 4 is by removing the compound that protection obtains formula 5;
If wherein step 3. in the compound of formula 4 remove 7 protections and promptly obtain taxol, and if the protection that removes 7 and 10 simultaneously promptly obtains Docetaxel;
Its Chinese style 1 is:
Formula 2 is:
Formula 3 is:
Formula 4 is:
Formula 5 is:
Wherein R1 is a hydroxyl protecting group, as TBS (tertiary butyl dimethyl-silicon), TES (triethyl silicon), EE (ethoxyethyl group), THP (tetrahydropyrans), Troc (three chloroethyl oxygen carbonyls) or MOM (methoxyl methyl); R2 is Ac (ethanoyl) or hydroxyl protecting group, as TBS, and TES, EE, THP, Troc or MOM; R3 is a hydroxyl protecting group, as TBS, and TES, EE, THP, Troc or MOM, perhaps R3 is the ketal protecting group, for example to anisyl ketal or acetonyl ketal; R4 is H or ketal protecting group, for example to anisyl ketal or acetonyl ketal; R5 is Bz (benzoyl) or Boc (tertbutyloxycarbonyl), and when R5 is that Bz up-to-date style 5 compounds are taxol, when R5 was Boc, the compound of formula 5 was a Docetaxel.
Wherein step 1. the compound of Chinese style 1 and the compound of formula 2 carry out condensation reaction, used condensation reagent is DCC (a dicyclohexyl carbonyl diimine); Used catalyzer is DAMP (N, a N-lutidine); In condensation, the chirality that side chain is 2 ' is overturn, and wherein the consumption of condensation reagent is the 1-10 equivalent, and catalyst consumption is also at the 1-10 equivalent, and both calculate with the amount of 10-deacetylate Tetraol 10-DAB.
The temperature of condensation reaction is between 0 to 100 degree.
Concrete reaction formula is as follows:
Compare with background technology, semisynthesis step of the present invention is simpler, shortens for 3 steps than former invention, and yield rises to 55.9% from original 35.8%.This method reaction conditions gentleness is suitable for suitability for industrialized production.
Following embodiment just is used to illustrate the present invention, and unrestricted the present invention.
Embodiment 1 preparation taxol
Step 1:
50 digest compound 1a and 50 digests compound 2a and adds 5000 milliliters of toluene, adds 25 gram DMAP and 50 gram DCC, and being heated to 100 degree, to stir 8 hours afterreactions complete, filter, and pressure reducing and steaming toluene, the residuum column chromatography obtains 65 and digests compound 3a.Yield: 86.4%.
1H?NMR(500MHz，C
6D
6)δ：8.35(dd，J＝6.8，2.8Hz，2H)，7.83(br?d，J＝7.1Hz，2H)，7.50(d，J＝7.3Hz，1H)，7.42(s，1H)，7.40-7.32(m，2H)，7.30-7.15(m，7H)，7.00(t，J＝7.3Hz，1H)，6.95(s，1H)，6.90-6.85(m，4H)，6.60(br?t，J＝9.2Hz，1H)，6.12(d，J＝6.9Hz，1H)，5.97(br?s，1H)，5.45(s，2H)5.01(d，J＝8.3Hz，1H)，4.90(dd，J＝11.4，6.8Hz，1H)，4.80(br?s，1H)，4.54(d，J＝8.6Hz，1H)，4.40(d，J＝8.6Hz，1H)，4.28(d，J＝6.9Hz，1H)，3.35(s，3H)，2.80-2.70(m，1H)，2.56(s，3H)，2.54(dd，J＝15.2，9.2Hz，1H)，2.42(dd，J＝15.2，9.2Hz，1H)，2.30-2.18(m，1H)，2.13(s，3H)，2.08(s，3H)，1.95(s，3H)，1.83(br?s，1H)，1.35(s，3H)，1.23(s，3H).
Step 2:
65 digest compound 3a is dissolved in 1000 milliliters of dehydrated alcohols, 50 milliliters in the dilute hydrochloric acid of adding 2N, and stirred overnight at room temperature is neutralized to neutrality with saturated sodium bicarbonate, boils off solvent, and the residuum column chromatography obtains 50 and digests compound 4a.Yield: 85.7%.
1H?NMR(500MHz，C
6D
6)δ：8.50(d，J＝8.5Hz，1H)，8.46(d，J＝6.6Hz，1H)，7.63(d，J＝7.3Hz，1H)，7.56-7.50(m，2H)，7.35-7.21(m，6H)，7.10(t，J＝7.3Hz，1H)，7.03-6.97(m，2H)，6.85(d，J＝9.2Hz，1H)，6.64(s，1H)，6.56(dd，J＝9.2，8.9Hz，1H)，6.18(dd，J＝9.2，2.1Hz，1H)，6.06(d，J＝6.9Hz，1H)，5.55(s，2H)，4.99(dd，J＝7.6，1.9Hz，1H)，4.80-4.75(m，1H)，4.65(dd，J＝4.6，2.1Hz，1H)，4.49(s，2H)，4.12(d，J＝6.9Hz，1H)，3.56(d，J＝4.6Hz，1H)，2.90(d，J＝4.0Hz，1H)，2.73(dd，J＝15.7，8.9Hz，1H)，2.71-2.65(m，1H)，2.64(dd，J＝15.7，9.2Hz，1H)，2.25-2.16(m，1H)，2.23(s，3H)，2.05(s，3H)，2.02(s，3H)，1.85(s，3H)，1.74(s，1H)，1.17(s，3H)，1.14(s，3H).
Step 3:
40 digest compound 4a is dissolved in 50 milliliters of acetic acid, 500 milliliters of methyl alcohol, zinc powder 50 grams, reflux one hour, and the cooling back is revolved and is desolvated with the saturated sodium bicarbonate neutrality that neutralizes, and the residuum column chromatography obtains 25 gram taxols, is white solid.Through detections such as nuclear-magnetism optically-actives, the same with natural Japanese yew alcohol.Yield: 75.5%.
m.p.213-216℃
IR(KBr)：3482，1732，1653cm
-1；
[α]
D 25：-49.2°
1H?NMR(CDCl
3，500M)δ：8.12(d，J＝7.9Hz，2H)，7.71(d，J＝7.9Hz，2H)，7.58(t，J＝7.2Hz，1H)，7.53(m，5H)，7.40-7.30(m，5H)，6.98(d，J＝8.7Hz，1H)，6.25(s，1H)，6.18(bt，J＝8.9Hz，1H)，5.75(dd，J＝8.7，2.6Hz，1H)，5.63(d，J＝7.1Hz，1H)，4.92(bd，J＝8.8Hz，1H)，4.75(d，J＝2.1Hz，1H)，4.36(dd，J＝10.5，6.7Hz，1H)，4.29(d，J＝8.4Hz，1H)，4.17(d，J＝8.3Hz，1H)，3.76(d，J＝7.0Hz，1H)，3.54(bs，1H)，2.51(ddd，J＝15.3，9.5，5.8Hz，1H)，2.43(bs，1H)，2.35(s，1H)，2.33(dd，J＝15.3，8.7Hz，1H)，2.27(dd，J＝15.3，8.7Hz，1H)，2.25(s，3H)，2.20(s，3H)，1.90-1.85(m，1H)，1.75(s，3H)，1.65(s，3H)，1.20(s，3H)，1.11(s，3H)；
13C?NMR(CDCl
3，125M)δ203.5，172.6，171.2，170.3，167.1，167.0，142.1，137.8，133.6，133.6，133.0，132.0，130.2，129.1，129.0，128.8，128.7，128.4，127.1，127.0，84.4，81.0，79.0，76.4，75.4，74.8，73.3，72.3，72.2，58.6，55.0，45.6，43.1，35.6，35.6，26.8，22.6，21.8，20.9，14.9，9.5.
Embodiment 2 preparation Docetaxels
Step 1:
50 digest compound 1b and 50 digests compound 2b and adds 5000 milliliters of toluene, adds 25 gram DMAP and 50 gram DCC, and being heated to 100 degree, to stir 8 hours afterreactions complete, filter, and pressure reducing and steaming toluene, the residuum column chromatography obtains 65 and digests compound 3b.Yield: 90.9%.
1H?NMR(500MHz，CDCl
3)δ：8.35(d，J＝8.5Hz，2H)，8.06(m，1H)，7.83(d，J＝8.4Hz，2H)，7.64(m，2H)，7.48(m，2H)，7.36(m，5H)，6.25(m，1H)，6.20(t，J＝9.2Hz，1H)，5.66(d，J＝7.0Hz，1H)，5.57(m，1H)，5.43(d，J＝9.0Hz，1H)，5.23(dd，J＝3.1，9.0Hz，1H)，4.98(d，J＝9.0Hz，1H)，4.92(d，J＝7.1Hz，1H)，4.75(s，2H)，4.64(d，J＝3.0Hz，1H)，4.55(d，J＝7.1Hz，1H)，4.30(d，J＝9.0Hz，1H)，4.19(d，J＝9.0Hz，1H)，3.90(d，J＝12.1Hz，1H)，3.58(s，3H)，2.60(m，1H)，2.35(s，3H)，1.96(s，3H)，1.83(s，3H)，1.38(s，9H)，1.25(s，3H)，1.21(s，3H).
Step 2:
65 digest compound 3a is dissolved in 1000 milliliters of dehydrated alcohols, 50 milliliters in the dilute hydrochloric acid of adding 0.1N, and stirred overnight at room temperature is neutralized to neutrality with saturated sodium bicarbonate, boils off solvent, and the residuum column chromatography obtains 50 and digests compound 4a.Yield: 83.8%.
1H?NMR(500MHz，CDCl
3)δ：8.09(m，1H)，7.62(m，2H)，7.51(m，2H)，7.39(m，5H)，6.23(m，1H)，6.21(t，J＝9.2Hz，1H)，5.69(d，J＝7.0Hz，1H)，5.55(m，1H)，5.42(d，J＝9.0Hz，1H)，5.26(dd，J＝3.1，9.0Hz，1H)，4.96(d，J＝9.0Hz，1H)，4.90(d，J＝7.1Hz，1H)，4.77(s，2H)，4.64(d，J＝3.0Hz，1H)，4.58(d，J＝7.1Hz，1H)，4.33(d，J＝9.0Hz，1H)，4.17(d，J＝9.0Hz，1H)，3.90(d，J＝12.1Hz，1H)，2.62(m，1H)，2.37(s，3H)，1.98(s，3H)，1.85(s，3H)，1.37(s，9H)，1.26(s，3H)，1.20(s，3H).
Step 3:
40 digest compound 4b is dissolved in 100 milliliters of acetic acid, 500 milliliters of methyl alcohol, zinc powder 50 grams, reflux one hour, and the cooling back is revolved and is desolvated with the saturated sodium bicarbonate neutrality that neutralizes, and the residuum column chromatography obtains 20 gram Docetaxels, is white solid.Through detections such as nuclear-magnetism optically-actives, the same with natural Japanese yew alcohol.Yield: 73.0%.
m.p.232-234℃
IR(KBr)：3400，2900，1710cm
-1；
[α]
D 25：-36.2°
1H?NMR(CDCl
3，500M)δ：8.12(m，1H)，7.60(m，2H)，7.50(m，2H)，7.38(m，5H)，6.22(t，J＝9.0Hz，1H)，5.68(d，J＝7.0Hz，1H)，5.46(d，J＝9.0Hz，1H)，5.26(d，J＝9.0Hz，1H)，5.22(s，1H)，4.94(d，J＝9.0Hz，1H)，4.62(m，1H)，4.32(d，J＝9.0Hz，1H)，4.26(m，1H)，4.19(d，J＝9.0Hz，1H)，3.91(d，J＝7.0Hz，1H)，2.58(m，1H)，2.37(s，3H)，2.28(m，2H)，1.88(s，3H)，1.75(s，3H)，1.35(s，9H)，1.23(s，3H)，1.11(s，3H)；
13C?NMR(CDCl
3，125M)δ211.1，172.7，170.3，167.0，155.5，138.6，138.5，136.0，133.0，130.2，129.3?128.7，127.9，127.4，126.9，84.4，81.1，80.2，78.9，77.3，75.1，74.5，73.9，72.3，71.8，57.7，56.6，46.6，43.1，36.7，35.8，28.2，26.5，22.5，20.7，14.3，9.9.
Claims (2)
1, a kind of semisynthesis of taxol is characterized in that comprising the following step:
Step 1:
50 digest compound 1a and 50 digests compound 2a and adds 5000 milliliters of toluene, adds 25 gram 4-Dimethylamino pyridines and 50 gram dicyclohexylcarbodiimide, and being heated to 100 degree, to stir 8 hours afterreactions complete, filter, pressure reducing and steaming toluene, the residuum column chromatography obtains compound 3a;
Step 2:
65 digest compound 3a is dissolved in 1000 milliliters of dehydrated alcohols, 50 milliliters in the dilute hydrochloric acid of adding 2N, and stirred overnight at room temperature is neutralized to neutrality with saturated sodium bicarbonate, boils off solvent, and the residuum column chromatography obtains compound 4a;
Step 3:
40 digest compound 4a is dissolved in 50 milliliters of acetic acid, 500 milliliters of methyl alcohol, zinc powder 50 grams, reflux one hour, and the cooling back is revolved and is desolvated with the saturated sodium bicarbonate neutrality that neutralizes, and the residuum column chromatography obtains taxol.
2, a kind of semisynthesis of Docetaxel is characterized in that comprising the following step:
Step 1:
50 digest compound 1b and 50 digests compound 2b and adds 5000 milliliters of toluene, adds 25 gram DMAP and 50 gram DCC, and being heated to 100 degree, to stir 8 hours afterreactions complete, filter, and pressure reducing and steaming toluene, the residuum column chromatography obtains compound 3b;
Step 2:
65 digest compound 3b is dissolved in 1000 milliliters of dehydrated alcohols, 50 milliliters in the dilute hydrochloric acid of adding 0.1N, and stirred overnight at room temperature is neutralized to neutrality with saturated sodium bicarbonate, boils off solvent, and the residuum column chromatography obtains compound 4b;
Step 3:
40 digest compound 4b is dissolved in 100 milliliters of acetic acid, 500 milliliters of methyl alcohol, zinc powder 50 grams, reflux one hour, and the cooling back is revolved and is desolvated with the saturated sodium bicarbonate neutrality that neutralizes, and the residuum column chromatography obtains Docetaxel.
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101735179B (en) * | 2008-11-19 | 2012-09-12 | 上海百灵医药科技有限公司 | Method for preparing docetaxel, intermediate thereof and preparation method |
| CN102050804B (en) * | 2009-10-30 | 2012-11-28 | 上海百灵医药科技有限公司 | Methods for preparing docetaxel and intermediates thereof |
| WO2011134067A1 (en) * | 2010-04-29 | 2011-11-03 | 6570763 Canada Inc. | Novel amino acid molecule and uses thereof |
| CN111138386A (en) * | 2019-12-30 | 2020-05-12 | 重庆市碚圣医药科技股份有限公司 | Docetaxel semi-synthesis method |
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2007
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Non-Patent Citations (2)
| Title |
|---|
| Synthesis of novel thiol surrogate or Taxol:2’-deoxy-2’-mercaptopaclitaxel. Xin Qi et al.Tetrahedron,Vol.60 . 2004 |
| Synthesis of novel thiol surrogate or Taxol:2’-deoxy-2’-mercaptopaclitaxel. Xin Qi et al.Tetrahedron,Vol.60 . 2004 * |
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