CN105017048A - Alpha-fluoroalkyl-alpha-amino acid compound containing tetrasubstituted carbon chiral center and preparation method thereof - Google Patents
Alpha-fluoroalkyl-alpha-amino acid compound containing tetrasubstituted carbon chiral center and preparation method thereof Download PDFInfo
- Publication number
- CN105017048A CN105017048A CN201510377316.7A CN201510377316A CN105017048A CN 105017048 A CN105017048 A CN 105017048A CN 201510377316 A CN201510377316 A CN 201510377316A CN 105017048 A CN105017048 A CN 105017048A
- Authority
- CN
- China
- Prior art keywords
- fluoroalkyl
- alpha
- amino acid
- preparation
- acid compounds
- 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.)
- Pending
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
Belonging to the field of organic synthesis, the invention provides an alpha-fluoroalkyl-alpha-amino acid compound containing a tetrasubstituted carbon chiral center, and also discloses a preparation method of the compound. The method utilizes cheap and easily available fluoroalkyl-containing unsaturated ketone and chiral prosthetic group sulfinamide as the starting raw material, and by means of preparation of alpha, beta-unsaturated fluoroalkyl sulfenyl ketoimine, selective addition of an organic metallic reagent and chiral alpha, beta-unsaturated imine, removal of chiral prosthetic group, protection of amino group, and finally double-bond simple oxidation in order, the alpha-fluoroalkyl-alpha-amino acid compound containing the tetrasubstituted carbon chiral center can be obtained by entiomeric purity. The method provided by the invention has the advantages of cheap and easily available raw materials, simple operation of the synthesis method, good selectivity, high yield, and reaction with universal applicability, is a universal method for synthesis of the alpha-fluoroalkyl-alpha-amino acid compound containing the tetrasubstituted carbon chiral center, and has very good application prospects.
Description
Technical field
The invention belongs to organic synthesis field, particularly relate to a kind of fluorine-containing medicines, agricultural chemicals, chemical intermediate and synthetic method thereof, specifically a kind ofly contain alpha-fluoroalkyl-a-amino acid compounds of four replacement carbon chiral centres and preparation method thereof.
Background technology
Fluorinated amino acids is the very important alpha-non-natural amino acid of a class, because fluoro-containing group itself has stronger electron-withdrawing power, higher lipotropy and the larger characteristic such as sterically hindered, makes fluorinated amino acids show some special physiologically actives.Current many fluorinated amino acids have been used as the probe ((a) Vocadlo, the D.J. that follow the tracks of biochemical reaction; Mayer, C.; He, S.M.; Withers, S.G.Biochemistry 2000,39,117-126; (b) Namchuk, M.N.; McCarter, J.D.; Becalski, A.; Andrews, T.; Withers, S.G.J.Am.Chem.Soc.2000,122,1270-1277. (c) Dubios, J.; Dugave, C.; Foures, C.; Kaminsky, M.; Tabet, J.C.; Bory, S.; Gaudry, M.; Marquet, A.Biochemistry 1991,30,10506-10512.), enzyme inhibitors (Kollonitsch, J.; Patchett, A.A.; Marburg, S.; Maycock, A.L.; Perkins, L.M.; Doldouras, G.A.; Duggan, D.E.; Aster, S.D.Nature 1978,24,906-908.) and antitumor drug (Tsushima, T.; Kawada, K.; Ishihara, S.; Uchida, N.; Shiratori, O.; Higaki, J.; Hirata, M.Tetrahedron 1998,44,5375-5387.) etc., be widely used ((a) Kukhar, V.P. in the field such as biology, medicine, agricultural chemicals; Soloshonok, V.A. (eds.), Fluorine-containing Amino Acids:Synthesis and Properties, Wiley, Chichester, 1995; (b) Zanda, M.New J.Chem.2004,28,1401; (c) Koksch, B.; Sewald, N.; Hakubke, H.D.; Burger, K.; In:Biomedical Frontiers of Fluorine Chemistry, (Eds.:Ojima, I.; McCarthy, J.R.; Welch, J.T.), ACS Series 639Washington D.C., 1996,42; (d) Welch, J.T.; Eswarakrishnan, S.Fluorine in Bioorganic Chemistry; Wiley:New York, 1991; (e) Filler, R.; Kobayashi, Y.; Yagupolskii, L.M..Biomedical Aspects of Fluorine Chemistry:Elsevier:Amsterdam, 1993.) in various types of fluorinated amino acids, alpha-fluoroalkyl-a-amino acid is a wherein important class, because its potential physiologically active causes the extensive synthesis interest of chemist and biologists especially, but existing document mainly concentrates on synthesis aspect ((a) Sutherland, the A. of the alpha-fluoroalkyl-a-amino acid with three replacement carbon chiral centres for the synthesis report of alpha-fluoroalkyl-a-amino acid; Willis, C.L.Nat.Prod.Rep.2000,17,621; (b) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L.Tetrahedron 2004,60,6711; (c) Smits, R.; Cadicamo, C.D.; Burger, K.; Koksch, B.Chem.Soc.Rev. 2008,37,1727; (d) Czekelius, C.; Tzschucke, C.C.Synthesis 2010,543; (e) Sorochinsky, A.E.; Soloshonok, V.A.J.Fluorine Chem.2010,131,127.), and it is relatively less for the synthesis report of the alpha-fluoroalkyl-a-amino acid with four replacement carbon chiral centres, ((a) Wang, H. in α-trifluoromethyl-alpha-amino acid whose synthesis that existing report is also only confined to have four replacement carbon chiral centres; Zhao, X.; Li, Y.; Lu, L.Org.Lett.2006,8,1379; (b) Min, Q.-Q.; He, C.-Y.; Zhou, H.; Zhang, X.Chem.Commun.2010,46,8029; (c) Enders, D.; Gottfried, K.; Raabe, G.Adv.Synth.Catal.2010,352,3147; (d) Huguenot, F.; Brigaud, T.J.Org.Chem.2006,71,7075; (e) Martin, T.; Massif, C.; Wermester, N.; Linol, J.; Tisse, S.; Cardinael, P.; Coquerel, G.; Bouillon, J.-P.Tetrahedron:Asymmetry 2011,22,12; (f) Simon, J.; Nguyen, T.T.; Chelain, E.; Lensen, N.; Pytkowicz, J.; Chaume, G.; Brigaud, T.Tetrahedron:Asymmetry 2011,22,309; (g) Asensio, A.; Bravo, P.; Crucianelli, M.; Farina, A.; Fustero, S.; Soler, J.G.; Meille, S.V.; Panzeri, W.; Viani, F.; Volonterio, A.; Zanda, M.Eur.J.Org.Chem.2001,1449; (h) Blocker, M.; Immaneni, S.; Shaikh, A.Tetrahedron Lett.2014,55,5572; (i) Yang, J.; Min, Q.-Q.; He, Y.; Zhang, X.Tetrahedron Lett.2011,52,4675; (j) Morisaki, K.; Sawa, M.; Nomaguchi, J.-y.; Morimoto, H.; Takeuchi, Y.; Mashima, K.; Ohshima T.Chem.Eur.J.2013,19,8417.) and alpha-difluoromethyl-a-amino acid ((a) Liu, Y.-L.; Shi, T.-D.; Zhou, F.; Zhao, X.-L.; Wang, X.; Zhou, J.Org.Lett.2011,13,3826; (b) Liu, J.; Hu, J.Chem.Eur.J.2010,16,11443.) synthesis of the a-amino acid compounds, replaced for other alpha-fluoroalkyls with four replacement carbon chiral centres there is not yet bibliographical information so far.
In addition, because the alpha-fluoroalkyl-a-amino acid replacing carbon chiral centre containing four is of compact construction and stronger lipotropy, be introduced into polypeptide drug, the biological activity of such medicine can be improved significantly, it is not easily decomposed by enzyme catalysis in vivo, strengthen its penetrativity in vivo simultaneously, be conducive to medicine absorption in vivo.Therefore, develop a kind of universally, simple and effective ground, highly-solid selectively ground composite structure various, have that different fluoro-containing group replaces just become very important and very meaningful containing four methods replacing the alpha-fluoroalkyl-a-amino acid compounds of carbon chiral centres.
Summary of the invention
For above-mentioned technical problem of the prior art, the invention provides and a kind ofly contain alpha-fluoroalkyl-a-amino acid compounds of four replacement carbon chiral centres and preparation method thereof, described thisly have the technical problem that alpha-fluoroalkyl-a-amino acid compounds of four replacement carbon chiral centres and preparation method thereof solves in prior art the alpha-fluoroalkyl-a-amino acid compounds that cannot obtain four replacement carbon chiral centres.
The invention provides a kind of alpha-fluoroalkyl-a-amino acid compounds containing four replacement carbon chiral centres, its structural formula is as follows:
Wherein, R
1for alkyl, aryl, heteroaryl, benzyl or naphthyl, R
2for hydrogen, alkyl, aryl, heteroaryl or naphthyl, R
ffor containing fluoroalkyl, described alkyl is C
1-20alkyl or C
1-20haloalkyl, described aryl is phenyl or substituted-phenyl, substituting group in described substituted-phenyl be adjacent, para-orientation or polysubstituted methyl, ethyl, phenyl, methoxyl group, oxyethyl group, benzyloxy, trifluoromethyl, difluoromethyl, a methyl fluoride, fluorine, chlorine, bromine, ethanoyl or dimethylamino, described heteroaryl is furyl, thienyl, pyridyl, pyrazolyl, pyrryl, thiazolyl, oxazolyl, quinolyl, isoquinolyl, indyl, indazolyl, benzofuryl, benzothienyl, benzothiazolyl or benzoxazolyl, described benzyl is phenmethyl, described naphthyl is 1-naphthyl or 2-naphthyl, described is trifluoromethyl containing fluoroalkyl, difluoromethyl, a methyl fluoride, the C that single fluorine or polyfluoro replace
1-20alkyl or C
1-20haloalkyl, PG is carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc), tablet held before the breast by officials methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) oxygen carbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl group (Tfa), adjacent (to) nitrobenzenesulfonyl (Ns), pivaloyl group, benzoyl (Bz), trityl (Trt), 2, 4-dimethoxy-benzyl (Dmb), to methoxy-benzyl (PMB), or benzyl (Bn).
Present invention also offers above-mentioned a kind of preparation method containing the alpha-fluoroalkyl-a-amino acid compounds of four replacement carbon chiral centres, comprise the steps:
1) a preparation α, the step of β-unsaturated fluoroalkyl sulfinyl ketoimine, in organic solvent, with containing fluoroalkyl beta-unsaturated ketone and chiral auxiliary sulfinyl amine for starting raw material, the described mol ratio containing fluoroalkyl beta-unsaturated ketone and chiral auxiliary sulfinyl amine is 1:1 ~ 3, purity titanium tetraethoxide is dissolved in organic solvent together with above-mentioned raw materials, the described mol ratio containing fluoroalkyl beta-unsaturated ketone and purity titanium tetraethoxide is 1:2 ~ 6, α is obtained, β-unsaturated fluoroalkyl sulfinyl ketoimine by reflux, separatory, extraction;
2) under protection of inert gas, temperature controls below-10 DEG C, α, β-unsaturated fluoroalkyl sulfinyl ketoimine and organometallic reagent carry out addition reaction in organic solvent, described α, the mol ratio of β-unsaturated fluoroalkyl sulfinyl ketoimine and organometallic reagent is 1:2 ~ 4, carries out separatory, extraction obtains new adduct after reaction terminates;
3) one removes the step of chiral auxiliary sulfinyl amine, by step 2) addition reaction that obtains is dissolved in organic solvent, and add excessive hydrochloride aqueous solution at normal temperatures, stir, be spin-dried for solvent, obtain the compound being stripped of chiral auxiliary sulfinyl amine;
4) step of an amido protecting, by step 3) compound that obtains is dissolved in organic solvent, adds triethylamine, salt of wormwood, Benzoyl chloride, step 3) mol ratio of the compound that obtains and triethylamine, salt of wormwood and Benzoyl chloride is 1:1 ~ 2:1 ~ 2:2 ~ 4,60 ~ 90 DEG C of reacting by heating are spent the night, and are cooled to room temperature, separatory, extraction, dry, obtain new product;
5) oxidation step of a double bond, step 4) compound that obtains is dissolved in organic solvent, in system, pass into ozone gas to system at the temperature of less than-50 DEG C become blue, TLC follows the tracks of and reacts completely, add triphenyl phosphorus, step 4) mol ratio of the compound that obtains and triphenyl phosphorus is 1:1 ~ 3, stirring at room temperature reacts 3 hours, be spin-dried for solvent, products therefrom is dissolved in organic solvent, and in system, add 2-methyl 2-butylene, water, Textone, SODIUM PHOSPHATE, MONOBASIC, step 4) compound that obtains and 2-methyl 2-butylene, water, Textone, the mol ratio of SODIUM PHOSPHATE, MONOBASIC is 1:0.04 ~ 0.06:5 ~ 10:3 ~ 5:3 ~ 5, TLC tracks to and reacts completely, add aqueous sodium hydroxide solution and adjust pH value of solution=9, revolve and desolventize, aqueous phase dilute hydrochloric acid is neutralized to pH=3, extraction, merge organic phase, dry, be spin-dried for solvent and obtain the alpha-fluoroalkyl-a-amino acid compounds with four replacement carbon chiral centres,
6) step of a deaminizating protecting group, by step 5) compound that obtains adds excessive concentrated hydrochloric acid and in tube sealing, is heated to 90 ~ 105 DEG C of reactions and spend the night, after being cooled to room temperature, filter, filtrate is spin-dried for obtain the alpha-fluoroalkyl-a-amino acid compounds with four replacement carbon chiral centres of deprotection group;
7) step of an amino acid esterification, by step 6) compound that obtains is dissolved in alcohol, cryosel bath cooling, dripping sulfur oxychloride, step 6) compound that obtains is 1:4 ~ 8 with the mol ratio of sulfur oxychloride, finishes to return to room temperature post-heating and reflux, 15 ~ 30 hours, revolve and desolventize, add saturated sodium bicarbonate aqueous solution, stir, separatory, extraction, dry, be spin-dried for alpha-fluoroalkyl-a-amino acid ester compound that solvent must have four replacement carbon chiral centres.
Further, the described structural formula containing fluoroalkyl beta-unsaturated ketone is,
wherein said R
3for alkyl, aryl, heteroaryl, benzyl or naphthyl.
Further, the structural formula of described chiral auxiliary sulfinyl amine is:
wherein said R
4for alkyl, aryl, heteroaryl, benzyl or naphthyl.
Further, step 1) described in solvent be ether, tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether, isopropyl ether, dioxane, methylene dichloride, normal hexane or toluene.
Further, described organometallic reagent is organolithium reagent, and described organolithium reagent has R
1the structure of Li, step 2) in solvent used be ether, tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether, isopropyl ether, dioxane, normal hexane or toluene.
Further, remove the dioxane solution of the aqueous solution, the diethyl ether solution of hydrogenchloride, the methanol solution of hydrogenchloride or the hydrogenchloride that reagent used in the step of chiral auxiliary sulfinyl amine is hydrogenchloride at one, organic solvent used is ether, tetrahydrofuran (THF), methylene dichloride, trichloromethane, methyl alcohol or dioxane.
Further, in the step of an amido protecting, adopt carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc), tablet held before the breast by officials methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) oxygen carbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl group (Tfa), adjacent (to) nitrobenzenesulfonyl (Ns), pivaloyl group, benzoyl (Bz), trityl (Trt), 2, 4-dimethoxy-benzyl (Dmb), to methoxy-benzyl (PMB), or benzyl (Bn) is protected amino.
Further, described double bond oxidation method therefor is ozone oxidation, potassium permanganate oxidation, sodium periodate oxidation or three ruthenium oxide oxidation.
Further, also comprise the step of a separation and purification, adopt solvent extraction, silica gel column chromatography separating purification or ion-exchange chromatography to carry out separation and purification.
The invention provides a kind of universally, simple and effective ground, highly-solid selectively ground composite structure various, there is the method replacing the alpha-fluoroalkyl-a-amino acid of carbon chiral centres containing four that different fluoro-containing group replaces.
The present invention is by the inducing action of chiral auxiliary sulfinyl amine, first synthesize the different fluoroalkyl vinyl allylamine compounds replacing carbon chiral centre containing α-four with high optically pure, various structures, then by double bond oxidation prepare various structures, there is the alpha-fluoroalkyl-a-amino acid compounds replacing carbon chiral centres containing four that different fluoro-containing group replaces.
It is starting raw material containing fluoroalkyl beta-unsaturated ketone and chiral auxiliary sulfinyl amine that the present invention utilizes cheap and easy to get; pass through α successively; the preparation of β-unsaturated fluoroalkyl sulfinyl ketoimine; organometallic reagent and chiral alpha; the selectivity addition of β-unsaturated imines; removing of chiral auxiliary, amino protection, the simple oxidation finally by double bond just can obtain the alpha-fluoroalkyl-a-amino acid compounds replacing carbon chiral centre containing four with high enantiomeric purity.
Compared with the prior art, its technical progress is significant in the present invention.The present invention is raw materials used cheap and easy to get, and synthetic method is simple to operate, and selectivity is good, productive rate is high, reaction has general applicability, is a kind of method that general synthesis contains the alpha-fluoroalkyl-a-amino acid compounds of four replacement carbon chiral centres, has good application prospect.
Embodiment:
For illustrating better the present invention, enumerate following embodiment, but do not limit content of the present invention.
Embodiment 1
Will containing fluoroalkyl beta-unsaturated ketone 1, chiral sulfenamide, purity titanium tetraethoxide is dissolved in organic solvent, reflux 24 hours, and cancellation is reacted, and filters, and separatory extracts, and dry, column chromatography obtains product 2.
Further, be dissolved in organic solvent, protection of inert gas by product 2, under-40 DEG C of conditions, add organolithium reagent, after reaction terminates, cancellation is reacted, separatory, extraction, and dry, column chromatography obtains product 3.
Further, be dissolved in organic solvent by product 3, add the aqueous solution of hydrogenchloride under room temperature condition, stirring at room temperature 2 hours, is spin-dried for solvent, obtains product 4.
Further, be dissolved in organic solvent, add triethylamine, salt of wormwood, Benzoyl chloride by product 4, heated overnight is reacted, and is cooled to room temperature, and cancellation is reacted, separatory, extraction, and dry, steaming desolventizes, and column chromatography is purified, products therefrom 5.
Further, be dissolved in organic solvent by product 5, in system, pass into ozone gas to system under-78 DEG C of conditions become blue, TLC follows the tracks of and reacts completely, and add triphenyl phosphorus, stirring at room temperature reacts 3 hours, is spin-dried for solvent, obtains product 6.
Further, products therefrom 6 is dissolved in organic solvent, adds 2-methyl 2-butylene in system, water, Textone, SODIUM PHOSPHATE, MONOBASIC, TLC tracks to and reacts completely, add aqueous sodium hydroxide solution and adjust pH value of solution=9, revolve and desolventize, aqueous phase dilute hydrochloric acid is neutralized to pH=3, extraction, merge organic phase, dry, be spin-dried for solvent and obtain product 7.
Further, by product 7 and concentrated hydrochloric acid heated overnight, return to room temperature, filter, filtrate is spin-dried for, and obtains light yellow solid 8.
Further, be dissolved in organic solvent by product 8, cryosel bath cooling slowly drips sulfur oxychloride, finishes and returns to room temperature post-heating and reflux 24 hours, revolve and desolventize, add saturated sodium bicarbonate aqueous solution, stir half an hour, separatory, extraction, dry, be spin-dried for solvent and obtain product 9.
Further, described organic solvent is tetrahydrofuran (THF), ether, methyl alcohol, dioxane, methylene dichloride, the trimethyl carbinol, normal hexane, methyl tertiary butyl ether, glycol dimethyl ether, isopropyl ether or toluene.
The process of above-mentioned reaction describes as follows:
Further, described contains fluoroalkyl beta-unsaturated ketone, it is characterized in that this compound has following structural formula:
Further, described chiral auxiliary sulfinyl amine, is characterized in that this compound has following structural formula:
Further, described cancellation reaction agents useful for same is saturated aqueous ammonium chloride, saturated sodium-chloride water solution, saturated sodium bicarbonate aqueous solution or deionized water.
Further, described extraction solvent is ether, ethyl acetate, methylene dichloride, tetrahydrofuran (THF), normal hexane or toluene.
Further, described siccative is anhydrous sodium sulphate or anhydrous magnesium sulfate.
Embodiment 2
1g is added successively in reaction flask
666mg
3g Ti (OEt)
4, 45ml tetrahydrofuran (THF), 80 DEG C of back flow reaction 24 hours, be cooled to room temperature, add 30ml saturated sodium-chloride water solution, filter, filter cake ethyl acetate is washed, merging filtrate, separatory, extraction into ethyl acetate, merges organic phase, anhydrous sodium sulfate drying, cross and filter siccative, be spin-dried for solvent, rapid column chromatography (PE:EA=15:1), obtains product
1.3g, productive rate 86%.
mp:55-56℃；[α]
D 20-985.76(c＝0.70,CHCl
3)；FT-IR(KBr,cm
-1):ν2964,2932,1617,1583,1451,1197,1144,1126,1079,977,762,698；
1H NMR(400MHz,CDCl
3):δ8.00(d,J＝16.8Hz,1H),7.44-7.47(m,2H),7.27-7.30(m,3H),7.23(d,J＝16.8Hz,1H),1.25(s,9H)；
19F NMR(376MHz,CDCl
3):δ-66.26(s,3F)；
13C NMR(CDCl
3):δ158.66(q,J＝32.9Hz),143.77(q,J＝2.7Hz),134.65,130.86,128.89,128.35,118.88(q,J＝282.4Hz),115.09,60.58,22.89.
Under argon shield, in reaction tubes, add 1mL anhydrous diethyl ether and unsaturated imines
(75.8mg, 0.25mmol), is cooled to-40 DEG C, slowly drips the lithium reagent prepared
diethyl ether solution (0.75mmol), after dropwising, returns to room temperature, stirs, and TLC follows the tracks of reaction to complete.Add 5ml saturated aqueous ammonium chloride.Separatory, extracted with diethyl ether, anhydrous sodium sulfate drying.Rotary evaporation is except desolventizing, and rapid column chromatography obtains product
85.9mg, productive rate 90%.
[α]
D 20-100.92(c＝1.29,CHCl
3)；FT-IR(KBr,cm
-1):ν3329,3061,2926,2868,1713,1652,1578,1540,1450,1248,1074,962,750；
1H NMR(400MHz,CDCl
3):δ7.67(d,J＝7.3Hz,2H),7.46-7.22(m,8H),6.62,6.55(AB,J
AB＝16.4Hz,2H),4.13(s,1H),1.29(s,9H)；
19F NMR(376MHz,CDCl
3):δ-73.07(s,3F)；
13C NMR(101MHz,CDCl
3):δ137.04,136.46,135.54,129.07,128.72,128.68,128.66,128.33,127.07,125.37(q,J＝286.0Hz),124.45,68.79(q,J＝27.0Hz),57.08,22.62.
By 115mg
be dissolved in 5ml methyl alcohol, add the aqueous solution (2mol/L) of 3ml hydrogenchloride under room temperature, stirring at room temperature 3 hours, adds saturated sodium bicarbonate 5ml, separatory, extracted with diethyl ether, anhydrous sodium sulfate drying, and rotary evaporation, except desolventizing, obtains product
79.1mg, productive rate 95%.
[α]
D 26.5106.52(c＝1.002,MeOH)；FT-IR(KBr,cm
-1):ν3329,3061,2927,2854,1865,1733,1646,1575,1489,1373,1153,972,743；
1H NMR(400MHz,CDCl
3):δ7.74(d,J＝7.8Hz,2H),7.53-7.31(m,8H),6.96,6.74(AB,J
AB＝16.1Hz,2H),2.08(s,2H)；
19F NMR(376MHz,CDCl
3):δ-76.63(s,3F)；
13C NMR(101MHz,CDCl
3):δ138.59,136.17,132.12,128.79,128.52,128.42,128.36,128.27(d,J＝0.6Hz),127.25(d,J＝1.5Hz),126.88,126.77(q,J＝285.8Hz),63.28(q,J＝26.8Hz).
By 69mg
be dissolved in 2.5ml dioxane, in system, add triethylamine 25.3mg successively, salt of wormwood 34.6mg, Benzoyl chloride 105.4mg, be heated to 80 DEG C, stirring reaction spends the night, room temperature is cooled to after reaction terminates, add 5ml deionized water, separatory, extracted with diethyl ether, merge organic phase, anhydrous magnesium sulfate drying, is spin-dried for solvent, and rapid column chromatography obtains product
85.8mg, productive rate 90%.
mp:114-116℃；[α]
D 24-4.43(c＝1.48,CHCl
3)；FT-IR(KBr,cm
-1):ν3447,3299,3060,3028,1960,1882,1802,1685,1559,1487,1449,1287,1246,1159,970,746,693；
1H NMR(400MHz,CDCl
3):δ7.91-7.84(m,2H),7.69-7.24(m,13H),6.98(d,J＝16.2Hz,1H),6.89-6.79(m,2H)；
19FNMR(376MHz,CDCl
3):δ-74.29(s,3F)；
13C NMR(101MHz,CDCl
3):δ165.91,135.96,134.81,134.49(d,J＝1.1Hz),134.25,132.20,128.87,128.75,128.65,128.47,127.68,127.67,127.12,127.01,125.21(q,J＝285.8Hz),123.33,66.93(q,J＝26.8Hz).
By 110mg
be dissolved in 5ml methylene dichloride, in the mixing solutions of 2.5ml methyl alcohol, be cooled to-78 DEG C, pass into ozone to system in system and become blue, continue to stir, TLC tracks to reaction to be terminated, and is dissolved in 1.5ml tetrahydrofuran (THF) by 90mg triphenyl phosphorus, and adds in system, finish rear recovery room temperature, continue stirring reaction 2 hours, rotary evaporation, except desolventizing, obtains product
82mg, productive rate 95%.
mp:119-121℃；[α]
D 25-70.79(c＝0.96,CHCl
3)；
1H NMR(400MHz,CDCl
3):δ9.63(s,1H),7.87(d,J＝6.9Hz,2H),7.73-7.31(m,9H)；
19F NMR(376MHz,CDCl
3):δ-71.79(s,3F).
By 75mg
be dissolved in the 3ml trimethyl carbinol, in reaction system, add 1ml2-methyl-2 butylene successively under ice-water bath condition, 5ml deionized water, 108mg Textone, 144mg SODIUM PHOSPHATE, MONOBASIC, finishes insulation reaction half an hour, recover stirred overnight at room temperature, after reaction terminates, adjust pH=9 with 2mol/L sodium hydroxide solution, the rotary evaporation removing trimethyl carbinol, methylene dichloride is washed, and merges aqueous phase, be neutralized to pH=3 with dilute hydrochloric acid, dichloromethane extraction organic phase, merge organic phase, anhydrous sodium sulfate drying, is spin-dried for solvent and obtains product
72mg, productive rate 91%.
mp:143-144℃；[α]
D 26-40.30(c＝1.25,CHCl
3)；FT-IR(KBr,cm
-1):ν3443,3371,3227,3066,2922,2844,2601,1958,1892,1756,1677,1510,1262,1180,960,762,710；
1H NMR(400MHz,CDCl
3):δ8.51(s,2H),7.83(d,J＝7.6Hz,2H),7.64-7.27(m,8H)；
19F NMR(376MHz, CDCl
3):δ-71.79(s,3F)；
13C NMR(101MHz,CDCl
3):δ168.67,166.94,133.13,132.35,130.80,129.83,129.03,128.98,127.52,126.96,123.37(q,J＝286.3Hz),69.03(q,J＝28.2Hz).
By 65mg
add reaction tubes with 1ml concentrated hydrochloric acid, 100 DEG C of reacting by heating are spent the night, and after reaction terminates, stop heating recovering room temperature, solids removed by filtration, filtrate is spin-dried for, and obtains light yellow solid
42.5mg, productive rate 83%.
mp:>250℃；[α]
D 25+14.27(c＝1.21,H
2O)；
1H NMR(400MHz,D
2O):δ7.32-7.36(m,5H)；
19F NMR(376MHz,D
2O):δ-70.47(s,3F)；
13C NMR(101MHz,D
2O):δ166.48,130.74,129.55,129.37,127.08,123.20(q,J＝284.4Hz),67.90(q,J＝27.1Hz)。
The process prescription of above-mentioned reaction is as follows:
。
Claims (10)
1. replace alpha-fluoroalkyl-a-amino acid compounds of carbon chiral centre containing four, it is characterized in that its structural formula is as follows:
Wherein, R
1for alkyl, aryl, heteroaryl, benzyl or naphthyl, R
2for hydrogen, alkyl, aryl, heteroaryl or naphthyl, R
ffor containing fluoroalkyl, described alkyl is C
1-20alkyl or C
1-20haloalkyl, described aryl is phenyl or substituted-phenyl, substituting group in described substituted-phenyl be adjacent, para-orientation or polysubstituted methyl, ethyl, phenyl, methoxyl group, oxyethyl group, benzyloxy, trifluoromethyl, difluoromethyl, a methyl fluoride, fluorine, chlorine, bromine, ethanoyl or dimethylamino, described heteroaryl is furyl, thienyl, pyridyl, pyrazolyl, pyrryl, thiazolyl, oxazolyl, quinolyl, isoquinolyl, indyl, indazolyl, benzofuryl, benzothienyl, benzothiazolyl or benzoxazolyl, described benzyl is phenmethyl, described naphthyl is 1-naphthyl or 2-naphthyl, described is trifluoromethyl containing fluoroalkyl, difluoromethyl, a methyl fluoride, the C that single fluorine or polyfluoro replace
1-20alkyl or C
1-20haloalkyl, PG is carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc), tablet held before the breast by officials methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) oxygen carbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl group (Tfa), adjacent (to) nitrobenzenesulfonyl (Ns), pivaloyl group, benzoyl (Bz), trityl (Trt), 2, 4-dimethoxy-benzyl (Dmb), to methoxy-benzyl (PMB), or benzyl (Bn).
2. a kind of preparation method containing the alpha-fluoroalkyl-a-amino acid compounds of four replacement carbon chiral centres according to claim 1, is characterized in that comprising the steps:
1) a preparation α, the step of β-unsaturated fluoroalkyl sulfinyl ketoimine, in organic solvent, with containing fluoroalkyl beta-unsaturated ketone and chiral auxiliary sulfinyl amine for starting raw material, the described mol ratio containing fluoroalkyl beta-unsaturated ketone and chiral auxiliary sulfinyl amine is 1:1 ~ 3, purity titanium tetraethoxide is dissolved in organic solvent together with above-mentioned raw materials, the described mol ratio containing fluoroalkyl beta-unsaturated ketone and purity titanium tetraethoxide is 1:2 ~ 6, α is obtained, β-unsaturated fluoroalkyl sulfinyl ketoimine by reflux, separatory, extraction;
2) under protection of inert gas, temperature controls below-10 DEG C, α, β-unsaturated fluoroalkyl sulfinyl ketoimine and organometallic reagent carry out addition reaction in organic solvent, described α, the mol ratio of β-unsaturated fluoroalkyl sulfinyl ketoimine and organometallic reagent is 1:2 ~ 4, carries out separatory, extraction obtains new adduct after reaction terminates;
3) one removes the step of chiral auxiliary sulfinyl amine, by step 2) addition reaction that obtains is dissolved in organic solvent, and add excessive hydrochloride aqueous solution at normal temperatures, stir, be spin-dried for solvent, obtain the compound being stripped of chiral auxiliary sulfinyl amine;
4) step of an amido protecting, by step 3) compound that obtains is dissolved in organic solvent, adds triethylamine, salt of wormwood, Benzoyl chloride, step 3) mol ratio of the compound that obtains and triethylamine, salt of wormwood and Benzoyl chloride is 1:1 ~ 2:1 ~ 2:2 ~ 4,60 ~ 90 DEG C of reacting by heating are spent the night, and are cooled to room temperature, separatory, extraction, dry, obtain new product;
5) oxidation step of a double bond, step 4) compound that obtains is dissolved in organic solvent, in system, pass into ozone gas to system at the temperature of less than-50 DEG C become blue, TLC follows the tracks of and reacts completely, add triphenyl phosphorus, step 4) mol ratio of the compound that obtains and triphenyl phosphorus is 1:1 ~ 3, stirring at room temperature reacts 3 hours, be spin-dried for solvent, products therefrom is dissolved in organic solvent, and in system, add 2-methyl 2-butylene, water, Textone, SODIUM PHOSPHATE, MONOBASIC, step 4) compound that obtains and 2-methyl 2-butylene, water, Textone, the mol ratio of SODIUM PHOSPHATE, MONOBASIC is 1:0.04 ~ 0.06:5 ~ 10:3 ~ 5:3 ~ 5, TLC tracks to and reacts completely, add aqueous sodium hydroxide solution and adjust pH value of solution=9, revolve and desolventize, aqueous phase dilute hydrochloric acid is neutralized to pH=3, extraction, merge organic phase, dry, be spin-dried for solvent and obtain the alpha-fluoroalkyl-a-amino acid compounds with four replacement carbon chiral centres,
6) step of a deaminizating protecting group, by step 5) compound that obtains adds excessive concentrated hydrochloric acid and in tube sealing, is heated to 90 ~ 105 DEG C of reactions and spend the night, after being cooled to room temperature, filter, filtrate is spin-dried for obtain the alpha-fluoroalkyl-a-amino acid compounds with four replacement carbon chiral centres of deprotection group;
7) step of an amino acid esterification, by step 6) compound that obtains is dissolved in alcohol, cryosel bath cooling, dripping sulfur oxychloride, step 6) compound that obtains is 1:4 ~ 8 with the mol ratio of sulfur oxychloride, finishes to return to room temperature post-heating and reflux, 15 ~ 30 hours, revolve and desolventize, add saturated sodium bicarbonate aqueous solution, stir, separatory, extraction, dry, be spin-dried for alpha-fluoroalkyl-a-amino acid ester compound that solvent must have four replacement carbon chiral centres.
3. a kind of preparation method containing the alpha-fluoroalkyl-a-amino acid compounds of four replacement carbon chiral centres according to claim 2, is characterized in that the described structural formula containing fluoroalkyl beta-unsaturated ketone is:
wherein said R
3for alkyl, aryl, heteroaryl, benzyl or naphthyl.
4. a kind of preparation method containing the alpha-fluoroalkyl-a-amino acid compounds of four replacement carbon chiral centres according to claim 2, is characterized in that the structural formula of described chiral auxiliary sulfinyl amine is:
wherein said R
4for alkyl, aryl, heteroaryl, benzyl or naphthyl.
5. a kind of preparation method containing the alpha-fluoroalkyl-a-amino acid compounds of four replacement carbon chiral centres according to claim 2, is characterized in that: step 1) described in solvent be ether, tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether, isopropyl ether, dioxane, methylene dichloride or normal hexane or toluene.
6. a kind of preparation method containing the alpha-fluoroalkyl-a-amino acid compounds of four replacement carbon chiral centres according to claim 2, is characterized in that: described organometallic reagent is organolithium reagent, and described organolithium reagent has R
1the structure of Li, step 2) in solvent used be ether, tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether, isopropyl ether, dioxane, normal hexane or toluene.
7. a kind of preparation method containing the alpha-fluoroalkyl-a-amino acid compounds of four replacement carbon chiral centres according to claim 2, it is characterized in that: the dioxane solution removing the aqueous solution, the diethyl ether solution of hydrogenchloride, the methanol solution of hydrogenchloride or the hydrogenchloride that reagent used in the step of chiral auxiliary sulfinyl amine is hydrogenchloride at, organic solvent used is ether, tetrahydrofuran (THF), methylene dichloride, trichloromethane, methyl alcohol or dioxane.
8. a kind of preparation method containing the alpha-fluoroalkyl-a-amino acid compounds of four replacement carbon chiral centres according to claim 2, it is characterized in that: in the step of an amido protecting, adopt carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc), tablet held before the breast by officials methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilyl ethoxycarbonyl (Teoc), first (or second) oxygen carbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl group (Tfa), adjacent (to) nitrobenzenesulfonyl (Ns), pivaloyl group, benzoyl (Bz), trityl (Trt), 2, 4-dimethoxy-benzyl (Dmb), to methoxy-benzyl (PMB), or benzyl (Bn) is protected amino.
9. a kind of preparation method containing the alpha-fluoroalkyl-a-amino acid compounds of four replacement carbon chiral centres according to claim 2, is characterized in that: described double bond oxidation method therefor is ozone oxidation, potassium permanganate oxidation, sodium periodate oxidation or three ruthenium oxide oxidation.
10. a kind of preparation method containing the alpha-fluoroalkyl-a-amino acid compounds of four replacement carbon chiral centres according to claim 2, it is characterized in that: the step also comprising a separation and purification, adopt solvent extraction, silica gel column chromatography separating purification or ion-exchange chromatography to carry out separation and purification.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510377316.7A CN105017048A (en) | 2015-07-01 | 2015-07-01 | Alpha-fluoroalkyl-alpha-amino acid compound containing tetrasubstituted carbon chiral center and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510377316.7A CN105017048A (en) | 2015-07-01 | 2015-07-01 | Alpha-fluoroalkyl-alpha-amino acid compound containing tetrasubstituted carbon chiral center and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105017048A true CN105017048A (en) | 2015-11-04 |
Family
ID=54407410
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510377316.7A Pending CN105017048A (en) | 2015-07-01 | 2015-07-01 | Alpha-fluoroalkyl-alpha-amino acid compound containing tetrasubstituted carbon chiral center and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105017048A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440320A (en) * | 2018-05-09 | 2018-08-24 | 上海凌凯医药科技有限公司 | A kind of method of high chiral selectivity synthesis α-disubstituted a-amino acid |
| CN108976141A (en) * | 2018-06-27 | 2018-12-11 | 深圳市茵诺圣生物科技有限公司 | A kind of method of new and effective synthesis of chiral beta-amino acids |
| CN113527536A (en) * | 2020-04-21 | 2021-10-22 | 杭州德柯医疗科技有限公司 | Fluorine-containing polysaccharide high molecular compound and preparation method thereof |
| CN114685335A (en) * | 2020-12-30 | 2022-07-01 | 中国科学院上海有机化学研究所 | Hydrogen bond organic catalyst, preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0298029A1 (en) * | 1987-07-01 | 1989-01-04 | Ciba-Geigy Ag | Substituted imidazolones with a herbicidal activity |
| WO1999038839A1 (en) * | 1998-01-28 | 1999-08-05 | Taisho Pharmaceutical Co., Ltd. | Fluorine-containing amino acid derivatives |
| CN1990458A (en) * | 2005-12-27 | 2007-07-04 | 上海药明康德新药开发有限公司 | Process for preparing 4.4-difluoro-2-amino butyric acid with optical activity and ester thereof |
-
2015
- 2015-07-01 CN CN201510377316.7A patent/CN105017048A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0298029A1 (en) * | 1987-07-01 | 1989-01-04 | Ciba-Geigy Ag | Substituted imidazolones with a herbicidal activity |
| WO1999038839A1 (en) * | 1998-01-28 | 1999-08-05 | Taisho Pharmaceutical Co., Ltd. | Fluorine-containing amino acid derivatives |
| CN1990458A (en) * | 2005-12-27 | 2007-07-04 | 上海药明康德新药开发有限公司 | Process for preparing 4.4-difluoro-2-amino butyric acid with optical activity and ester thereof |
Non-Patent Citations (7)
| Title |
|---|
| HALVOR N, CHRISTENSEN等: "THE ACID STRENGTH OF THE AMINO GROUP AS A FACTOR IN THE TRANSPORT OF AMINO ACIDS", 《BIOCHIMICA ET BIOPHYSICA ACTA》 * |
| PENG LIU等: "Highly Regio- and Diastereoselective Addition of Organolithium Reagents to Chiral Fluoroalkyl a,b-Unsaturated N-tert-Butanesul finyl Fluoroalkyl Allylic Amines and a-Fluoroalkyl a-Amino Acids", 《ADVANCED SYNTHESIS & CATALYSIS》 * |
| PENG LIU等: "Highly Regio- and Diastereoselective Addition of Organolithium Reagents to Chiral Fluoroalkyl a,b-Unsaturated N-tert-Butanesul-finylKetimines: A General and Efficient Access to a-Tertiary Fluoroalkyl Allylic Amines and a-Fluoroalkyl a-Amino Acids", 《ADVANCED SYNTHESIS & CATALYSIS》 * |
| 于静等: "烯烃臭氧化反应中两性离子反应新进展", 《化工进展》 * |
| 方庭: "CAS号", 《STN REGISTRY》 * |
| 杨洁: "高立体选择性不对称合成α-三氟甲基-α-氨基酸的方法学研究", 《工程科技I辑》 * |
| 袁小明: "(Rs,m)叔丁基亚磺酰三氟甲基-α,β-不饱和酮亚胺Strecker反应及非对称NFSI类似物的合成研究", 《工程科技I辑》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440320A (en) * | 2018-05-09 | 2018-08-24 | 上海凌凯医药科技有限公司 | A kind of method of high chiral selectivity synthesis α-disubstituted a-amino acid |
| CN108976141A (en) * | 2018-06-27 | 2018-12-11 | 深圳市茵诺圣生物科技有限公司 | A kind of method of new and effective synthesis of chiral beta-amino acids |
| CN113527536A (en) * | 2020-04-21 | 2021-10-22 | 杭州德柯医疗科技有限公司 | Fluorine-containing polysaccharide high molecular compound and preparation method thereof |
| CN113527536B (en) * | 2020-04-21 | 2024-03-22 | 杭州德柯医疗科技有限公司 | Fluorine-containing polysaccharide high molecular compound and preparation method thereof |
| CN114685335A (en) * | 2020-12-30 | 2022-07-01 | 中国科学院上海有机化学研究所 | Hydrogen bond organic catalyst, preparation method and application thereof |
| CN114685335B (en) * | 2020-12-30 | 2023-07-07 | 中国科学院上海有机化学研究所 | Hydrogen bond organic catalyst, preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106279074B (en) | A kind of compound and preparation method thereof and the purposes in Bu Waxitan is synthesized | |
| CN104151352B (en) | Preparation method of sofosbuvir intermediate | |
| CN105017048A (en) | Alpha-fluoroalkyl-alpha-amino acid compound containing tetrasubstituted carbon chiral center and preparation method thereof | |
| CN102834370B (en) | The preparation method of 1-amino-1-alkoxy carbonyl-2-vinylcyclopropane | |
| JP4921646B2 (en) | 1- (3-Benzyloxypropyl) -5- (2-substituted propyl) indoline derivatives and methods of use thereof | |
| CN107522751A (en) | A kind of high steric-hindrance amino chiral ferrocene P, N, N part and preparation method and application | |
| CN104478877A (en) | Ledipasvir intermediate preparation method | |
| CN104447755B (en) | A kind of hexahydropyrrolo [2,3-b] indole-carboxylic acid ester compounds and synthetic method thereof | |
| CN101137621A (en) | Pyrrolidine derivative intermediate and its production method and application | |
| CN103086938A (en) | Ezetimibe synthesis method | |
| CN105949118A (en) | Preparation method of 2-aryl quinoline derivatives | |
| CN100532373C (en) | Fully-synthesizing method for (2R,3S)-epoxy-9-(aprylene-1-OL | |
| CN106366057B (en) | A kind of synthetic method of Suo Feibuwei intermediate | |
| CN108912032A (en) | It is a kind of（3S, 4R）The chemical synthesis process of -4- methylpyrrolidin- 3- base amino methanol t-butyl ester hydrochloride | |
| CN105732648A (en) | Nitrogen heterocyclic ring compound of pyrrolofuran and synthetic method | |
| CN105418547A (en) | Preparation for sofosbuvir key intermediate | |
| CN101759601A (en) | Method for preparing chiral alpha-unnatural amino acid by transition metal complex | |
| WO2006080401A1 (en) | Method for producing fluorinated proline derivative | |
| CN105330550B (en) | A kind of preparation method of optically active 1 cyclohexylethylamine | |
| CN103619815A (en) | Method for producing proline compound | |
| CN109705014B (en) | Novel chiral amine oxide ligand and preparation method thereof | |
| CN106380418B (en) | It is a kind of to use N-Methyl pyrrolidone/SOCl2The method for efficiently realizing ketoxime Beckmann rearrangement | |
| CN106117204A (en) | The preparation method of Lei Dipawei intermediate (1R, 3S, 4S) 2 Boc 2 azabicyclo [2.2.1] pentane 3 carboxylic acid | |
| CN104447439B (en) | One has optically active fluorine-containing alkylallyl amine compounds and preparation method | |
| CN105017251B (en) | A kind of Preparation Method And Their Intermediate of nk 1 receptor antagonist |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20151104 |