CN101020672A - Process of synthesizing docetaxel - Google Patents
Process of synthesizing docetaxel Download PDFInfo
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- CN101020672A CN101020672A CNA2006101483654A CN200610148365A CN101020672A CN 101020672 A CN101020672 A CN 101020672A CN A2006101483654 A CNA2006101483654 A CN A2006101483654A CN 200610148365 A CN200610148365 A CN 200610148365A CN 101020672 A CN101020672 A CN 101020672A
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- structural formula
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- docetaxel
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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 discloses process of synthesizing docetaxel, and the process is one condensation process of protected 10-deacetyl baccatin 10-DAB and synthesized chiral C-13 side chain. The process is simple, has mild reaction condition and is suitable for industrial production.
Description
Technical field
The present invention relates to the synthetic field of medicine, relate in particular to a kind of semisynthesis of cancer therapy drug Docetaxel.
Background technology
Docetaxel (docetaxel, structural formula 1) carrying out structure of modification on the basis of taxol (paclitael) obtains, leukemia and anti entity tumour activity with wide spectrum, its antitumour activity be taxol 1.3-12 doubly, be considered to so far one of the most significant cancer therapy drug of curative effect.The same complex structure with taxol of Docetaxel has numerous functional groups and chiral centre, and complete synthesis difficulty is very big.Semi-synthesis method is the effective chemical method of producing Docetaxel.
The semisynthesis of Docetaxel roughly can be divided into two classes in existing literature and the patent.The first kind is that the hydrolysis deprotection obtains Docetaxel (for example US6900342) then with the 10-deacetylate Tetraol 10-DAB and the condensation of five yuan of oxazole alkanoic acid side chains of protection; Second class is with the 10-deacetylate Tetraol 10-DAB of protection in highly basic (as butyllithium) effect down, under extremely low temperature and the quaternary lactan react, and then the hydrolysis deprotection obtains Docetaxel (for example US2005288520).(See Figure)
The first kind:
Second class:
Condition is relatively gentleer during the condensation of first kind method, but must use a large amount of condensation reagent DCC (dicyclohexyl carbonyl imines), and this reagent brings very big difficulty to follow-up purifying.The condition of second class methods is relatively harsher, and owing to used highly basic, the careless slightly 10 1 deacetylate Tetraol 10-DAB of raw material protection that also can cause decompose, and cause expensive significant loss; In addition, this method must be used excessive a lot of times side chain, not only follow-up purifying has been increased difficulty, and has increased production cost.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of synthetic method of Docetaxel, to solve defective of the prior art.
The synthetic method of Docetaxel provided by the present invention, concrete grammar are that the C-13 side chain by the 10-deacetylate Tetraol 10-DAB of structural formula (2) and structural formula (3) carries out condensation reaction and generates;
Wherein structural formula (2) is:
R wherein
1Be tertiary butyl dimethyl-silicon (TBS), triethyl silicon (TES), ethoxyethyl group (EE), tetrahydropyrans (THP), three chloroethyl oxygen carbonyls (Troc) or methoxyl methyl (MOM);
Wherein structural formula (3) is:
3
The C-13 side chain of structural formula (3) is
(4) or
(5);
When the C-13 side chain was structural formula (4), R4 was succinimide (Su); When the C-13 side chain was structural formula (5), R4 was H or succinimide (Su);
R
2, R
3Be anisyl ketal or acetonyl ketal.
Above-mentioned condensation reaction is to realize in ethyl acetate, methylene dichloride or toluene, and temperature of reaction is 0-65 ℃.
Wherein all buy Xi'an lark bio tech ltd as the compound of raw-material structural formula (2) and (3), lot identification mark is respectively 905-0601003 and 918-0602001.
Concrete synthetic route of the present invention such as figure below:
1. when the C-13 side chain was structural formula (4), reaction formula (1) was:
When the C-13 side chain was structural formula (5), reaction formula (2) was:
Reaction formula among the present invention (1) is to use the 10-deacetylate Tetraol 10-DAB (2) of protection and novel chiral side chain (4) condensation to make compound (5); the protection that removes side chain obtains compound (6), and the protection that removes 7 and 10 at last obtains Docetaxel (Docetaxol).Reaction formula (2) is to use the 10-deacetylate Tetraol 10-DAB (2) of protection and novel chiral side chain (5) condensation to make compound (7); the protection that removes side chain obtains compound (8); then with 2 ' chirality upset (wherein R4 ' is p-toluenesulfonyl or methane sulfonyl), the protection that removes 7 and 10 at last obtains Docetaxel (Docetaxol).
Reaction intermediate or final product can be further purified by the method for chromatography.
The characteristics of the synthetic method that the present invention relates to are: 1.Reaction formula 1 adopts different novel chiral side chains, makes butt joint reaction conditions milder, has avoided using the condensation reagent DCC that purifying is brought difficulty; 2. reaction formula 2 adopts strategy cleverly, docks with 2 ' opposite side chain of configuration, and upset obtains correct configuration then.The inventive method is suitable for suitability for industrialized production.
Other aspects of the present invention are because the disclosure of this paper is conspicuous to those skilled in the art.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Be interpreted as, these embodiment only are used to the present invention is described and are not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition that provides or advised according to manufacturer.
Unless otherwise defined or explanation, same meanings of being familiar with of all specialties used herein and scientific words and those skilled in the art.Any in addition method similar or impartial to described content and material all can be applicable in the inventive method.
Embodiment 1
Step 1:
50 digest compound 2a and 50 digests compound 4a and adds 5000 milliliters of methylene dichloride, adds 1 gram DMAP and 100 milliliters of triethylamines, and being heated to 40 degree, to stir 8 hours afterreactions complete, filter, and the pressure reducing and steaming methylene dichloride, the residuum column chromatography obtains 65 and digests compound 5a.Yield: 91.0%.
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 5a is dissolved in 2000 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 55 and digests compound 6a.Yield: 93.2%.
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:
55 digest compound 6a is dissolved in the solution of 500 milliliters of acetic acid, 50 milliliters in water, 50 milliliters of methyl alcohol, adds zinc powder 50 grams, reflux one hour, cooling back is revolved and is desolvated, the residuum column chromatography with the saturated sodium bicarbonate neutrality that neutralizes, obtain 32 gram Docetaxels, be white solid.
Yield: 83.7%.
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.
Embodiment 2
Step 1:
50 digest compound 2a and 50 digests compound 5a and adds 5000 milliliters of methylene dichloride, adds 1 gram DMAP and 100 gram DCC, and being heated to 80 degree, to stir 8 hours afterreactions complete, filter, and the pressure reducing and steaming methylene dichloride, the residuum column chromatography obtains 60 and digests compound 7a.Yield: 84.0%.
1H?NMR(500MHz，CDCl
3)δ：8.30(d，J＝8.5Hz，2H)，8.07(m，1H)，7.88(d，J＝8.4Hz，2H)，7.65(m，2H)，7.40(m，2H)，7.35(m，5H)，6.26(m，1H)，6.18(t，J＝9.0Hz，1H)，5.62(d，J＝7.2Hz，1H)，5.57(m，1H)，5.33(d，J＝9.0Hz，1H)，5.25(dd，J＝3.1，9.0Hz，1H)，4.92(d，J＝9.0Hz，1H)，4.85(d，J＝7.0Hz，1H)，4.79(s，2H)，4.60(d，J＝3.1Hz，1H)，4.43(d，J＝7.1Hz，1H)，4.32(d，J＝9.0Hz，1H)，4.15(d，J＝9.1Hz，1H)，3.95(d，J＝12.0Hz，1H)，3.55(s，3H)，2.58(m，1H)，2.38(s，3H)，1.95(s，3H)，1.85(s，3H)，1.32(s，9H)，1.24(s，3H)，1.19(s，3H).
Step 2:
60 digest compound 7a is dissolved in 2000 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 8a.Yield: 91.8%.
1H?NMR(500MHz，CDCl
3)δ：8.10(m，1H)，7.60(m，2H)，7.48(m，2H)，7.35(m，5H)，6.22(m，1H)，6.20(t，J＝9.2Hz，1H)，5.65(d，J＝7.0Hz，1H)，5.54(m，1H)，5.40(d，J＝9.0Hz，1H)，5.25(dd，J＝3.0，9.1Hz，1H)，4.93(d，J＝9.0Hz，1H)，4.86(d，J＝7.1Hz，1H)，4.78(s，2H)，4.65(d，J＝3.0Hz，1H)，4.49(d，J＝7.1Hz，1H)，4.38(d，J＝9.0Hz，1H)，4.13(d，J＝9.0Hz，1H)，3.92(d，J＝12.1Hz，1H)，2.60(m，1H)，2.38(s，3H)，1.96(s，3H)，1.84(s，3H)，1.35(s，9H)，1.28(s，3H)，1.12(s，3H).
Step 3:
20 digest compound 8a is dissolved in 500 milliliters of anhydrous methylene chlorides,-20 degree drip 7.5 milliliters of 20 milliliters of triethylamines and methylsulfonyl chlorides down successively, finish and slowly be warmed up to stirred overnight at room temperature, boil off solvent, residuum is dissolved in the ethyl acetate, the dilute hydrochloric acid washing with 1%, the saturated sodium bicarbonate washing, washing is revolved after the drying and is desolvated, and residuum is not directly used in down and reacts.
The residuum of previous step reaction is dissolved in 1000 ml methanol, and-10 spend the careful down solution (25 grams are dissolved in 100 ml waters) that drips Sodium Nitrite, finish and are stirred to the raw material disappearance, revolve and desolvate, the residuum column chromatography obtains 18 and digests compound 6a, yield: 90.0%.
Step 4:
30 digest compound 8a is dissolved in 500 milliliters of anhydrous methylene chlorides,-25 degree add triphenylphosphine 10 grams down, stir and add DEAD (diethyl azodiformate) 8 grams after 30 minutes again, finish and slowly be warming up to room temperature reaction to raw material and disappear, revolve and desolvate, the direct column chromatography of residuum obtains 28.5 and digests compound 6a, yield 95.0%.
Step 5:
30 digest compound 6a is dissolved in the solution of 300 milliliters of acetic acid, 30 milliliters in water, 30 milliliters of methyl alcohol, adds zinc powder 30 grams, reflux one hour, cooling back is revolved and is desolvated, the residuum column chromatography with the saturated sodium bicarbonate neutrality that neutralizes, obtain 16.8 gram Docetaxels, be white solid.Yield: 80.5%.
Claims (2)
1. the synthetic method of a Docetaxel is characterized in that this method is that C-13 side chain by the 10-deacetylate Tetraol 10-DAB of structural formula (2) and structural formula (3) carries out condensation reaction and generates;
Wherein structural formula (2) is:
R wherein
1Be tertiary butyl dimethyl-silicon, triethyl silicon, ethoxyethyl group, tetrahydropyrans, three chloroethyl oxygen carbonyl or methoxyl methyls;
Wherein structural formula (3) is:
The C-13 side chain of structural formula (3) is
Or
When the C-13 side chain was structural formula (4), R4 was a succinimide; When the C-13 side chain was structural formula (5), R4 was H or succinimide;
R
2, R
3Be anisyl ketal or acetonyl ketal.
2. synthetic method according to claim 1 is characterized in that condensation reaction is to realize in ethyl acetate, methylene dichloride or toluene, temperature of reaction is 0-65 ℃.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006101483654A CN101020672B (en) | 2006-12-28 | 2006-12-28 | Process of synthesizing docetaxel |
| PCT/CN2007/000225 WO2008080265A1 (en) | 2006-12-28 | 2007-01-22 | A synthesis method of docetaxel |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006101483654A CN101020672B (en) | 2006-12-28 | 2006-12-28 | Process of synthesizing docetaxel |
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| CN101020672A true CN101020672A (en) | 2007-08-22 |
| CN101020672B CN101020672B (en) | 2010-08-25 |
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| WO (1) | WO2008080265A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101525321B (en) * | 2008-03-06 | 2012-03-07 | 上海希迪制药有限公司 | Polyenic taxusol sesquihydrate crystal and preparation method thereof |
| CN106632297A (en) * | 2016-12-28 | 2017-05-10 | 吉林医药学院 | Docetaxel side chain 2'-derived novel taxanes antitumor compound as well as synthesis method and application 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 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2697522B1 (en) * | 1992-10-30 | 1994-11-25 | Rhone Poulenc Rorer Sa | Process for the preparation of taxane derivatives. |
| GB9512471D0 (en) * | 1995-06-20 | 1995-08-23 | Pharmacia Spa | Method for the preparation of taxol and its derivatives |
| US6143902A (en) * | 1999-06-21 | 2000-11-07 | Napro Biotherapeutics, Inc. | C-2 hydroxyl protected-N-acyl (2R,3S)-3-phenylisoserine N-imido activated esters and method for production thereof |
| PL194032B1 (en) * | 2002-12-19 | 2007-04-30 | Agropharm Sa | Method of manufacture of semi-finished products useful in paclitaxel synthesis |
-
2006
- 2006-12-28 CN CN2006101483654A patent/CN101020672B/en active Active
-
2007
- 2007-01-22 WO PCT/CN2007/000225 patent/WO2008080265A1/en active Application Filing
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101525321B (en) * | 2008-03-06 | 2012-03-07 | 上海希迪制药有限公司 | Polyenic taxusol sesquihydrate crystal and preparation method thereof |
| CN106632297A (en) * | 2016-12-28 | 2017-05-10 | 吉林医药学院 | Docetaxel side chain 2'-derived novel taxanes antitumor compound as well as synthesis method and application 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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| Publication number | Publication date |
|---|---|
| WO2008080265A1 (en) | 2008-07-10 |
| CN101020672B (en) | 2010-08-25 |
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