CN1197836C - Method for asymmetrically synthesizing secondary propiolic alcohol compound - Google Patents
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- CN1197836C CN1197836C CN 01105779 CN01105779A CN1197836C CN 1197836 C CN1197836 C CN 1197836C CN 01105779 CN01105779 CN 01105779 CN 01105779 A CN01105779 A CN 01105779A CN 1197836 C CN1197836 C CN 1197836C
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Abstract
The present invention relates to a method for synthesizing secondary propiolic alcohol compounds with high stereoselectivity. Chiral aminoalcohol or chiral amino diol is used as ligands, and the optically active secondary propiolic alcohol compounds are obtained by the addition reactions of alkyne at the end to aldehyde under the existence of a difluoromethanesulfonic acid metal reagent or trifluoromethanesulfonic acid metal reagent and alkali. The method has the advantages of mild reaction conditions, high stereoselectivity, low cost, etc.
Description
The present invention relates to a kind of method of asymmetric synthesis secondary propiolic alcohol compound
Optically pure secondary propiolic alcohol compound is the important building block of the more synthetic biologically active compounds of Stereoselective.Asymmetric metal alkynes is an important method of synthetic this compounds to the nucleophilic addition(Adn) of aldehyde, has only the addition reaction of the asymmetric metal alkynes of minority bibliographical information to aldehyde.Document J.Am.Chem.Soc.1994 for example, 116, alkynes boron is to the asymmetric reduction reaction of aldehyde in 3151, document Chem.Lett.1980, the alkynes lithium is to asymmetric reduction reaction of aldehyde etc., document J.Am.Chem.Soc.2000 in 255,122,1806 are reported in trifluoromethanesulfonic acid zinc, alkali and N, and N-dimethyl norephedrine exists down, and asymmetric terminal alkynes obtains the secondary propiolic alcohol compound of highly-solid selectively to the addition reaction of aldehyde.
The method that the purpose of this invention is to provide a kind of asymmetric synthesis secondary propiolic alcohol compound.
The invention provides a kind of method of asymmetric synthesis secondary propiolic alcohol compound, promptly with chiral amino alcohol or chiral amino glycol as part, after the coordination, add terminal alkynes and aldehyde reaction and generate secondary propiolic alcohol compound in aprotic solvent, reaction formula is as follows:
A is Difluore methane-sulfonic acid metal reagent or trifluoromethanesulfonic acid metal reagent, and the useful molecules general formula is described as M (OSO
2CF
2H)
nOr M (OSO
2CF
3)
n, wherein M=zinc, silver, cadmium, mercury, indium, lead, antimony, bismuth, ytterbium or tin, n=1-3.B is chiral amino alcohol or chiral amino glycol part and when above-mentioned reactant had the trifluoromethanesulfonic acid zincon, part used in the present invention only was the chiral amino glycol.Above-mentioned R
1Or R
2=C
1-20Aliphatic hydrocarbyl, aryl, substituted aryl or heteroaryl etc., described heteroatoms is N, O or S; Described alkali is triethylamine, diisopropyl ethyl amine, N, dinethylformamide, pyridine, 1,8-diazabicyclo [5.4.0] undecane-7-alkene (DBU), 1 contains the amine of lone-pair electron on 5-diazabicyclo [4.3.0] nonane-5-alkene nitrogen-atoms such as (DBN); Described chiral amino alcohol ligand is a N-methylephedrine (being N, N-dimethyl norephedrine) etc.; Described chiral amino glycol part is that general molecular formula is
Chirality 2-disubstituted amido-1-(4-substituted-phenyl)-1, ammediol, R=H, NO in the formula
2, SO
2Me, COCH
3, R
3Or R
4=C
1-6Alkyl or cycloalkyl, R
1And R
2, R
3And R
4It is identical or different group; Described aprotic solvent is toluene, methylene halide, haloform, tetracol phenixin, tetrahydrofuran (THF), acetonitrile, acetone, ethanol, methyl-sulphoxide etc.
Specifically, the inventive method is in the time of-10 ℃～100 ℃, in aprotic solvent, adds metal reagent, chiral amino alcohol or chiral amino glycol part, alkali, terminal alkynes and aldehyde, fully obtains secondary propiolic alcohol compound after the reaction.Aldehyde wherein: alkynes: part: metal reagent: the mol ratio of alkali is 1: 0.5-5: 0.5-5: 0.2-5: 0.1-5 is recommended as 1: 0.8-2: 0.8-2: 0.5-2: 0.5-2.Reaction times is 0.5-60 hour, also can prolong the reaction times in the reaction or increase the reactant consumption.
The present invention compares with the technology of bibliographical information, reaction conditions gentleness, stereoselectivity height, the chiral ligand low price, and Difluore methane-sulfonic acid zinc cheaply is easy to get, and chiral ligand 2-(N, the N-disubstituted amido)-and 1-(4-substituted-phenyl)-1, ammediol is also more practical than N-methylephedrine.
Following examples help to understand the present invention, but are not limited to content of the present invention
Embodiment 1
(S)-preparation of 1-cyclohexyl-3-phenyl-2-propine-1-alcohol
Under nitrogen protection, Difluore methane-sulfonic acid zinc (180mg, 0.55mmol; 1.1eq) and (-)-N, N-dimethyl norephedrine (108mg, 0.602mmol; 1.2eq) toluene (2mL) solution in, add triethylamine (61mg, 0.602mmol; 1.2eq), mixing solutions at room temperature stirs 2h, adds phenylacetylene (61mg; 0.6mmol, 1.2eq), add hexamethylene aldehyde (58mg) behind the stirring 0.5h under the room temperature; stir 12h, add saturated aqueous ammonium chloride (3mL), extracted with diethyl ether (3 * 10mL).The organic solvent that merges washs anhydrous sodium sulfate drying with saturated nacl aqueous solution.Product obtains 96mg (S)-1-cyclohexyl-3-phenyl-2-propine-1-alcohol with the silica gel column chromatography separation, and yield is 90%.The 97%ee value is measured with chirality HPLC post.
1H?NMR(300MHz，CDCl
3)δ7.38-7.45(m，2H)，7.30-7.24(m，3H)，4.40-4.30(d，J＝6.0Hz，1H)，2.00-1.58(m，1H)，1.36-1.05(m，11H)。
Embodiment 2
(S)-preparation of 4-methyl isophthalic acid-phenyl-1-pentyne-3-alcohol
Under nitrogen protection, Difluore methane-sulfonic acid zinc (180mg, 0.55mmol; 1.1eq) and (-)-N, N-dimethyl norephedrine (108mg, 0.602mmol; 1.2eq) toluene (2mL) solution in, add triethylamine (61mg, 0.602mmol; 1.2eq), mixing solutions at room temperature stirs 2h, adds phenylacetylene (61mg; 0.6mmol, 1.2eq), add isobutyric aldehyde (43mg) behind the stirring 0.5h under the room temperature; stir 24h, add saturated aqueous ammonium chloride (3mL), extracted with diethyl ether (3 * 10mL).The organic solvent that merges washs anhydrous sodium sulfate drying with saturated nacl aqueous solution.Product obtains 44mg (S)-4-methyl isophthalic acid-phenyl-1-pentyne-3-alcohol with the silica gel column chromatography separation, and yield is 92%.The 97%ee value is measured with chirality HPLC post.
1H?NMR(300MHz，CDCl
3)δ7.4(m，2H)，7.25(m.3H)，4.38(d，J＝6.0Hz，1H)，2.04(d，J＝5.7Hz，1H)，1.97(m，1H)，1.05(dd，J＝6.7Hz，6H)。
Embodiment 3
In the following table in the sequence number 7 mol ratio of aldehyde, alkynes, part, metal reagent and alkali be 1: 2.0: 2.0: 0.8: 3.0, the mol ratio of aldehyde, alkynes, part, metal reagent and alkali is 1: 0.6: 2 in the sequence number 11,12: 2: 5, the mol ratio of aldehyde, alkynes, part, metal reagent and alkali was 1: 2.0: 0.5 in the sequence number 15: 5: 0.5.
aAbsolute configuration is definite according to comparing with known compound.
bThe ee value is measured with chirality HPLC post.Experimental procedure and other experiment condition are with embodiment 1:
Sequence number aldehyde alkyne reaction time (h) yield % absolute configuration ee%
1 hexamethylene aldehyde phenylacetylene, 12 90 S 97
2 hexamethylene aldehyde benzene butine, 12 87 S 99.7
3 ring propionic aldehyde benzene octynes, 12 79 S 95
4 different propionic aldehyde
24 82 S 93
5 different propionic aldehyde phenyl-allylene 12 84 S 92.5
6 2-ethyl butyraldehyde 2-pyridine acetylene, 12 85 S 97.5
7 enanthaldehyde p-nitrophenyl acetylene, 12 86 S 89
8 uncle's butyraldehyde phenylacetylenes, 12 85 S 94
9 propenal meta-methoxy phenylacetylenes, 12 81 S 86.6
10 furfural benzene butine, 12 78 S 98
11 NSC 43794 phenylacetylenes, 24 45 S 96
12 phenyl aldehyde benzene pentynes, 24 42 S 95.5
13
Phenylacetylene 24 57 S 93
14
Cyclopropyne 24 63 R 88
15 paranitrobenzaldehyde phenylacetylenes, 60 44 S 90
Embodiment 4
(R)-preparation of 1-cyclohexyl-3-phenyl-2-propine-1-alcohol
Under nitrogen protection; trifluoromethanesulfonic acid zinc (200mg, 0.55mmol is 1.1eq) with (1S; 2S)-(+)-N; the N-dimethylamino)-and 1-(4-nitrophenyl)-1, ammediol (127mg, 0.602mmol; 1.2eq) THF (2mL) solution in; the adding triethylamine (61mg, 0.602mmol, 1.2eq); mixing solutions at room temperature stirs 2h; the adding phenylacetylene (61mg, 0.6mmol, 1.2eq); add hexamethylene aldehyde (58mg) after stirring 0.5h under the room temperature; stir 12h, add saturated aqueous ammonium chloride (3mL), extracted with diethyl ether (3 * 10mL).The organic solvent that merges washs anhydrous sodium sulfate drying with saturated nacl aqueous solution.Product obtains 96mg (R)-1-cyclohexyl-3-phenyl-2-propine-1-alcohol with the silica gel column chromatography separation, and yield is 73%.The 97%ee value is measured with chirality HPLC post.
1H?NMR(300MHz，CDCl
3)δ7.38-7.45(m，2H)，7.30-7.24(m.3H)，4.40-4.30(d，J＝6.0Hz，1H)，2.00-1.58(m，1H)，1.36-1.05(m，11H)。
Embodiment 5
(R)-preparation of the preparation of 4-methyl isophthalic acid-phenyl-1-pentyne-3-alcohol
Under nitrogen protection; trifluoromethanesulfonic acid zinc (360mg; 1mmol, 2eq) and (1S, 2S)-(+)-N; N-dicyclohexyl amino)-1-(4-formylphenyl)-1; (0.602mmol in methylene dichloride 1.2eq) (2mL) solution, adds DBU (0.602mmol to ammediol; 1.2eq); mixing solutions at room temperature stirs 2h, adds phenylacetylene (122mg, 1.2mmol; 2.4eq); stir under the room temperature add behind the 0.5h isobutyric aldehyde (86mg, 2.4eq), 80 ℃ of reactions 5 hours; add saturated aqueous ammonium chloride (3mL), extracted with diethyl ether (3 * 10mL).The organic solvent that merges washs anhydrous sodium sulfate drying with saturated nacl aqueous solution.Product obtains 88mg (R)-4-methyl isophthalic acid-phenyl-1-pentyne-3-alcohol with the silica gel column chromatography separation, and yield is 61%.The 87%ee value is measured with chirality HPLC post.
1H?NMR(300MHz，CDCl
3)δ7.4(m，2H)，7.25(m，3H)，4.38(t，J＝6.0Hz，1H)，2.04(d，J＝5.7Hz，1H)，1.97(m，1H)，1.05(dd，J＝6.7Hz，6H)。
Embodiment 6
In the following table
aAbsolute configuration is definite according to comparing with known compound.
bThe ee value is measured with chirality HPLC post.
cToluene is as solvent.
dTHF is as solvent.Trifluoromethanesulfonic acid zinc in the sequence number 1,2 and 5: part: alkynes: aldehyde: alkali=2: 1: 1.2: 1.1: 1.2, other trifluoromethanesulfonic acid zinc: part: alkynes: aldehyde: alkali=1.2: 1: 1.2: 1.1: 1.2. experimental procedure and other condition were with embodiment 4:
Yield % absolute configuration ee% during sequence number aldehyde alkyne reaction
B, cEe%
C, d
Between (h)
a
1 hexamethylene aldehyde uncle butine, 12 73 R 91 97
2 ring propionic aldehyde octadecynes, 12 64 R 85 94
3 different propionic aldehyde
12 61 R 88 93
4 2-ethyl butyraldehyde 3-pyridine acetylene, 12 65 R 79 97.5
5 CH
3(CH
2)
15CHO phenylacetylene 12 67 R 76 93.5
6 furfural benzene butine 24 45 R-95.5
7 NSC 43794 benzene heptyne, 24 35 R 74 93
8 phenyl aldehydes
24 38 R 75 99
Embodiment 7
(S)-preparation of 1-cyclohexyl-3-phenyl-2-hexin-1-alcohol
Under nitrogen protection, and Difluore methane-sulfonic acid zinc (180mg, 0.55mmol, 1.1eq) and (1S, 2S)-(+)-N, N-dimethylamino)-1-(4-nitrophenyl)-1, ammediol (127mg, 0.602mmol, CH 1.2eq)
3In CN (2mL) solution, add 1, and 5-diazabicyclo [4.3.0] nonane-5-alkene (0.1mmol, 0.2eq), mixing solutions at room temperature stirs 2h, adding benzene pentyne (61mg, 0.6mmol, 1.2eq), add isobutyric aldehyde (58mg) after stirring 0.5h under the room temperature, stir 12h, add saturated aqueous ammonium chloride (3mL), extracted with diethyl ether (3 * 10mL).The organic solvent that merges washs anhydrous sodium sulfate drying with saturated nacl aqueous solution.Product obtains 96mg (R)-1-cyclohexyl-6-phenyl-2-hexin-1-alcohol with the silica gel column chromatography separation, and yield is 89%.The 93%ee value is measured with chirality HPLC post.
1H?NMR(300MHz，CDCl
3)δ7.10-7.25(m，5H)，4.40-4.30(d，J＝6.8Hz，1H)，2。29(m，2H)，2.15(2H，m)，2.00-1.58(m，1H)，1.36-1.05(m，8H)。
Embodiment 8
(R)-preparation of 1-cyclopropyl-3-phenyl-2-propine-1-alcohol
Under nitrogen protection; Difluore methane-sulfonic acid zinc (327mg, 1mmol is 2eq) with (1S; 2S)-(+)-N; the N-dimethylamino)-and 1-(4-nitrophenyl)-1, ammediol (127mg, 0.602mmol; 1.2eq) toluene (2mL) solution in; the adding triethylamine (132mg, 1.2mmol, 2.4eq); mixing solutions at room temperature stirs 2h; the adding phenylacetylene (132mg, 1.2mmol, 2.4eq); add ring propionic aldehyde (83mg) after stirring 0.5h under the room temperature; 60 ° of G stir 1h, add saturated aqueous ammonium chloride (3mL), extracted with diethyl ether (3 * 10mL).The organic solvent that merges washs anhydrous sodium sulfate drying with saturated nacl aqueous solution.Product obtains 88mg (R)-1-cyclopropyl-3-phenyl-2-propine-1-alcohol with the silica gel column chromatography separation, and yield is 92%.The 77%ee value is measured with chirality HPLC post.
1H?NMR(300MHz，CDCl
3)δ7.4(m，2H)，7.25(m.3H)，4.38(d，J＝6.0Hz，1H)，2.04(d，J＝5.7Hz，1H)，1.97(m，1H)，1.05(d，J＝6.7Hz，4H)。
Embodiment 9
Experimental procedure and other experiment condition are with embodiment 4 in the following table:
Sequence number aldehyde alkyne reaction time yield % absolute configuration
aEe%
c
(h)
1 hexamethylene aldehyde benzene butine, 12 86 R 98
2 ring propionic aldehyde benzene octynes, 18 76 R 93
3 different propionic aldehyde are to thiophenyl phenylacetylene 12 67 R 94
4 2-ethyl butyraldehyde 2-furans acetylene, 12 75 R 96.5
5 CH
3(CH
2)
15CHO phenylacetylene 12 67 R 90.5
6 furfural n-heptylacetylenes, 24 45 R 93.5
7 NSC 43794 phenylacetylenes, 24 35 R 95
8 phenyl aldehyde 3-thiophene acetylene, 24 61 R 91
9 phenyl aldehydes
24 38 R 97
aAbsolute configuration is definite according to comparing with known compound.
bThe ee value is measured with chirality HPLC post.
cTHF is as solvent.
Embodiment 10
(R)-preparation of 1-cyclohexyl-3-p-methoxyphenyl-valerylene-1-alcohol
Under nitrogen protection, Difluore methane-sulfonic acid zinc (540mg, 1.6mmol, 3.3eq) and (1S, 2S)-(+)--N-methyl-N-butyl amino)-1-phenyl-1, ammediol (97.5mg, 0.502mmol, CHCl 1.0eq)
3(2mL) in the solution, add 1,8-diazabicyclo [5.4.0] undecane-7-alkene (0.602mmol, 1.2eq), mixing solutions at room temperature stirs 6h, adds anisole acetylene (79mg, 0.6mmol, 1.2eq or 316mg, 2.4mmol, 4.8eq), add hexamethylene aldehyde (67mg) after stirring 0.5h under the room temperature, stir 12h, add saturated aqueous ammonium chloride (3mL), extracted with diethyl ether (3 * 10mL).The organic solvent that merges washs anhydrous sodium sulfate drying with saturated nacl aqueous solution.Product obtains 124mg (R)-1-cyclohexyl-3-p-methoxyphenyl-valerylene-1-alcohol with the silica gel column chromatography separation, and yield is 83%.The 76%ee value is measured with chirality HPLC post.
1H?NMR(300MHz，CDCl
3)δ7.2(m，2H)，6.9(m.2?H)，4.5(d，J＝6.2Hz，1H)，3.8(s，3H)，2.5(m，1H)，1.45-1.55(m，9H)。
Embodiment 11
(R)-preparation of the 1-tertiary butyl-5-phenyl-valerylene-1-alcohol
Under nitrogen protection; trifluoromethanesulfonic acid zinc (200mg, 0.55mmol is 1.1eq) with (1S; 2S)-(+)-N; the N-dimethylamino)-and 1-(4-methylsulfonyl phenyl)-1, ammediol (164mg, 0.602mmol; 1.2eq) methyl-sulphoxide (2mL) solution in; the adding diisopropyl ethyl amine (77mg, 0.602mmol, 1.2eq); mixing solutions at room temperature stirs 2h; adding benzene butine (78mg, 0.6mmol, 1.2eq); add tertiary butyl formaldehyde (47mg) after stirring 0.5h under the room temperature; 50 ° of G stir 12h, add saturated aqueous ammonium chloride (3mL), extracted with diethyl ether (3 * 10mL).The organic solvent that merges washs anhydrous sodium sulfate drying with saturated nacl aqueous solution.Product obtains 108mg (the R)-1-tertiary butyl-5-phenyl-valerylene-1-alcohol with the silica gel column chromatography separation, and yield is 91%.The 88%ee value is measured with chirality HPLC post.
1H?NMR(300MHz，CDCl
3)δ716(m，5H)，4.25(d，J＝6.4Hz，1H)，2.44(m，4H)，1.01(s，6H)。
Embodiment 12
(S)-preparation of 1-cyclopropyl-3-phenyl-2-propine-1-alcohol
Under nitrogen protection, and the Difluore methane-sulfonic acid cadmium (224mg, 0.55mmol, 1.1eq) and (1S, 2S)-(+)-N, N-dimethylamino)-1-(4-nitrophenyl)-1, ammediol (127mg, 0.602mmol, CH 1.2eq)
3In CN (2mL) solution, add triethylamine (61mg, 0.602mmol, 1.2eq), mixing solutions at room temperature stirs 2h, adds phenylacetylene (61mg, 0.6mmol, 1.2eq or 46mg, 0.45mmol, 0.9eq), add ring propionic aldehyde (58mg) after stirring 0.5h under the room temperature, 85 ° of G stir 8h down, add saturated aqueous ammonium chloride (3mL), extracted with diethyl ether (3 * 10mL).The organic solvent that merges washs anhydrous sodium sulfate drying with saturated nacl aqueous solution.Product obtains 96mg (S)-1-cyclopropyl-3-phenyl-2-propine-1-alcohol with the silica gel column chromatography separation, and yield is 80%.The 76%ee value is measured with chirality HPLC post.
1H?NMR(300MHz，CDCl
3)δ7.4(m，2H)，7.25(m.3H)，4.38(d，J＝6.0Hz，1H)，2.04(d，J＝5.7Hz，1H)，1.97(m，1H)，1.05(d，J＝6.7Hz，4H)。
Embodiment 13
(S)-preparation of 2-methyl-7-(N-methyl-2-pyrroles)-4-heptyne-3-alcohol
Under nitrogen protection; silver trifluoromethanesulfonate (141mg; 0.55mmol; 1.1eq) and N-methylephedrine (0.602mmol; 1.2eq) methylene dichloride (2mL) solution in; the adding lutidine (61mg, 0.602mmol, 1.2eq); mixing solutions at room temperature stirs 2h; adding N-methyl-2-pyrroles's butine (80mg, 0.6mmol, 1.2eq); add isobutyric aldehyde (43mg) after stirring 0.5h under the room temperature; 85 ° of G stir 5h down, add saturated aqueous ammonium chloride (3mL), extracted with diethyl ether (3 * 10mL).The organic solvent that merges washs anhydrous sodium sulfate drying with saturated nacl aqueous solution.Product obtains 102mg (S)-2-methyl-7-(N-methyl-2-pyrroles)-4-heptyne-3-alcohol with the silica gel column chromatography separation, and yield is 90.5%.The 57%ee value is measured with chirality HPLC post.
1H?NMR(300MHz，CDCl
3)δ6.8(m，1H)，6.4(m，1H)，5.9(m，2H)，3.5(s，3H)，3.35(s，2H)，2.0(s，1H)。
Embodiment 14
(S)-preparation of 2-methyl-7-phenyl-4-heptyne-3-alcohol
Under nitrogen protection; Difluore methane-sulfonic acid bismuth (94mg; 0.2mmol, 0.2eq) and (1S, 2S)-(+)-N; the N-dimethylamino)-1-(4-nitrophenyl)-1; ammediol (127mg, 0.602mmol is in acetone 1.2eq) (2mL) solution; add pyrimidine (1.8mmol; 3.6eq), mixing solutions at room temperature stirs 2h, adds benzene butine (61mg; 0.6mmol; 1.2eq), adding isobutyric aldehyde (43mg) behind the stirring 0.5h under the room temperature, 85 ° of G stir 5h down; add saturated aqueous ammonium chloride (3mL), extracted with diethyl ether (3 * 10mL).The organic solvent that merges washs anhydrous sodium sulfate drying with saturated nacl aqueous solution.Product obtains 103mg (S)-2-methyl-7-phenyl-4-heptyne-3-alcohol with the silica gel column chromatography separation, and yield is 93%.The 71%ee value is measured with chirality HPLC post.
1H?NMR(300MHz，CDCl
3)δ7.4(m，2H)，7.25(m.3H)，4.38(d，J＝6.0Hz，1H)，2.1-2.15(m，4H)2.04(d，J＝5.7Hz，1H)，1.97(m，1H)，1.05(dd，J＝6.7Hz，6H)。
Embodiment 15
(R)-preparation of 1-phenyl-3-dodecyne-2-alcohol
Under nitrogen protection; trifluoromethanesulfonic acid indium (286mg; 0.55mmol, 1.1eq) and (1S, 2S)-(+)-N; the N-dimethylamino)-1-(4-nitrophenyl)-1; ammediol (127mg, 0.602mmol is in chloroform 1.2eq) (2mL) solution; add methylethyl amine (0.602mmol; 1.2eq), mixing solutions at room temperature stirs 2h, adds hendecyne (91mg; 0.6mmol; 1.2eq), adding phenyl aldehyde (64mg) behind the stirring 0.5h under the room temperature, 0 ° of G stirs 24h down; add saturated aqueous ammonium chloride (3mL), extracted with diethyl ether (3 * 10mL).The organic solvent that merges washs anhydrous sodium sulfate drying with saturated nacl aqueous solution.Product obtains 131mg (R)-1-phenyl-2-dodecyne-1-alcohol with the silica gel column chromatography separation, and yield is 93%.The 71%ee value is measured with chirality HPLC post.
1H?NMR(300MHz，CDCl
3)δ7.35(m，2H)，7.20(m，3H)，5.3(s，1H)，2.3(m，2H)，1.55(m，4H)，1.35(m，4H)，0.9-1.0(m，13H)。
Claims (5)
1. the method for a synthesizing secondary propiolic alcohol compound, when it is characterized in that-10 ℃～100 ℃, with chiral amino alcohol or chiral amino glycol as part, add alkali, in the aprotic solvent of Difluore methane-sulfonic acid metal reagent or trifluoromethanesulfonic acid metal reagent after the coordination, add terminal alkynes and aldehyde reaction 0.5-60h, described aldehyde: alkynes: part: Difluore methane-sulfonic acid metal reagent or trifluoromethanesulfonic acid metal reagent: the mol ratio of alkali is 1: 0.5-5: 0.5-5: 0.2-5: 0.1-5, generate optically pure secondary propiolic alcohol compound, and when reactant has the trifluoromethanesulfonic acid zincon, part only is the chiral amino glycol, and described aldehyde has general molecular formula
Described alkynes has general molecular formula
Above-mentioned R
1Or R
2Be C
1-20Aliphatic hydrocarbyl, aryl, substituted aryl or heteroaryl, described alkali is the amine that contains lone-pair electron on the nitrogen-atoms.
2. the method for synthesizing secondary propiolic alcohol compound as claimed in claim 1, the metal that it is characterized in that described Difluore methane-sulfonic acid metal reagent or trifluoromethanesulfonic acid metal reagent is zinc, silver, cadmium, mercury, indium, lead, antimony, bismuth, ytterbium or tin.
3. the method for synthesizing secondary propiolic alcohol compound as claimed in claim 1 is characterized in that described chiral amino alcohol ligand is the chirality N-methylephedrine, and described chiral amino glycol part is that molecular formula is
Chirality 2-disubstituted amido-1-(4-substituted-phenyl)-1, ammediol, R=H, NO in the formula
2, SO
2Me, COCH
3, R
3Or R
4=C
1-6Alkyl or cycloalkyl, R
3And R
4It is identical or different group.
4. the method for synthesizing secondary propiolic alcohol compound as claimed in claim 1 is characterized in that aprotic solvent is toluene, methylene halide, haloform, tetracol phenixin, tetrahydrofuran (THF), acetonitrile, acetone, methyl-sulphoxide; Described alkali is triethylamine, diisopropyl ethyl amine, N, dinethylformamide, pyridine, 1,8-diazabicyclo [5.4.0] undecane-7-alkene, 1,5-diazabicyclo [4.3.0] nonane-5-alkene.
5. the method for synthesizing secondary propiolic alcohol compound as claimed in claim 1, it is characterized in that aldehyde: alkynes: chiral amino alcohol ligand: metal reagent: the mol ratio of alkali is 1: 0.8-2: 0.8-2: 0.5-2: 0.5-2.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6586644B2 (en) * | 2001-10-05 | 2003-07-01 | Erick M. Carreira | Process for producing optically active propargyl alcohols |
| CN1331601C (en) * | 2003-05-16 | 2007-08-15 | 中国科学院上海有机化学研究所 | Method of Chiral alkamine ligand used as catalyst of asymmetric addition process for terminal alkyne to fluoroalkylaryl ketone |
| US7439400B2 (en) | 2003-04-04 | 2008-10-21 | Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences | Amino alcohol ligand and its use in preparation of chiral proparglic tertiary alcohols and tertiary amines via enantioselective addition reaction |
| CN106188106A (en) * | 2016-07-06 | 2016-12-07 | 罗梅 | Zinc complex crystal |
| US11773118B2 (en) * | 2019-02-21 | 2023-10-03 | Obi Pharma, Inc. | Methods of making high enantioselective secondary alcohols |
-
2001
- 2001-03-23 CN CN 01105779 patent/CN1197836C/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CN1314333A (en) | 2001-09-26 |
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