CN1216036C - Chiral alkamine ligand and its application in asymmetrical addition of terminal alkyne para imine - Google Patents
Chiral alkamine ligand and its application in asymmetrical addition of terminal alkyne para imine Download PDFInfo
- Publication number
- CN1216036C CN1216036C CN 03116192 CN03116192A CN1216036C CN 1216036 C CN1216036 C CN 1216036C CN 03116192 CN03116192 CN 03116192 CN 03116192 A CN03116192 A CN 03116192A CN 1216036 C CN1216036 C CN 1216036C
- Authority
- CN
- China
- Prior art keywords
- group
- alkyl
- protecting group
- benzyl
- electron
- 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.)
- Expired - Fee Related
Links
Abstract
The present invention provides novel chiral ligand (1R, 2R)-2-N, N-substituted-1-(4-substituted phenyl)-3-O-substituted-1-propanol, which has the following structure general formula, wherein R<1> and R<2> are amino protecting groups; R<3> is oxy protecting groups; Z is H, or electron-withdrawing groups or electron-donating groups. The ligand is applied to asymmetric synthesis, is especially applied to the asymmetric synthesis of precursors of DPC961 and DPC083, adopts a technical method of the asymmetric addition of chiral ligand participative alkyne copper or alkyne zinc p-trifluoromethyl imino and is capable of efficiently synthesizing high-activity inhibitor DPC961 and DPC083 of HIV transferase in the mode of chirality.
Description
Technical field
The present invention relates to a kind of new chiral ligand and be used for the purposes of the asymmetric addition of terminal alkyne para imine.
Background technology
Human immune system's defective virus (HIV, Human immunodeficiency virus) is easily undergone mutation, and this can cause chemical sproof generation.As everyone knows, there have been some transferase inhibitor medicines to be found and to be used for the treatment of HIV and similar disease, such as azidothymidine or AZT.DPC 961 and DPC 083 are s-generation HIV non-nucleoside transferase inhibitor (NNRTIs, non-nucleoside reverse transcriptaseinhibitors), with the transferase inhibitor medicine Efavirenz (Sustiva that has gone on the market
TM) compare stronger activity is arranged.DPC-961 and DPC 083 carrying out at present clinical study test (Journal of MedicinalChemistry vol.43, NO.10,2000,2019-2030).
Some method is used to the synthetic of DPC 961 and DPC 083.These the synthetic DPC 961 of reported method and DPC 083 be substep recrystallization by diastereomer split or be cis-selectivity 1 by substrate control, the 4-addition, these methods all need to adopt chirality prothetic group (Journal of OrganicChemistry vol.68, no.3,2003,754-761; Tetrahedron Letter vol.41,2000,3015-3019).Recently, WO 0170707 has reported that the asymmetric addition method of a chiral ligand control is used for synthetic DPC 961.Yet need use excessive greatly chiral ligand and excessive greatly highly basic (lithiumalkyl and LHMDS) in the method, and react and need carry out at subzero 20 degree, the condition harshness is difficult for industrialization.
Summary of the invention
The problem to be solved in the present invention provides the new chiral ligand of a class.
The problem that the present invention also will solve provides the application that above-mentioned part is used for asymmetric synthesis, is used for the asymmetric addition of Terminal Acetylenes to imines, and the high optical activity of product and reaction conditions as mild as a dove make this technology have good industrial prospect.Application in particular for the technology of the precursor of the DPC 961 of direct synthesis of optically active and DPC 083, promptly alkynes copper that participates in by new chiral ligand amino alcohol or alkynes zinc generate product uncle ammonia to the asymmetric addition of trifluoromethyl imido intermediate, and this compound promptly generates product HIV through easy conversion and moves enzyme inhibitor medicine DPC 961 and DPC 083.
The invention provides the new chiral ligand of a class (1R, 2R)-2-N, N-replacement-1-substituted-phenyl-3-O-replacement-1-propyl alcohol, its general structure is as follows:
R wherein
1, R
2Be amino protecting group, R
3It is the oxygen protecting group; Z is H, electron-withdrawing group or electron donating group.Described electron-withdrawing group is recommended as halogen, CH
3O, OH, NO
2, CF
3, CH
3SO
2Perhaps CH
3CH
2SO
2, described electron donating group is recommended as especially C of alkyl
1～C
20Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, especially recommending Z is H, Cl, Br, CH
3SO
2Perhaps NO
2Recommend R
1, R
2=Me.; Z=NO
2., further recommend R
1=R
2=Me; Z=NO
2R
3=tBu especially recommends R
1, R
2=Me; Z=NO
2R
3Silica-based or the trityl of=tertiary butyl dimethyl, the chiral ligand of recommendation are the compound of following structure:
Further the chiral ligand of recommending is the compound of following structure:
R wherein
1, R
2, R
3As previously mentioned, further recommend R
1=R
2=Me.
Especially the chiral ligand of Tui Jianing is the compound of following structure
Above-mentioned chiral ligand synthetic with
Protect through conventional last protecting group method for raw material and to obtain
The method of last protecting group is with reference to T.W Greene et al., Protectivegroups in Organic Synthesis 3rd Ed.John Wiley 1999.For example
In 2 amino can be in organic solvent realize the protection of amino earlier again with the reductive agent reduction with corresponding alkanoic or aromatic aldehyde condensation, for example formic acid, NaBH of reductive agent wherein
4, KBH
4LiAlH
4Or Pd/C etc.; Perhaps use R
1X or R
2X carries out amido protecting under the effect of organic solvent neutralization bases, wherein X is a halogen; Under acid catalysis, realize the tertiary butyl protection of terminal hydroxy group with iso-butylene, perhaps use R
3Cl realizes the R of terminal hydroxy group
3Protection obtains above-mentioned part; Above-mentioned reaction conditions is conventional reaction conditions, and described alkali is mineral alkali or organic bases, for example K
2CO
3, Na
2CO
3, NaOH, KOH, NEt
3Deng.Described organic solvent is for example: alcohol, halogenated alkane, ether etc.Concrete example as, reflux with formaldehyde and formic acid and can realize amino two methyl protection, use NaBH again with the phenyl aldehyde condensation
4Reduction can realize amino benzyl protection.
The invention provides the application of above-mentioned chiral ligand, be used for asymmetric reduction reaction, comprise being used for the asymmetric addition of Terminal Acetylenes imines.Specifically, can be used for the technology that asymmetric synthesis has following structural compounds:
Y is H, electron-withdrawing group or electron donating group in the formula, and described electron-withdrawing group is recommended as halogen, CH
3O, OH, NO
2, CF
3, CH
3SO
2Perhaps CH
3CH
2SO
2, described electron donating group is recommended as especially C of alkyl
1～C
20Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, further recommending Y is H, Cl, Br, CH
3SO
2, CH
3CH
2SO
2, NO
2Perhaps F, especially recommending Y is Cl or F.
P is H or amino protecting group,
Rf is fluorine-containing alkyl, is recommended as C
1-C
20Contain fluoroalkyl, further be recommended as C
1-C
4Contain fluoroalkyl, R is a trialkyl silyl, aryl, alkyl or cycloalkyl are recommended as C
1-C
20Alkyl or cycloalkyl, further be recommended as C
1-C
4Alkyl or cyclopropane, the heteroaryl that described aryl is recommended as phenyl, naphthyl, substituted-phenyl, contain N, S or O is pyridyl, furyl, thienyl, pyrryl, pyranyl etc. for example;
Comprise the steps:
(a) (1R, 2R)-2-N, N-replacement-1-substituted-phenyl-3-O-replacement-1-propyl alcohol has following structure with chiral ligand
R in the formula
1, R
2, R
3Z as previously mentioned;
Be mixed in the organic solvent with a kind of Terminal Acetylenes and metal-salt, add organic bases again, described Terminal Acetylenes is
R as previously mentioned;
(b) substrate of the following structure of adding
Y, P, Rf are as previously mentioned in the formula;
Reaction formula is as follows:
Reaction recommends to add proton source cancellation reaction, separates obtaining product then.Described proton source is recommended saturated aqueous ammonium chloride, water, rare or concentrated hydrochloric acid, perhaps aqueous citric acid solution.
The reaction mole proportioning of part and substrate imido is recommended as 0.1-3 in the aforesaid method: 1, further be recommended as 0.5-3: and 1, especially be recommended as 1.2-1.5: 1.
The reaction mole proportioning of metal-salt and substrate imido is recommended as 0.1-3 in the aforesaid method: 1, further be recommended as 0.5-3: and 1, especially be recommended as 1.2-1.5: 1.
The mol ratio of part and Terminal Acetylenes is recommended as 0.1-3 in the aforesaid method: 1, further be recommended as 0.5-3: and 1, especially be recommended as 1.2-1.5: 1.
Described metal-salt is recommended as zinc salt or mantoquita, further is recommended as Zn (II) or Cu salt, further is recommended as ZnCl
2, ZnBr
2, ZnF
2, ZnI
2, Zn (OTf)
2, Zn (SO
3CF
2H)
2, CuCl
2, CuBr
2, Cu (OTf)
2CuCl, CuBr, CuI, CuOTf especially is recommended as Zn (OTf)
2Perhaps Zn (SO
3CF
2H)
2.
Organic bases is recommended as the amine that contains lone-pair electron on the nitrogen-atoms, further recommends MeNiPr
2, HNEt
2, NiPr
3, Pyridine, piperidine, EtNiPr
2, NBu
3, NEt
3, especially be recommended as NEt
3
The reaction mole proportioning 1-4 of organic bases and substrate imido: 1, be recommended as 3: 1
Organic solvent is recommended as non-protonic solvent or ether in the aforesaid method, further is recommended as THF, dioxane, Et
2O, benzene, DME, toluene, n-hexane, and cyclohexane or their mixture, especially the solvent of Tui Jianing is a toluene.
Temperature of reaction is between 0 ℃ and 100 ℃ in the aforesaid method, is recommended as 0 ℃ and 50 ℃, and especially the recommendation response temperature is 20～40 ℃.
Recommend part of the present invention to be used for the technology that asymmetric synthesis has following structural compounds:
Reaction formula is as follows:
P in the formula, Rf are as previously mentioned;
Further recommend part of the present invention to be used for the technology of the following structural compounds of asymmetric synthesis, reaction formula is as follows:
Especially recommend part of the present invention to be applied to the technology of synthetic following structural compounds
Comprise the steps:
When (a) being recommended in 20～40 ℃, (1R, 2R)-2-N, N-replacement-1-(4-substituted-phenyl)-3-O-replacement-1-propyl alcohol has following structure with chiral ligand
R wherein
1, R
2Be amino protecting group, R
3It is the oxygen protecting group; R
1, R
2Be recommended as methyl, R
3Be recommended as the tertiary butyl, Z is recommended as H, Cl, Br, CH
3SO
2Perhaps NO
2
Be mixed in the organic solvent with Terminal Acetylenes and Zn (II) salt or Cu salt, recommendation is dissolved in non-protonic solvent, add a kind of organic bases again, wherein Terminal Acetylenes as previously mentioned, be recommended as cyclopropyl acethlene, mantoquita or divalent zinc salt are recommended as trifluoromethanesulfonic acid zinc, and protic solvent is recommended as toluene, organic bases is recommended as triethylamine
(b) add the substrate that following structure is arranged, recommendation response 10 hours,
(c) add proton source cancellation reaction;
(d) separation obtains product.
Unless otherwise indicated, the alkyl of the present invention hydrocarbon functional group of saturated fatty that refers to side chain or straight chain; Recommending alkyl is 1 to 20 carbon number, further is recommended as the hydrocarbon functional group of saturated fatty of the side chain or the straight chain of 1 to 4 carbon number, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl etc.Halogen is fluorine, chlorine, bromine or iodine.
Among the present invention, R
1And R
2Be that any suitable amino protecting group includes but not limited to alkyl, substituted alkyl, benzyl, substituted benzyl or N-trialkyl silyl protecting group etc.Above-mentioned amino protecting group is recommended as C
1-C
20Alkyl, substituted alkyl, benzyl, substituted benzyl or N-trialkyl silyl protecting group etc.Substituting group on described alkyl or the benzyl is recommended phenyl, naphthyl, halogen, nitro, C
1～C
3Hydroxyl, C
1～C
3Hydroxyalkyl, C
1～C
3Alkoxyl group, CN etc.P, R
1And R
2C for example
1-C
4Alkyl, C is arranged
1-C
4Alkyl replace or do not have the benzyl of replacement; To methoxy-benzyl; To nitrobenzyl; P-chlorobenzyl; 2,4 dichloro benzyls; 2, the 4-dimethoxy-benzyl; Or the trimethyl silicon based protecting group of N-; other amino protecting group is with reference to T.W.Greene et al.; Protective groups in Organic Synthesis 3rd Ed.John Wiley 1999, the amino protecting group that pp.494-653. recommends is to methoxy-benzyl.
Among the present invention, P is H or any suitable amino protecting group, and amino protecting group as mentioned above.
Among the present invention, R
3Be that any suitable oxygen protecting group includes but not limited to alkyl, substituted alkyl, benzyl, substituted benzyl or O-trialkyl silyl protecting group etc.Above-mentioned oxygen protecting group is recommended as C
1-C
20Alkyl, substituted alkyl, benzyl, substituted benzyl or O-trialkyl silyl protecting group.Substituting group on described alkyl or the benzyl is recommended phenyl, naphthyl, halogen, nitro, C
1～C
3Hydroxyl, C
1～C
3Hydroxyalkyl, C
1～C
3Alkoxyl group, CN etc.R
3C for example
1-C
4Alkyl, diphenyl-methyl, tertiary butyl dimethyl be silica-based, C is arranged
1-C
4Alkyl replace or do not have the benzyl of replacement, to methoxy-benzyl, to nitrobenzyl, p-chlorobenzyl, 2,4 dichloro benzyls, 2, the 4-dimethoxy-benzyl is to methoxy-benzyl; To nitrobenzyl; P-chlorobenzyl; 2,4 dichloro benzyls; 2, the 4-dimethoxy-benzyl; Or the silica-based protecting group of tertiary butyl dimethyl.Other oxygen protecting group is with reference to T.W.Greene et al., Protective groups in Organic Synthesis 3rd Ed.John Wiley 1999, and the oxygen protecting group that pp.17-245. recommends is the tertiary butyl.
Part provided by the invention can further be applied to the synthetic of DPC 961 and DPC 083, and synthetic method is:
DPC 961 through the reduction after obtain DPC 083 (Journal of Medicinal Chemistry vol.43, NO.10,2000,2019-2030).
The invention provides a kind of new part, this part is applied to asymmetric synthesis, especially alkynes copper that participates in by this part or alkynes zinc generate product alkynes third ammonia to the asymmetric addition of trifluoromethyl imido intermediate, the ee value is up to 99%, chiral ligand in the high optical activity of product and reaction conditions as mild as a dove and the reaction can easily reclaim repeated use, and these advantages make this technology have good industrial prospect.This compound promptly generates product HIV through easy conversion and moves enzyme inhibitor medicine DPC 961 and DPC 083.
Following examples help to understand this patent but are not limited thereto scope.
Embodiment 1
(1R, 2R)-2-N, N-dimethylamino 3-is to nitre phenyl-1, the preparation of ammediol:
Reference literature Jiang, B.; Chen, Z.L.; Tang, X.X.Org.Lett.2002,4,3451. is synthetic
Embodiment 2
(1R, 2R)-3-tert.-butoxy-2-N, N dimethylamino-1-is to the preparation of nitre phenyl-1-propyl alcohol:
Under 0-5 ℃, vitriol oil 0.8g is added dropwise to that (1R, 2R)-2-N, N-dimethylamino-3-is to nitre phenyl-1, ammediol (1.8g, CH 7.5mmol)
2Cl
2(20mL) in the solution.Keep 0-5 ℃ to feed isobutene gas one hour down.Be added dropwise to vitriol oil 0.2g again, mixture is got back to room temperature vigorous stirring reaction 5-7h and is fed isobutene gas continuously.Mixture is as cold as 0-5 ℃ and adds saturated K
2CO
3Solution.Organic phase drying (Na
2SO
4) concentrate the back recrystallization purifying and get 100.0-101.3 ℃ of ligand 1 .44g (65%) .mp; [α]
D 20=+23.5 (c, 1.00, CHCl
3); FTIR (KBr) 3333,2972,1606,1523,1357,1197,861cm
-1 1HNMR (300MHz, CDCl
3) δ 8.19 (d, J=8.8Hz, 2H), 7.60 (d, J=8.4Hz, 2H), 4.59 (d, J=9.9Hz, 1H), 3.34 (dd, J=3.0Hz, and 9.9Hz, 1H), 3.21 (dd, J=6.5Hz, and 10Hz, 1H), 2.56 (m, 1H), 2.47 (s, 6H), 1.06 (s, 9H);
13CNMR (75MHz, CDCl
3) δ 150.6,147.6,128.46,123.49,73.3,70.3,69.8,56.0,41.8,27.4; MS (EI) m/e 223 (M+-73,3), 209 (21), 144 (68), 88 (100), 71 (10), 57 (31); Anal.calcd.for C
15H
24N
2O
4: C, 60.81; H, 8.11; N, 9.46.Found:C, 60.72; H, 8.26; N, 914.
Embodiment 3
(1R, 2R)-3-tertiary butyl dimethyl Si base-2-N, N dimethylamino-1-is to the preparation of nitre phenyl-1-propyl alcohol: (1R, 2R)-2-N, N-dimethylamino-3-is to nitre phenyl-1, and (1.946g 8.1mmol) is dissolved in CH to ammediol
2Cl
2(30mL), 0 ℃ add down TBDMSCl (1.28g, 5.3mmol) and imidazoles (1.4g, 20.6mmol) the mixture stirring aftertreatment of spending the night gets product 2.72g.FTIR (KBr) 3344,2954,1606,1525,1349cm
-1 1HNMR (300MHz, CDCl
3) δ 8.25-8.20 (d, J=8.5Hz, 2H), 7.6-7.55 (d, J=8.5Hz, 2H), 4.65 (d, J=9.7Hz, 1H), 3.77-3.6 (dd, J=11.3Hz, 2.7Hz 1H), 3.5-3.45 (dd, J=11.3Hz, 6.0Hz 1H 2.50 (m, 7H), 1.85 (s, 8H), 0.1 (s, 6H);
13CNMR (75MHz, CDCl
3) δ 150.2,147.4,128.0,123.3,69.0,57.1,41.6,25.7,17.9 ,-5.9; MS (EI) m/e297 (M+-57,0.3), 209 (8.2), 202 (100) .Anal.calcd.for C
17H
30N
2O
4Si:C, 57.60; H, 8.53; N, 7.90.Found:C, 57.82; H, 8.18; N, 7.77.
Embodiment 4
(1R, 2R)-3-three benzyloxies-2-N, N dimethylamino-1-is to the preparation of nitre phenyl-1-propyl alcohol:
(1R, 2R) 2-N, N-dimethylamino-3-are to nitre phenyl-1, and (1.946g 8.1mmol) is dissolved in CH to ammediol
2Cl
2(50mL), 0 ℃ add down triphenylmethyl chloride (3.34g, 12mmol) and triethylamine (2mL) the mixture stirring aftertreatment of spending the night get product 4.8g.FTIR (KBr) 3344,2954,1606,1525,1349cm
-1 1HNMR (300MHz, CDCl
3) δ 8.09-8.06 (d, J=8.4Hz, 2H), 7.36-7.33 (d, J=8.6Hz, 2H), 7.25-7.17 (m, 5H), 4.27 (d, J=10.0Hz, 1H), 3..28 (dd, J=10.2Hz, 6.4Hz 1H), 3.01 (dd, J=10.7Hz, 3.9Hz 1H), 2.71 (m, 1H), 2.45 (s, 6H), 0.1 (s, 6H);
13CNMR (75MHz, CDCl
3) δ 150.1,147.6,143.6,128.9,128.8,128.7,128.6,128.4,128.1,127.9,127.8,127.3,123.7,87.7,70.9,70.6,58.6,41.6
Embodiment 5
(1R, 2R)-2-N-benzyl-N-methylamino--3-is to nitre phenyl-1, the preparation of ammediol:
(1R, 2R)-2-amino-3-is to nitre phenyl-1, ammediol (2.12g, 10mmol) and phenyl aldehyde (1.2g 10.5mmol) adds in the methyl alcohol (10mL), adds CuSO again
4(0.2g).Mixture back flow reaction 7hr, cool to room temperature filters, and adds THF (10mL) in the filtrate. add NaBH then in batches
4(0.4g).Mixture back flow reaction 2hr postcooling. add the 5%HCl souring soln.Concentrating with extracted with diethyl ether. resistates and HCHO (10mL) and HCOOH (10mL) back flow reaction 8hr. cooling neutralize with NaOH.CH
2Cl
2Extraction, NaSO
4Drying gets the direct the next step of 1.2g product behind the recrystallization purifying again.
Embodiment 6
(1R, 2R)-3-tertiary butyl dimethyl Si base-2-N-benzyl-N-methylamino--1-(to the nitre phenyl)-1-propyl alcohol:
(1R, 2R)-2-N-benzyl-N-methylamino--3-is to nitre phenyl-1, and ammediol (632mg) is dissolved in CH
2Cl
2(15mL), be chilled to add again under 0 ℃ TERT-BUTYL DIMETHYL CHLORO SILANE (300mg, 2mmol) and phonetic azoles (136mg, 2mmol).Mixture reaction spends the night. and aftertreatment gets product 600mg.FTIR(KBr)3344，2972，1606，1525，1348cm
-1；
1HNMR(300MHz，CDCl
3)δ8.17(d，J＝8.8Hz，2H)，7.50(d，J＝8.4Hz，2H)，7.38-7.31(m，5H)，4.70(d，J＝9.6Hz，1H)，4.04(d，J＝13.0Hz，1H)，3.77-3.55(m，3H)，2.70(m，1H)，2.43(s，3H)，0.90(s，9H)，0.01(s，6H)；
13CNMR(75MHz，CDCl
3)δ150.6，147.6，138.46，129.2，128.8，128.4，127.7，123.69，70.3，69.8，60.1，58.0，37.5，26.0，18.3，-5.4；MS(EI)m/e?415(M+-15，0.9)，278(100)，91(73)；
Embodiment 7
(1R, 2R)-3-(triphenyl methoxyl group)-2-N-benzyl-N-methylamino--1-(to the nitre phenyl)-1-propyl alcohol:
(1R, 2R)-2-N-benzyl-N-methylamino--3-is to nitre phenyl-1, and (380mg 1.2mmol) is dissolved in CH to ammediol
2Cl
2(15mL), 0 ℃ add down triphenylmethyl chloride (334mg, 1.2mmol) and Et
3N (0.2mL).Separate after stirring is spent the night product 500mg.mp58.0-59.3℃；FTIR(KBr)3314，2926，1602，1521，1346cm
-1；
1HNMR(300MHz，CDCl
3)δ8.07(d，J＝8.8Hz，2H)，7.40-7.19(m，22H)，4.30(d，J＝9.6Hz，1H)，3.94(d，J＝13.0Hz，1H)，3.73(d，J＝6.8Hz，1H)，3.36(m，1H)，3.06(m，1H)2.89(m，1H)，2.33(s，3H)；
13CNMR(75MHz，CDCl
3)δ150.6，147.6，143.46，138.2，129.3，128.8，128.7，128.6，128.4，128.0，127.7?127.4，123.7，87.8，70.5，69.8，60.1，58.0，37.0；MS(EI)m/e?406(M+-152，24.9)，243(100)；Anal.calcd.for?C
15H
24N
2O
4：C，77.42；H，6.09；N，5.02.Found：C，77.26；H，6.06；N，4.65..
Embodiment 8
(1R, 2R)-3-(triphenyl methoxyl group)-2-N, N-dimethylamino-1-(phenyl)-1-propyl alcohol synthetic (1R, 2R)-2-N, N-dimethylamino-1-(phenyl)-1, (1.95g 10mmol) is dissolved in CH to ammediol
2Cl
2(50mL), 0 ℃ add down triphenylmethyl chloride (3.33g, 12mmol) and the aftertreatment of triethylamine (2mL) stirred overnight at room temperature get product 4.0g.FTIR (KBr) 3344,2954,1609,1525,1349cm
-1 1HNMR (300MHz, CDCl
3) δ 7.26-7.06 (m, 20H), 4.87 (d, J=10.0Hz, 1H), and 3.76 (dd, J=10.2Hz, 6.4Hz 1H), 3.51 (dd, J=10.7Hz, 3.9Hz 2H), 2.80 (m, 1H), 2.38 (s, 6H);
13CNMR (75MHz, CDCl
3) δ 143.6,138.9,128-129 (16C), 125.7-126.6 (4C), 84.9,72.9,68.6,69.6,49.6,39.6.
Embodiment 9
(1R, 2R)-3-(triphenyl methoxyl group)-2-N, N-dimethylamino-1-(to the methylsulfonyl phenyl)-1-propyl alcohol synthetic
(1R, 2R)-2-N, N-dimethylamino-1-(to the methylsulfonyl phenyl)-1, (5.46g 20mmol) is dissolved in CH to ammediol
2Cl
2(80mL), 0 ℃ add down triphenylmethyl chloride (6.8g, 25mmol) and the aftertreatment of triethylamine (4mL) stirred overnight at room temperature get product 9.10g.FTIR(KBr)3344，2954，1609，1525，1349cm
-1；
1HNMR(300MHz，CDCl
3)δ7.48-7.40(d，J＝8.4Hz，2H)，7.27-7.19(d，J＝8.6Hz，2H)，7.12-7.04(m，15H)，4.86(d，J＝10.0Hz，1H)，3.72(dd，J＝10.2Hz，6.4Hz?1H)，3.56(dd，J＝10.2Hz，6.4Hz?2H)，2.94(s，3H)，2.81(m，1H)，2.38(s，6H)；
13CNMR(75MHz，CDCl
3)δ143.8，143.0，138.6，135.0，129-126(16C)，84.9，72.9，69.6，68.0，49.6，41.0，39.6.
Embodiment 10
Cyclopropyl acethlene is to the addition of imido
Under 25 ℃, the amino alcohol part (1R, 2R)-3-tert.-butoxy-2-N, N-dimethylamino-1-to nitre phenyl-1-propyl alcohol (2.96g, 10mmol) and Zn (OTf)
2(3.6g 10mmol) is dissolved in the toluene (10mL).Add NEt again
3(2.1mL, 15mmol).Add after one hour cyclopropyl acethlene (1.2mL, 12mmol) and to the imido of methoxy-benzyl protection (3.69g, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated citric acid cancellation reaction.Ethyl acetate extraction.Organic phase merge dry back concentrate product (95% productive rate, 99.3%ee), water reclaims part with in the sodium hydroxide and back.
Embodiment 11
DPC 961 must prepare
N-is dissolved in 10%aqueous CH to the DPC 961 (2mmol) of methoxy-benzyl protection
3CN (10mL), and the adding ceric ammonium nitrate (4.4g, 8mmol).25 ℃ were reacted 4 hours.System dilute with water ethyl acetate extraction.Get DPC 961 (80% productive rate) after concentrating.
Embodiment 12
Cyclopropyl acethlene is to the addition of imido
Under 25 ℃, the amino alcohol part (1R, 2R)-3-tertiary butyl dimethyl Si base-2-N, N-dimethylamino-1-to nitre phenyl-1-propyl alcohol (3.54g, 10mmol) and Zn (OTf)
2(3.6g 10mmol) is dissolved in the toluene (10mL).Add NEt again
3(2.1mL, 15mmol).Add after one hour cyclopropyl acethlene (1.2mL, 12mmol) and to the imido of methoxy-benzyl protection (3.69g, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated citric acid cancellation reaction.Ethyl acetate extraction.Organic phase merge dry back concentrate product (72% productive rate, 99.1%ee).
Embodiment 13
Cyclopropyl acethlene is to the addition of imido
Under 25 ℃, the amino alcohol part (1R, 2R)-3-triphenyl methoxyl group-2-N, N-dimethylamino-1-to nitre phenyl-1-propyl alcohol (4.82g, 10mmol) and Zn (OTf)
2(3.6g 10mmol) is dissolved in the toluene (10mL).Add NEt again
3(2.1mL, 15mmol).Add after one hour cyclopropyl acethlene (1.2mL, 12mmol) and to the imines of methoxy-benzyl protection (3.69g, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated citric acid cancellation reaction.Ethyl acetate extraction.Organic phase merge dry back concentrate product (76%yield, 98.0%ee).
Embodiment 14
Cyclopropyl acethlene is to the addition of imido
Under 25 ℃, the amino alcohol part (1R, 2R)-3-triphenyl methoxyl group-2-N-benzyl-N-methylamino-1-to nitre phenyl-1-propyl alcohol (5.58g, 10mmol) and Zn (OTf)
2(3.6g 10mmol) is dissolved in the toluene (10mL).Add NEt again
3(2.1mL, 15mmol).Add after one hour cyclopropyl acethlene (1.2mL, 12mmol) and to the imines of methoxy-benzyl protection (3.69g, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated aqueous ammonium chloride cancellation reaction.Ethyl acetate extraction.Organic phase merge dry back concentrate product (80%yield, 51.0%ee).
Embodiment 15
Cyclopropyl acethlene is to the addition of imido
Under 25 ℃, the amino alcohol part (1R, 2R)-3-triphenyl methoxyl group-2-N-benzyl-N-methylamino-1-to nitre phenyl-1-propyl alcohol (5.58g, 10mmol) and Cu (OTf)
2(3.6g 10mmol) is dissolved in the toluene (10mL).Add NEt again
3(2.1mL, 15mmol).Add after one hour cyclopropyl acethlene (1.2mL, 12mmol) and to the imines of methoxy-benzyl protection (3.69g, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated citric acid cancellation reaction.Ethyl acetate extraction.Organic phase merge dry back concentrate product (68% productive rate, 98.0%ee).
Embodiment 16
Cyclopropyl acethlene is to the addition of imido
Under 25 ℃, the amino alcohol part (1R, 2R)-3-tertiary butyl dimethyl Si base-2-N, N dimethylamino-1-to nitre phenyl-1-propyl alcohol (354mg, 1mmol) and Zn (OTf)
2(0.36g 1mmol) is dissolved in the toluene (10mL).Add NEt again
3(0.21mL, 1.5mmol).Add after one hour cyclopropyl acethlene (1.2mL, 12mmol) and to the imines of methoxy-benzyl protection (3.69g, 10mmol).Mixture reacts 10hr down for 25 ℃.Dilute hydrochloric acid cancellation reaction.Ethyl acetate extraction.Organic phase merge dry back concentrate product.(75% productive rate, 98.1%ee).
Embodiment 17
Cyclopropyl acethlene is to the addition of imido
Under 25 ℃, the amino alcohol part (1R, 2R)-3-triphenyl methoxyl group-2-N-benzyl-N-methylamino-1-to nitre phenyl-1-propyl alcohol (558mg, 1mmol) and Cu (OTf)
2(0.36g 1mmol) is dissolved in the toluene (10mL).Add NEt again
3(0.21mL, 1.5mmol).Add after one hour cyclopropyl acethlene (1.2mL, 12mmol) and to the imines of methoxy-benzyl protection (3.69g, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated citric acid cancellation reaction.Ethyl acetate extraction.Organic phase merge dry back concentrate product (67%yield, 45%ee).
Embodiment 18
Tertiary butyl acetylene is to the addition of imido
Under 25 ℃, the amino alcohol part (1R, 2R)-3-tertiary butyl dimethyl Si base-2-N, N-dimethylamino-1-to nitre phenyl-1-propyl alcohol (3.54g, 10mmol) and Zn (OTf)
2(3.6g 10mmol) is dissolved in the toluene (10mL).Add HNiPr again
2(2.0mL).Add after one hour tertiary butyl acetylene (1.3mL, 12mmol) and to the imines of methoxy-benzyl protection (3.69g, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated citric acid cancellation reaction.Ethyl acetate extraction.Organic phase merge dry back concentrate product (45%yield, 96.5%ee).
Embodiment 19
Cyclopropyl acethlene is to the addition of imido
Under 25 ℃, the amino alcohol part (1R, 2R)-3-tertiary butyl dimethyl Si base-2-N, N-dimethylamino-1-to nitre phenyl-1-propyl alcohol (3.54kg, 10mol) and Zn (OTf)
2(3.6kg 10mol) is dissolved in the toluene (10L).Add again triethylamine (2.0L, 15mol).Add after one hour cyclopropyl acethlene (1.2L, 12mol) and to the imido of methoxy-benzyl protection (3.69kg, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated citric acid cancellation reaction.Ethyl acetate extraction.Organic phase merge dry back concentrate product (90.9%yield, 99.1%ee)
Embodiment 20
Phenylacetylene is to the addition of imido
Under 25 ℃, the amino alcohol part (1R, 2R)-3-tert.-butoxy-2-N, N-dimethylamino-1-to nitre phenyl-1-propyl alcohol (2.96g, 10mmol) and Zn (OTf)
2(3.6g 10mmol) is dissolved among the THF (10mL).Add NEt again
3(2.1mL, 15mmol).Add after one hour phenylacetylene (1.1mL, 12mmol) and to the imido of methoxy-benzyl protection (3.69g, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated citric acid cancellation reaction.Ethyl acetate extraction.Organic phase merge dry back concentrate product (91%yield, 99.0%ee).
Embodiment 21
Cyclopropyl acethlene is to the addition of imido
Under 25 ℃, the amino alcohol part (1R, 2R)-3-tertiary butyl dimethyl Si base-2-N, N-dimethylamino-1-to nitre phenyl-1-propyl alcohol (3.54g, 10mmol) and Zn (OTf)
2(3.6g 10mmol) is dissolved in the toluene (10mL).Add NEt again
3(2.1mL, 15mmol).Add after one hour cyclopropyl acethlene (1.2mL, 12mmol), 50 ℃ in mixture reaction 2hr is again to 25 degree, add again imido to the methoxy-benzyl protection (3.69g, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated citric acid cancellation reaction.Ethyl acetate extraction.Organic phase merge dry back concentrate product (81%yield, 97.1%ee).
Embodiment 22
Cyclopropyl acethlene is to the addition of imido
Under 25 ℃, the amino alcohol part (1R, 2R)-3-tertiary butyl dimethyl Si base-2-N, N-dimethylamino-1-to nitre phenyl-1-propyl alcohol (3.54g, 10mmol) and ZnBr
2(2.3g 10mmol) is dissolved in the toluene (10mL).Add NEt again
3(2.1mL, 15mmol).Add after one hour cyclopropyl acethlene (1.2mL, 12mmol), 50 ℃ in mixture reaction 2hr is again to 25 degree, add again imido to the methoxy-benzyl protection (3.69g, 10mmol).Mixture reacts 10hr down for 25 ℃.Saturated citric acid cancellation reaction.Ethyl acetate extraction.Organic phase merge dry back concentrate product (31%yield, 63.1%ee).
Claims (10)
1 one kinds of chiral amino alcohol ligands have following general structure:
, R wherein
1, R
2Be amino protecting group, R
3It is the oxygen protecting group; Z is H, electron-withdrawing group or electron donating group, and described amino protecting group comprises alkyl, substituted alkyl, benzyl, substituted benzyl or trialkyl silyl protecting group; Described oxygen protecting group comprises C
1～C
20Alkyl, replace C
1～C
20Alkyl, benzyl, substituted benzyl or trialkyl silyl protecting group, the substituting group on described alkyl or the benzyl comprises phenyl, naphthyl, halogen, nitro, C
1～C
3Hydroxyl, C
1～C
3Hydroxyalkyl, C
1～C
3Alkoxyl group, CN, described electron-withdrawing group are halogen, CH
3O, OH, NO
2, CF
3, CH
3SO
2Perhaps CH
3CH
2SO
2, described electron donating group is C
1～C
20Alkyl.
2. part as claimed in claim 1 has following general structure:
R wherein
1, R
2, R
3According to claim 1.
3. the described part of claim 1 has following general structure:
4. part as claimed in claim 1 is characterized in that described electron donating group is C
1～C
4Alkyl, described trialkyl silyl is the silica-based or trityl of tertiary butyl dimethyl.
5. the application of the part of claim 1 in asymmetric synthesis, the technology that it is characterized in that being used for synthesizing following structure chipal compounds:
Wherein P is H or amino protecting group, and Rf contains C
1～C
20Fluoroalkyl, R is trialkyl silyl, C
1～C
20Alkyl, C
3～C
10Cycloalkyl or aryl, Y is H, electron-withdrawing group or electron donating group, described amino protecting group, electron-withdrawing group or electron donating group are according to claim 1.
6. technology as claimed in claim 4 is characterized in that comprising the steps:
(a) (1R, 2R)-2-N, N-replacement-1-substituted-phenyl-3-O-replacement-1-propyl alcohol has following structure with chiral ligand
R wherein
1, R
2, R
3Z according to claim 1;
Be mixed in a kind of organic solvent with Terminal Acetylenes and metal-salt, described Terminal Acetylenes is
R such as preceding
Described, add organic bases again;
(b) adding has the substrate of following structure to react
P is H or amino protecting group as claimed in claim 1 in the formula, and Rf and Y are as described in the claim 4.
7. the described technology of claim 6 is characterized in that reacting the back and adds proton source cancellation reaction, separates obtaining product, chiral ligand by in the alkali and water extract again and reclaim use.
8. as technology as described in the claim 6, it is characterized in that being used for synthetic following structure chipal compounds
Comprise the steps:
(a) (1R, 2R)-2-N, N-replacement-1-(4-substituted-phenyl)-3-O-replacement-1-propyl alcohol has following structure with chiral ligand
R wherein
1, R
2And R
3According to claim 1; Z is H, Cl, Br, CH
3SO
2Perhaps NO
2Be mixed in the organic solvent with Terminal Acetylenes and Zn (II) salt or Cu salt, described Terminal Acetylenes is
R adds organic bases again as described in the claim 5;
(b) add the substrate that following structure is arranged
(a) add proton source cancellation reaction;
(b) separate and to obtain product, in the water alkali and reclaim part.
9. as technology as described in the claim 6, wherein the reaction mole proportioning of organic bases, part and substrate imido is 1-4: 0.1-3: 1.
10. as technology as described in the claim 6, described metal-salt is for comprising ZnCl
2, ZnBr
2, ZnF
2, ZnI
2, Zn (OTf)
2, Zn (SO
3CF
2H)
2, CuCl
2, CuBr
2, Cu (OTf)
2, a kind of in interior Zn (II) or Cu salt of CuCl, CuBr, Cu (OTf), CuI; Described organic bases is dimethyl Isopropylamine, diethylamine, tri-isopropyl amine, pyridine, piperidines, ethyl diisopropylamine, Tributylamine or triethylamine.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03116192 CN1216036C (en) | 2003-04-04 | 2003-04-04 | Chiral alkamine ligand and its application in asymmetrical addition of terminal alkyne para imine |
| US10/551,770 US7439400B2 (en) | 2003-04-04 | 2003-06-16 | Amino alcohol ligand and its use in preparation of chiral proparglic tertiary alcohols and tertiary amines via enantioselective addition reaction |
| PCT/CN2003/000462 WO2004087628A1 (en) | 2003-04-04 | 2003-06-16 | An amino alcohol ligand and its use in preparation of chiral proparglic tertiary alkohols and tertiary amines via enantioselective additon reaction |
| EP03816495A EP1614672B1 (en) | 2003-04-04 | 2003-06-16 | An amino alcohol ligand and its use in preparation of chiral proparglic tertiary alkohols and tertiary amines via enantioselective additon reaction |
| AU2003248217A AU2003248217A1 (en) | 2003-04-04 | 2003-06-16 | An amino alcohol ligand and its use in preparation of chiral proparglic tertiary alkohols and tertiary amines via enantioselective additon reaction |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03116192 CN1216036C (en) | 2003-04-04 | 2003-04-04 | Chiral alkamine ligand and its application in asymmetrical addition of terminal alkyne para imine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1442403A CN1442403A (en) | 2003-09-17 |
| CN1216036C true CN1216036C (en) | 2005-08-24 |
Family
ID=27797100
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03116192 Expired - Fee Related CN1216036C (en) | 2003-04-04 | 2003-04-04 | Chiral alkamine ligand and its application in asymmetrical addition of terminal alkyne para imine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1216036C (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100548991C (en) * | 2005-07-22 | 2009-10-14 | 中国科学院上海有机化学研究所 | 4,4-dibasic-3,4-dihydro-2 (1H)-quianzolinones |
| CN102093166B (en) * | 2010-11-18 | 2014-04-09 | 中国农业大学 | Method for synthesizing marine natural product by using high optical activity enantiomer |
| CN103664816B (en) * | 2011-01-06 | 2016-03-02 | 中国科学院上海有机化学研究所 | The one kettle way asymmetric synthesis technique of hiv reverse transcriptase inhibitor Sustiva compounds |
| CN102060786A (en) * | 2011-01-20 | 2011-05-18 | 天津大学 | 4-(substituted-1,3-diyne)-4-(trifluoromethyl)-3,4-dihydro substituted quinazoline-2-ketone compound as well as preparation method and application thereof |
| CN102180915B (en) * | 2011-03-25 | 2014-08-13 | 南京理工大学 | D-fructopyranose derived saccharide beta-alkamine and synthesis method thereof |
| CN102372533B (en) * | 2011-11-01 | 2014-08-13 | 浙江新华制药有限公司 | Unsymmetrical addition method of fluoroalkyl contained arone using tartaric acid derivative catalytic terminal alkyne zinc reagent |
-
2003
- 2003-04-04 CN CN 03116192 patent/CN1216036C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1442403A (en) | 2003-09-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2007291113A (en) | PROCESS FOR PRODUCING tert-BUTYL (E)-(6-[2-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-[METHYL(METHYLSULFONYL)AMINO]PYRIMIDIN-5-YL]VINYL]-(4R,6S)-2,2-DIMETHYL[1,3]DIOXAN-4-YL)ACETATE | |
| CN101080399A (en) | Process for producing optically active epoxy compound, complex for use in the process, and process for producing the same | |
| CN1226293C (en) | Method for preparing 2-(2-hydroxyphenyl)-2h-benzotriazole | |
| CN1216036C (en) | Chiral alkamine ligand and its application in asymmetrical addition of terminal alkyne para imine | |
| CN1131864C (en) | Chemical synthesis of morpholine derivatives | |
| CN1662484A (en) | Process for preparing (r)-aryloxypropionic acid ester derivatives | |
| TWI397380B (en) | Method for producing α-amino acid including phosphorus and its production intermediate | |
| CN1197864C (en) | Process for preparation of pyrazolo pyridazine derivatives | |
| CN103664816B (en) | The one kettle way asymmetric synthesis technique of hiv reverse transcriptase inhibitor Sustiva compounds | |
| CN1243725C (en) | Process for the preparation of nitrile compounds | |
| CN1449865A (en) | Method of Chiral alkamine ligand used as catalyst of asymmetric addition process for terminal alkyne to fluoroalkylaryl ketone | |
| CN1668599A (en) | Process for preparing quinolone antibiotic intermediates | |
| CN87105804A (en) | The preparation method of halogenation-3-halo-2-hydroxypropyl trimethyl ammonium | |
| CN1224609C (en) | Process for preparation of arylethanolamine derivatives having anti-obesity and anti-diabetic properties | |
| CN1642937A (en) | Process for making chiral 1,4-disubstituted piperazines | |
| CN1183771A (en) | Process for preparing racemic and enantiomeric 1 -(pyridyl) -2 -cyclohexylethylamine | |
| CN1255404C (en) | Process for preparing substd. imidazopyridine compound | |
| CN1147498C (en) | Method for preparing oxazaphosphorin-2-amines | |
| CN1028994C (en) | Process for lithiation of 1,3-bis (trifluoromethyl) benzene | |
| CN1245165A (en) | Process for preparing s-aryl-semi-cystine and its derivatives | |
| CN1199729A (en) | Process to chloroketones using oxazolines | |
| CN1769266A (en) | Process for preparing biphenyl compounds | |
| CN1176091C (en) | Vitamin D precursor of phosphine oxide | |
| CN1278249A (en) | Biphenyl derivatives as pharmaceuticals | |
| CN1100760C (en) | Process for preparation of arylamides of heteroaromatic carboxylic acids |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20050824 Termination date: 20180404 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |