CN114437060B - Preparation method of (R) -and (S) -3-quinuclidinol - Google Patents

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

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CN114437060B
CN114437060B CN202011212637.9A CN202011212637A CN114437060B CN 114437060 B CN114437060 B CN 114437060B CN 202011212637 A CN202011212637 A CN 202011212637A CN 114437060 B CN114437060 B CN 114437060B
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quinuclidinol
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quinuclidinone
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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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    • 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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    • B01J2231/641—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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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, 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 to 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), revatoprate (Revatopate) for the long-term maintenance treatment of Chronic Obstructive Pulmonary Disease (COPD), solifenacin (Solifenacin) for the treatment of Overactive Bladder syndrome (OAB), and the drug tasalidine (Talsalidine) for the treatment of Alzheimer's Disease, AD) (J.Med.chem.2005, 48 (21): 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. Li Shubin, etc. (3-quinuclidinol resolution study [ J ]. Anhui chemical, 2009, 35 (1): 31-33.) in methanol solution, using potassium borohydride reduction method to reduce 3-quinuclidinone hydrochloride into racemic 3-quinuclidinol, using mixed solvent of V (propanol): V (acetone) =3:1 as reaction medium, using D- (+) -dibenzoyltartaric acid as resolving agent to resolve racemic mixture, recrystallizing the obtained solid to obtain (R) -3-quinuclidinol, ee value 98%, and yield 20.4%. Similarly, ji et al (US 7309699, [ P ] resolve 17.9g of (+/-) -1-azabicyclo [2.2.2] octyl-3-benzoate using (L) -tartaric acid in ethanol solution and hydrolyze the resolved product with 15% sodium hydroxide solution to give 1.35g of (R) -3-quininol. 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): 625-628.) synthesized the chemical catalyst Xyl-Skewphos-PICA-Ru which can be used for catalyzing the asymmetric hydrogenation of 3-quinuclidinone to prepare (R) -3-quinuclidinol, and the ee value of (R) -3-quinuclidinol is 88% after the reaction for 4 hours with the molar ratio of the substrate to the catalyst being 10 ten thousand/1, 4.3kg of the substrate in the reaction process. 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 isopropanol 2 [(S)-Binap][(R)-iphan]And t the 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 RuCl 2 [(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
xu Liang, etc. (CN 105085513A) uses (S, S) -xylskiwphos-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) -xylskiwphos-RuBr-QUIMA and the action of alkali are used to asymmetrically hydrogenate and reduce 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%, the reaction formula is as follows:
Figure BDA0002759320150000033
xu Liang and the like (a nitrogen-containing heterocyclic ligand transition metal complex and preparation and catalytic application thereof: PCT/CN 2011/080207), a biphase diamine catalyst such as binap, quima and the like is used for catalyzing asymmetric hydrogenation of endocyclic nitrogen heterocycles and derivatives thereof and other aryl alkyl ketones or esters, the molar ratio of a substrate to the catalyst in the reaction process is 1000, and the ee value of (S) -3-quinuclidinol is 96% under the hydrogen pressure of 20 MPa. A small amount of metal chiral catalyst is used in the reaction process of preparing (R) -3-quinuclidinol 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 difficult to recycle and cause certain pollution to the environment.
Several successful asymmetric hydrogenation experiments have been reported in US patents 7378560 and US2008/0249308, both of which use 2-aminomethylpyridine derivatives as ligands. In particular, U.S. Pat. No. 5, 7378560 shows very high selectivity to tert-butyl substituted ketones. While patent US2008/0249308 provides a relatively versatile catalyst, exhibiting moderate to good stereoselectivity. At present, the best optical purity of (R) -3-quinine 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, further describing 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:
the 3-quinuclidinone is asymmetrically hydrogenated and reduced under the action of chiral catalyst RuXY-Diphosphine-bimaH and alkali to obtain the 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
wherein X, Y can be chlorine, bromine, iodine, acetate, triflate or hydrogen, respectively;
when is of formula(I) In the nitrogen-containing heterocyclic ligand transition metal complex of (1), wherein R 1 Represents a chiral or achiral organic hydrocarbon group; r is 2 ，R 3 ，R 4 And R 5 And R 6 The same or different, and is aliphatic hydrocarbon with 1-6 carbon atoms or aromatic group with 6-12 carbon atoms; r 7 Can 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; r 8 Represents a chiral or achiral organic hydrocarbon group such as methyl, phenyl, etc.
As a preferred embodiment of the present invention, when X and Y are OAc, they are nitrogen-containing heterocyclic ligand transition metal complexes of the formula (I) -1, (I) -2 or (I) -3, and the structures thereof are shown below:
Figure BDA0002759320150000051
or->
Figure BDA0002759320150000052
Or (R)>
Figure BDA0002759320150000053
As a preferred embodiment of the present invention, the bisphosphine ligand includes, but is not limited to, the following phosphine ligands and derivatives thereof: binap, biphep, BPE, DIPAMP, DIOP, duphos, C n * -Tunephos, segphos, chiraphos, skewphos, phanephos, norphos and DuanPhos and other phosphine ligands. In the diamine ligand, R 6 May be hydrogen alone when R is 6 When 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 above 6 The group can be alkyl or aryl, 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 can be aryl such as phenyl, benzyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl and methyl-p-isopropylphenyl. 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. R 6 May be hydrogen alone when R is 6 When 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 above 6 The 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 a secondary amine and a tertiary amine, the structures include but are not limited to the following:
Figure BDA0002759320150000062
such structures include, but are not limited to, 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, as exemplified by the following:
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 to 80MPa and the reaction temperature of 20 ℃ to 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 R 1 Represents a chiral or achiral organic hydrocarbon group; r is 2 ，R 3 ，R 4 ，R 5 And R 6 The same or different, and is aliphatic hydrocarbon with 1-6 carbon atoms or aromatic group with 6-12 carbon atoms; r 7 Can 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; r 8 Represents 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 RuCl 2 -[(R)-Binap]-[(S)-Bn-bimaH] 2 Preparation of (Compound Nos. 1 to 7)
650mg of o-phenylenediamine and 1.98g of L-phenylalanine were added to 20ml of a toluene solution, heated to 120 ℃ and refluxed for 2 days, the reaction was monitored by mass spectrometry to completion, and the crude product solution was spin-dried and recrystallized from ethanol to give 1.15g of 1-benzimidazole-2-phenylethylamine as a white solid in a yield of 81%. 250mg of (R) -BINAP and 122mg of [ RuCl ] 2 (p-cymene)] 2 Placing 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 and process for preparing sameRu(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 [ 2], [ Ru (bezene) Cl, under an argon atmosphere 2 ] 2 Placing into a 10ml Schlenk bottle, replacing with argon, adding 3mL DMF, reacting at 120 deg.C for 30min, cooling to room temperature, adding 96mg NaOAc, concentrating, filtering, and drying to obtain diacetate [ (R) - (+) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl group]Ruthenium (II) was directly used in the next reaction without purification. Prepared diacetate radical [ (R) - (+) -2,2 '-di (diphenylphosphino) -1,1' -binaphthyl group]Ruthenium (II) and 23.7mg of the benzotriazole derivative are added into a Schlenk bottle, stirred for 8 hours at normal temperature and pumped to dryness to obtain 100.2mg of red solid with the 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 are added into a 10mL reaction bottle, 9mg of potassium tert-butoxide and the catalyst compound number 2-1 (0.76mg, S/C = 10000) are added, the reaction kettle is sealed, hydrogen is filled into the reaction kettle, and the reaction kettle is stirred and reacted for 16 hours at 25 ℃. After completion of the reaction, the reaction was monitored by GC to obtain 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 (8 mmol) and 3mL of isopropanol were added to a 10mL reaction flask, 9mg of potassium tert-butoxide (0.08mol, 1mol%) and a catalyst (S/C = 10000) were added, the autoclave was closed, hydrogen 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 (8 mmol) and 3mL of isopropanol are added into a 10mL reaction bottle, alkali (0.08mol, 1mol%) and a catalyst compound number 2-13 (0.8mg, S/C = 10000) are added, the reaction bottle is placed into a high-pressure reaction kettle for sealing, hydrogen is filled into 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 to give the results shown in table 2:
TABLE 2 optimization of bases
Figure BDA0002759320150000131
Examples 20 to 22: solvent optimization
In a glove box, a 10mL reaction flask was charged with 1g of 3-quinuclidinone (8 mmol) and 3mL of a solvent, and potassium tert-butoxide 9mg (0.08mol, 1mol%) and (catalyst compound No. 2-13 (0.8mg, s/C = 10000) were added, and the autoclave was closed, charged with hydrogen 30bar, and stirred at 25 ℃ for 16 hours, after completion of the reaction, the reaction was monitored by GC, and the results were 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 (8 mmol) and 3mL of a solvent were put into a 10mL reaction flask, 9mg (0.08mol, 1mol%) of potassium tert-butoxide and the catalyst compound nos. 2 to 13 (0.8mg, S/C = 10000) were added, the autoclave was closed, hydrogen 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 (0.8 mol) and 250mL of isopropanol were added to a reaction vessel, 0.9g (8mol, 1mol%) of potassium tert-butoxide and 80mg (S/C = 10000) of (R, S) -dichloro-substituted benzylbenzimidazole catalyst (compound No. 2-13) were added to the reaction vessel, the reaction vessel was closed, then hydrogen 50bar was charged, and the reaction vessel was stirred at 25 ℃ for 16 hours. After completion of the reaction, the reaction was monitored in situ by GC to give results of 99% conversion, 99% ee. The reaction mixture was stirred with concentrated hydrochloric acid, recrystallized from ethyl acetate, filtered and dried to obtain 91g of (R) -3-quinuclidinol having an ee value of 99.5% by weight, in 89.5% yield.
Example 28: asymmetric preparation of (S) -3-quinuclidinol
In a glove box, 1g of 3-quinuclidinone (8 mmol) and 3mL of isopropanol were added to a 50mL reaction vessel, 9mg of potassium tert-butoxide (0.08mol, 1 mol%) and 0.8mg of (S, R) -dichloro-substituted benzylbenzimidazole catalyst (2-20) (S/C = 10000) were added, the vessel was placed in an autoclave, the vessel was sealed, charged with hydrogen 30bar, and stirred at 25 ℃ for 16 hours. After completion of the reaction, the reaction was monitored by GC, resulting in 99% conversion, 99% ee. The reaction formula is as follows:
Figure BDA0002759320150000151
examples 29-31 expansion of the substrate ketones
In a glove box, 3mL of the corresponding ketone (8 mmol) and isopropanol were added to a 50mL reaction vessel, and 9mg (0.08mol, 1mol%) of potassium tert-butoxide and 0.8mg (S/C = 10000) of (S, R) -dichloro-substituted benzylbenzimidazole catalyst (2-13) were added, and the vessel was placed in an autoclave and closed, charged with hydrogen 30bar, and 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 (6)

1. The benzimidazole nitrogen-containing heterocyclic ligand transition metal complex is characterized in that:
Figure FDA0004112681160000011
2. a process for the preparation of (R) -and (S) -3-quinuclidinol, comprising the steps of:
the asymmetric hydrogenation reduction of 3-quinuclidinone is carried out by utilizing chiral catalyst RuXY-Diphosphine-bimaH and alkali to obtain optical pure 3-quinuclidinol, wherein the chiral catalyst RuXY-Diphosphine-bimaH is benzimidazole nitrogen heterocyclic ligand transition metal complex as claimed in claim 1:
Figure FDA0004112681160000012
3. a process for the preparation of (R) -and (S) -3-quinuclidinol as claimed in claim 2, 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 FDA0004112681160000013
2)
Figure FDA0004112681160000014
the solvent of the salt decomposition reaction in the step 1) is any one of methanol, ethanol and acetone, and the alkali is any one of sodium carbonate, potassium carbonate, sodium hydroxide, ammonia water, potassium tert-butoxide, sodium methoxide and sodium ethoxide.
4. A process for the preparation of (R) -and (S) -3-quinuclidinol according to claim 2, characterized in that: the asymmetric hydrogenation reaction pressure is 0.1MPa-80MPa, and the reaction temperature is 20 ℃ to 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.
5. A process for the preparation of (R) -and (S) -3-quinuclidinol according to claim 2, characterized in that: the base for the asymmetric hydrogenation reaction 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.
6. A process for the asymmetric hydrogenation of simple ketones, characterized in that a transition metal complex of a nitrogen-containing heterocyclic benzimidazole ligand according to claim 1 is used as a catalyst.
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