CN101289432B - Novel isoserine ester derivates and method for preparing same - Google Patents
Novel isoserine ester derivates and method for preparing same Download PDFInfo
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- CN101289432B CN101289432B CN2007100397641A CN200710039764A CN101289432B CN 101289432 B CN101289432 B CN 101289432B CN 2007100397641 A CN2007100397641 A CN 2007100397641A CN 200710039764 A CN200710039764 A CN 200710039764A CN 101289432 B CN101289432 B CN 101289432B
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- -1 isoserine ester Chemical class 0.000 title claims abstract description 74
- 238000000034 method Methods 0.000 title claims abstract description 34
- BMYNFMYTOJXKLE-UHFFFAOYSA-N DL-isoserine Natural products NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 title claims abstract description 24
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims abstract description 61
- 229960003668 docetaxel Drugs 0.000 claims abstract description 61
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 238000002360 preparation method Methods 0.000 claims abstract description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 21
- 229940123237 Taxane Drugs 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 29
- 239000002585 base Substances 0.000 claims description 26
- 238000010511 deprotection reaction Methods 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- 239000003513 alkali Substances 0.000 claims description 14
- 235000016408 Podocarpus macrophyllus Nutrition 0.000 claims description 10
- 244000162450 Taxus cuspidata Species 0.000 claims description 10
- 235000009065 Taxus cuspidata Nutrition 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 239000010953 base metal Substances 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 235000002639 sodium chloride Nutrition 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 238000005406 washing Methods 0.000 description 11
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000009833 condensation Methods 0.000 description 8
- 230000005494 condensation Effects 0.000 description 8
- 239000007859 condensation product Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 238000003381 deacetylation reaction Methods 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical class [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002152 aqueous-organic solution Substances 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- OVMSOCFBDVBLFW-VHLOTGQHSA-N 5beta,20-epoxy-1,7beta,13alpha-trihydroxy-9-oxotax-11-ene-2alpha,4alpha,10beta-triyl 4,10-diacetate 2-benzoate Chemical compound O([C@@H]1[C@@]2(C[C@H](O)C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000002185 docetaxel anhydrous group Chemical group 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 1
- 229940122255 Microtubule inhibitor Drugs 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229930014667 baccatin III Natural products 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 150000004625 docetaxel anhydrous derivatives Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N ferric oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 231100000782 microtubule inhibitor Toxicity 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Epoxy Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to an isoserine ester derivative or the salt of taxanes shown in the formula II; an R1, an R2 and an R3 in the formula are the same or different hydroxyl protecting groups. The invention further provides a preparation method for the compound and a method for further preparing an anticancer drug docetaxel according to the isoserine ester derivative. The preparation method forthe compound which is high in yield and simple in steps is suitable for the industrial preparation of the docetaxel.
Description
Technical field
The present invention relates to chemosynthesis and pharmaceutical field.Particularly, the present invention relates to a kind of new taxanes isoserine ester and preparation method thereof, and the method that further makes the antitumor drug docetaxel.
Background technology
Docetaxel (docetaxel claims the Japanese yew terpene again) is a kind of antitumor drug, and it has the structure of formula I:
Formula I
Docetaxel belongs to antitumour drug microtubule inhibitor, is on the architecture basics of natural antitumor drug taxol, through a kind of new antitumor drug that obtains behind the structural modification.Docetaxel has stronger tumor-killing effect with respect to taxol, and more tumour cell is had lethal effect, absorb faster, eliminate slowlyer, action times longer three, big characteristics were that a new generation has more active taxoid derivatives.
Reported the method for some synthetic docetaxels in the document:
Usually, ((baccatin III) is raw material to docetaxel, prepares by semi-synthetic with the 10-deacetylation crust Ka Ting that derives from plant.
10-deacetylation crust Ka Ting
At document Tetrahedron Letters the 34th volume; the 38th phase; described by 7 in the 6049-6052 page or leaf (1993); 10-two (trichloro-ethoxycarbonyl (TROC)-10-deacetylation crust Ka Ting (III) and side chain (4S; 5R)-N-tertbutyloxycarbonyl-2; 2-dimethyl-4-phenyl-5-thiazolidyl formic acid prepares the isoserine ester derivative, prepares docetaxel through four-step reaction then, sees reaction formula 1.
Reaction formula 1
In Chinese patent CN1048983, aforesaid method is improved, just can obtain target compound docetaxel (reaction formula 2) as long as carry out three-step reaction after obtaining the isoserine ester derivative, become so more in production, yield improves (yield is about 40%).
Reaction formula 2
Though the method for above-mentioned two kinds of synthetic docetaxels is applied in the production of domestic and international docetaxel at present, these methods still exist tangible deficiency:
1. the condensation yield of Japanese yew alkyl parent nucleus and side chain is not high, the condensation product complexity, and separating difficulty is big.
2. the gained condensation product is further preparing in the docetaxel process, and yield is lower, and operation steps is many.
" Japanese yew alkyl parent nucleus " of the prior art expression contains the group of following primary structure:
Japanese yew alkyl parent nucleus P
" side chain " of the prior art is the compound that expression can form following main structure at last:
Side chain S
In addition; because 10-deacetylation crust Ka Ting (III) comes from natural extract; it is limited to originate; the price height; therefore condensation yield and follow-up reaction yield are very big to the cost impact of docetaxel; this area presses for the new docetaxel synthetic method of exploration and intermediate improves the yield that synthesizes docetaxel, simplifies, optimizes the synthesis technique of docetaxel.
Summary of the invention
The present invention just provided new taxanes isoserine ester and preparation method thereof, and provides compound thus further to prepare the method for docetaxel.
In a first aspect of the present invention, a kind of compound is provided, described compound is the taxanes isoserine ester shown in the formula II or its salt:
Formula II
R wherein
1, R
2And R
3Be identical or different hydroxyl protecting group.
In an embodiment of the invention, the R in the described compound
1, R
2And R
3In acidity, alkalescence or neutral environment, the hydroxyl protecting group that under mild conditions, can remove.
In a preference of the present invention, R
1, R
2And R
3Be selected from independently of one another: carbobenzoxy-(Cbz), tertiary butyl oxygen carbonyl, tribromo-acetyl base, trifluoroacetyl group, 1-ethoxyethyl group, triethyl silyl or TMS; Preferred tribromo-acetyl base, trifluoroacetyl group, 1-ethoxyethyl group, triethyl silyl or TMS.
In yet another embodiment of the present invention, the R in the described compound
1And R
2Be tribromo-acetyl base, R
3Be 1-ethoxyethyl group or triethyl silyl.
In a second aspect of the present invention, the preparation method of compound shown in the formula II is provided,
Formula II
R wherein
1, R
2And R
3Be identical or different hydroxyl protecting group;
Described method comprises:
In the presence of coupler, make the reaction of Japanese yew alkyl parent nucleus shown in compound or its salt shown in the formula III and the formula IV:
Formula II
R wherein
3Be hydroxyl protecting group;
Formula IV
R wherein
1And R
2Be identical or different hydroxyl protecting group.
In an embodiment of the invention, R
1, R
2And R
3In acidity, alkalescence or neutral environment, the hydroxyl protecting group that under mild conditions, can remove.
In a preference of the present invention, R
1, R
2And R
3Be selected from independently of one another: carbobenzoxy-(Cbz), tertiary butyl oxygen carbonyl, tribromo-acetyl base, trifluoroacetyl group, 1-ethoxyethyl group, triethyl silyl or TMS; Preferred tribromo-acetyl base, trifluoroacetyl group, 1-ethoxyethyl group, triethyl silyl or TMS.
In an embodiment of the invention, described coupler is inorganic base metal alkali or organic alkali metal alkali.
In a preference of the present invention, described coupler is sodium hydride, n-Butyl Lithium, two (trimethyl silicon based) Lithamides or hexamethyl two silica-based sodium amides.
In another preference of the present invention, the organic solvent to reactionlessness is preferably used in above-mentioned reaction, and more preferred solvent is tetrahydrofuran (THF), N, dinethylformamide, methylene dichloride, chloroform or acetone.The preferred amounts of solvent is the weight of formula IV compound to solvent: volume ratio is 1:1～1:200, more preferably 1:3～1:150, most preferably 1:5～1:100.
In another preference of the present invention, above-mentioned reaction is preferably carried out under-100～25 ℃, more preferably-70 ℃～10 ℃, most preferably at-60 ℃.
In another preference of the present invention, above-mentioned reaction was preferably finished in 1 minute～24 hours, and preferred 2 minutes～12 hours, more preferably 3 minutes～6 hours, most preferably 5 minutes～3 hours.
In another preference of the present invention, above-mentioned reaction is preferably carried out under the anhydrous and oxygen-free condition, preferably carries out under rare gas elementes such as nitrogen or argon gas.
In a third aspect of the present invention, a kind of method for preparing docetaxel is provided, described method comprises step: (i) method preparation formula II compound mentioned above,
Formula II
R wherein
1, R
2And R
3Be identical or different hydroxyl protecting group;
(ii) under mild conditions, formula II compound is carried out a step or a multistep deprotection reaction.
In an embodiment of the invention, a described step or multistep deprotection reaction carry out in acid or alkali.
In a preference of the present invention, described deprotection reaction is to carry out in the aqueous solution of the about 3～pH of pH about 9.
In another preference of the present invention, described deprotection reaction is to carry out in the solution that contains acid, and described acid is selected from: formic acid, acetate, hydrofluoric acid or their mixture, preferable formic acid or hydrofluoric acid; Described solution is selected from: the aqueous solution, organic solution or aqueous organic solution.
In another preference of the present invention; described deprotection reaction is to carry out in containing the organic solution of alkali; described alkali is selected from: ammoniacal liquor, hydrazine hydrate, sodium hydroxide, potassium hydroxide or their mixture; be preferably ammoniacal liquor; wherein said organic solvent is a polar aprotic solvent, is selected from tetrahydrofuran (THF), methyl alcohol, ethanol or acetonitrile.
In an embodiment of the invention, described deprotection reaction carries out under-50～100 ℃.
In a preference of the present invention,, more preferably under-10 ℃～20 ℃ temperature, carry out described deprotection reaction preferably at-30 ℃～60 ℃.
In another preference of the present invention, described being reflected in 0.5 hour～80 hours finished, and preferred 1 hour～60 hours, more preferably 2 hours～50 hours.
In a fourth aspect of the present invention, the purposes of compound shown in the formula III in the taxanes isoserine ester shown in the preparation formula II or its salt or docetaxel is provided,
Formula III,
R wherein
3Be hydroxyl protecting group;
Formula II
R wherein
1, R
2And R
3Be identical or different hydroxyl protecting group.
In a preference of the present invention, R
1, R
2And R
3In acidity, alkalescence or neutral environment, the hydroxyl protecting group that under mild conditions, can remove.
In another preference of the present invention, R
1, R
2And R
3Be selected from independently of one another: carbobenzoxy-(Cbz), tertiary butyl oxygen carbonyl, tribromo-acetyl base, trifluoroacetyl group, 1-ethoxyethyl group, triethyl silyl, TMS; Preferred tribromo-acetyl base, trifluoroacetyl group, 1-ethoxyethyl group, triethyl silyl, TMS.
Adopt method of the present invention to prepare the method for docetaxel, the yield height, easy and simple to handle, be more suitable for producing.
Preferred implementation
The inventor is through extensive and deep research; adopt a kind of new synthetic method to synthesize the taxanes isoserine ester that a class has structural formula II with high yield; use routine means easily then, by this taxanes isoserine ester intermediate through deprotection reaction and then made docetaxel.Wherein, the inventor selects the used side chain of the used parent nucleus of the present invention and the present invention and makes up, and adopts new method of condensing to obtain high condensation rate, and obtained high yield in follow-up docetaxel preparation.
Compare with existing docetaxel semisynthesis, prepare in the method for docetaxel in the present invention, the condensation yield height of parent nucleus and side chain, condensation product is simpler relatively, is easy to separate; And the gained condensation product is further preparing in the docetaxel process, the yield height, and operation steps is few, is particularly suited for producing.The inventor has finished the present invention on this basis.
Taxanes isoserine ester
As used herein, term " taxanes isoserine ester ", " isoserine ester ", " formula II compound " and " the taxanes isoserine ester with formula II structure " are used interchangeably, and all refer among the present invention suc as formula the new compound shown in the II.
The invention provides taxanes isoserine ester or its salt with formula II structure:
Formula II
R wherein
1, R
2And R
3Be identical or different hydroxyl protecting group.
At any group that can protect hydroxyl of this used term " hydroxyl protecting group " expression, it should keep stable in reaction process, is removing under the situation of other structure in saboteur not after the reaction.This type of group can be referring to " protecting group in the organic synthesis " (T.W.Greene, press of East China University of Science) and " protecting group " (" Protecting Groups ", P.Kocienski, Thieme Publishers).
The specific examples of hydroxyl protecting group comprises carbobenzoxy-(Cbz), tertiary butyl oxygen carbonyl, tribromo-acetyl base, trifluoroacetyl group, 1-ethoxyethyl group, triethyl silyl, TMS etc.Particularly preferred tribromo-acetyl base, trifluoroacetyl group, 1-ethoxyethyl group, triethyl silyl, TMS among the present invention.
Universal method
The present invention prepares compound (II) by high yield; use then routine easily means prepare docetaxel; particularly select suitable hydroxyl protecting group and side chain, the isoserine ester is produced in reaction with Japanese yew alkyl parent nucleus in the presence of coupler, and deprotection obtains docetaxel then.
Term as used herein " mild conditions " be meant side reaction in the reaction process seldom and not among the saboteur other structure reaction conditions.For example, described condition can be: temperature is-50～100 ℃, preferably at-30 ℃～60 ℃, more preferably-10 ℃～20 ℃ temperature; PH is about 3～9; Reaction times is about 0.5 hour～and 80 hours, preferred 1 hour～60 hours, more preferably 2 hours～50 hours.
Indication of the present invention " side chain " is:
Formula III
R wherein
3Be hydroxyl protecting group, it is stable particularly to be chosen in reaction process, but the group that in afterreaction, removes easily.
" the Japanese yew alkyl parent nucleus " of indication of the present invention is:
Formula IV
R wherein
1And R
2Be identical or different hydroxyl protecting group.Particularly select and can go up high yield and highly selective protection at 10-deacetylation crust Ka Ting (III), and group stable in reaction process but that in afterreaction, remove easily.
R
1, R
2And R
3Be selected from independently of one another: carbobenzoxy-(Cbz), tertiary butyl oxygen carbonyl, tribromo-acetyl base, trifluoroacetyl group, 1-ethoxyethyl group, triethyl silyl, TMS; Preferred tribromo-acetyl base, trifluoroacetyl group, 1-ethoxyethyl group, triethyl silyl, TMS.
In preferred implementation of the present invention, the R in the described compound
1And R
2Be tribromo-acetyl base, R
3Be 1-ethoxyethyl group or triethyl silyl.
A. the preparation of parent nucleus compound IV
Compound IV can be prepared through a step or polystep reaction by 10-deacetylation crust Ka Ting (III), and reaction process is as follows:
Reaction formula A
The inventor selects the position and the kind of hydroxyl protecting group on the parent nucleus, thereby has determined to adopt the parent nucleus of above-mentioned formula IV.The condensation yield height of the parent nucleus of formula IV and side chain, condensation product is simpler relatively, is easy to separate; And the gained condensation product is further preparing in the docetaxel process, the yield height, and operation steps is few, is particularly suited for producing.
Concrete grammar and condition can be with reference to " protecting group in the organic synthesis " (T.W.Greene, press of East China University of Science) and " protecting group " (" Protecting Groups ", P.Kocienski, Thieme Publishers).
B. the preparation of taxanes isoserine ester
By in the presence of coupler, make formula III compound or its salt and formula IV Japanese yew alkyl parent nucleus react preparation formula II compound.
Reaction formula B
In this reaction, described coupler is inorganic base metal alkali or organic alkali metal alkali.
In an embodiment of the invention, described coupler is sodium hydride, n-Butyl Lithium, two (trimethyl silicon based) Lithamide or hexamethyl two silica-based sodium amides.
The organic solvent to reactionlessness is preferably used in above-mentioned reaction, and more preferred solvent is tetrahydrofuran (THF), N, dinethylformamide, methylene dichloride, chloroform or acetone.The preferred amounts of solvent is that formula IV compound is 1:1～1:200 to solvent ratios, more preferably 1:3～1:150, most preferably 1:5～1:100 (weight: volume).
Reaction times preferably finished in 1 minute～24 hours, and preferred 2 minutes～12 hours, more preferably 3 minutes～6 hours, most preferably 5 minutes～3 hours.
Above-mentioned reaction is preferably carried out under the anhydrous and oxygen-free condition, preferably carries out under rare gas elementes such as nitrogen or argon gas.Preferred-100～25 ℃ of temperature of reaction, more preferably-70 ℃～10 ℃, most preferably at-60 ℃.
The condensation rate of this step reaction is higher than the condensation rate (being about 80%) of prior art, and can be up to more than 95%, and produce isomer hardly, can separate with crystallization method by conventional and easy column chromatography and obtain condensation product, even can not need to carry out column chromatography for separation, cost is low, is fit to produce on a large scale.
C. the preparation of docetaxel
Adopt the taxanes isoserine ester (formula II compound) of reaction formula B gained among the present invention, it is carried out simple deprotection reaction obtain docetaxel.
Reaction formula C
This deprotection reaction can carry out according to the method for routine under the situation of other structure among the saboteur not, and can be through a step or a multistep deprotection reaction.These class methods can be referring to " protecting group in the organic synthesis " (T.W.Greene, press of East China University of Science) and " protecting group " (" Protecting Groups ", P.Kocienski, Thieme Publishers).
Deprotection reaction of the present invention can carry out in pH is about 3～9 the aqueous solution.Can adopt acid or alkali to carry out deprotection reaction, for example: described deprotection reaction can carry out in the solution that contains acid, and described acid is selected from: formic acid, acetate, hydrofluoric acid or their mixture, preferable formic acid or hydrofluoric acid; Described solution is selected from: the aqueous solution, organic solution or aqueous organic solution).Described deprotection reaction also can carry out in containing the organic solution of alkali; described alkali is selected from: ammoniacal liquor, hydrazine hydrate, sodium hydroxide, potassium hydroxide or their mixture; be preferably ammoniacal liquor, wherein said organic solvent is a polar aprotic solvent, is selected from tetrahydrofuran (THF), methyl alcohol, ethanol or acetonitrile.
Preferably under-50～100 ℃, carry out,, more preferably under-10 ℃～20 ℃ temperature, carry out described deprotection reaction preferably at-30 ℃～60 ℃.Reaction was generally finished in about 0.5 hour～80 hours, and preferred 1 hour～60 hours, more preferably 2 hours～50 hours.
This docetaxel yield of reaction is at least more than 85% in step, and can be up to 95%, and mild condition, easy handling.And according to the literature, the yield of docetaxel only is 78% in the prior art.In addition, reaction product docetaxel of the present invention can carry out separation and purification by simple column chromatography or direct crystallization, is fit to scale operation.
Advantage of the present invention
In sum, the present invention has following advantage:
(1) provide a kind of new taxanes isoserine ester and production method thereof, the condensation yield height of used Japanese yew alkyl parent nucleus and Isoserine derivatives in this method, condensation product is simple, and separating difficulty is low, and has reduced production cost thus;
(2) provide a kind of novel method of producing docetaxel, this method obtained docetaxel with high yield, and operation steps is few by taxanes isoserine ester of the present invention is carried out simple deprotection, and product is easy to separate, and has reduced production cost thus.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be 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 of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and umber calculate by weight.
Embodiment 1:2 '-triethyl silyl-7, the preparation of 10-two (tribromo-acetyl base) docetaxel
With 7; 10-two (tribromo-acetyl base) Ba Kating (III) (20g) is dissolved among the THF; nitrogen protection; be cooled to-65 ℃; be added dropwise to two (trimethyl silicon based) Lithamides of 1.5N, be added dropwise to then 1-tertbutyloxycarbonyl-3-triethyl silicane oxygen base-4-phenyl-azetidinone tetrahydrofuran solution (21g, 100ml); be warming up to-50 ℃, reaction 40min.Add saturated aqueous common salt (600ml), ethyl acetate (400ml * 2) aqueous layer extracted, organic layer water (300ml) saturated aqueous common salt (300ml) washing, anhydrous sodium sulfate drying, be concentrated into driedly, crystallization obtains product 28g (yield 95%) in ethyl acetate and normal hexane mixed solution then.
MS(m/z)：1232(M+Na)。
1HNMR(500MHz)δ0.45(6H，t)，0.81(9H，m)，1.14(3H，s)，1.24(2H，m)，1.37(9H，s)，1.69(3H，s)，1.73(2H，m)，1.80-1.94(2H，m)，2.40(3H，s)，2.50(1H，m)，3.70(1H，m)，4.27(2H，m)，4.46(1H，d)，4.78(1H，m)，4.89(1H，m)，4.94(3H，m)，5.00(1H，m)，5.05(1H，m)，5.01(1H，t)，5.47(1H，d)，5.84(1H，t)，6.09(1H，s)，6.70(1H，m)，7.39(4H，d)，7.46(3H，m)，7.55(1H，t)，8.12(2H，d)。
Embodiment 2: by 2 '-triethyl silyl-7,10-two (tribromo-acetyl base) docetaxel prepares docetaxel
At room temperature, with 2 '-triethyl silyl-7,10-two (tribromo-acetyl base) docetaxel (10g) is dissolved in 200ml methyl alcohol/tetrahydrofuran (THF), is added dropwise to the 24ml2N ammonia soln.Behind the stirring reaction 3 hours, concentration of reaction solution is to small volume under vacuum, and dilute with water is used ethyl acetate extraction then.Extraction liquid saturated common salt water washing, anhydrous sodium sulfate drying is evaporated to driedly, and crystallization obtains 6.2g (yield 94%) in ethyl acetate and normal hexane mixed solution then.
MS(m/z):808(M+1)。
1HNMR(500MHz)δ1.25(3H，s)，2.14(1H，m)，2.42(2H，m)，2.46(3H，s)，2.69(1H，m)，3.97(1H，d)，4.21(1H，d)，4.39(1H，d)，4.66(1H，d)，4.69(1H，m)，4.85(2H，s)，4.98(1H，d)，5.03(1H，m)，5.34(1H，bd)，5.51(1H，bd)，5.60(1H，dd)，5.75(1H，d)，6.27(1H，bt)，6.28(1H，s)，7.37～7.45(5H，m)，7.57(2H，t)，7.69(1H，t)，8.17(2H，d)
Embodiment 3:2 '-(1-oxyethyl group) ethyl-7, the preparation of 10-two (tribromo-acetyl base) docetaxel
With 7; 10-two (trichloro-ethoxycarbonyl) Ba Kating (III) (11g) is dissolved among the THF; nitrogen protection; be cooled to-65 ℃; add 1.5N hexamethyl two silica-based sodium amides; stir 10min, begin to be added dropwise to 1-tertbutyloxycarbonyl-3-triethyl silicane oxygen base-4-phenyl-azetidinone tetrahydrofuran solution (12g, 50ml).Be warming up to-50 ℃, continue reaction 30min.Add saturated aqueous common salt (300ml), ethyl acetate (200ml * 2) aqueous layer extracted, organic layer water (150ml) saturated aqueous common salt (150ml) washing, anhydrous sodium sulfate drying is concentrated into driedly, and silica gel column chromatography gets product 14g (yield 91%).
MS(m/z)：1190(M+Na)。
1HNMR(500MHz)δ1.13(10H，m)，1.31(4H，m)，1.36(1H，m)，1.39(9H，s)，1.62(4H，m)，1.64(1H，m)，1.75(2H，m)，2.27(3H，s)，3.29(1H，m)，3.51(1H，m)，4.11(2H，m)，4.28(2H，m)，4.38(1H，s)，4.84(1H，d)，4.93(2H，m)，5.12(1H，s)，5.61(1H，d)，5.97(1H，t)，7.35(1H，t)，7.39(4H，m)，7.84-7.88(4H，m)，8.17(2H，d)
Embodiment 4: by 2 '-(1-oxyethyl group) ethyl-7,10-two (tribromo-acetyl base) docetaxel prepares docetaxel
With 2 '-(1-oxyethyl group) ethyl-7; 10-two (tribromo-acetyl base) docetaxel (100g) is dissolved in the acetonitrile (4L), adds pyridine (250ml), is cooled to-8 ℃; begin to drip hydrofluoric acid (600ml), keep temperature of reaction to be no more than-3 ℃ (needing 90min approximately) simultaneously.Be added dropwise to complete the back and continue reaction 22h at 0 ℃.
In reaction solution, add the dilution of 24L ethyl acetate, 1N hydrochloric acid (20L * 2) washing then, water 10L ethyl acetate extraction merges organic phase, saturated sodium bicarbonate (20L * 5) washing, saturated sodium-chloride (7.5L * 1) washing.Add and to be evaporated to behind the anhydrous sodium sulfate drying driedly, silica gel column chromatography gets product 60g (yield 87%).
Embodiment 5:2 ', 7, the preparation of 10-three (triethyl silyl) docetaxel
With 1-tertbutyloxycarbonyl-3-triethyl silicane oxygen base-4-phenyl-azetidinone (21g) and 7,10-two (trichloro-ethoxycarbonyl) Ba Kating (III) (20g) is dissolved among the THF nitrogen protection; be cooled to-65 ℃; add 1.5N hexamethyl two silica-based sodium amides, be warming up to-50 ℃, reaction 40min.Add saturated aqueous common salt (600ml), ethyl acetate (400ml * 2) aqueous layer extracted, organic layer water (300ml) saturated aqueous common salt (300ml) washing, anhydrous sodium sulfate drying, be concentrated into driedly, crystallization gets product 25g (yield 85%) in ethyl acetate and normal hexane.
MS(m/z)：1172(M+Na)。
1HNMR(500MHz)δ0.55(18H，m)，0.86(27H，m)，0.94(6H，m)，1.08(1H，m)，1.18(9H，s)，1.52(3H，s)，1.63(3H，s)，1.71(2H，m)，1.99(1H，s)，2.36(3H，s)，3.65(1H，d)，4.03(2H，m)，4.32(1H，m)，4.25(1H，d)，4.55(1H，s)，4.93(2H，m)，5.04(1H，s)，5.43(1H，d)，5.81(1H，t)，7.20(1H，t)，7.36(4H，m)，7.51(1H，d)，7.61(2H，m)，7.71(1H，m)，8.00(2H，d)。
Embodiment 6: by 2 ', 7,10-three (triethyl silyl) docetaxel prepares docetaxel
By 2 ', 7,10-three (triethyl silyl) docetaxel prepares the method for docetaxel with embodiment 4 (yield 92%).
Embodiment 7:2 '-(1-oxyethyl group) ethyl-7, the preparation of 10-two (triethyl silyl) docetaxel
With 1-tertbutyloxycarbonyl-3-(1-oxyethyl group) oxyethyl group-4-phenyl-azetidinone (10g) and 7; 10-two (triethyl silyl) Ba Kating (III) (10g) is dissolved among the THF; nitrogen protection; be cooled to-65 ℃; add two (trimethyl silicon based) Lithamides of 1.5N; be warming up to-50 ℃, reaction 40min.Add saturated aqueous common salt (300ml), ethyl acetate (200ml * 2) aqueous layer extracted, organic layer water (150ml) saturated aqueous common salt (150ml) washing, anhydrous sodium sulfate drying, be concentrated into driedly, crystallization gets product 12g (yield 81%) in ethyl acetate and normal hexane.
MS(m/z)：1130(M+Na)。
1HNMR(500MHz)δ0.55(13H，m)，0.90(18H，m)，1.01(10H，m)，1.26(4H，m)，1.32(1H，m)，1.37(9H，s)，1.50(4H，m)，1.65(1H，m)，1.74(2H，m)，2.23(3H，s)，3.34(1H，m)，3.61(1H，m)，4.01(2H，m)，4.33(2H，m)，4.48(1H，s)，4.81(1H，d)，4.90(2H，m)，5.04(1H，s)，5.40(1H，d)，5.84(1H，t)，7.15(1H，t)，7.30(4H，m)，7.64-7.75(4H，m)，7.97(2H，d)
Embodiment 8: by 2 '-(1-oxyethyl group) ethyl-7,10-two (triethyl silyl) docetaxel prepares docetaxel
By 2 '-(1-oxyethyl group) ethyl-7,10-two (triethyl silyl) docetaxel prepares the method for docetaxel with embodiment 4 (yield 95%).
Embodiment 9:2 '-triethyl silyl-7, the preparation of 10-two (trichloro-ethoxycarbonyl) docetaxel
With 1-tertbutyloxycarbonyl-3-triethyl silicane oxygen base-4-phenyl-azetidinone (12g) and 7; 10-two (trichloro-ethoxycarbonyl) Ba Kating (III) (11g) is dissolved among the THF; nitrogen protection; be cooled to-65 ℃; add 1.5N hexamethyl two silica-based sodium amides; be warming up to-50 ℃, continue reaction 30min.Add saturated aqueous common salt (300ml), ethyl acetate (200ml * 2) aqueous layer extracted, organic layer water (150ml) saturated aqueous common salt (150ml) washing, anhydrous sodium sulfate drying is concentrated into driedly, and silica gel column chromatography gets product 14g (yield 89%).
MS(m/z)：1180(M+Na)。
1HNMR(500MHz)δ0.55(6H，t)，0.85(11H，m)，0.99(3H，s)，1.04(3H，s)，1.24(2H，m)，1.37(9H，s)，1.69(3H，s)，1.76(2H，m)，1.80-1.99(2H，m)，2.40(3H，s)，2.50(1H，m)，3.70(1H，m)，4.09(2H，m)，4.46(1H，d)，4.78(1H，m)，4.89(1H，m)，4.94(3H，m)，5.00(1H，m)，5.05(1H，m)，5.39(1H，t)，5.47(1H，d)，5.84(1H，t)，6.09(1H，s)，7.20(1H，m)，7.39(4H，d)，7.64(3H，m)，7.75(1H，t)，8.02(2H，d)
Embodiment 10: by 2 '-triethyl silyl-7,10-two (trichloro-ethoxycarbonyl) docetaxel prepares docetaxel
2 '-triethyl silyl-7,10-two (trichloro-ethoxycarbonyl) docetaxel (20g) is dissolved in THF, begin heating, temperature rises to 30 ℃, begins to drip formic acid, and controlled temperature is lower than 40 ℃, drip off and be heated to 40 ℃, keep this thermotonus to spend the night, (n-hexane/ethyl acetate=2/1 is v/v) until reacting completely in the TLC monitoring.
After reaction finishes, add the 400m ethyl acetate, with pure water (200ml * 2) washing, saturated sodium bicarbonate (200ml * N) be washed till neutrality, saturated sodium-chloride (300ml) washing, anhydrous sodium sulfate drying, dense doing, silica gel column chromatography gets product 11g (yield 85%).
By NMR and MS spectrum analysis and with the national standard product relatively, the structure of the docetaxel that identity basis the present invention makes and known drug (docetaxel) structure is identical, and activity experiment shows that it has and has the identical or better activity of docetaxel now.
Summed up the substituting group of preparation docetaxel intermediate among the embodiment in the following table 1
Substituting group in the table 1. embodiment title compound
| Embodiment | R 1 | R 2 | R 3 |
| 1 | The tribromo-acetyl base | The tribromo-acetyl base | Triethyl silyl |
| 3 | The tribromo-acetyl base | The tribromo-acetyl base | (1-oxyethyl group) ethyl |
| 5 | Triethyl silyl | Triethyl silyl | Triethyl silyl |
| 7 | Triethyl silyl | Triethyl silyl | (1-oxyethyl group) ethyl |
| 9 | Trichloro-ethoxycarbonyl | Trichloro-ethoxycarbonyl | Triethyl silyl |
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (6)
1. one kind as shown in the formula the taxanes isoserine ester cpds shown in the II or its salt:
Formula II
R wherein
1, R
2And R
3Be hydroxyl protecting group, R
1And R
2Be tribromo-acetyl base, R
3Be triethyl silyl.
2. the preparation method of the described formula II compound of claim 1, described method comprises:
In the presence of coupler, make the reaction of Japanese yew alkyl parent nucleus shown in compound or its salt shown in the formula III and the formula IV:
Formula III
R wherein
3Be triethyl silyl;
Formula IV
R wherein
1And R
2Be the tribromo-acetyl base.
3. method as claimed in claim 2, described coupler are inorganic base metal alkali or organic alkali metal alkali.
4. method as claimed in claim 3, described coupler are two (trimethyl silicon based) Lithamides.
5. method by the described compound docetaxel of claim 1 may further comprise the steps:
(i) according to the described method preparation formula of claim 2 II compound,
Formula II
R wherein
1, R
2And R
3Be hydroxyl protecting group, R
1And R
2Be tribromo-acetyl base, R
3Be triethyl silyl;
(ii) in containing the organic solution of alkali formula II compound is carried out a step or a multistep deprotection reaction, described deprotection reaction carries out under-50～100 ℃.
6. method as claimed in claim 5, described coupler are two (trimethyl silicon based) Lithamides, and described alkali is ammoniacal liquor, and described organic solvent is a tetrahydrofuran (THF).
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| Iwao Ojima,et al.A HIGHLY EFFICIENT ROUTE TO TAXOTERE BY THE β-LACTAM SYNTHON METHOD.Tetrahedron Letters34 26.1993,34(26),4149-4152. |
| Iwao Ojima,et al.A HIGHLY EFFICIENT ROUTE TO TAXOTERE BY THE β-LACTAM SYNTHON METHOD.Tetrahedron Letters34 26.1993,34(26),4149-4152. * |
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