CN1793141A - Process for synthesizing 5,5' bit connected 1,1'-diphenyl kind axle chirality ligand - Google Patents
Process for synthesizing 5,5' bit connected 1,1'-diphenyl kind axle chirality ligand Download PDFInfo
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- CN1793141A CN1793141A CN 200510112233 CN200510112233A CN1793141A CN 1793141 A CN1793141 A CN 1793141A CN 200510112233 CN200510112233 CN 200510112233 CN 200510112233 A CN200510112233 A CN 200510112233A CN 1793141 A CN1793141 A CN 1793141A
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Abstract
The invention relates to 5, 5' connecting 1, 1'-biphenyl class axis chirality ligand. It uses 2-bromine-4-anisole ketone as raw material to take oxidation and esterification to gain compounding V, which would gain 5, 5'-dihydroxy-1, 1'-biphenyl -2, 2'-bimethyl formate that would react with saturated dihalide to gain 5,5'-connecting-(R) and (S)configuration compounding that would take reaction with chirality alkamine to gain (R) and (S) type amide class compounding, finally using methylsulfonyl chloride to gain the target compound under the condition of spasmolytol existing. It could be used in kinds of asymmetry reaction, has high reacting activity and solid selection, and bright application prospect.
Description
Technical field
The present invention relates to a kind of method of chemical technology field, specifically, relate to 1 of a kind of 5,5 ' connection, the synthetic method of 1 '-diphenyl kind axle chirality ligand.
Background technology
Asymmetry catalysis synthetic key is how to design and the chiral catalyst of synthetic highly selective and catalytic activity, and wherein chiral ligand is the source that catalyzer produces asymmetric induction and control.C
2Type chirality bisoxazoline part, because the singularity of its structure, be widely used in the asymmetric reaction of metal catalytic, as the asymmetric oxidation reaction of asymmetric cyclopropanization reaction, intramolecularly Wacker-Type cyclization, alkene and intramolecularly [2+1] cycloaddition reaction or the like.Through the development over 30 years, existing a large amount of chiral oxazoline part emerges, and the chiral oxazoline part that particularly contains various chiral side chains is developed in succession.Its axis chiral side chain has obtained using widely in part because of its distinctive rigid structure.The axle chirality ligand BINAP that contains binaphthyl structure through years of researches accumulation successfully is applied to suitability for industrialized production to have on optically active compound.The successful industrial applications of BINAP has advanced the application of axle chirality on ligand design is synthetic greatly.Contain a chiral side chain De oxazoline part and also be developed in succession, and be applied in the asymmetric reaction of various metal catalytics.
Find through literature search prior art, E.J.Corey etc. are at " Tetrahedron Letters " (tetrahedron communication) (Vol.36, No.48, deliver pp.8745-8748) " The FirstEnantioselective Synthesis of the Chemotactic Factor Sirenin by anIntramolecular[2+1] Cyclization Using a New Chiral Catalyst " (a class novel chiral catalyzer has realized for the first time that by intramolecularly [2+1] cyclization the Sirenin enantioselectivity is synthetic), the design concept of the axle chirality ligand that proposes in this article all is to add two bigger groups at biaryl standard shaft ortho position, obtains stable axle chirality by their steric hindrance.Its deficiency is that these two bigger groups have also limited the rotating angle of biphenyl, have promptly limited interfacial angle.And the size of interfacial angle has been proved catalytic activity and the selectivity that affects asymmetric catalysis.The axle chirality ligand of design and synthesizing new is one of the focus of scholar's research that organises for this reason.
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, provide a kind of 5,1 of 5 ' connection, the synthetic method of 1 '-diphenyl kind axle chirality ligand, broken through the design concept of present axle chirality ligand, make the variation range of its interfacial angle become bigger, thereby can filter out axle chirality ligand with better asymmetry catalysis effect.
The present invention is achieved by the following technical solutions, and the present invention is that raw material makes compound V through oxidation and esterification with 2-bromo-4-anisole ketone.Compound V makes 5 through copper powder coupling and demethylation reaction, 5 '-dihydroxyl-1,1 '-biphenyl-2,2 '-dioctyl phthalate methyl esters VII.Compound VI I obtains 5 by the reaction with alkylene dihalide then, 5 '-position (R) that link and (S) configuration blended compound VIII, then by obtaining (R) and (S) the amides IX of configuration, utilize Methanesulfonyl chloride in the presence of triethylamine, to make a series of (R) and (S) the target ligand II and the III of configuration at last with the reaction of various chiral amino alcohols.
Described a series of (R) and (S) the target ligand II and the III of configuration, its structural formula is as follows respectively:
In the formula: n=5,6,7,8,9 or 10;
R
1=hydrogen, phenyl, naphthyl, the alkyl of benzyl or 1-8 carbon;
R
2=hydrogen, phenyl, naphthyl, the alkyl of benzyl or 1-8 carbon;
R
3=hydrogen, phenyl, naphthyl, the alkyl of benzyl or 1-8 carbon;
R
4=hydrogen, phenyl, naphthyl, the alkyl of benzyl or 1-8 carbon.
Compound IV-VII and axle have (R) and (S) structural formula of the compound VIII of configuration and IX is as follows in the method for the present invention:
Axle has the compound VIII of (R) configuration and the structural formula of IX is:
Axle has the compound VIII of (S) configuration and the structural formula of IX is:
N, R in the said structure
1, R
2, R
3And R
4As previously mentioned.
Below the inventive method is further described, concrete steps are as follows:
(1) prepares compound IV from 2-bromo-4-anisole ketone
In the presence of the liquid bromine, 2-bromo-4-anisole ketone is converted into 2-bromo-4-methoxybenzoic acid IV in aqueous sodium hydroxide solution in aqueous sodium hydroxide solution.Wherein aqueous sodium hydroxide solution concentration is 5-20%; The mol ratio of 2-bromo-4-anisole ketone and liquid bromine is 1: 4-6; Temperature of reaction is 20-70 ℃; Reaction times is 12-20 hour.
(2) prepare compound V from compound IV
In the presence of the thionyl chloride, compound IV can be converted into 2-bromo-4-methoxyl methyl benzoate V in methanol solution.Wherein the mol ratio of compound IV and thionyl chloride is 1: 1-10; Temperature of reaction is 20-80 ℃; Reaction times is 1-12 hour.
(3) prepare compound VI from compound V
In the presence of copper powder, compound V can be converted into 5,5 '-dimethoxy-1,1 '-biphenyl-2,2 '-dioctyl phthalate methyl esters VI.Wherein the mol ratio of compound V and copper powder is 1: 2-5; Temperature of reaction is 150-180 ℃; Reaction times is 2-24 hour.
(4) prepare compound VI I from compound VI
In the presence of the sulfur alcohol, compound VI and aluminum chloride effect obtain 5 in methylene dichloride, 5 '-dihydroxyl-1,1 '-biphenyl-2,2 '-dioctyl phthalate methyl esters VII.Wherein the mol ratio of compound VI and aluminum chloride is 1: 3-6; Temperature of reaction is 0-25 ℃; Reaction times is 2-6 hour.
(5) from the compound VI I preparation (R) and (S) compound VIII of configuration
In organic solvent in the presence of the salt of wormwood, compound VI I and saturated dihalide hydrocarbon reaction can make 5,5 '-(R) that link and (S) configuration blended 5,5 '-alkane, two Oxy-1s, 1 '-biphenyl-2,2 '-dioctyl phthalate methyl esters VIII.Wherein 5,5 '-dihydroxyl-1,1 '-biphenyl-2, the mol ratio of 2 '-dioctyl phthalate methyl esters and alkylene dihalide is 1: 1-1.5; Temperature of reaction is 20-100 ℃; Reaction times is 8-72 hour.Organic solvent can be DMF, acetonitrile, acetone etc.
Alkylene dihalide is
M=3,4,5,6,7 or 8 wherein; X and X ' are chloro, bromo or iodo, and X and X ' may be identical or different.
(6) from (R) or (S) configuration of compound VIII preparation (R) or (S) the Compound I X of configuration
In the presence of salt of wormwood, (R) and (S) configuration mixture VIII and the reaction of various chiral amino alcohol can obtain spool having (R) and (S) the amides diastereomeric compound IX of configuration respectively.Wherein the mol ratio of mixture VIII and chiral amino alcohol is 1: 3-10; Temperature of reaction is 50-120 ℃; Reaction times is 4-12 hour.
(7) from (R) or (S) configuration of compound IX preparation (R) or (S) the Compound I I and the III of configuration.
In dichloromethane solution in the presence of triethylamine and the Methanesulfonyl chloride, axle have (R) or (S) the amides diastereomeric compound IX of configuration can be converted into axle and have (R) or (S) the Compound I I or the III of configuration.Wherein the mol ratio of Compound I X, triethylamine and Methanesulfonyl chloride is 1: 5-25: 3-12; Temperature of reaction is a room temperature; Reaction times is 12-36 hour.
The catalyzer that the present invention makes is the central chirality of Han You oxazoline both, also contains the axle chirality of biphenyl class simultaneously.Such part can be applicable in the asymmetric reaction of various metal catalytics, as asymmetric cyclopropanization reaction, intramolecularly Wacker-Type cyclization, the asymmetric oxidation reaction of alkene and intramolecularly [2+1] cycloaddition reaction etc., have very high reactive behavior and stereoselectivity, have application promise in clinical practice.
Embodiment
To help further to understand the present invention by following embodiment, but not limit content of the present invention.
Embodiment 1
(1) prepares compound IV from 2-bromo-4-anisole ketone
Under ice bath, (2.8mL 35.1mmol) slowly drips that (4.5g 111.4mmol) in the aqueous solution (10mL), stirs 10min, and (2.1g 9.2mmol) drips extremely in the above-mentioned reaction solution, at room temperature stirs 15h with 2-bromo-4-anisole ketone again to NaOH with bromine.After reaction finishes, add sodium sulfite aqueous solution, to eliminate unreacted sodium hypobromite.Use ethyl acetate extraction, isolate neutral compound, use 6N hydrochloric acid acidifying water under ice bath again, a large amount of white solids occur.Filter and obtain white solid IV (2.0g, 95%).
1H?NMR(CDCl
3，300MHz)8.05(d，J＝8.7Hz，1H，Ar-H)，7.23(d，J＝2.7Hz，1H，Ar-H)，6.91(dd，J＝8.7，2.7Hz，1H，Ar-H)，3.87(s，3H，OCH
3)。
(2) prepare compound V from compound IV
Under ice bath, (2.9mL, (4.5g in methyl alcohol 19.3mmol) (10mL) solution, rises to room temperature and reflux, and TLC monitors reaction 38.7mmol) slowly to drop to 2-bromo-4-methoxybenzoic acid IV with thionyl chloride.React when 2h and finish, steam and remove excessive thionyl chloride and methyl alcohol, with the ethyl acetate dilution, wash with water, wash with saturated sodium carbonate, organic phase gets product V (4.3g, 91%) with anhydrous magnesium sulfate drying.
1H?NMR(CDCl
3，400MHz)7.87(d，J＝9.2Hz，1H，Ar-H)，7.19(d，J＝2.0Hz，1H，Ar-H)，6.87(dd，J＝9.2，2.0Hz，1H，Ar-H)，3.90(s，3H，OCH
3)，3.84(s，3H，OCH
3)。
(3) prepare compound VI from compound V
Under nitrogen, with 2-bromo-4-methoxyl methyl benzoate V (7.3g, 29.6mmol) and activated copper powder (7.0g 0.1mol) is heated to 160-170 ℃ of stirring reaction 15h.The cooling back adds ethyl acetate, filters, and with the washed with dichloromethane copper powder of heat, steaming desolventizes, and obtains product VI (3.0g, 61%) with ethyl acetate and sherwood oil recrystallization.
1H?NMR(CDCl
3，400MHz)8.02(d，J＝8.8Hz，2H，Ar-H)，6.92(dd，J＝8.8，2.8Hz，2H，Ar-H)，6.69(d，J＝2.8Hz，2H，Ar-H)，3.85(s，6H，OCH
3)，3.61(s，6H，OCH
3)。
(4) prepare compound VI I from compound VI
Under ice bath, with the 3mL sulfur alcohol drop to aluminum chloride (0.8g, in 3mL dichloromethane solution 6.0mmol), stirring and dissolving.(0.3g, 5mL dichloromethane solution 1.0mmol) drops in the above-mentioned solution, reacts 2h down at 0 ℃, rises to room temperature reaction 0.5h with compound VI under ice bath.Use the frozen water cancellation, use ethyl acetate extraction, use anhydrous magnesium sulfate drying, steaming desolventizes, and crosses post with sherwood oil and ethyl acetate.Separate and obtain target product VII (0.1g, 33%).
1H?NMR(CD
3COCD
3，400MHz)7.87(d，J＝8.8Hz，2H，Ar-H)，6.88(dd，J＝8.8，2.4Hz，2H，Ar-H)，6.64(d，2H，J＝2.4Hz，Ar-H)，3.52(s，6H，OCH
3)。
(5) prepare compound VIII from compound VI I
With compound VI I (1.0g, 3.3mmol), (1.4g, 9.9mmol) and 1, (0.6mL 3.3mmol) adds in the 200mL DMF solution the hot dibromo of 8-Anhydrous potassium carbonate, at room temperature stirs 72h.With reacting liquid filtering, remove DMF under reduced pressure, cross post with ethyl acetate and sherwood oil and obtain product VII I (0.8g, 55%).
1H?NMR(CDCl
3，400MHz)7.94(d，J＝8.4Hz，2H，Ar-H)，6.91(dd，J＝8.4，2.4Hz，2H，Ar-H)，6.76(d，J＝2.4Hz，2H，Ar-H)，4.40(t，J＝7.6Hz，2H，OCH)，4.37(t，J＝7.6Hz，2H，OCH)，3.62(s，6H，OCH
3)，1.89-2.01(m，2H，CH
2)，1.55-1.67(m，2H，CH
2)，1.20-1.53(m，8H，CH
2)。
(6) prepare Compound I X (R from compound VIII
1=i-Pr, R
2=R
3=R
4=H)
With compound VIII (0.3g, 0.7mmol), Anhydrous potassium carbonate (0.4g, 2.9mmol), the L-valerian ammonia alcohol (0.7mL, 6.5mmol) and 2mL methyl alcohol be added in two mouthfuls of flasks of 5mL, be heated to 50 ℃, TLC follows the tracks of reaction.Deng reacting the end back with the methylene dichloride dilution, wash organic phase, use anhydrous magnesium sulfate drying, steaming desolventizes, and gets product IX (0.24g, 60%).
(7) prepare Compound I I (R from Compound I X
1=i-Pr, R
2=R
3=R
4=H) and III (R
1=i-Pr, R
2=R
3=R
4=H)
With above-mentioned product IX (0.16g 0.3mmol) is dissolved in the 10mL methylene dichloride, and add triethylamine (0.5mL, 3.6mmol).(0.1mL 1.1mmol), at room temperature reacted 18 hours, and TLC is almost constant to add Methanesulfonyl chloride under ice bath.The dilution that adds methylene chloride washes with water, and anhydrous magnesium sulfate drying is used in the saturated common salt washing.Steaming desolventizes, and crosses post with ethyl acetate and sherwood oil and obtains two target product II (14.9mg) and III (46.8mg).
II：
1H?NMR(CDCl
3，400MHz)7.76(s，J＝8.4Hz，2H，Ar-H)，6.86(dd，J＝8.4，2.4Hz，2H，Ar-H)，6.83(d，J＝2.4Hz，2H，Ar-H)，4.40(t，J＝7.6Hz，2H，OCH)，4.37(t，J＝7.6Hz，2H，OCH)，4.03-4.15(m，4H，OCH?and?NCH)，3.65-3.75(m，4H，OCH
2)，1.87-1.97(m，4H，CH)，1.55-1.68(m，4H，CH)，1.43-1.54(m，2H，CH)，1.37(m，4H，CH
2)，1.20-1.32(m，2H，CH)，0.93(d，J＝6.8Hz，6H，CH
3)，0.79(d，J＝6.8Hz，6H，CH
3)。
III：
1H?NMR(CDCl
3，400MHz)7.71(s，2H，Ar-H)，6.85-6.93(m，4H，Ar-H)，4.43(t，J＝7.6Hz，2H，OCH)，4.30(t，J＝7.6Hz，2H，OCH)，4.03-4.20(m，4H，OCH?and?NCH)，3.75-3.90(m，4H，OCH
2)，1.90-2.01(m，2H，CH
2)，1.48-1.80(m，6H，CH)，1.42(m，4H，CH
2)，1.20-1.35(m，2H，CH)，0.81(d，J＝6.8Hz，6H，CH
3)，0.80(d，J＝6.8Hz，6H，CH
3)。
Embodiment 2
(1) prepares compound IV from 2-bromo-4-anisole ketone
Under ice bath, (2.7mL 34.2mmol) slowly drips that (4.5g 111.4mmol) in the aqueous solution (20mL), stirs 10min, and (1.3g 5.7mmol) drips to above-mentioned reaction solution, at 50 ℃ of stirring 15h down with 2-bromo-4-anisole ketone again to NaOH with bromine.After reaction finishes, add sodium sulfite aqueous solution, to eliminate unreacted sodium hypobromite.Use ethyl acetate extraction, isolate neutral compound, use 6N hydrochloric acid acidifying water under ice bath again, a large amount of white solids occur.Filter and obtain white solid IV (1.2g, 92%).
(2) prepare compound V from compound IV
Under ice bath, (3.2mL, (1.0g in methyl alcohol 4.3mmol) (10mL) solution, rises to room temperature and reflux, and TLC monitors reaction 42.8mmol) slowly to drop to 2-bromo-4-methoxybenzoic acid IV with thionyl chloride.React when 1h and finish, steam and remove excessive thionyl chloride and methyl alcohol, with the ethyl acetate dilution, wash with water, wash with saturated sodium carbonate, organic phase gets product V (1.0g, 94%) with anhydrous magnesium sulfate drying.
(3) prepare compound VI from compound V
Under nitrogen, with 2-bromo-4-methoxyl methyl benzoate V (1.8g, 7.3mmol) and activated copper powder (2.3g 36.2mmol) is heated to 160-170 ℃ of stirring reaction 20h.The cooling back adds ethyl acetate, filters, and with the washed with dichloromethane copper powder of heat, steaming desolventizes, and obtains product VI (0.76g, 63%) with ethyl acetate and sherwood oil recrystallization.
(4) prepare compound VI I from compound VI
Under ice bath, with the 3mL sulfur alcohol drop to aluminum chloride (0.8g, in 3mL dichloromethane solution 6.0mmol), stirring and dissolving.(0.6g, 10mL dichloromethane solution 2.0mmol) drops in the above-mentioned solution, reacts 1h down at 0 ℃, rises to room temperature reaction 1.5h with compound VI under ice bath.Use the frozen water cancellation, use ethyl acetate extraction, use anhydrous magnesium sulfate drying, steaming desolventizes, and crosses post with sherwood oil and ethyl acetate.Separate and obtain target product VII (0.08g, 26%).
(5) prepare compound VIII from compound VI I
With compound VI I (0.8g, 2.6mmol), (1.1g, 7.9mmol) and 1, (0.5mL 2.7mmol) adds in the 180mL acetonitrile solution the hot dibromo of 8-Anhydrous potassium carbonate, stirs 72h under reflux.With reacting liquid filtering, remove acetonitrile under reduced pressure, cross post with ethyl acetate and sherwood oil and obtain product VII I (0.7g, 60%).
(6) prepare Compound I X (R from compound VIII
1=i-Pr, R
2=R
3=R
4=H)
With compound VIII (0.3g, 0.7mol), Anhydrous potassium carbonate (0.4g, 2.9mol), the L-valerian ammonia alcohol (0.4mL, 3.7mmol) and 2mL methyl alcohol be added in two mouthfuls of flasks of 5mL, be heated to backflow, TLC follows the tracks of reaction.Deng reacting the end back with the methylene dichloride dilution, wash organic phase, use anhydrous magnesium sulfate drying, steaming desolventizes, and gets product IX (0.20g, 50%).
(7) prepare Compound I I (R from Compound I X
1=i-Pr, R
2=R
3=R
4=H) and III (R
1=i-Pr, R
2=R
3=R
4=H)
With above-mentioned product IX (0.16g 0.3mmol) is dissolved in the 10mL methylene dichloride, and add triethylamine (1.0mL, 7.2mmol).(0.3mL 3.4mmol), at room temperature reacted 18 hours, and TLC is almost constant to add Methanesulfonyl chloride under ice bath.The dilution that adds methylene chloride washes with water, and anhydrous magnesium sulfate drying is used in the saturated common salt washing.Steaming desolventizes, and crosses post with ethyl acetate and sherwood oil and obtains two target product II (15.1mg) and III (45.5mg).
Embodiment 3
(1) prepares compound IV from 2-bromo-4-anisole ketone
Under ice bath, (1.6mL 20.3mmol) slowly drips that (3.5g 86.6mmol) in the aqueous solution (40mL), stirs 10min, and (1.5g 6.6mmol) drips to above-mentioned reaction solution, at 70 ℃ of stirring 15h down with 2-bromo-4-anisole ketone again to NaOH with bromine.After reaction finishes, add sodium sulfite aqueous solution, to eliminate unreacted sodium hypobromite.Use ethyl acetate extraction, isolate neutral compound, use 6N hydrochloric acid acidifying water under ice bath again, a large amount of white solids occur.Filter and obtain white solid IV (0.9g, 61%).
(2) prepare compound V from compound IV
Under ice bath, (1.6mL, (1.0g in methyl alcohol 4.3mmol) (10mL) solution, rises to room temperature and reflux, and TLC monitors reaction 21.4mmol) slowly to drop to 2-bromo-4-methoxybenzoic acid IV with thionyl chloride.React when 1h and finish, steam and remove excessive thionyl chloride and methyl alcohol, with the ethyl acetate dilution, wash with water, wash with saturated sodium carbonate, organic phase gets product V (1.0g, 94%) with anhydrous magnesium sulfate drying.
(3) prepare compound VI from compound V
Under nitrogen, with 2-bromo-4-methoxyl methyl benzoate V (0.5g, 2.0mmol) and activated copper powder (0.3g 4.7mmol) is heated to 160-170 ℃ of stirring reaction 24h.The cooling back adds ethyl acetate, filters, and with the washed with dichloromethane copper powder of heat, steaming desolventizes, and obtains product VI (0.15g, 45%) with ethyl acetate and sherwood oil recrystallization.
(4) prepare compound VI I from compound VI
Under ice bath, with the 3mL sulfur alcohol drop to aluminum chloride (0.8g, in 3mL dichloromethane solution 6.0mmol), stirring and dissolving.(0.4g, 5mL dichloromethane solution 1.3mmol) drops in the above-mentioned solution, rises to room temperature reaction 2.5h with compound VI under ice bath.Use the frozen water cancellation, use ethyl acetate extraction, use anhydrous magnesium sulfate drying, steaming desolventizes, and crosses post with sherwood oil and ethyl acetate.Separate and obtain target product VII (0.05g, 17%).
(5) prepare compound VIII from compound VI I
With compound VI I (1.0g, 3.3mmol), (1.1g, 7.9mmol) and 1, (1.0g 2.7mmol) adds in the 180mL DMF solution stirring at room 72h to the hot diiodo-of 8-to Anhydrous potassium carbonate.With reacting liquid filtering, remove acetonitrile under reduced pressure, cross post with ethyl acetate and sherwood oil and obtain product VII I (0.8g, 55%).
(6) prepare Compound I X (R from compound VIII
1=i-Pr, R
2=R
3=R
4=H)
This synthetic method is consistent with (6) among the embodiment 1.
(7) prepare Compound I I (R from Compound I X
1=i-Pr, R
2=R
3=R
4=H) and III (R
1=i-Pr, R
2=R
3=R
4=H)
This synthetic method is consistent with (7) among the embodiment 1.
The foregoing description synthetic method is simple, and yield is higher.Step 5 can be other macrocylc compound syntheticly provides effective synthetic method.
Claims (10)
1. one kind 5,1 of 5 ' connection, the synthetic method of 1 '-diphenyl kind axle chirality ligand, it is characterized in that, with 2-bromo-4-anisole ketone is that raw material makes compound V through oxidation and esterification, compound V makes 5 through copper powder coupling and demethylation reaction, 5 '-dihydroxyl-1,1 '-biphenyl-2,2 '-dioctyl phthalate methyl esters VII, compound VI I obtains 5 by the reaction with alkylene dihalide then, 5 '-position (R) that link and (S) configuration blended compound VIII obtain (R) and (S) the amides IX of configuration by reacting with various chiral amino alcohols then, utilize Methanesulfonyl chloride to make a series of (R) and (S) the target ligand II and the III of configuration at last in the presence of triethylamine, described target ligand II and III, its structural formula is as follows respectively:
In the formula: n=5,6,7,8,9 or 10; R
1=hydrogen, phenyl, naphthyl, the alkyl of benzyl or 1-8 carbon; R
2=hydrogen, phenyl, naphthyl, the alkyl of benzyl or 1-8 carbon; R
3=hydrogen, phenyl, naphthyl, the alkyl of benzyl or 1-8 carbon; R
4=hydrogen, phenyl, naphthyl, the alkyl of benzyl or 1-8 carbon.
2. 1 of 5,5 ' connection as claimed in claim 1, the synthetic method of 1 '-diphenyl kind axle chirality ligand is characterized in that, concrete steps are as follows:
(1) prepares compound IV from 2-bromo-4-anisole ketone
In the presence of the liquid bromine, 2-bromo-4-anisole ketone is converted into 2-bromo-4-methoxybenzoic acid IV in aqueous sodium hydroxide solution in aqueous sodium hydroxide solution, and the mol ratio of 2-bromo-4-anisole ketone and liquid bromine is 1: 4-6;
(2) prepare compound V from compound IV
In the presence of the thionyl chloride, compound IV is converted into 2-bromo-4-methoxyl methyl benzoate V in methanol solution, and wherein the mol ratio of compound IV and thionyl chloride is 1: 1-10;
(3) prepare compound VI from compound V
In the presence of copper powder, compound V is converted into 5,5 '-dimethoxy-1,1 '-biphenyl-2, and 2 '-dioctyl phthalate methyl esters VI, wherein the mol ratio of compound V and copper powder is 1: 2-5;
(4) prepare compound VI I from compound VI
In the presence of the sulfur alcohol, compound VI and aluminum chloride effect obtain 5 in methylene dichloride, 5 '-dihydroxyl-1, and 1 '-biphenyl-2,2 '-dioctyl phthalate methyl esters VII, wherein the mol ratio of compound VI and aluminum chloride is 1: 3-6;
(5) from the compound VI I preparation (R) and (S) compound VIII of configuration
In organic solvent in the presence of the salt of wormwood, compound VI I and saturated dihalide hydrocarbon reaction make 5,5 '-(R) that link and (S) configuration blended 5,5 '-alkane, two Oxy-1s, 1 '-biphenyl-2,2 '-dioctyl phthalate methyl esters VIII, wherein 5,5 '-dihydroxyl-1,1 '-biphenyl-2, the mol ratio of 2 '-dioctyl phthalate methyl esters and alkylene dihalide is 1: 1-1.5;
(6) from (R) or (S) configuration of compound VIII preparation (R) or (S) the Compound I X of configuration
In the presence of salt of wormwood, (R) and (S) reaction of configuration mixture VIII and various chiral amino alcohol obtains axle respectively and has (R) and (S) the amides diastereomeric compound IX of configuration, and wherein the mol ratio of mixture VIII and chiral amino alcohol is 1: 3-10;
(7) from (R) or (S) configuration of compound IX preparation (R) or (S) the Compound I I and the III of configuration,
In dichloromethane solution in the presence of triethylamine and the Methanesulfonyl chloride, axle have (R) or (S) the amides diastereomeric compound IX of configuration be converted into axle and have (R) or (S) the Compound I I or the III of configuration, wherein the mol ratio of Compound I X, triethylamine and Methanesulfonyl chloride is 1: 5-25: 3-12.
3. 1 of 5,5 ' connection as claimed in claim 2, the synthetic method of 1 '-diphenyl kind axle chirality ligand is characterized in that, and in described (1), aqueous sodium hydroxide solution concentration is 5-20%, and temperature of reaction is 20-70 ℃, and the reaction times is 12-20 hour.
4. 1 of 5,5 ' connection as claimed in claim 2, the synthetic method of 1 '-diphenyl kind axle chirality ligand is characterized in that, and in described (2), temperature of reaction is 20-80 ℃, and the reaction times is 1-12 hour.
5. 1 of 5,5 ' connection as claimed in claim 2, the synthetic method of 1 '-diphenyl kind axle chirality ligand is characterized in that, and in described (3), temperature of reaction is 150-180 ℃, and the reaction times is 2-24 hour.
6. 1 of 5,5 ' connection as claimed in claim 2, the synthetic method of 1 '-diphenyl kind axle chirality ligand is characterized in that, and in described (4), temperature of reaction is 0-25 ℃, and the reaction times is 2-6 hour.
7. 1 of 5,5 ' connection as claimed in claim 2, the synthetic method of 1 '-diphenyl kind axle chirality ligand, it is characterized in that in described (5), temperature of reaction is 20-100 ℃, reaction times is 8-72 hour, and organic solvent is DMF, acetonitrile or acetone, and described alkylene dihalide is
M=3,4,5,6,7 or 8 wherein, X and X ' are chloro, bromo or iodo.
8. 1 of 5,5 ' connection as claimed in claim 2, the synthetic method of 1 '-diphenyl kind axle chirality ligand is characterized in that, and in described (6), temperature of reaction is 50-120 ℃, and the reaction times is 4-12 hour.
9. 1 of 5,5 ' connection as claimed in claim 2, the synthetic method of 1 '-diphenyl kind axle chirality ligand is characterized in that, and in described (7), temperature of reaction is a room temperature, and the reaction times is 12-36 hour.
As claim 1 or 2 described 5,5 ' connect 1, the synthetic method of 1 '-diphenyl kind axle chirality ligand is characterized in that, compound IV-VII and axle have (R) and (S) structural formula of the compound VIII of configuration and IX is as follows:
Axle has the compound VIII of (R) configuration and the structural formula of IX is:
Axle has the compound VIII of (S) configuration and the structural formula of IX is:
In the formula: n=5,6,7,8,9 or 10; R
1=hydrogen, phenyl, naphthyl, the alkyl of benzyl or 1-8 carbon; R
2=hydrogen, phenyl, naphthyl, the alkyl of benzyl or 1-8 carbon; R
3=hydrogen, phenyl, naphthyl, the alkyl of benzyl or 1-8 carbon; R
4=hydrogen, phenyl, naphthyl, the alkyl of benzyl or 1-8 carbon.
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| CNB2005101122331A CN100348597C (en) | 2005-12-29 | 2005-12-29 | Process for synthesizing 5,5' bit connected 1,1'-diphenyl kind axle chirality ligand |
| JP2008547838A JP5280858B2 (en) | 2005-12-29 | 2006-12-29 | 1,1'-Biphenyls Axial Chirality Ligand Linked at 5,5 'Position and Method for Producing the Same |
| CNA2006800491401A CN101346359A (en) | 2005-12-29 | 2006-12-29 | 5, 5' position connecting 1, 1'-biphenyl shaft chiral ligand and its synthesizing method |
| US12/159,440 US7754891B2 (en) | 2005-12-29 | 2006-12-29 | 5,5′-Position linked 1,1′-biphenyl axial chiral ligand and method for preparing the same |
| PCT/CN2006/003696 WO2007073699A1 (en) | 2005-12-29 | 2006-12-29 | 5,5'-linked 1,1'-biphenyl axial chiral ligands and preparation methods thereof |
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| CNB2005101122331A CN100348597C (en) | 2005-12-29 | 2005-12-29 | Process for synthesizing 5,5' bit connected 1,1'-diphenyl kind axle chirality ligand |
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| CNA2006800491401A Pending CN101346359A (en) | 2005-12-29 | 2006-12-29 | 5, 5' position connecting 1, 1'-biphenyl shaft chiral ligand and its synthesizing method |
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| CN116102406A (en) * | 2022-09-19 | 2023-05-12 | 清华大学 | Polysubstituted axial chiral diphenyl diphenol compound and preparation method and application thereof |
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| PL340767A1 (en) * | 1997-11-12 | 2001-02-26 | Penn State Res Found | Reaction involving use of a metal containing catalyst based on chiral aminoxazolinic ligands |
| ATE324943T1 (en) * | 1999-09-20 | 2006-06-15 | Penn State Res Found | CHIRAL PHOSPHINS, THEIR COMPLEXES WITH TRANSITION METALS AND THEIR USE IN ASYMMETRIC SYNTHESIS REACTIONS |
| DE60238367D1 (en) * | 2001-04-27 | 2011-01-05 | Sumitomo Chemical Co | Asymmetric copper complex and its use in cyclopropanation reaction |
| CN1146472C (en) * | 2001-11-16 | 2004-04-21 | 中国科学院上海有机化学研究所 | Catalyst for catalyzing unsymmetrical hetero-Diels-Alder reaction, its preparation and application |
| JP2004161963A (en) * | 2002-11-15 | 2004-06-10 | Takasago Internatl Corp | Polymer-carried optically active binaphthyl-type oxazoline compound |
| CN100364981C (en) * | 2003-01-29 | 2008-01-30 | 北京大学 | Chiral dibenz [a,c] suberyl diallyl double oxazoline ligand compound and its preparation and application |
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