CN103664837B - A kind of preparation method of high purity Cabazitaxel intermediate - Google Patents
A kind of preparation method of high purity Cabazitaxel intermediate Download PDFInfo
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Abstract
The invention belongs to technical field of medicine synthesis; be specifically related to compound (2 α; 5 β; 7 β; 10 β; 13 α)-4-(acetoxyl group)-13-({ (2R; 3S)-3-[(tert-butoxycarbonyl) amino]-2--[2-methoxyl group-2-third-2-base) oxygen base]-3-PHENYLPROPIONYL } oxygen base)-1; 7; 10-trimethoxy-9-oxo-5,20-epoxy-11-alkene-2-yl benzoic acid ester (Compound II per, i.e. " 7; 10,13-trimethoxy-10-DAB ").The invention still further relates to high purity (2 α, 5 β, 7 β, 10 β, 13 α)-4-(acetoxyl group)-13-({ (2R, 3S)-3-[(tert-butoxycarbonyl) amino]-2--[2-methoxyl group-2-third-2-base) oxygen base]-3-PHENYLPROPIONYL } oxygen base)-1-hydroxyl-7, 10-dimethoxy-9-oxo-5, the preparation method of 20-epoxy-11-alkene-2-yl benzoic acid ester (compound 1), described preparation method comprises the step of silica gel chromatography column chromatography and recrystallization, in the Compound I obtained by described preparation method, the content of impurities Compound II per and compound III significantly reduces.Described Compound I, III can be used for preparing anticarcinogen Cabazitaxel.
Description
Technical field
The invention belongs to technical field of medicine synthesis; be specifically related to high purity Cabazitaxel intermediate; i.e. (2 α; 5 β; 7 β; 10 β; 13 α)-4-(acetoxyl group)-13-({ (2R; 3S)-3-[(tert-butoxycarbonyl) amino]-2--[2-methoxyl group-2-third-2-base) oxygen base]-3-PHENYLPROPIONYL } oxygen base)-1-hydroxyl-7; 10-dimethoxy-9-oxo-5; the preparation method of 20-epoxy-11-alkene-2-yl benzoic acid ester (Compound I), and in preparation process, relate to the structural confirmation of Compound II per.
Background technology
Cabazitaxel is developed by Sanofi-Aventis company, and the applying date of its compound patent ZL96192886.7 is on March 25th, 1996, and obtains mandate on August 3rd, 2005.In June, 2010, Cabazitaxel is approved listing by U.S. FDA.Its structural formula is:
The chemical name of Cabazitaxel: (2 α, 5 β, 7 β, 10 β, 13 α)-4-acetoxyl group-13-({ (2R, 3S)-3-[(tertbutyloxycarbonyl) is amino]-2-hydroxyl-3-hydrocinnamoyl } oxygen base)-1-hydroxyl-7,10-dimethoxy-9-oxygen-5,20-epoxy yew-11-alkene-2-yl benzoic acid ester; CAS registration number is 183133-96-2.
According to the current bulk drug research conditions to Cabazitaxel, in preparation process, inevitably all employ intermediate " compound III ", i.e. 7,10-dimethoxy-10-DAB, as CN96192886.7, CN201110162562.2.The syntheti c route used is summarized as substep methylation method and a step methylation method, is all to use 10-DABIII to be starting raw material, is shown below:
Compound III is the key intermediate of Cabazitaxel, and the purity of compound III is the factor that contriver must consider.
(2 α; 5 β; 7 β; 10 β; 13 α)-4-(acetoxyl group)-13-({ (2R; 3S)-3-[(tert-butoxycarbonyl) amino]-2--[2-methoxyl group-2-third-2-base) oxygen base]-3-PHENYLPROPIONYL } oxygen base)-1-hydroxyl-7,10-dimethoxy-9-oxo-5,20-epoxy-11-alkene-2-yl benzoic acid ester (Compound I) is important Cabazitaxel intermediate.Compound I is prepared from by compound III.
The preparation of Compound I generally adopts following scheme preparation: first as described in patent US20060281914, prepare compound IV:
Compound IV again with compound III condensation, as described in patent US6307071B1, thus prepare Cabazitaxel midbody compound I.
Compound IV Excess quantities in the reaction of this step, reacts thoroughly to make 7,10-dimethoxy DAB (i.e. compound III) as far as possible; The reaction of this step can adopt LHMDS (LHMDS) to be catalyzer.The Compound I crude product that this reaction obtains as extraction, washing according to general aftertreatment means is viscous liquid.
Because Compound I distance objective compound Cabazitaxel only has the comparatively simple dehydroxylation protective reaction of a step; this reaction is comparatively simple; if therefore Compound I is not done refinement treatment to carry out subsequent reactions; huge challenge is brought, so the optimum way obtaining high purity Cabazitaxel obtains highly purified Compound I by giving the purifying of target compound.And the report of current document not in Compound I is refined.
Summary of the invention:
The prerequisite obtaining high-purity compound I analyzes to show that ordinary method is prepared Compound I and produced which kind of impurity.
Need to prepare compound III before preparation Compound I, find that there is an impurity to be difficult to remove when preparing compound III (as previous reaction formula), contriver is through repeatedly testing proof, and the content of this specific impurities is generally in 3.0 ~ 8.0% scopes.Contriver thinks, the preparation of compound III utilizes the difference of hydroxyl reaction activity on 10-DABIII and then regioselectivity to methylate.From structure, the hydroxyl steric hindrance of 1 is maximum, is difficult to carry out methylation reaction; The activity of 13 hydroxyls is then slightly weaker than 7,10 hydroxyls.So no matter be that substep methylates, or a step methylates, and all can produce 7,10,13 all methylated specific impurities.Infer that this specific impurities structural formula is such as formula shown in (1):
Contriver has prepared this compound, by with compound III
1the comparative study of HNMR spectrogram can confirm that this compound is really Compound II per.
Compound III, II's
1hNMR spectrum elucidation is as follows:
Compound II per and compound III structural difference less, not easily remove.In follow-up reaction, Compound II per methylates due to its 13 hydroxyls, therefore can not participate in reaction, estimates that in the removal of next step reaction can be a good selection.
Contriver has carried out theoretical analysis to Compound I crude product impurity: compound IV is due to Excess quantities, have more remaining in the product, but more easily remove, and compound III also has a small amount of residual, also can contain the silica-based amine of a certain amount of hexamethyl two (HMDS) in crude product in addition, also have a certain amount of Compound II per simultaneously.The existence of these impurity causes crude product to be rendered as viscous liquid.
So the key of obtained high-purity compound I removes impurity compound II and compound III.
The present invention relates to the preparation method of high-purity compound I, described preparation method comprises the step of silica gel chromatography column chromatography and recrystallization.Silica gel chromatography column chromatography effectively can remove the silica-based amine of hexamethyl two (HMDS), can also remove the compound IV that polarity spectrum is larger; Though have certain removal effect for compound III, but can not remove completely; The Compound II per removal effect very close with Compound I for structure is not good.The step of recrystallization for removal Compound II per and compound III effect better.
The preparation method of high-purity compound I of the present invention can also include but not limited to other conventional treatment methods, as steps such as extraction, washings.
One embodiment of the invention prepare high-purity compound I for using preparation method of the present invention, and described preparation method comprises the step of silica gel chromatography column chromatography and recrystallization.Wherein, adopt silica gel chromatographic column Chromatographic purification to for crude Compound I, eluent selects the mixture of a kind of solvent in methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, tert.-butyl acetate, sherwood oil, Skellysolve A, pentamethylene, normal hexane, hexanaphthene and normal heptane or several solvent.
Another embodiment of the present invention prepares high-purity compound I for using preparation method of the present invention, and described preparation method comprises the step of silica gel chromatography column chromatography and recrystallization.Wherein, the step of the recrystallization in described method, several solvent mixture of the one in trichloromethane, methylene dichloride, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, tert.-butyl acetate, sherwood oil, Skellysolve A, pentamethylene, normal hexane, hexanaphthene and normal heptane selected by solvent.
One embodiment of the invention prepare high-purity compound I for using preparation method of the present invention, and described preparation method comprises the step of silica gel chromatography column chromatography and recrystallization.Wherein, adopt silica gel chromatographic column Chromatographic purification to for crude Compound I, eluent selects the mixture of a kind of solvent in methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, tert.-butyl acetate, sherwood oil, Skellysolve A, pentamethylene, normal hexane, hexanaphthene and normal heptane or several solvent; Wherein, the step of the recrystallization in described method, several solvent mixture of the one in trichloromethane, methylene dichloride, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, tert.-butyl acetate, sherwood oil, Skellysolve A, pentamethylene, normal hexane, hexanaphthene and normal heptane selected by solvent.
Another embodiment of the present invention prepares high-purity compound I for using preparation method of the present invention, described preparation method comprises the step of silica gel chromatography column chromatography and recrystallization, and wherein silica gel chromatography column chromatography uses ethyl acetate and normal hexane to carry out gradient elution.
Another embodiment of the present invention prepares high-purity compound I for using preparation method of the present invention, described preparation method comprises the step of silica gel chromatography column chromatography and recrystallization, the wherein step of recrystallization, selects methylene dichloride/normal hexane system or ethyl acetate/petroleum ether system to carry out recrystallization.Adopt impurities Compound II per in the obtained Compound I of described method can control 0.1%, reach purification effect ideal.
A preferred version of the present invention is that described re-crystallization step uses trichloromethane or methylene dichloride, is that solvent carries out recrystallization with the binary mixed solvent of normal hexane or normal heptane.
Adopt the preparation method of high-purity compound I of the present invention, the specific impurities Compound II per in Compound I and compound III can be made to control in 0.1% scope.Thus significantly reduce follow-up Cabazitaxel preparation technology risk, make the degree that Cabazitaxel purity can reach desirable.Purifying is appropriate for opportunity, and method is simple.
Accompanying drawing explanation
Fig. 1: hydrogen spectrum (HNMR) of Compound I
Fig. 2: hydrogen spectrum (HNMR) of Compound II per
Fig. 3: hydrogen spectrum (HNMR) of compound III
Fig. 4: typical HPLC spectrogram after Compound I purifying
Embodiment
Following examples, for illustration of the present invention, but are not used for limiting the scope of the invention.
Reference example 1: the preparation of compound IV
In reaction flask, add (3R, 4S)-3-hydroxy-4-phenyl-2-azetidinone of anhydrous THF, 300g of 10L, stir.It is-30 ~-35 DEG C that system is cooled to interior temperature, adds tosic acid monohydrate.Temperature control-30 ~-35 DEG C drips 2-methoxyl group propylene, insulation reaction 5h.Reaction is finished, and adds 260g triethylamine cancellation reaction.The Boc acid anhydrides of 500g and the DMAP of 52g are added system, is warming up to 55 ~ 60 DEG C, insulation reaction 7h.Reaction is finished, and adds 5.9L normal heptane, stirs 10mIn.Filter, gained filtrate 40 DEG C of concentrating under reduced pressure, suction filtration, at 25 ~ 30 DEG C, vacuum-drying obtains compound IV 450g.
Reference example 2: the preparation of Compound I crude product
Add the compound IV of 20L anhydrous THF, 400g, the compound III of 400g in 50L reactor respectively, stir, it is-55 ~-60 DEG C that system is cooled to interior temperature.Temperature control drips the LHMDS/THF solution of 1 equivalent wherein.Drip and finish, be warming up to 0 ~ 5 DEG C of insulation reaction.Reaction is finished, and adds 1.2L shrend and to go out reaction, add 21L extraction into ethyl acetate.Separatory gets organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, suction filtration.Filtrate 35 ~ 40 DEG C is evaporated to the crude product 800g of dry Compound I.
Reference example 3: the preparation of Cabazitaxel
Successively by THF, Compound I, 0.2M hydrochloric acid in 10L reaction flask, stirring reaction 3h at 20 ~ 25 DEG C.Reaction is finished, and adds the saturated NaHCO of 577.6ml in system
3cancellation is reacted, and is extracted with ethyl acetate 3L × 3.Saturated common salt water washing 3L × 3, now aqueous phase pH=6 ~ 7.Anhydrous sodium sulfate drying, suction filtration.35 ~ 40 DEG C are evaporated to dry.Be dissolved in by gained solid in 4L methylene dichloride, add 10L normal heptane under stirring, after stirring, standing 1h then suction filtration, filtration cakes torrefaction obtains Cabazitaxel, and yield is about 90%.
Embodiment 1:
Refining of Compound I
Column chromatography purification is carried out to the crude product 800g of Compound I, first uses n-hexane/ethyl acetate=2/1 wash-out (about 4L), then use n-hexane/ethyl acetate=1/1 wash-out instead, collect the component (about 10L) that enriched compound I purity is high.At 35 ~ 40 DEG C, concentrate eluant is to dry.Obtain white solid 506g.With the normal hexane recrystallization of methylene dichloride/20 of 3 times of volumes times volume.Obtain Compound I sterling 330g.
Specific impurities detects in use high performance liquid chromatography chromatogram area normalization method, and the content of Compound II per is 0.0888%, compound III does not detect.
1hNMR, chemical shift/ppm:0.960 ~ 0.969,6H, d; 1.256,6H, d; 1.387,9H, m; 1.509,4H, m; 1.688 ~ 1.706,2H, m; 1.814,3H, s; 2.287,3H, s; 2.660 ~ 2.683,1H, m; 2.978,3H, s; 3.207,3H, s; 3.286,3H, s; 3.585 ~ 3.598,1H, d; 3.707 ~ 3.740,1H, m; 4.018,2H, d; 4.287 ~ 4.303,1H, d; 4.427,1H, s; 4.681,1H, s; 4.833 ~ 4.867,1H, m; 4.948 ~ 4.967,1H, d; 5.348 ~ 5.362,1H, d; 5.784 ~ 5.818,1H, m; 7.130,1H, s; 7.378 ~ 7.408,4H, m; 7.630 ~ 7.691,3H, m; 7.736 ~ 7.765,1H, m; 7.979 ~ 7.994,2H, d.
Embodiment 2:
Refining of Compound I
Column chromatography purification is carried out to the crude product 800g of Compound I, first uses normal heptane/ethyl acetate=2/1 wash-out (about 5L), then use normal heptane/ethyl acetate=1/1 wash-out instead, collect the component (about 10L) that enriched compound I purity is high.At 35 ~ 40 DEG C, the concentrated elutriant being rich in Compound I is extremely done.Obtain white solid 510g.With the normal heptane recrystallization of trichloromethane/20 of 3.5 times of volumes times volume.Obtain Compound I sterling 327g.
Specific impurities detects in use high performance liquid chromatography chromatogram area normalization method, and the content of Compound II per is 0.042%, compound III does not detect.
Embodiment 3:
Refining of Compound I
Column chromatography purification is carried out to the crude product 800g of Compound I, first uses normal heptane/isopropyl acetate=1/1 wash-out (about 4L), then use normal heptane/isopropyl acetate=1/2 wash-out instead, collect the component (about 12L) that enriched compound I purity is high.At 35 ~ 40 DEG C, the concentrated elutriant being rich in Compound I is extremely done.Obtain white solid 510g.With the normal heptane recrystallization of isopropyl acetate/20 of 3.5 times of volumes times volume.Obtain Compound I sterling 365g.
Specific impurities detects in use high performance liquid chromatography chromatogram area normalization method, and the content of Compound II per is 0.035%, compound III does not detect.
Embodiment 4:
The preparation of Compound II per
Add in 250ml there-necked flask 114g methyl iodide, 5g compound III, 50mL DMF stir.Add the NaH of 0.9g, system is muddy, releases a large amount of gas in batches; T
in=20 ~ 25 DEG C of insulation reaction 5h.T
in=23 DEG C of insulation reaction, add 5ml shrend and to go out reaction.Add ethyl acetate 50ml × 3, saturated aqueous common salt 50ml × 3, anhydrous sodium sulfate drying.Suction filtration, concentrated by rotary evaporation is to doing to obtain yellow oil, and silicagel column is separated white solid 1.12g, i.e. Compound II per.
Claims (4)
1. a preparation method for the Cabazitaxel intermediate shown in formula (2), in the compound that described preparation method obtains, contained formula (1) impurity compound and formula (3) compounds content significantly reduce,
It is characterized in that, described preparation method comprises the step of silica gel chromatography column chromatography and recrystallization; Wherein, described silica gel chromatography column chromatography steps eluent used is: the mixed solvent of n-hexane-ethyl acetate or normal heptane-ethyl acetate or normal heptane-isopropyl acetate;
Described re-crystallization step solvent for use is the mixed solvent of methylene dichloride-normal hexane or trichloromethane-normal heptane or isopropyl acetate-normal heptane.
2. preparation method according to claim 1, it is characterized in that, step is as follows: carry out column chromatography purification to the crude product 800g of compound (2), first use 4L n-hexane/ethyl acetate=2/1 wash-out, then use n-hexane/ethyl acetate=1/1 wash-out instead, collect the component 10L that enriched compound I purity is high, at 35 ~ 40 DEG C, concentrate eluant is to dry, obtain white solid 506g, with the normal hexane recrystallization of methylene dichloride/20 of 3 times of volumes times volume, obtain compound (2).
3. preparation method according to claim 1, it is characterized in that, step is as follows: carry out column chromatography purification to the crude product 800g of compound (2), first use 5L normal heptane/ethyl acetate=2/1 wash-out, use normal heptane/ethyl acetate=1/1 wash-out again instead, collect the component 10L that enriched compound (2) purity is high, at 35 ~ 40 DEG C, the concentrated elutriant being rich in compound (2) is extremely done, obtain white solid 510g, with the normal heptane recrystallization of trichloromethane/20 of 3.5 times of volumes times volume, obtain compound (2).
4. preparation method according to claim 1, it is characterized in that, step is as follows: carry out column chromatography purification to the crude product 800g of compound (2), first use 4L normal heptane/isopropyl acetate=1/1 wash-out, use normal heptane/isopropyl acetate=1/2 wash-out again instead, collect the component 12L that enriched compound (2) purity is high, at 35 ~ 40 DEG C the concentrated elutriant being rich in compound (2) as, obtain white solid 510g, with the normal heptane recrystallization of isopropyl acetate/20 of 3.5 times of volumes times volume, obtain compound (2).
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| CN102887877A (en) * | 2012-11-05 | 2013-01-23 | 江苏红豆杉生物科技股份有限公司 | Method for purifying cabazitaxel |
| CN103012331A (en) * | 2012-12-28 | 2013-04-03 | 北京科莱博医药开发有限责任公司 | Preparation method of cabazitaxel and intermediate thereof |
| CN103217493A (en) * | 2013-03-30 | 2013-07-24 | 神威药业集团有限公司 | Method for measuring cabazitaxel related substances by using HPLC (High Performance Liquid Chromatography) method |
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| CN102887877A (en) * | 2012-11-05 | 2013-01-23 | 江苏红豆杉生物科技股份有限公司 | Method for purifying cabazitaxel |
| CN103012331A (en) * | 2012-12-28 | 2013-04-03 | 北京科莱博医药开发有限责任公司 | Preparation method of cabazitaxel and intermediate thereof |
| CN103217493A (en) * | 2013-03-30 | 2013-07-24 | 神威药业集团有限公司 | Method for measuring cabazitaxel related substances by using HPLC (High Performance Liquid Chromatography) method |
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Effective date of registration: 20160323 Address after: 611130, No. two, section 666, Xinhua Avenue, Chengdu Cross Straits science and Technology Industry Development Zone, Wenjiang District, Sichuan, China Patentee after: SICHUAN KELUN DRUG RESEARCH INSTITUTE CO., LTD. Address before: 100043 sunshine medicine science and Technology Park, No. 77, ancient South Street, Beijing, Shijingshan District 216 Patentee before: Beijing Sun-Novo Pharmaceutical Research Co., Ltd. |