CN1709864A - Taxol and its analogue side chain synthesizing method - Google Patents
Taxol and its analogue side chain synthesizing method Download PDFInfo
- Publication number
- CN1709864A CN1709864A CNA2005100826760A CN200510082676A CN1709864A CN 1709864 A CN1709864 A CN 1709864A CN A2005100826760 A CNA2005100826760 A CN A2005100826760A CN 200510082676 A CN200510082676 A CN 200510082676A CN 1709864 A CN1709864 A CN 1709864A
- Authority
- CN
- China
- Prior art keywords
- side chain
- tertiary butyl
- taxol
- methyl
- analogue
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
This invention has disclosed a kind of synthetic method to paclitaxol and side chain of its analogue. This invention using low-cost alpha- glycolic acid as raw material, the asymmetry addition reaction induced by chirality tertiary butyl sulfinamide as committed step, prepares paclitaxol and polyene paclitaxol side chain. The chemical product quotiety of key reaction is high, protecting group is easy to control and operate, synthesis process is short.
Description
Technical field
The present invention relates to the synthetic method of a kind of taxol and analogue side chain thereof, specifically, relate to a kind of based on the taxol of chirality tertiary butyl sulfinyl amine schiffbase and the new synthetic method of analogue side chain thereof.
Background technology
Taxol (pacilitaxel), Americanized scholar Wall in 1967 and Wani etc. are at first from Pacific yew (yewtree, the diterpene-kind compound with unique antitumour activity that Taxus.brevifolia) extracts in the bark.This medicine enters the III clinical trial phase in nineteen ninety, obtains the drugs approved by FDA listing end of the year 1992, is used for the treatment of ovarian cancer and the mammary cancer invalid to conventional chemotherapy.Nineteen ninety-five, China Beijing XieHe medicine Factory and Haikou pharmaceutical factory separately win two kind new medicine authentication codes, become second country that produces taxol and injection liquid thereof in the world.Because the anticancer mechanism of its uniqueness and the antitumour activity of broad-spectrum high efficacy, taxol is the cancer therapy drug of hottest point behind adriamycin and Platinol cisplatin.
Taxol is a kind of efficient cytotoxin, has unique anticancer mechanism.It acts on tubulin.Microtubule is eukaryotic a kind of scleroproein, is closely related with the mitotic division of cell, and for rapid splitted tumour cell, taxol " freezes " mitotic spindle, thereby makes tumour cell stop at G2 phase and M phase, until death.Taxol shows wide spectrum and antitumour activity efficiently, and there is cytotoxicity in people's ovarian cancer, mammary cancer, cervical cancer, lung cancer, CNS cancer, melanoma, liver cancer and leukemia cell system etc.Its antitumour activity is higher than cancer therapy drugs commonly used such as thiazole furan quinoline, cis-platinum, etoposide, Zorubicin and Fluracil.
Taxol is the baroque natural product that perennial bark of Ramulus et folium taxi cuspidatae extracts, Docetaxel is the semi-synthetic derivative of taxol, they are as the antitumor drug that promotes microtubule polymerization in the cancer cells, be at present clinical in one of the most effective cancer therapy drug (Schiff, P.B.; Horwitz, S.B.Proc.Natl.Acad.Sci.USA1980,77,1561; Fant, J.; Horwitz, S.B.Nature 1979,277, and 665).It is reported that the content of taxol in bark of Ramulus et folium taxi cuspidatae is about about 2/10000ths (Wani, M.C.; Taylor, H.L.; Wall, M.E.; Coggin, P.; McPhail, A.T.J.Am.Chem.Soc.1971,93,2325.1986,42,4451), the taxol consumption of a course of treatment an of cancer patient needs from three to five century-old giving birth to the bark of Ramulus et folium taxi cuspidatae to obtain approximately.Because Chinese yew belongs to precious endangered species, resource scarcity, poor growth, the whole world only have 11 kinds, and population density is little, and the self-reproduction degree is low.Taxol is many to be extracted from bark, but content is extremely low, has only 0.06-0.07%.Extracting taxol from bark of Ramulus et folium taxi cuspidatae is to be cost to destroy resource, totally unfavorable to environment and species conservation.According to estimates, only be used for the cancer that other medicines are failed to respond to any medical treatment, promptly need taxol 70kg every year.Wait other aspects if consider the compatibility of drugs application, annual requirement may surpass 300kg, is roughly equal to 750,000 strains trees/year.With present extraction and separation method, big like this supply can threaten retaining for a long time of Chinese yew genus plants undoubtedly and the area distributes, and therefore, the alternate resources that adopts various means to seek taxol and analogue thereof has become current research focus.
Artificial semisynthesis is the unique feasible method that obtains said medicine at present.Discover that contain the female ring structure 10-deacetylate crust card fourth III (10-deacetylbaccatin III) than the taxol of horn of plenty in leaf of Japanese Yew, its content in leaf is up to gram per kilogram (Chauviere, a G.; Guenard, D.; Picot, F.; Potier, P.C.R.Senaces Acad.Sci., Ser 21981,293, and 501; Gureitte-Voegelein, F.; Senilh, V.; David, B.; Guenard, D.; Potier, P.Tetrehadron 1986,42, and 4451).Simultaneously, 10-deacetylate crust card fourth III also is the main by product when bark of Ramulus et folium taxi cuspidatae extracts taxol.Because the recyclability of leaf resource; angle from species and ecological protection; set out by 10-deacetylate crust card fourth III (compound 3); engage with paclitaxel lateral chain (compound 1 or 2) by semisynthesis and to prepare taxol and derivative (formula 1) thereof; be the important behave of keeping human kind sustainable development, have great social significance and economic worth.
Formula 1, artificial semi-synthetic taxol and derivative thereof
Object and its mirror image can not superimposed phenomenon be called chirality (chirality).There are two kinds of enantiomers of mirror image each other at least in chipal compounds.Having the levo form of enantiomer each other and dextrorotatory form equal proportion, to mix what form be a racemic modification that does not have optically-active, splits out one of them levo form or dextrorotatory form and then have opticity, and promptly optically pure compound just is called as " chipal compounds ".
In semisynthesis, the effectively synthetic of optically pure taxol and Docetaxel side chain is the key technical problem that needs solution at present.At present known taxol that is subjected to patent protection and Docetaxel side chain be synthetic to mainly contain following several method:
1) be initiator with optical purity phenylethylamine or optical purity to the schiffbase 4 that anisole ethamine prepares, obtain tetra-atomic ring beta-lactam intermediate 6 by the 2+2 cycloaddition reaction taking place with α-alpha-Acetoxyacetyl chloride 5, the side chain 1 and beta-lactam type side chain 2 (formula 2, the US5939561 that prepare the straight chain type again by some step reactions; US5608102).
Formula 2 is the feedstock production paclitaxel lateral chain with optical purity phenylethylamine or optical purity to anisole ethamine
2) Alpha-hydroxy the acetate ((1R that protects with triisopropyl silicon, 2S) 2-phenyl-hexalin) ester 7 is an initiator, under the alkaline effect, by the schiffbase 9 with trimethyl silicane protection take place the nucleophilic cyclizations with 80% yield and greater than the 95%d.e value prepare beta-lactam intermediate 10 (formula 3, US 6218553; US6187916; WO9418164).
Formula 3 is with Alpha-hydroxy acetate ((1R, 2S) 2-phenyl-hexalin) ester of triisopropyl silicon protection
Be the feedstock production paclitaxel lateral chain
3) the Threonine methyl esters 11 with the protection of phenylbenzene tertiary butyl silicon is a raw material; preparation schiffbase 12; compound 12 obtains beta-lactam intermediate 13 by with alpha-Acetoxyacetyl chloride 5 the 2+2 cycloaddition reaction taking place with 84% productive rate and 90% cis-selectivity again; slough the Threonine methyl esters by the reaction of 4 steps again and obtain beta-lactam intermediate 17 (formulas 4, EP 0525589).
Formula 4, the Threonine methyl esters of protecting with phenylbenzene tertiary butyl silicon is the feedstock production paclitaxel lateral chain
4) set out by cinnamic acid or its methyl esters 18, obtain intermediate 19 by asymmetric Sharpless amine hydroxylating with 69% yield and 82%d.e value, again by recrystallization and four-step reaction prepare the paclitaxel lateral chain of optically pure straight chain type and Docetaxel side chain (formula 5, US 5859281; US6350905).
Formula 5 is the feedstock production paclitaxel lateral chain with cinnamic acid or its methyl esters
Summary of the invention
The object of the present invention is to provide the new synthetic method of a kind of taxol and analogue side chain thereof, it is used for taxol and the artificial semisynthetic optically pure side chain of Docetaxel by a new synthetic method preparation.Advantages such as this method has the chemical yield and the cis-selectivity height of committed step, and protecting group is easy to regulation and control, and is easy and simple to handle, and synthesis step is short.
Technical scheme of the present invention is as follows:
The synthetic method of taxol of the present invention and analogue side chain thereof; it is to form enol intermediate and optically pure tertiary butyl sulfinyl amine schiffbase 22 effect generation asymmetric reduction reactions by the protected Alpha-hydroxy acetic ester 25 of hydroxyl under the highly basic condition; 2 hydroxyls of cis-selectivity preparation are protected, 3 tertiary butyl sulfinyls are protection and optically pure 2-hydroxyl-3-alanine ester intermediates 26 3 replacements; this intermediate has (2R; 3S) or (2S, 3R) three-dimensional configuration.
Protected Alpha-hydroxy acetic ester 25 of hydroxyl and chirality tertiary butyl sulfinyl amine schiffbase 22
Optically pure tertiary butyl sulfinyl amine inductive asymmetric reduction reaction
Hydroxyl protecting group of the present invention is: the methyl of ether chain series, the tertiary butyl, benzyl, the aromatic base that methoxyl group replaces, methoxymethyl, ethoxyl methyl, 2,2,2-trichlorine ethoxyl methyl, 2-trimethyl silicane ethoxyl methyl, Bian oxygen ylmethyl, the siloxy methyl, 2-methoxy ethoxy methyl, 4-methoxyl group phenoxymethyl; Or silicon ether series is trimethyl silicon based, and triethyl is silica-based, triisopropylsilyl, and dimethyl ethyl is silica-based, and the dimethyl sec.-propyl is silica-based, and the dimethyl tertiary butyl is silica-based, and tert-butyl diphenyl is silica-based; Or the valeryl of carbonyl series, trihalogen acetyl, benzoyl, methoxy methyl acyl group, ethoxy acetyl, propoxy-formyl radical, isopropoxy formyl radical, tert.-butoxy formyl radical, phenylol formyl radical substituting group.
Ester group protecting group of the present invention is: the saturated or undersaturated alkyl of the straight chain of 1 to 16 carbon atom or side chain, the replacement of 3 to 8 yuan of rings, the cyclic alkyl of non-replacement, aromatic base, sulfydryl or dibasic amido.
The substituting group of tertiary butyl sulfinyl amine schiffbase of the present invention is: saturated and alkyl insatiable hunger of the straight chain of 1 to 16 carbon atom or side chain, the replacement of 3 to 8 yuan of rings, the cyclic alkyl of non-replacement, the heteroatoms aromatic base of replacement, non-replacement etc.
Solvent for use of the present invention is: THF, ether, dme, di-tert-butyl ether, t-butyl methyl ether, tertiary butyl ether, isopropyl ether, sherwood oil, dioxane, benzene, toluene, dimethylbenzene, DMF etc.
Alkali of the present invention is: lithium diisopropyl amido, diisopropyl amido sodium, two (trimethyl silicane) amido lithium, two (trimethyl silicane) amido sodium, butyllithium, tert-butyl lithium, phenyl lithium, highly basic such as sodium alkoxide, potassium tert.-butoxide.
The present invention is by the described intermediate 26 optically pure side chain intermediate 28 of preparation and 30 and have an analogue of different substituents on hydroxyl of further deriving of setting out.
The preparation of the side chain 28 of straight chain type side chain 27 and beta-lactam type
Preparation with straight chain type side chain 30 of different substituents
The chiral reagent of optically pure tertiary butyl sulfinyl amine for developing in recent years is because tertiary butyl sulfinyl amine has asymmetric induction ability preferably (Ellman, J.A. for containing big tertiary butyl steric group in asymmetric catalysis synthesis; Owens, T.D.; Tang, T.P.Acc.Chem.Res.2002,35,984.Qin, Y.; Wang, C.; Huang, Zh.; Xiao, X.; Jiang, Y.J.Org.Chem.2004,69,8533).Simultaneously, tertiary butyl sulfinyl has and the tert-butoxycarbonyl similar characteristics, under acidic conditions, be easy to from product, remove, thereby, in the preparation process of taxol and Docetaxel side chain, can be used as protecting group and use.The present invention is a raw material with low-cost Alpha-hydroxy acetate, as committed step, prepares taxol and Docetaxel side chain by chirality tertiary butyl sulfinyl amine inductive asymmetric reduction reaction.
Formula 6, the protected Alpha-hydroxy acetic ester 25 of hydroxyl and chirality tertiary butyl sulfinyl amine schiffbase 22
As shown in Equation 6, research work is at first from the preparation of protected Alpha-hydroxy acetic ester 25 of hydroxyl and chirality tertiary butyl sulfinyl amine schiffbase 22.Acetic ester 25 through esterification, is protected high yield preparation to hydroxyl by Alpha-hydroxy acetate 23 again.Chirality tertiary butyl sulfinyl amine schiffbase 22 can be by optically pure tertiary butyl sulfinyl amine reference literature method at CuSO
4Or KHSO
4Catalytic dehydration down with preparation (Huang, the Zh. of the high yield of aldehyde 20 condensations; Zhang, M.; Xiao, X.; Qin, Y.Synlett 2005,1334).
Formula 7, optically pure tertiary butyl sulfinyl amine inductive asymmetric reduction reaction
Committed step as shown in Equation 7; the protected Alpha-hydroxy acetic ester 25 of hydroxyl is peeled off α-hydrogen under the alkaline effect; the enol negative ion attack chirality tertiary butyl sulfinyl amine schiffbase 22 that is generated; prepare that 2 hydroxyls are protected high chemical yield and high cis-selectivity, 3 (R)-tertiary butyl sulfinyl protections with 3 replacements (2R, 3S)-2-hydroxyl-3-alanine ester intermediate 26.The chemical yield of this committed step and cis-selectivity are mainly by R
2The characteristic of group and the type of alkali determine R
1Group is less relatively to the influence of reaction.In the patented invention process contriver's high spot reviews dissimilar R
2Group and alkali are to the influence of reaction.The R that is investigated
2Types of radicals has: the 1) methyl of ether chain series, the tertiary butyl, benzyl and p-methoxyphenyl, methyl ether methyl etc.; 2) silicon ether series is trimethyl silicon based, triisopropylsilyl, and tertiary butyl dimethyl is silica-based etc.; 3) tertiary butyl formyl radical of carbonyl series, benzoyl, methoxy methyl acyl group, Boc and CBz etc.The alkali of being investigated has highly basic such as butyllithium, tert-butyl lithium, lithium diisopropylamine, two (trimethyl silicane) Lithamide, two (trimethyl silicane) sodium amide, sodium alkoxide, potassium tert.-butoxide.By test as can be known, use ether solvent and lithium diisopropylamine, two (trimethyl silicane) Lithamide to be alkali, R
2Be the substrate of carbonic acid series, compound 25 and 22 reacts at low temperatures and can obtain best yield and cis-selectivity.The protected Alpha-hydroxy acetic ester of hydroxyl 25 with (R)-the asymmetric reduction reaction result such as the table one of tertiary butyl sulfinyl amine schiffbase 22.
Formula 8, the crystalline structure of adduct 26i
Table one, acetic ester 25 with (R)-tertiary butyl sulfinyl amine schiffbase 22 asymmetric reduction reaction results
a
| ?Entry | ??22(R) | ?25(R 1，R 2) | ??Base | ??Yield％?of?26(26∶26’) |
| ??1 | ??22a，Ph | ?25a，R 1＝BnO，R 2＝Et 3Si | ??LDA | ??26a，14％+isomers |
| ??2 | ??22a，Ph | ?25b，R 1＝BnO， ?R 2＝ tBuMe 2Si | ??LDA | ??26b，5％(26b’，8％； ??26b”+26b，13％) |
| ??3 | ??22a，Ph | ?25c，R 1＝BnO，R 2＝ ?4-MeoPh | ??LDA | ??26c，too?complicated |
| ??4 | ??22a，Ph | ?25d，R 1＝BnO，R 2＝Bn | ??LDA | ??26d，No?reaction |
| ??5 | ??22a，Ph | ?25e，R 1＝BnO，R 2＝ tBuCO | ??LDA | ??26e，too?complicated |
| ??6 | ??22a，Ph | ?25f，R 1＝BnO，R 2＝PhCO | ??LDA | ??26f，too?complicated |
| ??7 | ??22a，Ph | ?25g，R 1＝BnO，R 2＝MeOCO | ??LDA | ??26g，25.1％(26g∶26g’3.9∶1) |
| ??8 | ??22a，Ph | ?25h，R 1＝BnO，R 2＝BnOCO | ??LDA | ??26h，57％+isomers |
| ??9 | ??22a，Ph | ??25i，R 1＝BnO，R 2＝ tBuOCO | ??LDA | ??26i，75.3％(100％) |
| ??10 | ??22a，Ph | ??25j，R 1＝MeO，R 2＝ tBuOCO | ??LDA | ??26j，57.5％(7d∶7d’＝22∶1) |
| ??11 | ??22a，Ph | ??25k，R 1＝BnS，R 2＝ tBuOCO | ??LDA | ??26k，67.2％(100％) |
| ??12 | ??22a，Ph | ??25l，R 1＝Allyl，R 2＝ tBuOCO | ??LDA | ??26l，90％(100％) |
| ??13 | ??22a，Ph | ??25i，R 1＝BnO，R 2＝ tBuOCO | ??BuLi | ??26i，37.9％(100％) |
| ??14 | ??22a，Ph | ??25i，R 1＝BnO，R 2＝ tBuOCO | ? tBuLi | ??26i，43％(100％) |
| ??15 | ??22a，Ph | ??25i，R 1＝BnO，R 2＝ tBuOCO | ??LHM ??DS | ??26i，97％(100％) |
| ??16 b | ??22a，Ph | ??25i，R 1＝BnO，R 2＝ tBuOCO | ??LHM ??DS | ??26i，50％(100) |
| ??17 c | ??22a，Ph | ??25i，R 1＝BnO，R 2＝ tBuOCO | ??LHM ??DS | ??26i，37.1％(100％) |
| ??18 d | ??22a，Ph | ??25i，R 1＝BnO，R 2＝ tBuOCO | ??LHM ??DS | ??26i，51.8％(100％) |
| ??19 e | ??22a，Ph | ??25i，R 1＝BnO，R 2＝ tBuOCO | ??LHM ??DS | ??26i，85.2％(100％) |
| ??20 | ??22a，Ph | ??25a，R 1＝BnO，R 2＝Et 3Si | ??LHM ??DS | ??26a，17.9％+isomers |
| ??21 | ??22a，Ph | ??25b，R 1＝BnO， ??R 2＝ tBuMe 2Si | ??LHM ??DS | ??26b，9.5％，(26b’，16％； ??26b”+26b，73％) |
| ??22 | ??22a，Ph | ??25g，R 1＝BnO，R 2＝MeOCO | ??LHM ??DS | ??26g，56.7％(26g∶26g’3.8∶1) |
| ??23 | ??22a，Ph | ??25h，R 1＝BnO，R 2＝BnOCO | ??LHM ??DS | ??26h，53％ f |
| ??24 | ??22a，Ph | ??25j，R 1＝MeO，R 2＝ tBuOCO | ??LHM ??DS | ??26j，96％(100％) |
| ??25 | ??22a，Ph | ??25l，R 1＝Allyl，R 2＝ tBuOCO | ??LHM ??DS | ??26l，95％(100％) |
| ??27 | ??22c，2-BrPh | ??25i，R 1＝BnO，R 2＝ tBuOCO | ??LHM | ??26n，92％ f |
| ??DS | ||||
| ??28 | ??22d，4-MeOPh | ??25i，R 1＝BnO，R 2＝ tBuOCO | ??LHM ??DS | ??26o，95％ |
| ??29 | ??22e，4-NO 2Ph | ??25i，R 1＝BnO，R 2＝ tBuOCO | ??LHM ??DS | ??26p，74％ f |
| ??30 | ??22f，2-pydinyl | ??25i，R 1＝BnO，R 2＝ tBuOCO | ??LHM ??DS | ??26q，96％ |
| ??31 | ??22g，2-furyl | ??25i，R 1＝BnO，R 2＝ tBuOCO | ??LHM ??DS | ??26r，76％ f |
a)at-78℃，1?eq.of?3，5?eq.of?6，5?eq.of?base；b)at-45℃?1?eq.of?3，5?eq.of?6，5?eq.ofbase；c)at-78℃，1?eq.of?3，1.5?eq.of?6，1.5?eq.of?base；d)at-78℃，1?eq.of?3，2.5?eq.of?6，2.5?eq.of?base；e)at-78℃，1?eq.of?3，3.5?eq.of?6，3.5?eq.of?base；f)?major?isomer’s?yield.
By table one result as can be known, under the effect of LHMDS, at low temperature-78 ℃, with 25i, 525j and 25l nucleophilic addition takes place respectively by 22a, can be with greater than 95% chemical yield and 100% non-mapping choosing
Selecting property obtains adduct 26i, 26j and 26l respectively, and they are the important as precursors that prepare the side chain that is connected with crust card fourth III.
Formula 8, the crystalline structure of adduct 26i
As shown in Equation 8, adduct 26 is defined as 2R, 3S in 2 and 3 s' absolute stereo configuration by the monocrystalline X-diffraction analysis of one of them compound 26i, and is consistent in the absolute stereo configuration of corresponding position with the side chain of taxol.
Formula 9, the preparation of the side chain 28 of straight chain type side chain 27 and beta-lactam type
As shown in Equation 9; set out by 26i, 26j or 26l; by hydrogenolysis or basic hydrolysis; slough the ester group protecting group and obtain (2R; 3S)-and 2-(tert.-butoxy carbonyldioxy)-3-phenyl-3-((R)-tertiary butyl sulfonamido) propionic acid 27, compound 27 can further obtain the beta-lactam side chain 28 of new texture with condensation reagent reaction cyclisation.
Formula 10 has the preparation of the straight chain type side chain 30 of different substituents
Boc protecting group in the compound 26 can by selectivity with trifluoroacetic acid slough pure 29.Compound 29 is prepared optically pure straight chain type side chain 30 (formula 10) with 2-methoxy propyl alkene reaction again.Compound 30 can be further used for preparing taxol and analogue thereof.
Embodiment
(R)-tertiary butyl sulfinyl amine schiffbase 22 by (R)-tertiary butyl sulfinyl amine reference literature method at KHSO
4Catalytic dehydration down with the preparation (Synlett 2005,1334) of the high yield of aldehyde 1 condensation.
Embodiment 1
(R)-the phenyl aldehyde tertiary butyl sulfinyl amine schiffbase 22a that contracts
Colourless liquid, [α]
20 D-122 ° (c 1.0, CHCl
3);
1H NMR (400MHz, CDCl
3) δ 1.27 (s, 9H), 7.46-7.55 (m, 3H), 7.85-7.88 (m, 2H), 8.60 (s, 1H) ppm.
Embodiment 2
(R)-the 4-chloro-benzaldehyde tertiary butyl sulfinyl amine schiffbase 22b that contracts
White solid, fusing point 45-47 ℃.[α]
20 D-79°(c?2.19，CHCl
3)；.
1H?NMR(400MHz，CDCl
3)δ1.26(s，9H)，7.44(d，J＝6.4Hz，2H)，7.78(d，J＝6.4Hz，2H)，8.55(s，1H)；
13C?NMR(CDCl
3)δ22.5，57.8，129.2，130.4，132.4，138.5，161.4ppm。
Embodiment 3
(R)-the adjacent bromobenzaldehyde tertiary butyl sulfinyl amine schiffbase 22c that contracts
Colourless liquid, [α]
20 D-211.3 ° (c 1.23, CHCl
3);
1H NMR (400MHz, CDCl
3) δ 8.94 (s, 1H), 8.00 (dd, J=7.6,2.0Hz, 1H), 7.60 (dd, J=7.6,0.8Hz, 1H), 7.28-7.39 (m, 2H), 1.24 (s, 9H).
Embodiment 4
(R)-the aubepine tertiary butyl sulfinyl amine schiffbase 22d that contracts
White solid, fusing point 90-92 ℃.[α]
20 D-70.4°(c?1.10，CHCl
3)；
1H?NMR(400MHz，CDCl
3)δ8.51(s，1H)，7.79(d，J＝8.5Hz，2H)，6.96(d，J＝8.5Hz，2H)，3.87(s，3H)，1.25(s，9H)ppm.
Embodiment 5
(R)-the paranitrobenzaldehyde tertiary butyl sulfinyl amine schiffbase 22e that contracts
Yellow solid, fusing point 138-139 ℃.[α]
20 D-60.4°(c?1.21，CHCl
3)；
1H?NMR(400MHz，CDCl
3)δ8.68(s，1H)，8.35(d，J＝7.2Hz，2H)，8.04(d，J＝7.2Hz，2H)，1.30(s，9H).
Embodiment 6
(R)-the 2-pyridylaldehyde tertiary butyl sulfinyl amine schiffbase 22f that contracts
Colourless liquid, [α]
20 D-171 ° (c 2.19, CHCl
3);
1H NMR (400MHz, CDCl
3) δ 1.29 (s, 9H), 7.39 (m, 1H), 7.80 (m, 1H), 8.00 (m, 1H), 8.70 (s, 1H), 8.74 (m, 1H) ppm.
Embodiment 7
(R)-the 2 furan carboxyaldehyde tertiary butyl sulfinyl amine schiffbase 22g that contracts
Colourless liquid, [α]
20 D-169 ° (c 1.19, CHCl
3);
1H NMR (400MHz, CDCl
3) δ 1.25 (s, 9H), 6.56 (d, J=3.6Hz, 1H), 7.00 (d, J=3.2Hz, 1H), 7.64 (t, J=0.8Hz, 1H), 8.39 (s, 1H) ppm.
Embodiment 8
The preparation of 2-oxyacetic acid Bian ester 24a
Get 30.0g (0.40mol) Alpha-hydroxy acetate 23 and be dissolved in the dry acetonitrile of 400mL, add 39.0mL (0.33mol) bromobenzyl, splash into 52.5mL (0.33mol) DBU under the ice-water bath, dropwise post-heating to 35 ℃.With in the reaction solution impouring frozen water, tell organic layer after 1 hour, water layer ethyl acetate extraction 3 times merge organic phase.(2 * 200mL) wash anhydrous sodium sulfate drying to organic phase with 2M hydrochloric acid.Filter, evaporated under reduced pressure solvent, crude product obtain colourless liquid 24a (45.0g, productive rate 84.0%) through the silicagel column separation and purification.
1H NMR (200MHz, CDCl
3) δ 7.18-7.24 (m, 5H), 5.22 (s, 2H), 4.17 (s, 2H), 2.04 (s, 1H) ppm.
Embodiment 9
2-hydroxy methyl acetate 24b is the Aldrich commodity
2-oxyacetic acid allyl ester 24c
Get 8.5g (0.11mol) Alpha-hydroxy acetate 23 and be dissolved in the dry acetonitrile, add 6.5mL (74.68mmol) allyl bromide 98, splash into 17.0mL (0.11mol) DBU under the room temperature.Dropwise back stirring at room 2 hours, remove solvent under reduced pressure after, resistates is dissolved in the 150mL methylene dichloride, and washs and saturated NaHCO with 1M dilute hydrochloric acid
3Washing.Organic phase is through anhydrous Na
2SO
4Drying after-filtration, decompression get 12.4g first product 24c for preparation 25l usefulness after steaming solvent.
Embodiment 10
The preparation of 2-triethyl siloxy acetate Bian ester 25a
Get 2.3g (13.86mmol) 24a and be dissolved in the 10mL pyridine, add 2.8mL (16.53mmol) chlorotriethyl silane, stirred overnight at room temperature.Reaction solution pours in the 1M dilute hydrochloric acid, dichloromethane extraction three times.Merge organic phase, organic phase is through anhydrous Na
2SO
4Dry after-filtration.Remove solvent under reduced pressure, crude product obtains colourless liquid 25a (3.4g, productive rate 87.6%) through the silicagel column separation and purification.
1H?NMR(200MHz，CDCl
3)δ7.34(m，5H)，5.17(s，2H)，4.27(s，2H)，0.95(t，J＝7.8Hz，9H)，0.64(m，6H)ppm。
Embodiment 11
The preparation of 2-tertiary butyl dimethyl Si guanidine-acetic acid Bian ester 25b
2.6g (15.66mmol) 24a is dissolved in the 10mL methylene dichloride, adds 2.7g (14.71mmol) imidazoles and 0.4g (3.27mmol) DMAP, stirred overnight at room temperature after adding 2.8g (18.58mmol) TERT-BUTYL DIMETHYL CHLORO SILANE.Remove solvent under reduced pressure, crude product obtains colourless liquid 25b (4.0g, productive rate 91.1%) through the silicagel column separation and purification.
1H?NMR(200MHz，CDCl
3)δ7.25-7.34(m，5H)，5.16(s，2H)，4.27(s，2H)，0.90(s，9H)，0.09(s，6H)ppm。
Embodiment 12
The preparation of 2-(p methoxy phenol base) acetate Bian ester 25c
2.50g (15.06mmol) 24a is dissolved in the dry THF, adds 1.2mL (12.0mmol) PBr
3, stirred overnight at room temperature.Reaction solution washes with water, separates organic phase, and dichloromethane extraction water three times merges organic phase.The anhydrous sodium sulfate drying after-filtration removes solvent under reduced pressure, and crude product obtains the alpha-brominated acetate Bian of colourless liquid ester (3.20g, productive rate 92.8%) through the silicagel column separation and purification.
1H?NMR(200MHz，CDCl
3)δ7.36(m，5H)，5.19(s，2H)，3.86(s，2H)ppm。The alpha-brominated acetate Bian of above-mentioned 3.20g (13.97mmol) ester is dissolved in the dry THF, and ice-water bath adds 1.87g (15.1mmol) down
tBuOK, stirred overnight at room temperature.In reaction solution impouring water, separate organic phase, water ethyl acetate extraction three times merge organic phase, the anhydrous sodium sulfate drying after-filtration.Remove solvent under reduced pressure, crude product obtains product 25c through the silicagel column separation and purification.
1H?NMR(200MHz，CDCl
3)δ7.35(m，5H0，6.83(m，4H)，5.23(s，2H)，4.61(s，2H)，3.76(s，3H)ppm.
Embodiment 13
The preparation of 2-Bian oxygen base carbonyldioxy acetate Bian ester 25d
It is soluble in water to get 3.80g (0.05mol) 23, adds 10.50g (0.13mol) NaHCO
3, stirring at room does not add 0.5g (1.55mmol) four butyl bromation amine to there being the bubble back of emerging, and adds 15mL (0.13mol) cylite then.After the reflux 1 hour, conditioned reaction liquid pH value is to neutral, and ethyl acetate extraction three times merges organic phase.Organic phase is through anhydrous Na
2SO
4Dry after-filtration removes solvent under reduced pressure, and crude product obtains colourless liquid 25d (10.5g, productive rate 82.0%) through the silicagel column separation and purification.
1H?NMR(200MHz，CDCl
3)δ7.34(m，10H)，4.65(s，2H)，4.68(s，2H)，1.90(m，2H)ppm。，
Embodiment 14
The preparation of 2-PIVALIC ACID CRUDE (25) guanidine-acetic acid Bian ester 25e
3.0g (18.1mmol) 24a is dissolved in the dry methylene chloride, adds 3.0mL (21.6mmol) Et behind adding 2.6mL (21.1mmol) tertiary butyl formyl chloride
3N, stirred overnight at room temperature, reaction solution washes with water.Separate organic phase, water dichloromethane extraction three times merge organic phase, and the anhydrous sodium sulfate drying after-filtration removes solvent under reduced pressure, and crude product obtains colourless liquid 25e (4.3g, productive rate 93%) through the silicagel column separation and purification.
1HNMR(200MHz，CDCl
3)δ7.25(m，5H)，5.08(s，2H)，4.54(s，2H)，1.13(s，9H)ppm。
Embodiment 15
The preparation of 2-benzoyloxy acetate Bian ester 25f
2.5g (15.1mmol) 24a is dissolved in the 10mL dry methylene chloride, adds 3.1mL (22.3mmol) Et behind adding 2.5mL (21.5mmol) Benzoyl chloride
3N, stirred overnight at room temperature.Reaction solution washes with water, separates organic phase, and water dichloromethane extraction three times merge organic phase.The anhydrous sodium sulfate drying after-filtration removes solvent under reduced pressure, and crude product obtains colourless liquid 25f (3.8g, productive rate 93.4%) through the silicagel column separation and purification.
1H?NMR(200MHz，CDCl
3)δ8.10(d，J＝5.2Hz，2H)，7.33-7.49(m，8H)，5.22(s，2H)，4.89(s，2H)ppm。
Embodiment 16
The preparation of 2-methoxyl group carbonyldioxy acetate Bian ester 25g
Getting 2.5g (15.1mmol) 24a is dissolved among the dry 15mL THF, gradation adds 0.8g (20.0mmol) NaH (60% content), and stirring at room adds 1.3mL (16.87mmol) methyl-chloroformate after half an hour, after the stirring at room 3 hours, in reaction solution impouring water.Separate organic phase, water ethyl acetate extraction three times merge organic phase, the anhydrous sodium sulfate drying after-filtration.Remove solvent under reduced pressure.Crude product obtains colorless liquid product 25g (2.6g, productive rate 76.9%) through the silicagel column separation and purification.
1H?NMR(300MHz，CDCl
3)δ7.34(m，5H)，5.22(s，2H)，4.68(s，2H)，3.84(s，3H)ppm。
Embodiment 17
The preparation of 2-Bian oxygen base carbonyldioxy acetate Bian ester 25h
2.5g (15.1mmol) 24a is dissolved in the 10mL dry methylene chloride, adds 2.8mL (18.4mmol) DBU, stirring at room behind adding 2.5mL (17.6mmol) chloroformic acid benzyl ester.Reaction solution separates organic phase with the washing of 1M dilute hydrochloric acid, and water dichloromethane extraction three times merge organic phase, and the anhydrous sodium sulfate drying after-filtration removes solvent under reduced pressure, and crude product obtains colourless liquid 25h (3.3g, productive rate 73.0%) through the silicagel column separation and purification
1H NMR (200MHz, CDCl
3) δ 7.36 (m, 10H), 5.20 (s, 4H), 4.68 (s, 2H) ppm.
Embodiment 18
The preparation of 2-tert.-butoxy carbonyldioxy acetate Bian ester 25i
11.2g (67.5mmol) 24a is dissolved in the 100mL dry methylene chloride, adds 14.8g (67.8mmol) Boc
2O, ice-water bath drip down the 5mL dichloromethane solution of 1.65g (13.5mmol) DMAP, after dropwising, and stirring at normal temperature half an hour.Remove solvent under reduced pressure, crude product obtains white solid 6c (16.9g, productive rate 94.0%) through the silicagel column separation and purification.
1H?NMR(200MHz，CDCl
3)δ7.34(m，5H)，5.19(s，2H)，4.59(s，2H)，1.47(s，9H)ppm。
Embodiment 19
The preparation of 2-tert.-butoxy carbonyldioxy methyl acetate 25j
7.0g (77.8mmol) 24b is dissolved in the 50mL dry methylene chloride, adds 17.0g (77.8mmol) Boc
2O, ice-water bath drip down the 5mL dichloromethane solution of 1.9g (15.6mmol) DMAP, after dropwising, and stirring at normal temperature half an hour.Remove solvent under reduced pressure, crude product obtains colorless liquid product 25j (14.6g, productive rate 98.3%) through the silicagel column separation and purification.
1H?NMR(400MHz，CDCl
3)δ4.57(s，2H)，3.78(s，3H)，1.51(s，9H)ppm。
Embodiment 20
The preparation of α-tert.-butoxy carboxylic acid group acetate sulphur Bian ester 25k
5.0g (18.8mmol) 24i is dissolved in the methyl alcohol, adds 2.5g Pd/C (10%), stirred overnight at room temperature.Remove solvent after the filtration under reduced pressure, crude product is dissolved in the dry methylene chloride, adds 3.8g (18.45mmol) DCC and 3.9mL (28.0mmol) Et
3N and 2.1mL (17.7mmol) benzyl sulfhydrate, stirred overnight at room temperature, reaction solution washes with water, separates organic phase, water dichloromethane extraction three times, merge organic phase, the anhydrous sodium sulfate drying after-filtration removes solvent under reduced pressure, and crude product is through the silicagel column separation and purification, obtain colourless liquid 25k (3.3g, productive rate 62.3%).
1H?NMR(200MHz，CDCl
3)δ7.30-7.24(m，5H)，4.71(s，2H)，4.18(s，2H)，1.50(s，9H)ppm。
Embodiment 21
The preparation of α-tert.-butoxy carboxylic acid group allyl acetate 25l
The 12.4g24c first product is dissolved in the 100mL dry methylene chloride, adds 17.6g (80.6mmol) Boc
2Behind the O, ice-water bath drips the 5mL dichloromethane solution of 1.8g (14.7mmol) DMAP down, after dropwising, and stirring at normal temperature 1 hour.Remove solvent under reduced pressure, crude product obtains weak yellow liquid 25l (14.6g, productive rate 65.4%) through the silicagel column separation and purification.
1H?NMR(400MHz，CDCl
3)δ5.96-5.86(m，1H)，5.29(m，2H)，4.69(d，J＝6.0Hz，2H)，4.60(s，2H)，1.51(s，9H)ppm。
Embodiment 22
Alpha-hydroxy protection acetic ester 25 with (R)-tertiary butyl sulfinyl amine schiffbase 22 asymmetric reduction reactions prepare the general process of propionic acid Bian ester 26
(5.0mmol) places reaction flask, N with compound 25
2After the protection, add the THF of fresh dried, be cooled to-78 ℃, add organic bases (5.0mmol), add compound 22 (1.0mmol) after 1 hour.Add saturated NH after 6 hours-78 ℃ of reactions
4Organic layer is told in Cl solution cancellation reaction.Water layer ethyl acetate extraction 3 times merge organic layer, and anhydrous sodium sulfate drying filters, and evaporated under reduced pressure solvent, crude product obtain compound 26 through the silicagel column separation and purification, and yield and cis-selectivity yield see Table one.
(2R, 3S)-2-(triethyl siloxy)-3-phenyl-3-((R)-tertiary butyl sulfonamido) propionic acid Bian ester 26a
26a, colourless liquid.
1H?NMR(400MHz，CDCl
3)δ7.18-7.40(m，10H)，5.02(d，2H)，4.64(dd，J＝9.2，6.0Hz，1H)，4.53(d，J＝6.0Hz，1H)，4.01(d，J＝9.2Hz，1H)，1.17(s，9H)，0.84(t，J＝10.8Hz，9H)，0.50(m，6H)ppm.
(2R, 3S)-2-(triethyl siloxy)-3-phenyl-3-((R)-tertiary butyl sulfonamido) propionic acid Bian ester 26b
26b, colourless liquid.
1H?NMR(400MHz，CDCl
3)δ7.20-7.40(m，10H)，5.02(d，J＝2.0Hz，2H)，4.63(dd，J＝9.2，6.0Hz，1H)，4.48(d，J＝6.5Hz，1H)，4.00(d，J＝9.2Hz，1H)，1.17(s，9H)，0.81(s，9H)，-0.08(s，3H)，-0.11(s，3H)ppm；
26b ', colourless liquid.
1H?NMR(400MHz，CDCl
3)δ7.18-7.38(m，10H)，5.01(d，J＝2.0Hz，2H)，4.73(t，J＝5.2Hz，1H)，4.60(d，J＝4.8Hz，1H)，4.37(d，J＝4.8Hz，1H)，1.18(s，9H)，0.86(s，9H)，-0.01(s，3H)，-0.13(s，3H)ppm.
26b " and the mixture of 26b , colourless liquid.
1H?NMR(400MHz，CDCl
3)δ7.18-7.38(m，10H)，5.22(d，J＝12.0Hz，1H，minor)，5.15(d，J＝12.0Hz，1H，minor)，5.11(d，J＝12.0Hz，1H，major)，5.01(d，J＝12.0Hz，1H，major)，4.90(d，J＝9.0Hz，1H，minor)，4.78(t，J＝5.2Hz，1H，major)，4.42(d，J＝5.2Hz，1H，minor)，4.39(m，2H，major)，4.38(d，J＝2.0Hz，1H，minor)，1.22(s，9H，major)，1.13(s，9H，minor)，0.84(s，9H，major)，0.74(s，9H，minor)，-0.07(s，3H，major)，-0.17(s，3H，major)，-0.20(s，3H，minor)，-0.45(s，3H，minor)ppm；
13C?NMR(400MHz，CDCl
3)δ170.8(major)，170.4(minor)，139.4(major)，138.1(minor)，135.1(major)，135.0(minor)，128.6，128.4，128.36，128.26，128.21，128.10，128.05，127.98，127.70，127.43，127.26，76.8(major)，76.51(minor)，66.98(minor)，66.91(major)，61.47(minor)，61.31(major)，56.5(major)，55.5(minor)，25.4，25.3，22.5，22.2，17.9，-5.5(minor)，-5.7(major)，-5.9(minor)，-6.3(major)ppm.
Embodiment 23
(2R, 3S)-2-(methoxyl group carbonyldioxy)-3-phenyl-3-((R)-tertiary butyl sulfonamido) propionic acid Bian ester 26g
26g, sticking shape liquid.
1H?NMR(400MHz，CDCl
3)δ7.24-7.41(m，10H)，5.28(d，J＝2.8Hz，1H)，5.20(d，J＝12.0Hz，1H)，5.16(d，J＝12.0Hz，1H)，5.03(dd，J＝10.0，2.8Hz，1H)，4.14(d，J＝9.6Hz，1H)，3.75(s，3H)，1.14(s，9H)ppm.
26g ', white solid.
1H?NMR(400MHz，CDCl
3)δ7.19-7.41(m，10H)，5.41(d，J＝4.8Hz，1H)，5.13(d，J＝11.6Hz，1H)，5.06(d，J＝11.6Hz，1H)，4.92(t，J＝5.2Hz，1H)，4.23(d，J＝5.3Hz，1H)，3.79(s，3H)，1.17(s，9H)ppm.
Embodiment 24
(2R, 3S)-2-(Bian oxygen base carbonyldioxy)-3-phenyl-3-((R)-tertiary butyl sulfonamido) propionic acid Bian ester 26h
26h, sticking shape liquid.
1H?NMR(400MHz，CDCl
3)δ7.35(m，10H)，5.32(d，J＝2.8Hz，1H)，5.15(q，J＝12.8Hz，2H)，5.11(q，J＝16.8，4.4Hz，2H)，5.03(dd，J＝10.0，3.2Hz，1H)，4.13(d，J＝10.0Hz，1H)，1.12(s，9H)ppm；
13C?NMR(400MHz，CDCl
3)δ167.2，154.1，137.7，134.7，134.6，128.64，128.58，128.53，128.4，128.2，128.1，127.1，78.7，70.3，67.6，60.3，56.7，22.4ppm.
Embodiment 25
(2R, 3S)-preparation of 2-(tert.-butoxy carbonyldioxy)-3-phenyl-3-((R)-tertiary butyl sulfonamido) propionic acid Bian ester 26i
26i, white solid, fusing point 148-149 ℃ .IR (KBr) 3296,2975,1746,1497,1458,1426,1395,1366,1291,1243,1208,1160,1113,1046,1009,956,862cm
-1 1H NMR (400MHz, CDCl
3) δ 7.22-7.41 (m, 10H), 5.27 (d, J=0.8Hz, 1H), 5.17 (s, 1H), 5.01 (d, J=9.6Hz, 1H), 4.14 (d, J=9.6Hz, 1H), 1.39 (s, 9H), 1.15 (s, 9H) ppm;
13C NMR (400MHz, CDCl
3) δ 167.5,152.1,137.8,134.6,128.5,128.4,128.0,127.1,83.3,77.6,67.4,60.4,56.6,27.4,22.3ppm; MS (+) FAB, m/z 476[M+H]
+.
Embodiment 26
(2R, 3S)-preparation of 2-(tert.-butoxy carbonyldioxy)-3-phenyl-3-((R)-tertiary butyl sulfonamido) methyl propionate 26j
26j, white solid.
1H?NMR(400MHz，CDCl
3)δ7.24-7.43(m，10H)，5.25(d，J＝2.8Hz，1H)，5.01(dd，J＝10.0，2.8Hz，1H)，4.16(d，J＝10.0Hz，1H)，1.41(s，9H)，1.19(s，9H)ppm；
13C?NMR(400MHz，CDCl
3)δ168.1，152.2，138.0，128.6，128.1，127.1，83.4，77.63，60.3，56.7，52.4，27.5，22.5，22.4ppm.
26j ', sticking shape liquid.
1H?NMR(400MHz，CDCl
3)δ7.24-7.43(m，10H)，5.40(d，J＝4.8Hz，1H)，4.97(t，J＝5.6Hz，1H)，3.76(d，J＝7.2Hz，1H)，3.65(s，3H)，1.46(s，9H)，1.12(s，9H)ppm.
Embodiment 27
(2R, 3S)-preparation of 2-(tert.-butoxy carbonyldioxy)-3-phenyl-3-((R)-tertiary butyl sulfonamido) propionic acid sulphur Bian ester 26k
26k, sticking shape liquid.
1H?NMR(400MHz，CDCl
3)δ7.20-7.40(m，10H)，5.38(d，J＝2.8Hz，1H)，5.01(dd，J＝10.4，2.8Hz，1H)，4.11(s，2H)，1.37(s，9H)，1.12(s，9H)ppm.
Embodiment 28
2R, 3S)-preparation of 2-(tert.-butoxy carbonyldioxy)-3-phenyl-3-((R)-tertiary butyl sulfonamido) allyl propionate 26l
26l, sticking shape liquid.
1H?NMR(400MHz，CDCl
3)δ7.27-7.43(m，5H)，5.88(m，1H)，5.36(dd，J＝11.6，1.2Hz，1H)，5.28(dd，J＝11.6，1.2Hz，1H)，5.24(d，J＝2.8Hz，1H)，5.00(dd，J＝10.0，3.2Hz，1H)，4.65(dd，J＝5.6，1.2Hz，2H)，4.14(d，J＝10.0Hz，1H)，1.43(s，9H)，1.19(s，9H)ppm；
13C?NMR(400MHz，CDCl
3)δ167.4，152.2，138.0，131.1，128.5，128.1，127.2，119.1，83.3，77.7，66.2，60.5，56.7，27.5，27.4，22.4ppm.
Embodiment 29
(2R, 3S)-preparation of 2-(tert.-butoxy carbonyldioxy)-3-o-bromophenyl-3-((R)-tertiary butyl sulfonamido) propionic acid Bian ester 26n
26n, white solid.
1H?NMR(400MHz，CDCl
3)δ7.57(d，J＝7.6Hz，1H)，7.46(d，J＝8.0Hz，1H)，7.37(m，6H)，7.16(t，J＝7.6Hz，1H)，5.49(dd，J＝10.4，2.4Hz，1H)，5.37(d，J＝2.4Hz，1H)，5，25(dd，J＝9.2，4.8Hz，2H)，4.36(d，J＝10.8Hz)，1.35(s，9H)，1.11(s，9H)ppm.
Embodiment 30
(2R, 3S)-preparation of 2-(tert.-butoxy carbonyldioxy)-3-p-methoxyphenyl-3-((R)-tertiary butyl sulfonamido) propionic acid Bian ester 26o
26o, sticking shape liquid.
1H?NMR(400MHz，CDCl
3)δ7.28-7.40(m，5H)，6.85(d，J＝4.8Hz，2H)，5.22(d，J＝3.6Hz，1H)，5.15(dd，J＝1.6Hz，2H)，4.93(dd，J＝9.6，3.2Hz，1H)，4.07(d，J＝9.4Hz，1H)，3.77(s，3H)，1.40(s，9H)，1.14(s，9H)ppm.
Embodiment 31
(2R, 3S)-2-(tert.-butoxy carbonyldioxy)-3-(p-nitrophenyl)-3-((R)-tertiary butyl sulfonamido) propionic acid Bian ester 26p
26p, white solid.
1H?NMR(400MHz，CDCl
3)δ8.19(d，J＝8.8Hz，2H)，7.60(d，J＝8.8Hz，2H)，7.33(m，5H)，5.25(d，J＝2.8Hz，1H)，5.19(dd，J＝14.4，2.4Hz，2H)，4.30(d，J＝10.4Hz，1H)，1.41(s，9H)，1.15(s，9H)ppm；
Embodiment 32
(2R, 3S)-2-(tert.-butoxy carbonyldioxy)-3-(2 '-pyridyl)-3-((R)-tertiary butyl sulfonamido) propionic acid Bian ester 26q
26q，。
1H?NMR(400MHz，CDCl
3)δ8.53(d，J＝4.8Hz，1H)，7.65(dt，J＝7.6，1.6Hz，1H)，7.52(d，J＝8.0Hz，1H)，7.35(m，5H)，7.17(dd，J＝7.2，4.8Hz，1H)，5.58(d，J＝3.2Hz，1H)，5.109d，J＝8.4Hz，2H)，5.09(dd，J＝9.2，3.2Hz，1H)，4.91(d，J＝9.2Hz，1H)，1.41(s，9H)，1.18(s，9H)ppm.
Embodiment 33
(2R, 3S)-2-(tert.-butoxy carbonyldioxy)-3-(2 '-furyl)-3-((R)-tertiary butyl sulfonamido) propionic acid Bian ester 26r
26p, sticking shape liquid.
1H?NMR(400MHz，CDCl
3)δ7.35(m，5H)，6.49(d，J＝1.2Hz，1H)，6.32(m，1H)，5.49(d，J＝3.6Hz，1H)，5.20(dd，J＝8.0，2.0Hz，2H)，5.02(dd，J＝10.8，2.8Hz，1H)，3.91(d，J＝10.8Hz，1H)，1.43(s，9H)，1.14(s，9H)ppm.
Embodiment 34
By propionic acid Bian ester 26i preparation (2R, 3S)-2-(tert.-butoxy carbonyldioxy)-3-phenyl-3-((R)-tertiary butyl sulfonamido) propionic acid 27
Compound 26i (1.010g, 2.2mmol)) is dissolved in the methyl alcohol, adds the 10%Pd (OH) that 0.234g contains 50% moisture
2, stirring at room is 10 hours under the 200psi hydrogen pressure.Filter, evaporated under reduced pressure solvent, crude product obtain white solid product 27 (0.784g, 92.6% yield) through the silicagel column separation and purification.
27, white solid, [α]
20 D° (c 2.19, CHCl
3); IR (KBr) cm
-1 1H NMR (400MHz, CDCl
3) δ 7.20-7.50 (m, 5H), 5.74 (br, 2H), 5.17 (s, 1H), 5.13 (s, 1H), 1.37 (s, 9H), 1.10 (s, 9H) ppm;
13C NMR (400MHz, CDCl
3) δ ppm; Anal.Calcd forC
18H
27NO
6S:C, 56.08; H, 7.06; N, 3.63; O, 24.90; S, 8.32.Found; C; H; N; S; MS (+) FAB, m/z 000[M+H]+; HRMS (+) FAB calcd for[M+H]
+:+386.1559 Found[M+H]
+:+000.0000.
Embodiment 34
By methyl propionate 26j preparation (2R, 3S)-2-(tert.-butoxy carbonyldioxy)-3-phenyl-3-((R)-tertiary butyl sulfonamido) propionic acid 27
(0.50g 1.25mmol) is dissolved in the 5mL methyl alcohol, adds the saturated Na of 5mL with 26j
2CO
3Solution, stirring at room 5 hours.Reaction finishes, and in reaction solution impouring 10mL frozen water, regulates pH to 7 with 0.5M dilute hydrochloric acid, uses 10mL ethyl acetate extraction three times.Merge organic phase, through anhydrous MgSO
4Dry after-filtration, the pressure reducing and steaming solvent.Resistates gets compound 27 (0.43g, 89.0%) behind column chromatography purification.
Embodiment 35
By propionic acid 27 preparation (2R, 3S)-2-(tert.-butoxy carbonyldioxy)-3-phenyl-3-((R)-tertiary butyl sulfinyl)-beta-lactam 28
With 27 (0.385g 1.0mmol) is dissolved in the dry acetonitrile of 10mL, add 2-chloro-1-methyl-iodide for pyridine (0.383g, 1.5mmol) and triethylamine (0.202g, 2.0mmol), be heated to 60 ℃ 6 hours.Remove solvent under reduced pressure, crude product obtains white solid product 28 (0.140g, 36.4%) through the silicagel column separation and purification.
1HNMR(400MHz，CDCl
3)δ7.43(m，5H)，5.74(d，J＝6.0Hz，1H)，5.37(d，J＝6.0Hz，1H)，1.16(s，9H)，1.03(s，9H)ppm.
Embodiment 36
(4R, 5S)-2,2-dimethyl-4-(formic acid Bian ester)-5-phenyl-N-((R)-tertiary butyl sulfonamido) azoles alkane 30a
Compound 26i is dissolved in the dichloromethane solution of 20% trifluoroacetic acid, stirring at room removes excessive trifluoroacetic acid and dichloromethane solution under reduced pressure after half an hour.Resistates adds 10% sodium hydrogen carbonate solution, and uses ethyl acetate extraction.Merge organic phase, the anhydrous magnesium sulfate drying after-filtration removes under reduced pressure and obtains 29a behind the solvent and can be directly used in next step reaction.
1H?NMR(400MHz，CDCl
3)δ7.28-7.489m，10H)，5.29(d，J＝12.0，1H)，5.18(d，J＝12.0Hz，1H)，4.88(dd，J＝8.8，2.0Hz，1H)，4.55(dd，J＝5.2，2.0Hz，1H)，4.12(d，J＝8.8Hz，1H)，3.30(d，J＝4.8Hz，1H)，1.58(s，9H)，1.14(s，9H)ppm.
The tosic acid of 29a and 1.5 normal 2-methoxyl group propylene and catalytic amount is dissolved in the dry DMF stirring at room 12 hours.Reaction finishes, with in the sodium hydrogen carbonate solution of reaction solution impouring 10% and use ethyl acetate extraction.Merge organic phase, the anhydrous magnesium sulfate drying after-filtration, decompression steams solvent and obtains azoles alkane 30a through column chromatography for separation.
Claims (7)
1, the synthetic method of a kind of taxol and analogue side chain thereof; it is characterized in that: it is to form enol intermediate and optically pure tertiary butyl sulfinyl amine schiffbase (22) effect generation asymmetric reduction reaction by the protected Alpha-hydroxy acetic ester of hydroxyl (25) under the highly basic condition; 2 hydroxyls of cis-selectivity preparation are protected, 3 tertiary butyl sulfinyls are protection and optically pure 2-hydroxyl-3-alanine ester intermediates (26) 3 replacements; this intermediate has (2R; 3S) or (2S, 3R) three-dimensional configuration.
Protected Alpha-hydroxy acetic ester of hydroxyl (25) and chirality tertiary butyl sulfinyl amine schiffbase (22)
Optically pure tertiary butyl sulfinyl amine inductive asymmetric reduction reaction
2, the synthetic method of taxol as claimed in claim 1 and analogue side chain thereof is characterized in that: described hydroxyl protecting group is: the methyl of ether chain series, the tertiary butyl, benzyl, the aromatic base that methoxyl group replaces, methoxymethyl, ethoxyl methyl, 2,2,2-trichlorine ethoxyl methyl, 2-trimethyl silicane ethoxyl methyl, Bian oxygen ylmethyl, siloxy methyl, 2-methoxy ethoxy methyl, 4-methoxyl group phenoxymethyl; Or silicon ether series is trimethyl silicon based, and triethyl is silica-based, triisopropylsilyl, and dimethyl ethyl is silica-based, and the dimethyl sec.-propyl is silica-based, and the dimethyl tertiary butyl is silica-based, and tert-butyl diphenyl is silica-based; Or the valeryl of carbonyl series, trihalogen acetyl, benzoyl, methoxy methyl acyl group, ethoxy acetyl, propoxy-formyl radical, isopropoxy formyl radical, tert.-butoxy formyl radical, phenylol formyl radical substituting group.
3, the synthetic method of taxol as claimed in claim 1 and analogue side chain thereof; it is characterized in that: described ester group protecting group is: the saturated or undersaturated alkyl of the straight chain of 1 to 16 carbon atom or side chain; the replacement of 3 to 8 yuan of rings, the cyclic alkyl of non-replacement; aromatic base, sulfydryl or dibasic amido.
4, the synthetic method of taxol as claimed in claim 1 and analogue side chain thereof, it is characterized in that: the substituting group of described tertiary butyl sulfinyl amine schiffbase is: saturated and alkyl insatiable hunger of the straight chain of 1 to 16 carbon atom or side chain, the replacement of 3 to 8 yuan of rings, the cyclic alkyl of non-replacement, the heteroatoms aromatic base of replacement, non-replacement etc.
5, the synthetic method of taxol as claimed in claim 1 and analogue side chain thereof is characterized in that: solvent for use is: THF, ether, dme, di-tert-butyl ether, t-butyl methyl ether, tertiary butyl ether, isopropyl ether, sherwood oil, dioxane, benzene, toluene, dimethylbenzene, DMF etc.
6, the synthetic method of taxol as claimed in claim 1 and analogue side chain thereof, it is characterized in that: described alkali is: lithium diisopropyl amido, diisopropyl amido sodium, two (trimethyl silicane) amido lithium, two (trimethyl silicane) amido sodium, butyllithium, tert-butyl lithium, phenyl lithium, highly basic such as sodium alkoxide, potassium tert.-butoxide.
7, the synthetic method of taxol as claimed in claim 1 and analogue side chain thereof is characterized in that: set out by described intermediate (26) and further derive preparation optically pure side chain intermediate (28) and (30) and have the analogue of different substituents on hydroxyl.
The preparation of the side chain 28 of straight chain type side chain 27 and beta-lactam type
Preparation with straight chain type side chain 30 of different substituents
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2005100826760A CN1709864A (en) | 2005-07-08 | 2005-07-08 | Taxol and its analogue side chain synthesizing method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2005100826760A CN1709864A (en) | 2005-07-08 | 2005-07-08 | Taxol and its analogue side chain synthesizing method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1709864A true CN1709864A (en) | 2005-12-21 |
Family
ID=35706159
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005100826760A Withdrawn CN1709864A (en) | 2005-07-08 | 2005-07-08 | Taxol and its analogue side chain synthesizing method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1709864A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102010383A (en) * | 2010-11-24 | 2011-04-13 | 上海博速医药科技有限公司 | Method for preparing docetaxel chiral side chain intermediate |
| CN102134208A (en) * | 2010-01-27 | 2011-07-27 | 爱斯特（成都）医药技术有限公司 | [R, R] methylphenidate intermediates and analogs thereof, and their synthesis and uses |
| CN103086924A (en) * | 2013-01-17 | 2013-05-08 | 暨明医药科技（苏州）有限公司 | Synthetic method of docetaxel and intermediate of docetaxel |
| CN104356156A (en) * | 2014-10-24 | 2015-02-18 | 江苏红豆杉药业有限公司 | Preparation method of four-membered ring taxane side chain compound |
| WO2015074605A1 (en) * | 2013-11-22 | 2015-05-28 | 天士力控股集团有限公司 | Taxanes compounds, preparation method therefor, and uses thereof |
| CN104356157B (en) * | 2014-10-24 | 2017-08-18 | 江苏红豆杉药业有限公司 | A kind of preparation method of chiral four-membered ring taxane side chain compound |
-
2005
- 2005-07-08 CN CNA2005100826760A patent/CN1709864A/en not_active Withdrawn
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102134208A (en) * | 2010-01-27 | 2011-07-27 | 爱斯特（成都）医药技术有限公司 | [R, R] methylphenidate intermediates and analogs thereof, and their synthesis and uses |
| CN102134208B (en) * | 2010-01-27 | 2014-05-14 | 爱斯特（成都）医药技术有限公司 | [R,R]-methylphenidate intermediate and analogue thereof and their synthesis and application |
| CN102010383A (en) * | 2010-11-24 | 2011-04-13 | 上海博速医药科技有限公司 | Method for preparing docetaxel chiral side chain intermediate |
| CN102010383B (en) * | 2010-11-24 | 2012-08-15 | 上海博速医药科技有限公司 | Method for preparing docetaxel chiral side chain intermediate |
| CN103086924A (en) * | 2013-01-17 | 2013-05-08 | 暨明医药科技（苏州）有限公司 | Synthetic method of docetaxel and intermediate of docetaxel |
| WO2015074605A1 (en) * | 2013-11-22 | 2015-05-28 | 天士力控股集团有限公司 | Taxanes compounds, preparation method therefor, and uses thereof |
| KR20160079135A (en) * | 2013-11-22 | 2016-07-05 | 장쑤 태슬리 디이 파마슈티컬 컴퍼니 리미티드 | Taxanes compounds, preparation method therefor, and uses thereof |
| EP3081560A4 (en) * | 2013-11-22 | 2017-04-26 | Jiangsu Tasly Diyi Pharmaceutical Co., Ltd. | Taxanes compounds, preparation method therefor, and uses thereof |
| US10253007B2 (en) | 2013-11-22 | 2019-04-09 | Jiangsu Tasly Diyi Pharmaceutical Co., Ltd. | Taxanes compounds, preparation method therefor, and uses thereof |
| RU2686675C1 (en) * | 2013-11-22 | 2019-04-30 | Цзянсу Тасли Дии Фармасьютикал Ко., Лтд. | Taxane compounds and also the production method and use thereof |
| RU2686675C9 (en) * | 2013-11-22 | 2019-09-26 | Цзянсу Тасли Дии Фармасьютикал Ко., Лтд. | Taxane compounds and also the production method and use thereof |
| KR102350002B1 (en) | 2013-11-22 | 2022-01-10 | 장쑤 태슬리 디이 파마슈티컬 컴퍼니 리미티드 | Taxanes compounds, preparation method therefor, and uses thereof |
| CN104356156A (en) * | 2014-10-24 | 2015-02-18 | 江苏红豆杉药业有限公司 | Preparation method of four-membered ring taxane side chain compound |
| CN104356157B (en) * | 2014-10-24 | 2017-08-18 | 江苏红豆杉药业有限公司 | A kind of preparation method of chiral four-membered ring taxane side chain compound |
| CN104356156B (en) * | 2014-10-24 | 2017-10-31 | 江苏红豆杉药业有限公司 | A kind of preparation method of four-membered ring taxane side chain compound |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1080256C (en) | Novel beta-lactams, methods for the preparation of taxanes and sidechain-bearing taxanes | |
| CN1200731A (en) | Intermediary compounds for the hemisynthesis of taxanes and prepn. processes therefor | |
| CN1102829A (en) | Synthese of taxol, taxol analogs and their intermediates with variable A-ring side chain structures and compositions thereof | |
| CN1075718A (en) | Metal alkoxide | |
| CN1709864A (en) | Taxol and its analogue side chain synthesizing method | |
| CN1340048A (en) | Production of isoflavone derivatives | |
| CN1942460A (en) | One pot synthesis of taxane derivatives and their conversion to paclitaxel and docetaxel | |
| CN1759093A (en) | Azide free process for preparing 1,2-diamino compounds | |
| CN1324017C (en) | Process for preparing 5-(1, 3-oxazol-2-yl) benzoic acid derivatives | |
| CN1074681A (en) | Chromene and relevant leukotriene B 4Antagonist | |
| CN1974550A (en) | Process for the preparation of compounds having a CF2O bridge | |
| CN1105358A (en) | N-substituted azabicycloheptane derivatives, the preparation and use thereof | |
| CN1927830A (en) | Compound of optically pure sulfenamides and application thereof | |
| CN1319596A (en) | Synthesis of 3,6-dialkyl 5,6-dihydro-4-hydroxide-2H-pyran-2-ketone | |
| CN1161347C (en) | Novel methods for preparation of taxanes using oxazolidine intermediates | |
| CN1116850A (en) | Optically active beta-aminoalkoxyborane complex | |
| CN1461301A (en) | Benzo [b] thiophene derivative and process for producing the same | |
| CN101054355A (en) | Compound of optically pure disulfenamides and application thereof | |
| CN1216039A (en) | Process to prepare taxol | |
| CN1252788A (en) | Process for preparing pharmaceutical compounds | |
| CN101080416A (en) | Method for producing thiophene glycoside derivatives | |
| CN1139586C (en) | Process for stereoselective preparation of hetero-bicyclic alcohol enantiomer | |
| CN1102644A (en) | Condensed pyridine type mevalonolactone intermediate and process for its production | |
| CN1133641C (en) | Thiophosphamino acid ester compound containing 3'-azido-deoxythymidine and its preparing process | |
| CN1479714A (en) | Optically active amine derivative and method of synthesis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C04 | Withdrawal of patent application after publication (patent law 2001) | ||
| WW01 | Invention patent application withdrawn after publication |