CN101962350A - Beta-aryl homoallylic amine compound with optical activity, synthesis method and application - Google Patents

Beta-aryl homoallylic amine compound with optical activity, synthesis method and application Download PDF

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CN101962350A
CN101962350A CN2010102525542A CN201010252554A CN101962350A CN 101962350 A CN101962350 A CN 101962350A CN 2010102525542 A CN2010102525542 A CN 2010102525542A CN 201010252554 A CN201010252554 A CN 201010252554A CN 101962350 A CN101962350 A CN 101962350A
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aromatic
beta
aminated compounds
optically active
propyl group
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林国强
田平
刘敏
沈安
徐明华
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The invention relates to a beta-aryl homoallylic amine compound with optical activity, a synthesis method and an application. The compound has the structural formula as shown in the specification and is prepared by utilizing a chirality N-tertiary butyl sulfimide amine asymmetrical aryl allylation reaction promoted by metal zinc or indium. The compound can be synthesized into an important intermediate of a DPPIV inhibitor in an enantioselectivity mode.

Description

A kind of have optically active beta-aromatic high allyl aminated compounds, synthetic method and an application
Technical field
The present invention relates to a kind of the have synthetic method of the high bright propyl group aminated compounds of optically active beta-aromatic and the synthetic application of a DPPIV inhibitor important intermediate.。
Background technology
Diabetes (90% is type ii diabetes) are the important diseases of serious harm human life health.According to the data that International Diabetes Federation provides, present global diabetic subject surpasses 2.5 hundred million people, and China patient has also exceeded 0.5 hundred million.The principal character of type ii diabetes is the shortage of hyperglycemia, insulin resistant and insulin secretion.Existing medicine energy glucose level control reduces the occurrence probability of complication, but the comparison severe side effect is generally all arranged, and can not fundamentally control, cure type ii diabetes.
DPP IV (Dipeptidyl peptidase IV, pepx) is a kind of high specific serine protease, and multiple physiological action is arranged, particularly can passivation GLP-1 (glucagon-like peptide-1).Studies show that if increase the content of GLP-1 in diabetic subject's body, effectively lowering blood glucose improves the state of an illness.In addition, GLP-1 can slow down emptying, the reduction appetite of stomach, from subjective minimizing feed behavior, reduces sugar and takes in.If can suppress the activity of DPP IV, then increase the quantity of endogenous GLP-1, strengthen the incretin effect, GLP-1 is prolonged action time, reduce the level of antagonism metabolite.Therefore, seek selective d PP IV inhibitor and become the novel antidiabetic important channel of discovery.Numerous in the world drugmakers such as Merck, Novartis, GlaxoSmithKline, Tabacco, Pfizer company etc. have all developed novel DPP IV inhibitor, wherein sitagliptin phosphate (Sitagliptinphosphate, the JANUVIA of Merck company research and development RM) obtaining FDA (Food and Drug Adminstration) (FDA) approval list marketing the end of the year 2006, the Vildagliptin of Novartis company exploitation went on the market in Europe in 2007.
2006, S.D.Edmondson etc. reported an example very effective oral DPP IV inhibitor 14 (J.Med.Chem.2006,49,3614.).Two chiral centres of this compound mainly are that the enol form Claisen rearrangement reaction by chipal compounds 15 makes up.Key intermediate compound 16 in the building-up process is the aminocompounds that contain two keys, and methyl substituted pair of key is consistent with the effect of not having the two keys that replace, all is to become acid for the back of rupturing.The beta-aromatic high allyl aminated compounds 16 of stereoselective synthesis of optically active can finally obtain DPP IV inhibitor 14.
Figure BSA00000228173600021
Up to now, the method for the beta-aromatic high allyl aminated compounds of the structure racemization of having reported mainly contains following several: the aza-Barbier type aryl allylation reaction of (1) imines; (2) the aryl allylation reaction of the catalytic imines of Pd; (3) acid catalyzed three components (aldehyde, amine and allyl tributyltin reagent) allylation reaction.
About the method for enantioselectivity ground synthesis of chiral beta-aromatic high allyl aminated compounds, some example reports are arranged also.Calendar year 2001, R.Yanada (J.Org.Chem.2001,66,7516.; J.Org.Chem.2001,68,6745.) reported the aza-Barbier type allylation reaction between the promoted chirality prothetic group of In inductive imines 17 and cinnamyl bromine 2a, with medium productive rate (60%) and good selectivity (82: 6: 4: 8) obtained beta-aromatic high allyl aminated compounds 18.
Figure BSA00000228173600022
2007, J.-W.Cai (Eur.J.Org.Chem.2007,74,1594.) group reported the asymmetric allylation between catalytic different aldehyde, amine and allyl tributyltin reagent three components that replace of aqueous phase chirality camphorsulfonic acid (CSA), obtains beta-aromatic high allyl aminated compounds 22 with good productive rate.The reaction the substrate suitability better, but cis-selectivity (76: 24-89: 11) and enantioselectivity (52-78%ee) only reach medium level.
2007, J.L.Leighton (J.Am.Chem.Soc.2007,129,14552.; Angew.Chem.Int.Ed.2008,47,3037.) group has reported the aryl allylation reaction of high enantioselectivity imines, can obtain the different product of cis-selectivity with very high productive rate respectively by protecting group on the regulation and control imines nitrogen.When substrate imines 24 benzyl class groups, reaction obtains trans product 26 with＞95%ee; When on the imines 25 being aryl class group, reaction obtains the product 27 of cis based on＞93%ee.After this, this group has further developed placed in-line imines allylation reaction again.The olefin metathesis reaction original position is directly carried out the aryl allylation reaction to imines after generating the allyl group silica reagent, obtains the beta-aromatic high allyl aminated compounds of different replacements with medium productive rate and higher selectivity.
As mentioned above, though the construction process of beta-aromatic high allyl aminated compounds has all obtained a lot of chemists' concern all the time, the method that highly selective makes up optically pure this compounds is very limited also.
Summary of the invention
The purpose of this invention is to provide a class and have the high bright propyl group aminated compounds of optically active beta-aromatic.
Purpose of the present invention also provides a kind of synthetic synthetic method with the high bright propyl group aminated compounds of optically active beta-aromatic.
Another object of the present invention has provided the application that an a kind of above-mentioned class has the high bright propyl group aminated compounds of optically active beta-aromatic, is used for synthetic DPPIV inhibitor important intermediate.
The high bright propyl group aminated compounds of optically active beta-aromatic of the present invention has following structural formula:
Figure BSA00000228173600041
Wherein, R=C 1-12Alkyl, C 1-12Haloalkyl, thiazolinyl, aryl, heteroaryl, benzyl, 1-naphthyl, 2-naphthyl or ester group; Ar=aryl or heteroaryl; Described thiazolinyl is vinyl, styryl or substituted phenylethylene base; Described aryl is the phenyl of phenyl or replacement; The substituting group of the phenyl of described replacement be adjacent, or methyl, ethyl, phenyl, methoxyl group, oxyethyl group, benzyloxy, trifluoromethyl, difluoromethyl, a methyl fluoride, fluorine, chlorine, bromine, iodine, nitro, methylsulfonyl or the dimethylamino of contraposition; Described heteroaryl is pyridyl, furyl, thienyl, pyrazolyl, pyrryl, thiazolyl, oxazolyl, quinolyl, isoquinolyl, indyl, indazolyl, benzofuryl, benzothienyl, benzothiazolyl or benzoxazolyl; Described benzyl is a phenmethyl; Described ester group is C 1-12Alkyl ester group, benzyl ester group or phenyl ester group.PG=protecting group, described protecting group are tertiary butyl sulfinyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or ethanoyl.
Compound of the present invention can have following structural formula:
Figure BSA00000228173600051
Figure BSA00000228173600071
Compound of the present invention can be by following step (1), step (1) and (2), and step (1), (2) and (3), five kinds of steps of step (1), (2) and (4) or step (1), (2) and (5) obtain:
(1); in organic solvent, under the room temperature and in the presence of the additive, N-tertiary butyl sulfenimide 1 or 8, aryl allyl halide reagent 2, activated zinc powder or the reaction of indium powder obtained the high bright propyl group aminated compounds 3 or 9 of beta-aromatic of optically active tertiary butyl sulfinyl protection in 0.5～8 hour.
The mol ratio of described N-tertiary butyl sulfenimide 1, aryl allyl halide reagent 2, activated zinc powder or indium powder, additive is 1: 1～2: 1～2: 0.5～1;
(2), the high bright propyl group aminated compounds 3 or 9 of beta-aromatic of tertiary butyl sulfinyl protection is dissolved in the methyl alcohol, adds 1 of 4M hydrochloric acid, the 4-dioxane solution, stirring at room 0.5-8 hour, concentrate and to obtain the high bright propyl group aminated compounds 4 or 10 of optically active beta-aromatic;
Described compound 3 or 9 and the mol ratio of hydrochloric acid be 1: 1～10;
(3), the product 4 or 10 of (2) is dissolved in the methylene dichloride, then to wherein adding triethylamine and acetic anhydride (Ac 2O), stirring at room 0.5-8 hour, the aftertreatment purifying can obtain the high bright propyl group aminated compounds 5 or 11 of beta-aromatic of optically active ethanoyl protection;
The mol ratio of described compound 3 or 9, triethylamine and acetic anhydride is 1: 1～10: 1～10;
(4), the product 4 or 10 of (2) is dissolved in the methylene dichloride, then to wherein adding triethylamine and tertbutyloxycarbonyl acid anhydrides (Boc 2O), stirring at room 0.5-8 hour, the aftertreatment purifying can obtain the high bright propyl group aminated compounds 6 or 12 of beta-aromatic of optically active tertbutyloxycarbonyl protection;
The mol ratio of described compound 3 or 9, triethylamine and tertbutyloxycarbonyl acid anhydrides is 1: 1～10: 1～10;
(5), (2) product 4 or 10 is dissolved in the methylene dichloride, to wherein adding triethylamine and carbobenzoxy-(Cbz) succinimide ester, stirring at room 0.5-8 hour, the aftertreatment purifying can obtain the high bright propyl group aminated compounds 7 or 13 of beta-aromatic of optically active carbobenzoxy-(Cbz) protection then;
The mol ratio of described compound 3 or 9, triethylamine and CbzOSu is 1: 1～10: 1～10;
Compound 1,2,3,4,5,6,7,8,9,10,11,12 and 13 structural formula are as follows:
Described additive is lithium fluoride, Sodium Fluoride, Potassium monofluoride, cesium fluoride, magnesium fluoride, lithium chloride, sodium-chlor, Repone K, cesium chloride, magnesium chloride, lithiumbromide, Sodium Bromide, Potassium Bromide, cesium bromide, magnesium bromide, lithium iodide, sodium iodide, potassiumiodide, cesium iodide or magnesium iodide;
R and Ar are according to claim 1;
Ac is an ethanoyl; Boc is a tertbutyloxycarbonyl; Cbz is a carbobenzoxy-(Cbz);
X=chlorine, bromine, iodine, to Methyl benzenesulfonyl base oxygen, methyl sulphonyl oxygen, trifluoroacetyl oxygen base or trifyl oxygen;
X is chlorine, bromine, iodine, to Methyl benzenesulfonyl base oxygen, methyl sulphonyl oxygen, trifluoroacetyl oxygen base or trifyl oxygen; X 2=chlorine, bromine, iodine, to Methyl benzenesulfonyl base oxygen, methyl sulphonyl oxygen, trifluoroacetyl oxygen base or trifyl oxygen.
Method of the present invention can further describe:
The synthetic method of the high bright propyl group aminated compounds 3 of optically active beta-aromatic of the present invention can be represented with following reaction formula:
Figure BSA00000228173600092
In organic solvent, under the room temperature and in the presence of the additive, 0.25mmoL N-tertiary butyl sulfenimide (1), 0.5mmoL aryl allyl bromide 98 reagent (2) and 0.5mmoL activated zinc powder or the reaction of indium powder 0.5～8 hour.
The mol ratio of described N-tertiary butyl sulfenimide (1), aryl allyl bromide 98 reagent (2) activated zinc powder or indium powder and additive is 1: 1～2: 1～2: 0.5～1.
Adopt method proposal reactions system of the present invention under rare gas element, to carry out, as argon shield.
Adopting method recommendation response solvent of the present invention is N, dinethylformamide (DMF).
Wherein, R, Ar or X are as previously mentioned; Described additive (Additives) is lithium fluoride (LiF), Sodium Fluoride (NaF), Potassium monofluoride (KF), cesium fluoride (CsF), magnesium fluoride (MgF 2), lithium chloride (LiCl), sodium-chlor (NaCl), Repone K (KCl), cesium chloride (CsCl), magnesium chloride (MgCl 2), lithiumbromide (LiBr), Sodium Bromide (NaBr), Potassium Bromide (KBr), cesium bromide (CsBr), magnesium bromide (MgBr 2), lithium iodide (LiI), sodium iodide (NaI), potassiumiodide (KI), cesium iodide (CsI), magnesium iodide (MgI 2); Described organic solvent (Solvent) be acetone (Acetone), ethyl acetate (Ethyl acetate), tetrahydrofuran (THF) (THF), dioxane (1,4-Dioxane), ether (Et 2O), isopropyl ether ( iPr 2O), methyl tertiary butyl ether ( tBuOMe), toluene (Toluene), methylene dichloride (DCM), 1,2-ethylene dichloride (DCE), methyl alcohol (Methanol), ethanol (Ethanol), propyl alcohol (Propanol), Virahol (Isopropanol), HMPA (HMPA), methane amide (DMF) or ethanamide (DMA).
Above-mentioned reaction product can adopt organic solvent extraction, filtration, concentrate or the rapid column chromatography method is purified.
The principal character of this method is that the relative configuration amino and aryl of the substituting group on two chiral carbon atoms newly-generated in the product 3 is cis.No matter two keys in the reaction raw materials aryl allyl group halides 2 are that cis or the trans relative configuration that obtains product 3 are cis.
Adopt method of the present invention; specifically; at room temperature; 0.25mmoL N-tertiary butyl sulfenimide (1); 0.5mmoL aryl allyl bromide 98 reagent (2); 0.5mmoL activated zinc powder, 0.25mmoL lithium chloride reach in the exsiccant reaction tubes, system displacement argon shield; add 5mLDMF (or HMPA); stirring reaction is 2 hours under the room temperature, and 200mL ethyl acetate diluting reaction system is used aqueous hydrochloric acid, saturated sodium bicarbonate solution and the saturated common salt water washing of 1M successively; the anhydrous sodium sulfate drying organic phase; filter, concentrate rapid column chromatography.Concrete outcome is stated form as follows:
Figure BSA00000228173600101
Figure BSA00000228173600102
Figure BSA00000228173600111
Wherein, naphthyl is a naphthyl; Furanyl is a furyl.
The synthetic method such as the following reaction equation of the high bright propyl group aminated compounds 5 of beta-aromatic of ethanoyl protection:
Beta-aromatic high allyl aminated compounds 3 (0.2mmol) is dissolved in the 2.0mL methyl alcohol, add 0.5mL4N HCl in 1,4-dioxane (2.0mmol) reacted 30 minutes, concentrated, add in the 5mL methylene dichloride, the 2mmol triethylamine produces a large amount of white cigarettes, stirs to become settled solution in ten minutes, add the 2mmol diacetyl oxide, stirred overnight at room temperature.200mL ethyl acetate diluting reaction system, 3mL washes once, and saturated sodium-chloride water solution is washed once, anhydrous sodium sulfate drying, rapid column chromatography obtains white solid 5.
This method also can be used for the asymmetric aryl allylation reaction of the imines of glyoxylic ester:
Figure BSA00000228173600113
Wherein, R and organic solvent are as previously mentioned.
X 1=X 2=chlorine, bromine, iodine, to Methyl benzenesulfonyl base oxygen (OTs), methyl sulphonyl oxygen (OMs), trifluoroacetyl oxygen base (OCOCF 3) or trifyl oxygen (OTf); X 2=chlorine, bromine, iodine, to Methyl benzenesulfonyl base oxygen (OTs), methyl sulphonyl oxygen (OMs), trifluoroacetyl oxygen base (OCOCF 3) or trifyl oxygen (OTf).
Under the room temperature, 0.25mmoL N-tertiary butyl sulfenimide 8,0.5mmoL allyl bromide 98 reagent 2A, 0.5mmoL activated zinc powder, 0.25mmoL lithium chloride reach in the exsiccant reaction tubes, and system displacement argon shield adds 5m nitrogen dimethylformamide (DMF, Al 2O 3Drying treatment), stirring reaction is 2 hours under the room temperature, and 200mL ethyl acetate diluting reaction system is used aqueous hydrochloric acid, saturated sodium bicarbonate solution and the saturated common salt water washing of 1M successively, and the anhydrous sodium sulfate drying organic phase is filtered, and concentrates rapid column chromatography.Concrete experimental result is stated form as follows:
Figure BSA00000228173600121
Figure BSA00000228173600122
Compound 9a sloughs the sulfoxide prothetic group under acidic conditions can obtain the high bright propyl group aminated compounds 10a of optically active beta-aromatic, uses Boc again 2The O protection can obtain compound 12a.Compound 12a presses document (J.Med.Chem.2006,49,3614.) method can synthesize a DPPIV inhibitor 14.
Figure BSA00000228173600123
Specific implementation method
Following examples will help to understand the present invention, but can not limit content of the present invention.
Embodiment 1
Synthesizing of compound 3
Figure BSA00000228173600131
At room temperature; 0.25mmoL N-tertiary butyl sulfenimide (1); 0.5mmoL aryl allyl bromide 98 reagent (2); 0.5mmoL activated zinc powder; 0.25mmoL lithium chloride reaches in the exsiccant reaction tubes; system displacement argon shield; add 5mLDMF; stirring reaction is 2 hours under the room temperature, and 200mL ethyl acetate diluting reaction system is used aqueous hydrochloric acid, saturated sodium bicarbonate solution and the saturated common salt water washing of 1M successively; the anhydrous sodium sulfate drying organic phase; filter, concentrate, rapid column chromatography can obtain the high bright propyl group aminated compounds of beta-aromatic of chirality.Concrete characterization data is as follows:
Figure BSA00000228173600132
[α] D 24-40.8 (c 0.28, CHCl 3); 1H NMR (300MHz, CDCl 3): δ 1.01 (s, 9H), 3.57 (d, 1H, J=5.7Hz), 3.81 (dd, 1H, J=8.0,8.0Hz), 4.58 (dd, 1H, J=7.1,7.1Hz), 4.95 (d, 1H, J=17.1Hz), 5.04 (d, 1H, J=10.2Hz), 5.86-5.97 (m, 1H), 7.10-7.31 (m, 10H) ppm; 13C NMR (100MHz, CDCl 3) δ 22.4,56.2,56.5,64.1,117.6,126.9,127.8,128.0,128.3,128.5,128.8,137.1,140.2,140.4ppm; FT-IR (film, cm -1) v 3322,3063,2904,1468,1366,1062,760,701; ESI-MS (m/z, %): 328.0 (M ++ H), 350.0 (M ++ Na); HRMS (MALDI) for C 20H 26NOS +(M ++ H): calculated value calcd.) 328.17296, measured value (found) 328.1739.
Figure BSA00000228173600141
[α] D 25-52.5(c?1.00，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.03(s，9H)，3.57(d，1H，J＝6.4Hz)，3.82(dd，1H，J＝7.6，7.6Hz)，4.57(dd，1H，J＝7.0，7.0Hz)，4.96(d，1H，J＝16.8Hz)，5.06(d，1H，J＝10.0Hz)，5.82-5.91(m，1H)，6.96(d，2H，J＝8.4Hz)，7.15(d，2H，J＝6.4Hz)，7.25-7.30(m，3H)，7.39(d，2H，J＝8.0Hz)ppm； 13C?NMR(100MHz，CDCl 3)δ22.3，55.5，56.1，63.5，118.0，120.6，127.8，128.2，130.4，131.3，136.4，139.5，139.7ppm；FT-IR(film，cm -1)v?3196，3080，2952，2865，1487，1055，1010，702；ESI-MS(m/z，％)：408.0(M ++H)，430.0(M ++Na)；HRMS(MALDI)for?C 20H 24NOSBrNa +(M ++Na)：calcd.428.06542，found?428.0671.
Figure BSA00000228173600142
[α] D 25-47.2(c?0.98，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.04(s，9H)，3.52(d，1H，J＝6.4Hz)，3.77(dd，1H，J＝8.0，8.0Hz)，4.53(dd，1H，J＝7.2，7.2Hz)，4.99(d，1H，J＝16.8Hz)，5.10(d，1H，J＝10.4Hz)，5.79-5.88(m，1H)，6.95(d，2H，J＝8.4Hz)，7.01(d，2H，J＝8.4Hz)，7.41(dd，4H，J＝8.4，2.4Hz)ppm； 13CNMR(100MHz，CDCl 3)δ22.4，55.6，56.4，63.1，118.6，120.9，121.9，129.7，130.4，131.5，131.6，136.0，138.8，139.2ppm；FT-IR(film，cm -1)v?3324，2966，1489，1074，1057，1010，913，802；ESI-MS(m/z，％)：485.9(M ++H)，508.9(M ++Na)；HRMS(MALDI)for?C 20H 24NOSBr 2 +(M ++H)：calcd.483.99399，found?483.9951.
Figure BSA00000228173600151
[α] D 25-58.7(c?1.02，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.03(s，9H)，2.32(s，3H)，3.49(d，1H，J＝6.4Hz)，3.80(dd，1H，J＝7.8，7.8Hz)，4.52(dd，1H，J＝7.0，7.0Hz)，4.96(dt，1H，J＝17.2，2.4Hz)，5.06(d，1H，J＝10.4Hz)，5.82-5.91(m，1H)，6.96-6.99(m，2H)，7.04(d，2H，J＝8.4Hz)，7.11(d，2H，J＝8Hz)，7.39-7.42(m，2H)ppm； 13C?NMR(100MHz，CDCl 3)δ21.1，22.4，55.6，56.1，63.5，118.0，120.6，127.8，129.1，130.6，131.2，131.4，136.7，137.6，139.8ppm；FT-IR(film，cm -1)v?3224，2922，2852，1487，1051，1010，855，805；ESI-MS(m/z，％)：420.0(M ++H)，442.0(M ++Na)；HRMS(MALDI)for?C 21H 27NOSBr +(M ++H)：calcd.420.09912，found?420.1005.
Figure BSA00000228173600152
[α] D 25-48.3(c?0.99，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.05(s，9H)，3.46(d，1H，J＝5.6Hz)，3.76-3.82(m，4H)，4.53(dd，1H，J＝6.4，6.4Hz)，4.97(d，1H，J＝17.6Hz)，5.08(d，1H，J＝10.0Hz)，5.83-5.92(m，1H)，6.83(d，2H，J＝8.0Hz)，6.97(d，2H，J＝8.0Hz)，7.07(d，2H，J＝8.4Hz)，7.41(d，2H，J＝8.0Hz)ppm； 13C?NMR(100MHz，CDCl 3)δ22.5，55.2，55.6，56.2，63.2，113.7，118.1，120.7，129.1，130.6，131.5，131.7，136.6，139.8，159.2ppm；FT-IR(film，cm -1)v3287，2926，1515，1245，1179，1046，843，814；ESI-MS(m/z，％)：436.0(M ++H)，458.0(M ++Na)；HRMS(MALDI)for?C 21H 27NO 2SBr +(M ++H)：calcd.436.09404，found?436.0968.
Figure BSA00000228173600161
m.p.：210～212℃[α] D 25-18.4(c?0.34，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.04(s，9H)，3.64(d，1H，J＝6.8Hz)，3.92(dd，1H，J＝7.8，7.8Hz)，4.74(dd，1H，J＝7.2，7.2Hz)，4.98(d，1H，J＝17.2Hz)，5.05(d，1H，J＝10.4Hz)，5.85-5.94(m，1H)，7.01(d，2H，J＝8.0Hz)，7.29(dd，1H，J＝8.4，1.6Hz)，7.40-7.48(m，4H)，7.63(s，1H)，7.78-7.82(m，3H)ppm； 13C?NMR(100MHz，CDCl 3)δ22.4，55.7，56.3，63.8，118.2，120.8，125.5，126.1，126.2，127.2，127.6，128.1，128.2，130.6，131.5，133.03，133.05，136.6，137.2，139.6ppm；FT-IR(film，cm -1)v?3295，1487，1070，1045，919，761，751，477；ESI-MS(m/z，％)：458.1(M ++H)，478.0(M ++Na)；HRMS(MALDI)for?C 24H 27NOSBr +(M ++H)：calcd.456.09912，found?456.0990.
Figure BSA00000228173600162
[α] D 25-39.8(c?1.00，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.04(s，9H)，3.53(d，1H，J＝9.6Hz)，3.75(dd，1H，J＝10.6，10.6Hz)，4.52(dd，1H，J＝9.8，9.8Hz)，5.00(d，1H，J＝22.8Hz)，5.12(d，1H，J＝13.6Hz)，5.77-5.89(m，1H)，6.98(d，3H，J＝10.8Hz)，，7.27(s，1H)，7.37(d，1H，J＝11.2Hz)，7.44(d，2H，J＝10.8Hz)ppm； 13C?NMR(100MHz，CDCl 3)δ22.4，55.7，56.5，62.8，118.9，121.1，127.3，129.8，130.31，130.33，131.7，132.0，132.5，135.8，138.9，140.2ppm；FT-IR(film，cm -1)v3281，2953，1488，1648，1054，1046，920，816；ESI-MS(m/z，％)：475.9(M ++H)，498.0(M ++Na)；HRMS(MALDI)for?C 20H 23NOSCl 2Br +(M ++H)：calcd.474.00553，found?474.0071.
Figure BSA00000228173600171
m.p.：87～89℃[α] D 25-16.0(c?0.97，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.03(s，9H)，3.42(d，1H，J＝8.8Hz)，3.88(dd，1H，J＝7.6，7.6Hz)，4.60(dd，1H，J＝8.2，8.2Hz)，5.03(d，1H，J＝17.2Hz)，5.10(d，1H，J＝10.4Hz)，5.92-6.01(m，1H)，6.21(d，1H，J＝2.8Hz)，6.28(d，1H，J＝1.2Hz)，6.97(d，2H，J＝8.0Hz)，7.38-7.41(m，3H)ppm； 13C?NMR(100MHz，CDCl 3)δ22.4，54.2，56.4，58.3，108.7，110.3，117.8，120.7，130.2，131.5，136.8，139.2，142.1，153.0ppm；FT-IR(film，cm -1)v?3243，2959，1490，1151，1064，1047，1010，766，732；ESI-MS(m/z，％)：398.0(M ++H)，420.0(M ++Na)；HRMS(MALDI)for?C 18H 23NO 2SBr +(M ++H)：calcd.396.06274，found?396.0643.
Figure BSA00000228173600172
[α] D 25-45.8(c?1.02CHCl 3)； 1H?NMR(300MHz，CDCl 3)：δ1.10(s，9H)，3.29(d，1H，J＝7.8Hz)，3.61(dd，1H，J＝7.4，7.4Hz)，4.19(dd，1H，J＝14.7，7.5Hz)，5.13(d，1H，J＝17.1Hz)，5.21(d，1H，J＝10.2Hz)，6.00-6.22(m，2H)，6.58(d，1H，J＝16.2Hz)，7.11(d，2H，J＝8.7Hz)，7.23-7.36(m，5H)，7.45(d，2H，J＝8.1Hz)ppm； 13C?NMR(100MHz，CDCl 3)δ22.4，55.2，56.2，62.2，118.3，120.7，126.6，127.8，128.3，128.4，130.3，131.5，133.3，136.2，136.6，139.5ppm；FT-IR(film，cm -1)v?3228，2958，1488，1054，1042，1010，918，747；ESI-MS(m/z，％)：433.9(M ++H)，454.0(M ++Na)；HRMS(MALDI)for?C 22H 26NOSBrNa +(M ++Na)：calcd.454.08107，found?454.08171.
Figure BSA00000228173600181
[α] D 26-80.8(c?1.00，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ0.89(d，3H，J＝6.4Hz)，0.92(d，3H，J＝6.4Hz)，1.40-1.41(m.2H)，1.85-1.92(m，1H)，2.88(d，1H，J＝6.4Hz)，3.43(dd，1H，J＝7.2，7.2Hz)，3.56(dd，1H，J＝6.2，6.2Hz)，5.11(d，1H，J＝17.2Hz)，5.15(d，1H，J＝10.8Hz)，5.97-6.06(m，1H)，7.10(d，2H，J＝8.0Hz)，7.44(d，2H，J＝8.0Hz)ppm； 13C?NMR(100MHz，CDCl 3)δ21.6，22.6，23.3，24.1，43.0，55.3，56.1，58.7，117.3，120.5，130.5，131.5，138.2，140.0ppm；FT-IR(film，cm -1)v3461，3126，2960，1488，1367，1073，1015，915，819；ESI-MS(m/z，％)：388.0(M ++H)，410.0(M ++Na)；HRMS(MALDI)for?C 18H 28NOSBrNa +(M ++Na)：calcd.408.09672，found?408.09766.
Embodiment 2
Synthesizing of compound 5
Figure BSA00000228173600182
Beta-aromatic high allyl aminated compounds 3 (0.2mmol) is dissolved in the 2.0mL methyl alcohol, add 0.5mL 4N HCl in 1,4-dioxane (2.0mmol) reacted 30 minutes, concentrated, add in the 5mL methylene dichloride, the 2mmol triethylamine produces a large amount of white cigarettes, stirs to become settled solution in ten minutes, add the 2mmol diacetyl oxide, stirred overnight at room temperature.200mL ethyl acetate diluting reaction system, 3mL washes once, and saturated sodium-chloride water solution is washed once, anhydrous sodium sulfate drying, rapid column chromatography obtains white solid 5.Concrete characterization data is as follows:
Figure BSA00000228173600191
m.p.：163～165℃；[α] D 24-35.1(c?0.22，CHCl 3)； 1H?NMR(300MHz，CDCl 3)：δ1.81(s，3H)，3.73(dd，1H，J＝8.0，8.0Hz)，4.99(d，1H，J＝17.4Hz)，5.07(d，1H，J＝10.2Hz)，5.34(dd，1H，J＝8.1，8.1Hz)，5.87-5.98(m，2H)，7.08-7.13(m，4H)，7.22-7.30(m，6H)ppm； 13C?NMR(100MHz，CDCl 3)δ23.2，55.3，56.5，117.5，126.9，127.3，127.4，128.1，128.3，128.4，137.4，139.9，140.1，168.9ppm；FT-IR(film，cm -1)v?3354，3032，1650，1527，1370，911，758，699；ESI-MS(m/z，％)：266.2(M ++H)，288.1(M ++Na)；HRMS(MALDI)for?C 18H 19NONa +(M ++Na)：calcd.288.13589，found?288.13652.
Figure BSA00000228173600192
m.p.：187～189℃，[α] D 20-44.5(c?1.02，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.85(s，3H)，3.73(dd，1H，J＝7.8，7.8Hz)，4.99(d，1H，J＝17.2Hz)，5.10(d，1H，J＝10.0Hz)，5.32(dd，1H，J＝8.2，8.2Hz)，5.83-5.92(m，2H)，6.95(d，2H，J＝8.4Hz)，7.09-7.11(m，2H)，7.25-7.31(m，3H)，7.39(d，2H，J＝8.4Hz)ppm； 13CNMR(100MHz，CDCl 3)δ23.2，54.6，56.4，117.9，120.8，127.4，127.5，128.3，130.1，131.5，136.8，139.1，139.7，168.9ppm；FT-IR(film，cm -1)v3267，3082，1647，1541，1373，1276，896，748，699；ESI-MS(m/z，％)：343.9(M ++H)，367.8(M ++Na)；HRMS(MALDI)for?C 18H 18NOBrNa +(M ++Na)：calcd.66.04640，found?366.0474.
Figure BSA00000228173600193
m.p.：209～211℃；[α] D 19-34.6(c?1.02，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.84(s，3H)，3.66(dd，1H，J＝7.8，7.8Hz)，5.00(d，1H，J＝16.8Hz)，5.11(d，1H，J＝10.0Hz)，5.25(dd，1H，J＝8.0，8.0Hz)，5.78-5.87(m，2H)，6.94-6.98(m，4H)，7.39-7.42(m，4H)ppm； 13C?NMR(100MHz，CDCl 3)δ23.2，54.4，55.9，118.4，121.0，121.4，129.1，130.0，131.4，131.7，136.3，138.6，138.8，169.0ppm；FT-IR(film，cm -1)v?3332，3083，1653，1538，1489，1010，805，722；ESI-MS(m/z，％)：423.9(M ++H)；HRMS(MALDI)for?C 18H 17NOBr 2Na +(M ++Na)：calcd.443.95691，found443.95768.
Figure BSA00000228173600201
m.p.：197～199℃；[α] D 20-35.8(c?0.92，CHCl 3)； 1H?NMR(300MHz，CDCl 3)：δ1.86(s，3H)，2.32(s，3H)，3.72(dd，1H，J＝7.8，7.8Hz)，5.00(d，1H，J＝17.1Hz)，5.10(d，1H，J＝9.9Hz)，5.28(dd，1H，J＝8.1，8.1Hz)，5.70(d，1H，J＝8.4Hz)，5.82-5.94(m，1H)，6.95-7.00(m，4H)，7.09(d，2H，J＝7.8Hz)，7.40(d，2H，J＝8.1Hz)ppm； 13C?NMR(100MHz，CDCl 3)δ21.1，23.3，54.6，56.1，117.9，120.8，127.3，129.0，130.1，131.5，136.6，136.9，137.2，139.2，168.8ppm；FT-IR(film，cm -1)v?3343，2976，1651，1488，1371，1012，807，711；ESI-MS(m/z，％)：360.0(M ++H)，382.0(M ++Na)；HRMS(MALDI)for?C 19H 20NOBrNa +(M ++Na)：calcd.380.06205，found?380.06261.
Figure BSA00000228173600202
m.p.：183～185℃；[α] D 18-37.8(c?0.88，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.83(s，3H)，3.70(dd，1H，J＝7.8，7.8Hz)，3.78(s，3H)，4.99(d，1H，J＝16.8Hz)，5.10(d，1H，J＝10.4Hz)，5.26(dd，1H，J＝8.2，8.2Hz)，5.82-5.89(m，2H)，6.80-6.82(m，2H)，6.96(d，2H，J＝8.4Hz)，7.02(d，2H，J＝8.4Hz)，7.38-7.40(m，2H)ppm； 13C?NMR(100MHz，CDCl 3)δ23.3，54.7，55.2，55.9，113.7，118.0，120.8，128.5，130.1，131.5，131.7，136.9，139.2，158.9，168.8ppm；FT-IR(film，cm -1)v3331，2950，1652，1516，1257，1182，811，601；ESI-MS(m/z，％)：374.0(M ++H)，396.0(M ++Na)；HRMS(MALDI)for?C 19H 21NO 2Br +(M ++H)：calcd.374.07502，found374.07685.
Figure BSA00000228173600211
m.p.：213～215℃；[α] D 20-26.9(c0.98，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.87(s，3H)，3.83(dd，1H，J＝7.8，7.8Hz)，5.00(d，1H，J＝16.8Hz)，5.08(d，1H，J＝10.4Hz)，5.50(dd，1H，J＝8.4，8.4Hz)，5.86-5.94(m，2H)，6.99(d，2H，J＝8.0Hz)，7.23-7.26(m，1H)，7.40(d，2H，J＝7.2Hz)，7.46-7.48(m，2H)，7.58(s，1H)，7.76-7.82(m，3H)ppm； 13C?NMR(100MHz，CDCl 3)δ23.3，54.6，56.4，118.0，120.9，125.2，126.0，126.2，126.5，127.6，127.9，128.1，130.1，131.6，132.8，133.0，136.8，137.1，139.0，169.0ppm；FT-IR(film，cm -1)v?3348，3072，1654，1537，1488，1010，826，741；ESI-MS(m/z，％)：396.0(M ++H)，418.0(M ++Na)；HRMS(MALDI)for?C 22H 21NOBr +(M ++H)：calcd.394.08010，found?394.07850.
Figure BSA00000228173600212
m.p.：157～159℃；[α] D 20-44.8(c?0.99，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.84(s，3H)，3.63(dd，1H，J＝8.2，8.2Hz)，5.00(d，1H，J＝17.2Hz)，5.12(d，1H，J＝10.4Hz)，5.22(dd，1H，J＝8.2，8.2Hz)，5.76-5.87(m，2H)，6.92-6.97(m，3H)，7.23(s，1H)，7.34(d，1H，J＝8.4Hz)，7.43(d，2H，J＝8.4Hz)ppm； 13C?NMR(100MHz，CDCl 3)δ23.2，54.4，55.6，118.7，121.2，127.1，129.2，129.9，130.2，131.5，131.8，132.4，136.1，138.3，140.3，169.1ppm；FT-IR(film，cm -1)v3271，3065，1651，1552，1488，1012，815，764；ESI-MS(m/z，％)：413.8(M ++H)；HRMS(MALDI)forC 18H 17NOCl 2Br +(M ++H)：calcd.411.98651，found?411.98618.
Figure BSA00000228173600213
m.p.：108～110℃；[α] D 202.54(c?0.95，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.86(s，3H)，3.82(dd，1H，J＝8.0，8.0Hz)，5.05(d，1H，J＝16.8Hz)，5.12(d，1H，J＝10.0Hz)，5.43(dd，1H，J＝8.2，8.2Hz)，5.88-5.99(m，2H)，6.03(s，1H)，6.26(s，1H)，6.98(d，2H，J＝8.0Hz)，7.34(s，1H)，7.38(d，2H，J＝8.4Hz)ppm； 13CNMR(100MHz，CDCl 3)δ23.1，50.3，53.2，108.0，110.2，118.1，120.8，129.9，131.4，136.4，138.9，141.8，151.9，168.9ppm；FT-IR(film，cm -1)v?3324，1654，1539，1490，1074，1011，923，773；ESI-MS(m/z，％)：334.0(M ++H)，356.9(M ++Na)；HRMS(MALDI)for?C 16H 17NO 2Br +(M ++H)：calcd.334.04372，found?334.04419.
Figure BSA00000228173600221
m.p.：175～177℃；[α] D 20-19.0(c0.88，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.96(s，3H)，3.58(dd，1H，J＝7.8，7.8Hz)，4.98-5.04(m，1H)，5.19(d，1H，J＝17.2Hz)，5.25(d，1H，J＝10.0Hz)，5.51(d，1H，J＝9.2Hz)，6.00-6.10(m，2H)，6.42(d，1H，J＝16.0Hz)，7.14(d，2H，J＝8.4Hz)，7.23-7.25(m，1H)，7.29-7.30(m，4H)，7.45(d，2H，J＝8.0Hz)ppm； 13C?NMR(100MHz，CDCl 3)δ23.4，54.0，118.7，120.8，126.4，126.5，127.8，128.6，129.9，131.7，131.9，136.3，136.4，139.3，169.1ppm；FT-IR(film，cm -1)v?3309，2977，1651，1528，1488，1075，1011，749；ESI-MS(m/z，％)：370.1(M ++H)，392.1(M ++Na)；HRMS(MALDI)for?C 20H 20BrNNaO +(M ++Na)：calcd.392.06205，found?392.06274.
[α] D 20-48.1(c?0.98，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.51-1.61(m，1H)，1.85(s，3H)，1.91-1.98(m，1H)，2.55-2.70(m，2H)，3.43(dd，1H，J＝7.6，7.6Hz)，4.34-4.41(m，1H)，5.14(d，1H，J＝16.4Hz)，5.18(d，1H，J＝9.6Hz)，5.29-5.31(m，1H)，5.93-6.02(m，1H)，7.07(d，2H，J＝8.0Hz)，7.12(d，2H，J＝7.6Hz)，7.16-7.19(m，1H)，7.24-7.28(m，2H)，7.41(d，2H，J＝8.0Hz)ppm； 13C?NMR(100MHz，CDCl 3)δ23.3，32.4，33.9，52.0，54.1，117.9，120.5，125.9，128.2，128.4，129.7，131.5，137.0，139.8，141.5，169.6ppm；FT-IR(film，cm -1)v3327，2949，2926，1649，1535，1489，1010，922，701；ESI-MS(m/z，％)：372.0(M ++H)，394.0(M ++Na)；HRMS(MALDI)for?C 20H 23NOBr(M ++H)：calcd.372.09575，found?372.09501.
Figure BSA00000228173600231
m.p.：156～158℃；[α] D 20-81.8(c?0.81，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ0.84(d，3H，J＝2.8Hz)，0.86(d，3H，J＝2.8Hz)，1.13-1.20(m.1H)，1.25-1.33(m，1H)，1.51-1.61(m，1H)，1.86(s，3H)，3.39(dd，1H，J＝6.0，8.8Hz)，4.33-4.40(m，1H)，5.11-5.19(m，3H)，5.97-6.01(m，1H)，7.09-7.12(m，2H)，7.41-7.43(m，2H)ppm； 13C?NMR(100MHz，CDCl 3)δ21.5，23.3，23.6，24.9，41.3，50.5，54.4，117.9，120.4，129.9，131.5，137.1，140.1，169.4ppm；FT-IR(film，cm -1)v3304，2949，1649，1555，1073，1010，914，801；ESI-MS(m/z，％)：324.0(M ++H)，346.1(M ++Na)；HRMS(MALDI)for?C 16H 22BrNONa +(M ++Na)：calcd.346.07770，found?346.07729.
Embodiment 3
Synthesizing of compound 9
Figure BSA00000228173600232
Under the room temperature, 0.25mmoL N-tertiary butyl sulfenimide 8,0.5mmoL allyl bromide 98 reagent 2A, 0.5mmoL activated zinc powder, 0.25mmoL lithium chloride reach in the exsiccant reaction tubes, and system displacement argon shield adds 5mLDMF (Al 2O 3Drying treatment), stirring reaction is 2 hours under the room temperature, 200mL ethyl acetate diluting reaction system, use aqueous hydrochloric acid, saturated sodium bicarbonate solution and the saturated common salt water washing of 1M successively, the anhydrous sodium sulfate drying organic phase is filtered, concentrate, rapid column chromatography promptly obtains compound 9.Concrete characterization data is as follows:
Figure BSA00000228173600241
[α] D 2068.5(c?0.99，CHCl 3)； 1H?NMR(300MHz，CDCl 3)：δ1.09(s，9H)，1.26(t，3H，J＝7.2Hz)，3.67(dd，1H，J＝7.8，7.8Hz)，3.93(d，1H，J＝9.3Hz)，4.12-4.22(m，3H)，5.13(d，1H，J＝11.4Hz)，5.18(d，1H，J＝4.5Hz)，5.95-6.07(m，1H)，7.04(d，2H，J＝8.1Hz)，7.43(d，2H，J＝8.4Hz)ppm； 13C?NMR(100MHz，CDCl 3)δ14.1，22.5，53.4，56.4，61.8，62.4，118.0，121.1，130.1，131.6，136.4，138.3，171.9ppm；FT-IR(film，cm -1)v?3275，2983，1737，1489，1179，1074，1012，755；ESI-MS(m/z，％)：404.0(M ++H)，426.0(M ++Na)；HRMS(MALDI)forC 17H 24NO 3SBrNa +(M ++Na)：calcd.424.05525，found?424.0561.
Figure BSA00000228173600242
[α] D 20114.8(c1.08，CHCl 3)； 1H?NMR(400MHz，CDCl 3)：δ1.09(s，9H)，1.26(t，3H，J＝7.4Hz)，3.69(dd，1H，J＝7.8，7.8Hz)，3.92(d，1H，J＝9.2Hz)，4.13-4.21(m，3H)，5.12-5.18(m，2H)，5.97-6.06(m，1H)，7.11(d，2H，J＝8.0Hz)，7.27-7.29(m，2H)ppm； 13C?NMR(100MHz，CDCl 3)δ14.1，22.5，53.3，56.3，61.8，62.5，118.0，128.7，129.7，133.0，136.4，137.7，172.0ppm；FT-IR(film，cm -1)v3274，2982，1737，1493，1178，1080，1015，857；ESI-MS(m/z，％)：358.1(M ++H)，380.0(M ++Na)；HRMS(MALDI)for?C 19H 19NO 3Na +(M ++Na)：calcd.358.12382，found358.1246.
Figure BSA00000228173600251
[α] D 2079.9(c0.68，CHCl 3)； 1H?NMR(300MHz，CDCl 3)：δ1.05(s，9H)，1.25(t，3H，J＝7.2Hz)，3.69(dd，1H，J＝8.1，8.1Hz)，3.92(d，1H，J＝9.6Hz)，4.13-4.22(m，3H)，5.13-5.18(m，2H)，6.00-6.12(m，1H)，7.15-7.32(m，5H)ppm； 13CNMR(100MHz，CDCl 3)δ14.0，22.4，54.1，56.2，61.6，62.8，117.5，127.1，128.3，128.4，128.5，136.8，139.2，172.2ppm；FT-IR(film，cm -1)v?3280，2982，2961，1735，1178，1079，753，701；ESI-MS(m/z，％)：324.0(M ++H)，346.1(M +Na)；HRMS(MALDI)for?C 17H 25NO 3SNa +(M ++Na)：calcd.346.14474，found?346.1456.
Embodiment 4
Compound 12a's is synthetic
Figure BSA00000228173600252
Beta-aromatic high allyl aminated compounds 9a (0.2mmol) is dissolved in the 2.0mL methyl alcohol, add 0.5mL4N HCl in 1,4-dioxane (2.0mmol) reacted 30 minutes, concentrated, add in the 5mL methylene dichloride, the 2mmol triethylamine produces a large amount of white cigarettes, stirs to become settled solution in ten minutes, add 2mmol tertbutyloxycarbonyl acid anhydrides, stirred overnight at room temperature.200mL ethyl acetate diluting reaction system, 3mL washes once, and saturated sodium-chloride water solution is washed once, anhydrous sodium sulfate drying, rapid column chromatography obtains white solid 12a.

Claims (7)

1. high bright propyl group aminated compounds of optically active beta-aromatic is characterized in that described compound has following structural formula:
Figure FSA00000228173500011
Wherein, R=C 1-12Alkyl, C 1-12Haloalkyl, thiazolinyl, aryl, heteroaryl, benzyl, 1-naphthyl, 2-naphthyl or ester group; Ar=aryl or heteroaryl; Described thiazolinyl is vinyl, styryl or substituted phenylethylene base; Described aryl is the phenyl of phenyl or replacement; The substituting group of the phenyl of described replacement be adjacent, or methyl, ethyl, phenyl, methoxyl group, oxyethyl group, benzyloxy, trifluoromethyl, difluoromethyl, a methyl fluoride, fluorine, chlorine, bromine, iodine, nitro, methylsulfonyl or the dimethylamino of contraposition; Described heteroaryl is pyridyl, furyl, thienyl, pyrazolyl, pyrryl, thiazolyl, oxazolyl, quinolyl, isoquinolyl, indyl, indazolyl, benzofuryl, benzothienyl, benzothiazolyl or benzoxazolyl; Described benzyl is a phenmethyl; Described ester group is C 1-12Alkyl ester group, benzyl ester group or phenyl ester group; PG=protecting group, described protecting group are tertiary butyl sulfinyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or ethanoyl.
2. the high bright propyl group aminated compounds of a kind of optically active beta-aromatic as claimed in claim 1 is characterized in that described compound has following structural formula:
Figure FSA00000228173500012
Figure FSA00000228173500021
Figure FSA00000228173500031
3. the synthetic method of the high bright propyl group aminated compounds of optically active beta-aromatic as claimed in claim 1.It is characterized in that by following step (1), step (1) and (2), step (1), (2) and (3), five kinds of steps of step (1), (2) and (4) or step (1), (2) and (5) obtain:
(1); in organic solvent, under the room temperature and in the presence of the additive, N-tertiary butyl sulfenimide 1 or 8, aryl allyl halide reagent 2, activated zinc powder or the reaction of indium powder obtained the high bright propyl group aminated compounds 3 or 9 of beta-aromatic of optically active tertiary butyl sulfinyl protection in 0.5～8 hour.
The mol ratio of described N-tertiary butyl sulfenimide 1, aryl allyl halide reagent 2, activated zinc powder or indium powder, additive is 1: 1～2: 1～2: 0.5～1;
(2), the high bright propyl group aminated compounds 3 or 9 of beta-aromatic of tertiary butyl sulfinyl protection is dissolved in the methyl alcohol, adds 1 of 4M hydrochloric acid, the 4-dioxane solution, stirring at room 0.5-8 hour, concentrate and to obtain the high bright propyl group aminated compounds 4 or 10 of optically active beta-aromatic;
Described compound 3 or 9 and the mol ratio of hydrochloric acid be 1: 1～10;
(3), the product 4 or 10 of (2) is dissolved in the methylene dichloride, then to wherein adding triethylamine and acetic anhydride (Ac 2O), stirring at room 0.5-8 hour, the aftertreatment purifying can obtain the high bright propyl group aminated compounds 5 or 11 of beta-aromatic of optically active ethanoyl protection;
The mol ratio of described compound 3 or 9, triethylamine and acetic anhydride is 1: 1～10: 1～10;
(4), the product 4 or 10 of (2) is dissolved in the methylene dichloride, then to wherein adding triethylamine and tertbutyloxycarbonyl acid anhydrides (Boc 2O), stirring at room 0.5-8 hour, the aftertreatment purifying can obtain the high bright propyl group aminated compounds 6 or 12 of beta-aromatic of optically active tertbutyloxycarbonyl protection;
The mol ratio of described compound 3 or 9, triethylamine and tertbutyloxycarbonyl acid anhydrides is 1: 1～10: 1～10;
(5), (2) product 4 or 10 is dissolved in the methylene dichloride, to wherein adding triethylamine and carbobenzoxy-(Cbz) succinimide ester, stirring at room 0.5-8 hour, the aftertreatment purifying can obtain the high bright propyl group aminated compounds 7 or 13 of beta-aromatic of optically active carbobenzoxy-(Cbz) protection then;
The mol ratio of described compound 3 or 9, triethylamine and CbzOSu is 1: 1～10: 1～10;
Compound 1,2,3,4,5,6,7,8,9,10,11,12 and 13 structural formula are as follows:
Figure FSA00000228173500051
Described additive is lithium fluoride, Sodium Fluoride, Potassium monofluoride, cesium fluoride, magnesium fluoride, lithium chloride, sodium-chlor, Repone K, cesium chloride, magnesium chloride, lithiumbromide, Sodium Bromide, Potassium Bromide, cesium bromide, magnesium bromide, lithium iodide, sodium iodide, potassiumiodide, cesium iodide or magnesium iodide;
R and Ar are according to claim 1;
Ac is an ethanoyl; Boc is a tertbutyloxycarbonyl; Cbz is a carbobenzoxy-(Cbz);
X=chlorine, bromine, iodine, to Methyl benzenesulfonyl base oxygen, methyl sulphonyl oxygen, trifluoroacetyl oxygen base or trifyl oxygen;
X is chlorine, bromine, iodine, to Methyl benzenesulfonyl base oxygen, methyl sulphonyl oxygen, trifluoroacetyl oxygen base or trifyl oxygen; X 2=chlorine, bromine, iodine, to Methyl benzenesulfonyl base oxygen, methyl sulphonyl oxygen, trifluoroacetyl oxygen base or trifyl oxygen.
4. the high bright propyl group aminated compounds of optically active beta-aromatic as claimed in claim 3, synthetic method, it is characterized in that the organic solvent described in the step (1) is acetone, ethyl acetate, tetrahydrofuran (THF), dioxane, ether, isopropyl ether, methyl tertiary butyl ether, toluene, methylene dichloride, 1,2-ethylene dichloride, methyl alcohol, ethanol, propyl alcohol, Virahol, HMPA, methane amide or ethanamide.Recommend to use solvent to be methane amide.
5. the synthetic method of the high bright propyl group aminated compounds of optically active beta-aromatic as claimed in claim 4 is characterized in that the described reaction system of step (1) carries out under rare gas element.
6. the synthetic method of the high bright propyl group aminated compounds of optically active beta-aromatic as claimed in claim 3, it is characterized in that described reaction product by organic solvent extraction, filtration, concentrate or the rapid column chromatography method is purified.
7. the application of the high bright propyl group aminated compounds of optically active beta-aromatic as claimed in claim 1 is characterized in that being used for the intermediate or the synthetic DPPIV inhibitor of synthetic DPPIV inhibitor.
CN2010102525542A 2010-08-13 2010-08-13 Beta-aryl homoallylic amine compound with optical activity, synthesis method and application Pending CN101962350A (en)

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CN102408287A (en) * 2011-10-25 2012-04-11 兰州大学 Preparation method of chiral alpha-amino acid derivatives
CN104447439A (en) * 2014-10-29 2015-03-25 上海应用技术学院 Fluoroalkyl allyl amine compound with optical activity and preparation method of fluoroalkyl allyl amine compound
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CN107903196A (en) * 2017-11-08 2018-04-13 南京大学 Stimulate and strengthen protective immunological reaction compound, preparation method and its usage
CN113661166A (en) * 2019-01-09 2021-11-16 卫材R&D管理有限公司 Process for the synthesis of diazabicyclo [6.2.0] decane-related compounds

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