CN114437060A - Preparation method of (R) -and (S) -3-quinuclidinol - Google Patents

Preparation method of (R) -and (S) -3-quinuclidinol Download PDF

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CN114437060A
CN114437060A CN202011212637.9A CN202011212637A CN114437060A CN 114437060 A CN114437060 A CN 114437060A CN 202011212637 A CN202011212637 A CN 202011212637A CN 114437060 A CN114437060 A CN 114437060A
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quinuclidinol
transition metal
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稂琪伟
丁小兵
高爽
苏伟
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Shenzhen Catalys Technology Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
    • B01J31/2447—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring
    • B01J31/2452—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom
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    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
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    • B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
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Abstract

The invention discloses a preparation method of (R) -and (S) -3-quinuclidinol. The invention provides a chiral catalyst RuXY-Diphosphine-bimaH and a preparation method of (R) -and (S) -3-quinuclidinol, comprising the following steps: 3-quinuclidinone is subjected to asymmetric hydrogenation reduction under the action of a chiral catalyst RuXY-Diphosphine-bimaH and alkali to obtain optically pure 3-quinuclidinol, the reaction yield reaches over 95 percent, and the ee value of the product reaches over 99 percent. The preparation method has the advantages of mild conditions, simplicity and controllability, high yield and enantioselectivity, environmental friendliness, low cost and the like. In addition, the invention also discloses a method for efficiently preparing chiral alcohol by catalyzing asymmetric hydrogenation of various simple ketones by using the catalyst.

Description

Preparation method of (R) -and (S) -3-quinuclidinol
Technical Field
The invention belongs to the field of medicinal chemical synthesis, and particularly relates to a preparation method of (R) -and (S) -3-quinuclidinol.
Background
The conversion of prochiral ketones or esters into chiral alcohols is a very important chemical reaction and has very wide applications both industrially and academically (Mealy N, Castaner J. YM-905[ J. Drugs Future,1999,24(8): 871) 874.). (R) -3-quinuclidinol, chemically known as (R) - (-) -l-azabicyclo [2.2.2] octan-3-ol, is an important intermediate for many anticholinergic drugs, such as the novel anticholinergic drug Aclidinium bromide (Aclidinium bromide) for the long-term maintenance treatment of Chronic Obstructive Pulmonary Disease (COPD), Revatopate (Revatopate), Solifenacin (Solifenacin) for the treatment of Overactive Bladder syndrome (OAB), and the drug tasalidine (Talsaclidine) for the treatment of Alzheimer's Disease, AD) (J.Med.Chem.2005,48 (6597): 6606.).
Figure BDA0002759320150000011
The preparation method of (R) -3-quininol mainly comprises a chemical resolution method, a chemical asymmetric synthesis method, a kinetic resolution method and a biological asymmetric reduction method, wherein the chemical asymmetric synthesis method is concerned due to the advantages of high stereoselectivity, mild reaction conditions, environmental friendliness and the like (Org. Lett.,2010,12(12): 2690-2693.).
1.1 chemical resolution Process
Chemical resolution is one of the classical methods for obtaining chiral compounds. The method comprises the steps of reducing 3-quinuclidinone hydrochloride into racemic 3-quinuclidinol by a potassium borohydride reduction method in a methanol solution (3-quinuclidinol resolution research [ J ]. Anhui chemical industry, 2009, 35 (1): 31-33.), resolving the racemic mixture by using a mixed solvent of V (propanol) and V (acetone) 3:1 as a reaction medium and D- (+) -dibenzoyltartaric acid as a resolving agent, and recrystallizing the obtained solid to obtain (R) -3-quinuclidinol, wherein the ee value is 98%, and the yield is 20.4%. Similarly, Ji et al (US 7309699[ P ]) resolved 17.9g of (+/-) -1-azabicyclo [2.2.2] octyl-3-benzoate using (L) -tartaric acid in ethanol and the product of the resolution was hydrolyzed with 15% sodium hydroxide solution to give 1.35g of (R) -3-quinuclidinol. In a word, the chemical resolution method for preparing the (R) -3-quininol product with the single configuration needs to use a chiral chemical resolving agent, so that the steps are more, and the yield is lower.
1.2 chemical asymmetric catalysis
Tsutsumi et al (org. Process Res. Dev.2009,13(3): 625-. When the diphosphine ligand is Binap, the ee value of the (R) -3-quininol is only 47 percent when the molar ratio of the substrate to the catalyst is 1000/1. The reaction formula is as follows:
Figure BDA0002759320150000021
to increase the enantioselectivity of the reaction, Arian et al (org. Lett.2010,12(15):3380-3383.) used RuCl in isopropanol2[(S)-Binap][(R)-iphan]Andtthe BuOK composite catalyst system asymmetrically reduces 3-quinuclidinone into (R) -3-quinuclidinol, and the ee value is more than 97%. The reaction formula is as follows:
Figure BDA0002759320150000031
ohkuma, T.et al (J.Am.chem.Soc.2011,133, 10696-10699.) use RuCl2[(S)-daipen][(S)-xylbinap]In the catalyst system, 3-quinuclidinone is asymmetrically reduced into (R) -3-quinuclidinol when the molar ratio of a substrate to the catalyst is 10 ten thousand/1, the yield reaches 92%, and the ee value reaches 95%. The reaction formula is as follows:
Figure BDA0002759320150000032
xuliang et al (CN105085513A) uses (S, S) -xylskewphos-RuBr-Quima as chiral catalyst, firstly, 3-quinuclidinone hydrochloride is dissociated under the action of alkali to obtain 3-quinuclidinone, then, under the condition of no water and no oxygen, the chiral catalyst (S, S) -xylskewphos-RuBr-QUIMA and the action of alkali are used for carrying out asymmetric hydrogenation reduction on the 3-quinuclidinone to obtain (R) -3-quinuclidinol, the ee value of the product is more than 95%, and the conversion rate is more than 99.5%, wherein the reaction formula is as follows:
Figure BDA0002759320150000033
xuliang and the like (a nitrogen heterocyclic ligand transition metal complex and preparation and catalytic application thereof: PCT/CN2011/080207) applies biphosphine diamine catalysts such as binap, quima and the like to bridged nitrogen heterocycles and derivatives thereof and other aryl alkyl ketones or esters for catalyzing asymmetric hydrogenation, and the ee value of (S) -3-quinuclidinol is 96 percent under the hydrogen pressure of 20MPa with the molar ratio of a substrate to the catalyst being 1000 in the reaction process. A small amount of metal chiral catalyst is used in the reaction process of preparing (R) -3-quininol by chemical asymmetric catalysis, so that high yield can be obtained, but the metal chiral catalyst is high in price and complex in preparation process, the reaction cost is increased, and part of the catalyst is not easy to recycle and cause certain pollution to the environment.
Some successful asymmetric hydrogenation experiments are reported in US7378560 and US2008/0249308, both of which use 2-aminomethylpyridine derivatives as ligands. In particular, U.S. Pat. No. 6,737,8560 shows very high selectivity towards tert-butyl substituted ketones. While a relatively versatile catalyst, exhibiting moderate to good stereoselectivity, is provided in patent US 2008/0249308. At present, the best optical purity of (R) -3-quininol obtained by the asymmetric hydrogenation reaction is 97%, and in addition, most of ligands in a reported catalytic system are difficult to synthesize and have higher cost, and a catalyst with better selectivity still needs to be developed.
Disclosure of Invention
In view of the problems of the prior art, the present invention aims to provide a novel transition metal complex prepared by complexing a transition metal, a phosphine ligand and an azacyclic amine ligand, characterized in that the azacyclic amine ligand has a structural unit of benzimidazole. The invention also provides a synthesis method of the transition metal complex.
The invention also provides the application of the complex, namely the application of the complex in the catalytic asymmetric hydrogenation of simple ketone, and is further described as the asymmetric hydrogenation reaction of 3-quinuclidinone and derivatives thereof.
The invention is realized by the following technical scheme, and the preparation method of the (R) -and (S) -3-quinuclidinol comprises the following steps:
3-quinuclidinone is asymmetrically hydrogenated and reduced under the action of chiral catalyst RuXY-Diphosphine-bimaH and alkali to obtain optically pure 3-quinuclidinol.
Figure BDA0002759320150000041
The chiral catalyst RuXY-Diphosphine-bimaH is a benzimidazole nitrogen heterocyclic ligand transition metal complex, and the structure of the complex is as follows:
Figure BDA0002759320150000042
x, Y is chlorine, bromine, iodine, acetate, triflate or hydrogen;
when a nitrogen-containing heterocyclic ligand transition metal complex of formula (I), wherein R1Represents a chiral or achiral organic hydrocarbon group; r2，R3，R4And R5And R6The same or different, and is aliphatic hydrocarbon with 1-6 carbon atoms or aromatic group with 6-12 carbon atoms; r7Can be an aliphatic or aromatic substituent group such as methyl, ethyl, halogen, cyano, nitro, trifluoromethanesulfonyl, alkoxy, sulfydryl and the like which are substituted at the ortho position, the meta position or the para position on a benzene ring; r8Represents a chiral or achiral organic hydrocarbon group such as methyl, phenyl, etc.
In a preferred embodiment of the present invention, when X and Y are OAc, the metal complex is a nitrogen-containing heterocyclic ligand transition metal complex of the formula (I) -1, (I) -2 or (I) -3, and the structure thereof is as follows:
Figure BDA0002759320150000051
or
Figure BDA0002759320150000052
Or
Figure BDA0002759320150000053
As a preferred embodiment of the present invention, the bisphosphine ligand comprises, but is not limited to, the following phosphine ligands and derivatives thereof: binap, Biphep, BPE, DIPAMP, DIOP, Duphos, CnTunephos, Segphos, Chiraphos, Skewphos, Phanephos, Norphos, and DuanPhos, and other phosphine ligands. In the diamine ligand, R6May be hydrogen alone when R is6When not hydrogen, the aza-ammonia ligand (I) may be a chiral ligand with R or S configuration, or may not be chiral; r is as defined above6The group may be an alkyl or aryl group such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, 3, 5-dimethylbenzyl, 1-naphthyl, 2-naphthyl, and the like.
The following are preferred:
Figure BDA0002759320150000054
Figure BDA0002759320150000061
wherein the Ar group may be an aryl group such as a phenyl group, a benzyl group, a 3, 5-dimethylphenyl group, a 3, 5-di-t-butylphenyl group, a methyl-p-isopropylphenyl group or the like. The diphosphine ligand can be in R or S configuration, and when two chiral centers exist, the diphosphine ligand can be in R, R or S, S configuration.
As a preferable technical scheme of the invention, the benzimidazole nitrogen-containing heterocyclic ligand transition metal complex has a diamine ligand configuration which can be selected from an R or S configuration. R6Can be hydrogen alone when R6When not hydrogen, the aza-ammonia ligand may be a chiral ligand with R or S configuration, or may not be chiral; r is as defined above6The radicals can be alkyl or aryl radicals, such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, 3, 5-dimethylbenzyl, 1-naphthyl, 2-naphthyl. For example, when the bisphosphine ligand is preferably (R) -Binap, X, Y ═ Cl, bisThe amine ligand is preferably in (S) -configuration, and when the amine group on the benzimidazole ring is respectively a secondary amine and a tertiary amine, the structure includes but is not limited to the following structures:
Figure BDA0002759320150000062
when the bisphosphine ligand is preferably (R) -Binap, X, Y ═ OAc, the diamine ligand is preferably in the (S) -configuration, and the amine groups on the benzimidazole ring are secondary and tertiary amines, respectively, the structures include, but are not limited to, the following by way of example:
Figure BDA0002759320150000071
wherein, the R group can be an aliphatic or aromatic group substituent group such as methyl, ethyl, halogen, cyano, nitryl, trifluoromethanesulfonic group, alkoxy, sulfydryl and the like which are substituted at ortho-position, meta-position or para-position on a benzene ring.
As a preferred embodiment of the present invention, the nitrogen-containing heterocyclic ligand transition metal complex comprises:
Figure BDA0002759320150000072
specifically, the preparation method comprises the following steps:
1) firstly, carrying out salt decomposition on 3-quinuclidinone hydrochloride under the action of alkali to obtain 3-quinuclidinone;
2) then 3-quinuclidinone is asymmetrically hydrogenated and reduced under the action of chiral catalyst RuXY-Diphosphine-bimaH and alkali to obtain optically pure 3-quinuclidinol;
1)
Figure BDA0002759320150000081
2)
Figure BDA0002759320150000082
the solvent of the salt decomposition reaction in the step 1) is selected from any one of methanol, ethanol and acetone, and the alkali is selected from any one of sodium carbonate, potassium carbonate, sodium hydroxide, ammonia water, potassium tert-butoxide, sodium methoxide and sodium ethoxide.
The asymmetric hydrogenation reaction in the step 2) is carried out under the pressure of 0.1MPa-80MPa and the reaction temperature of 20-60 ℃.
The solvent for the asymmetric hydrogenation reaction in the step 2) is one or more mixed solvents selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, methanol, ethanol, n-propanol, isopropanol and tert-butanol.
The alkali for the asymmetric hydrogenation reaction in the step 2) is selected from one or a mixture of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium methoxide in any proportion.
As a preferred technical solution of the present invention, the synthetic route of the chiral catalyst RuXY-Diphosphine-bimaH mentioned in the above step 2) comprises:
Figure BDA0002759320150000083
Figure BDA0002759320150000091
the invention further provides a preparation method of the ligand, and the complex can be prepared by reacting transition metal, a double nitrogen ligand or a single nitrogen ligand and a diphosphine ligand or a monophosphine ligand in an organic solvent at the reaction temperature of 80-120 ℃ for 0.5-20 hours.
The invention further provides an asymmetric hydrogenation method of simple ketone, which uses the nitrogen heterocyclic ligand transition metal complex as a catalyst, and the reaction route is as follows:
Figure BDA0002759320150000092
the catalyst is the nitrogen heterocyclic ligand transition metal complex serving as a catalyst.
When a nitrogen-containing heterocyclic ligand transition metal complex of formula (I), wherein R1Represents a chiral or achiral organic hydrocarbon group; r2，R3，R4，R5And R6The same or different, and is aliphatic hydrocarbon with 1-6 carbon atoms or aromatic group with 6-12 carbon atoms; r7Can be an aliphatic or aromatic substituent group such as methyl, ethyl, halogen, cyano, nitro, trifluoromethanesulfonyl, alkoxy, sulfydryl and the like which are substituted at the ortho position, the meta position or the para position on a benzene ring; r8Represents a chiral or achiral organic hydrocarbon group such as methyl, phenyl, etc.
The beneficial effects of the invention compared with the prior art comprise:
the invention provides a novel benzimidazole heterocyclic ligand transition metal complex and a preparation method thereof, and the complex has the advantages of simple process and good reproducibility.
The invention also provides the application of the transition metal complex in catalyzing asymmetric hydrogenation reaction, wherein a protic solvent or an aprotic solvent can be used in the reaction, the reaction condition is mild, and the applicability is wide.
The transition metal complex provided by the invention is a series of excellent catalysts, and can realize the stereoselective conversion of aliphatic ketone such as 3-quinuclidinone to optical pure chiral 3-quinuclidinol under relatively mild conditions.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
Example 1: catalyst RuCl2-[(R)-Binap]-[(S)-Bn-bimaH]2Preparation of (Compound Nos. 1 to 7)
Adding 650mg of o-phenylenediamine and 1.98g of L-phenylalanine into 20ml of toluene solution, heating to 120 ℃, refluxing for 2 days, monitoring the reaction by mass spectrometry until the reaction is complete, spin-drying the crude product solution, and recrystallizing in ethanol to obtain 1.15g of 1-benzimidazole-2-phenylethylamine as a white solidThe yield was 81%. 250mg of (R) -BINAP and 122mg of [ RuCl ]2(p-cymene)]2Placing into 10mL Schlenk bottle, replacing with argon, adding 3mL DMF, reacting at 120 deg.C for 30min, cooling to room temperature, concentrating, filtering, and drying to obtain 187mg metal complex with yield>99 percent. Under the condition of argon, 95mg of the benzimidazole prepared in the previous step is added into a Schlenk bottle containing 187mg of the metal complex, argon is pumped out, 3mL of dichloromethane is added, stirring is carried out at normal temperature for 7 hours, then the solvent is pumped to 0.5mL, 5mL of n-hexane is added, solid is precipitated, and the yellow solid is filtered to obtain 200mg of yellow solid, wherein the yield is 97%. The reaction formula is as follows:
Figure BDA0002759320150000101
example 2: catalyst Ru (OAc)2-[(R)-Binap]-[(S)-Bn-bimaH]Preparation of (Compound No. 2-13) (the catalyst Compound Nos. 2-1 to 2-20 were each prepared according to this method)
62mg of (R) -BINAP and 25mg of [ Ru (bezene) Cl under an argon atmosphere2]2Placing into a 10mL Schlenk bottle, replacing with argon, adding 3mL of DMF, reacting at 120 ℃ for 30min, cooling to room temperature, adding 96mg of NaOAc, concentrating, filtering, and drying to obtain the prepared diacetate [ (R) - (+) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl group]Ruthenium (II) was directly used in the next reaction without purification. The prepared diacetate radical [ (R) - (+) -2,2 '-di (diphenylphosphino) -1,1' -binaphthyl group]Ruthenium (II) and 23.7mg of the above-mentioned benzodiazole derivative were put into a Schlenk flask, stirred at room temperature for 8 hours, and then drained to obtain 100.2mg of a red solid with a yield of 97.2%. The reaction formula is as follows:
Figure BDA0002759320150000111
example 3: free form of 3-quinuclidinone hydrochloride
370g of water and 50g of sodium hydroxide solid are added into a 1L reaction kettle, the temperature is reduced to 10 ℃ by stirring, 90g of 3-quinuclidinone hydrochloride is added into the reaction kettle, and the reaction is carried out by stirring. The reaction system is extracted three times by 500mL of dichloromethane, organic phases are combined, white solid is obtained after spin drying, and then nitrogen is introduced for storage. The reaction formula is as follows:
Figure BDA0002759320150000112
example 4: asymmetric hydrogenation of 3-quinuclidinone
In a glove box, 1g of 3-quinuclidinone and 3mL of isopropanol were added to a 10mL reaction flask, 9mg of potassium tert-butoxide and the catalyst compound No. 2-1(0.76mg, S/C ═ 10000) were added, the autoclave was closed, hydrogen gas was introduced at 30bar, and the reaction was stirred at 25 ℃ for 16 hours. After completion of the reaction, the reaction was monitored by GC to give a result of 88% conversion, 49% ee. The reaction formula is as follows:
Figure BDA0002759320150000121
examples 5 to 14: optimization of diamine ligands in catalysts
In a glove box, 1g of 3-quinuclidinone (8mmol) and 3mL of isopropanol were added to a 10mL reaction flask, 9mg (0.08mol, 1 mol%) of potassium tert-butoxide and a catalyst (S/C ═ 10000) were added, the autoclave was closed, hydrogen gas was introduced at 30bar, and the reaction was stirred at 25 ℃ for 16 hours. After completion of the reaction, the reaction was monitored by GC to give the results as in table 1:
TABLE 1 optimization of diamines in catalysts
Figure BDA0002759320150000122
Examples 15 to 19: optimization of bases
In a glove box, 1g of 3-quinuclidinone (8mmol) and 3mL of isopropanol were added to a 10mL reaction flask, and a base (0.08mol, 1 mol%) and the catalyst compound No. 2-13(0.8mg, S/C ═ 10000) were added thereto, and the mixture was placed in a high-pressure reaction vessel and sealed, charged with hydrogen gas at 30bar, and stirred at 25 ℃ for reaction for 16 hours. After completion of the reaction, the reaction was monitored by GC to give the results as shown in table 2:
TABLE 2 optimization of bases
Figure BDA0002759320150000131
Examples 20 to 22: solvent optimization
In a glove box, 1g of 3-quinuclidinone (8mmol) and 3mL of solvent were added to a 10mL reaction flask, 9mg (0.08mol, 1 mol%) of potassium tert-butoxide and (catalyst compound No. 2-13(0.8mg, S/C ═ 10000) were added, the autoclave was closed, hydrogen gas was charged at 30bar, and the reaction was stirred at 25 ℃ for 16 hours after completion, the reaction was monitored by GC to obtain the results as shown in table 3:
TABLE 3 optimization of solvents
Figure BDA0002759320150000132
Examples 23 to 26: optimization of bisphosphine ligands in catalysts
In a glove box, 1g of 3-quinuclidinone (8mmol) and 3mL of solvent were added to a 10mL reaction flask, 9mg (0.08mol, 1 mol%) of potassium tert-butoxide and the catalyst compound No. 2-13(0.8mg, S/C ═ 10000) were added, the autoclave was closed, hydrogen gas was introduced at 30bar, and the reaction was stirred at 25 ℃ for 16 hours. After completion of the reaction, the reaction was monitored by GC to give the results as in table 4:
TABLE 4 optimization of bisphosphines in catalysts
Figure BDA0002759320150000141
Figure BDA0002759320150000142
Example 27: (R) -3-quininol preparation amplification experiment
In a glove box, 100g of 3-quinuclidinone (0.8mol) and 250mL of isopropanol were added to a reaction kettle, 0.9g (8mol, 1 mol%) of potassium tert-butoxide and 80mg (S/C ═ 10000) of (R, S) -dichloro-substituted benzyl benzimidazole catalyst (compound No. 2-13) were added, the autoclave was closed, then hydrogen gas was introduced at 50bar, and the reaction was stirred at 25 ℃ for 16 hours. After completion of the reaction, the reaction was monitored in situ by GC to give a result of 99% conversion, 99% ee. Concentrated hydrochloric acid was added to the reaction solution, and the mixture was stirred, recrystallized from ethyl acetate, filtered, and dried to obtain 91g of (R) -3-quinuclidinol having an ee value of 99.5%, with a yield of 89.5%.
Example 28: asymmetric preparation of (S) -3-quinuclidinol
In a glove box, 1g of 3-quinuclidinone (8mmol) and 3mL of isopropanol were added to a 50mL reaction vessel, 9mg (0.08mol, 1 mol%) of potassium tert-butoxide and 0.8mg (S/C: 10000) of (S, R) -dichloro-substituted benzyl benzimidazole catalyst (2-20) were added, the vessel was placed in a high-pressure reaction vessel, closed, charged with hydrogen gas at 30bar, and stirred at 25 ℃ for 16 hours. After completion of the reaction, the reaction was monitored by GC and found to be 99% conversion in 99% ee. The reaction formula is as follows:
Figure BDA0002759320150000151
examples 29-31 expansion of the substrate ketones
In a glove box, a 50mL reaction kettle is added with corresponding ketone (8mmol) and isopropanol 3mL, potassium tert-butoxide 9mg (0.08mol, 1 mol%) and (S, R) -dichloro substituted benzyl benzimidazole catalyst (2-13)0.8mg (S/C ═ 10000) are added, the reaction kettle is sealed, hydrogen gas is filled in the reaction kettle for 30bar, and the reaction kettle is stirred at 25 ℃ for 16 hours. After completion of the reaction, the reaction was monitored by GC, and the results are shown in table 5. The reaction formula is as follows:
Figure BDA0002759320150000152
TABLE 5 extension of ketones
Figure BDA0002759320150000153
The above embodiments are preferred embodiments of the present invention, but the implementation manner of the present invention is not limited by the above embodiments, and any other changes, modifications, substitutions, combinations, simplifications which do not depart from the spirit and principle of the present invention should be regarded as equivalent replacements within the protection scope of the present invention.

Claims (10)

1. A process for the preparation of (R) -and (S) -3-quinuclidinol, comprising the steps of:
3-quinuclidinone is asymmetrically hydrogenated and reduced under the action of chiral catalyst RuXY-Diphosphine-bimaH and alkali to obtain optically pure 3-quinuclidinol.
Figure FDA0002759320140000011
2. The preparation method of (R) -and (S) -3-quinuclidinol according to claim 1, characterized in that the chiral catalyst RuXY-Diphosphine-bimaH is a benzimidazole class of transition metal complexes with nitrogen-containing heterocyclic ligands, and the structure is as follows:
Figure FDA0002759320140000012
x, Y is chlorine, bromine, iodine, acetate, triflate or hydrogen;
when a nitrogen-containing heterocyclic ligand transition metal complex of formula (I), wherein R1Represents a chiral or achiral organic hydrocarbon group; r is2，R3，R4，R5And R6The same or different, and is aliphatic hydrocarbon with 1-6 carbon atoms or aromatic group with 6-12 carbon atoms; r is7Can be an aliphatic or aromatic substituent group such as methyl, ethyl, halogen, cyano, nitro, trifluoromethanesulfonyl, alkoxy, sulfydryl and the like which are substituted at the ortho position, the meta position or the para position on a benzene ring; r8Representing chiral or achiral organic hydrocarbon radicals, e.g. methylPhenyl, and the like.
3. A benzimidazole nitrogen heterocyclic ligand transition metal complex is characterized in that the complex is a chiral catalyst RuXY-Diphosphine-bimaH, and when X and Y are OAc, the structure is shown as follows:
Figure FDA0002759320140000013
or
Figure FDA0002759320140000014
Or
Figure FDA0002759320140000015
When it is a nitrogen-containing heterocyclic ligand transition metal complex of the formula (I) -1, (I) -2 or (I) -3, wherein R is1Represents a chiral or achiral organic hydrocarbon group; r2，R3，R4，R5And R6The same or different, and is aliphatic hydrocarbon with 1-6 carbon atoms or aromatic group with 6-12 carbon atoms; r7Can be an aliphatic or aromatic substituent group such as methyl, ethyl, halogen, cyano, nitro, trifluoromethanesulfonyl, alkoxy, sulfydryl and the like which are substituted at the ortho position, the meta position or the para position on a benzene ring; r8Represents a chiral or achiral organic hydrocarbon group such as methyl, phenyl, etc.
4. The benzimidazole nitrogen-containing heterocyclic ligand transition metal complex according to claim 2, wherein the Diphosphine ligand Diphosphine comprises but is not limited to the following phosphine ligands and their derivatives: binap, Biphep, BPE, DIPAMP, DIOP, Duphos, CnTunephos, Segphos, Chiraphos, Skewphos, Phanephos, Norphos and DuanPhos and other phosphine ligands, e.g. RuX2-[(R)-Binap]-[(S)-Bn-bimaH](I) And the like, specifically as follows:
Figure FDA0002759320140000021
wherein the Ar group may be an aryl group such as a phenyl group, a benzyl group, a 3, 5-dimethylphenyl group, a 3, 5-di-t-butylphenyl group, a methyl-p-isopropylphenyl group or the like. The diphosphine ligand can be in R or S configuration, and when two chiral centers exist, the diphosphine ligand can be in R, R or S, S configuration.
5. The benzimidazole nitrogen-containing heterocyclic ligand transition metal complex according to claim 2, wherein the diamine ligand configuration can be selected from R or S configuration. R6May be hydrogen alone when R is6When not hydrogen, the aza-ammonia ligand may be a chiral ligand with R or S configuration, or may not be chiral; r is as defined above6The radicals can be alkyl or aryl radicals, such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, 3, 5-dimethylbenzyl, 1-naphthyl, 2-naphthyl. When the bisphosphine ligand is preferably (R) -Binap, X, Y ═ Cl, the diamine ligand is preferably in the (S) -configuration, and the amine groups on the benzimidazole ring are respectively secondary and tertiary amines, the structures include but are not limited to the following:
Figure FDA0002759320140000031
when the bisphosphine ligand is preferably (R) -Binap, X, Y ═ OAc, the diamine ligand is preferably in the (S) -configuration, and the amine groups on the benzimidazole ring are secondary and tertiary amines, respectively, the structures include, but are not limited to, the following:
Figure FDA0002759320140000032
Figure FDA0002759320140000041
wherein, the R group can be an aliphatic or aromatic group substituent group such as methyl, ethyl, halogen, cyano, nitryl, trifluoromethanesulfonic group, alkoxy, sulfydryl and the like which are substituted at ortho-position, meta-position or para-position on a benzene ring.
6. The benzimidazole nitrogen-containing heterocyclic ligand transition metal complex according to claim 3, wherein the nitrogen-containing heterocyclic ligand transition metal complex is preferably:
Figure FDA0002759320140000042
7. a process for the preparation of (R) -and (S) -3-quinuclidinol according to claim 1, wherein said step comprises:
1) firstly, carrying out salt decomposition on 3-quinuclidinone hydrochloride under the action of alkali to obtain 3-quinuclidinone;
2) then 3-quinuclidinone is asymmetrically hydrogenated and reduced under the action of chiral catalyst RuXY-Diphosphine-bimaH and alkali to obtain optically pure 3-quinuclidinol;
1)
Figure FDA0002759320140000043
2)
Figure FDA0002759320140000044
the solvent of the salt decomposition reaction in the step 1) is selected from any one of methanol, ethanol and acetone, and the alkali is selected from any one of sodium carbonate, potassium carbonate, sodium hydroxide, ammonia water, potassium tert-butoxide, sodium methoxide and sodium ethoxide.
8. A process for the preparation of (R) -and (S) -3-quinuclidinol according to claim 1, characterized in that: the asymmetric hydrogenation reaction pressure is 0.1-80 Mpa, and the reaction temperature is 20-60 ℃;
the solvent for asymmetric hydrogenation reaction is one or more mixed solvent selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, methanol, ethanol, n-propanol, isopropanol, and tert-butanol.
9. A process for the preparation of (R) -and (S) -3-quinuclidinol as claimed in claim 1, wherein: the base for asymmetric hydrogenation reaction is selected from potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium methoxide, or their mixture in any proportion.
10. A method for asymmetric hydrogenation of simple ketone is characterized in that benzimidazole nitrogen heterocyclic ligand transition metal complex compound with the following formula is used as a catalyst, and the reaction route is as follows:
Figure FDA0002759320140000051
when a nitrogen-containing heterocyclic ligand transition metal complex of formula (I), wherein R1Represents a chiral or achiral organic hydrocarbon group; r2，R3，R4，R5And R6The same or different, and is aliphatic hydrocarbon with 1-6 carbon atoms or aromatic group with 6-12 carbon atoms; r7Can be an aliphatic or aromatic substituent group such as methyl, ethyl, halogen, cyano, nitro, trifluoromethanesulfonyl, alkoxy, sulfydryl and the like which are substituted at the ortho position, the meta position or the para position on a benzene ring; r8Represents a chiral or achiral organic hydrocarbon group such as methyl, phenyl, etc.
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