Novel quinoline imidazole skeleton chiral nitrogen phosphine ligand compound as well as synthesis method and application thereof
By synthesizing quinoline-imidazole skeleton chiral phosphine ligand in asymmetric hydrogenation reaction and combining with metal catalysts, the problem that existing ligands are difficult to achieve efficient and highly stereoselective control in the reaction is solved, and the effect of efficient and highly enantioselective synthesis of dexmedetomidine hydrochloride is achieved.
Patent Information
- Application Number
- CN202510114095.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-24
- Publication Date
- 2025-04-11
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
In the asymmetric hydrogenation reaction, existing chiral nitrogen phosphine ligands are difficult to achieve efficient and highly stereoselective control, and there is a problem that chemical selectivity and stereoselectivity cannot be accurately regulated.
By using 2-chloroquinoline as the starting material, through a series of chemical reactions (including iodide reaction, C-N bond coupling reaction, intramolecular cyclosynthesis reaction, C-P bond coupling reaction and hydrogen silicon reduction reaction), the quinoline imidazole backbone chiral nitrogen phosphine ligand is synthesized and combined with a metal catalyst for asymmetric hydrogenation reaction.
The efficient and enantioselective synthesis of dexmedetomidine hydrochloride in asymmetric hydrogenation reaction was achieved, showing good reactivity and stereoselectivity, and has broad application prospects.
Smart Images
Figure QLYQS_1 
Figure QLYQS_2 
Figure QLYQS_3
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of asymmetric catalysis, and specifically provides a novel quinoline imidazole skeleton chiral nitrogen phosphine ligand compound and a synthesis method and application thereof. Background Art
[0002] Chiral compounds are widely found in natural products, bioactive molecules, and clinical drug molecules (or their key intermediates). In the field of new drug research, 820 of the more than 1,200 drugs under development are chiral molecules, accounting for nearly 70%. The research on chiral drugs has been very rapid in recent years, and major drug research and development companies have developed small molecule drugs. The proportion of single chiral compounds has gradually increased. The importance of chirality research is self-evident. Among all chiral compounds, chiral amine alcohols belong to a common class of chiral molecules, which are widely used in ligand synthesis, small molecule drugs, pesticides, natural compounds and functional materials. The asymmetric hydrogenation reaction catalyzed by organometallics has the advantages of mild reaction conditions, high efficiency and selectivity, and a wide range of substrates, and has received extensive attention and in-depth research. However, the core factor affecting the efficiency of asymmetric catalytic hydrogenation is the catalyst, which is composed of a metal center and a ligand. Due to the limitations of the periodic table, the types of transition metals available are limited. Therefore, the development of new chiral ligands has in fact become the most fundamental research topic in the field of asymmetric hydrogenation, running through the entire history of asymmetric hydrogenation.
[0003] In asymmetric hydrogenation reactions, the structure of chiral ligands has an important influence on the activity and stereoselectivity of the reaction. Therefore, chemists can achieve fine control of the reaction through reasonable ligand electrical properties and steric hindrance design. However, no ligand can solve all problems. Therefore, the development of chiral ligands and asymmetric catalytic systems with high efficiency, high selectivity and wide substrate applicability will be an eternal theme. Although chiral phosphine ligands or nitrogen-containing ligands are now very rich in both types and numbers, each ligand has its own unique properties; on the other hand, chiral nitrogen phosphine ligands are an important class of chiral ligands. Although they have made certain progress in the field of asymmetric catalysis, in some asymmetric hydrogenation reactions, there are still scientific problems such as the inability to accurately control chemical selectivity and stereoselectivity. Therefore, it is very necessary and urgent to develop new chiral nitrogen phosphine ligands to achieve efficient and high stereoselective control of asymmetric hydrogenation reactions. It has important theoretical significance and application value, and is also an important supplement to existing chiral nitrogen phosphine ligands. Summary of the invention
[0004] The invention aims to use 2-chloroquinoline as a starting material, and realize the synthesis of a series of quinoline imidazole skeleton compounds through iodination reaction at position 3, CN bond coupling reaction, intramolecular cyclization reaction, CP bond coupling reaction and silane reduction reaction. The novel nitrogen phosphine ligand can realize the asymmetric hydrogenation reaction catalyzed by Pd, Rh, Ir, Ru, Ni, Fe, Cu and Co metals to synthesize dexmedetomidine hydrochloride drug molecules. In the reaction process, the compound exhibits excellent reaction activity and enantioselectivity, and has broad application prospects.
[0005] In order to achieve the above object, the technical solution of the present invention is as follows:
[0006] On the one hand, the present invention provides a novel quinoline imidazole skeleton chiral nitrogen phosphine ligand compound, and its molecular structure (I) is as follows:
[0007]
[0008] Among them, R 1 , R 2 , R 3 Selected from aryl, such as phenyl, naphthyl, 9-anthryl; heteroaryl, such as thiophene, furan; electron-withdrawing substituents, such as trifluoromethyl, cyano, nitro; electron-donating substituents, such as methoxy, ethoxy, benzyloxy, methyl, ethyl, isopropyl, tert-butyl; halogen, such as fluorine, chlorine, bromine;
[0009] R 4 Selected from alkyl, such as tert-butyl, isopropyl, adamantyl, cycloalkyl, heterocycloalkyl; aryl, such as phenyl, 2,4,6-tri(methyl)phenyl, 2,4,6-tri(isopropyl)phenyl, 3,5-di(trifluoromethyl)phenyl, 3,5-di(tert-butyl)phenyl, 3,5-di(methyl)phenyl, 3,5-di(ethyl)phenyl, naphthyl, 9-anthryl; heteroaryl, such as thiophene, furan;
[0010] R 5 Selected from alkyl groups such as methyl, ethyl, propyl, isopropyl, tert-butyl, benzyl, cycloalkyl, heterocycloalkyl; aryl groups such as phenyl, o-tolyl, 3-chlorophenyl, 4-fluorophenyl, 4-phenylphenyl, naphthyl;
[0011] Furthermore, the present invention provides another chiral nitrogen phosphine ligand compound, the structure of which is shown in formula (II):
[0012]
[0013] Furthermore, the present invention provides a racemic nitrogen phosphine ligand compound, the structure of which is shown in formula (III):
[0014]
[0015] Furthermore, the chiral nitrogen phosphine ligand compound with quinoline imidazole skeleton of the present invention is selected from one of the structural formulas L1-L39;
[0016]
[0017] The quinoline imidazole skeleton chiral nitrogen phosphine ligand compound is of R configuration or S configuration.
[0018] 4. On the other hand, the present invention provides a method for synthesizing a quinoline imidazole skeleton chiral nitrogen phosphine ligand compound, the specific steps are as follows:
[0019]
[0020] S1, iodine compound 2 under inert atmosphere and low temperature conditions to obtain compound 3;
[0021] S2, coupling compound 3 with chiral amine alcohol 4 under inert atmosphere and high temperature to obtain compound 5;
[0022] S3, reacting compound 5 with methanesulfonyl chloride at low temperature, followed by intramolecular cyclization to generate compound 6;
[0023] S4, subjecting compound 6 to a CP bond coupling reaction with a diaryl or dialkylphosphine oxide compound 7 under palladium catalysis to obtain compound 8;
[0024] S5. Compound 8 is subjected to silanol reduction under high temperature conditions to generate the target product represented by formula (I).
[0025] Among them, each R 1 , R 2 , R 3 , R 4 , R 5 Has the meaning as defined in claim 1.
[0026] Further, in step S1: under nitrogen atmosphere, in a reaction tube equipped with a magnetic stirrer, 2 and tetrahydrofuran were added, then the temperature was lowered to -78°C and LDA was added dropwise. After the addition was completed, the mixture was stirred for 1 hour, and then an iodine solution in tetrahydrofuran was added and the mixture was moved to room temperature and stirred overnight. After the reaction was completed, saturated sodium thiosulfate was used for quenching, and ethyl acetate was used for extraction. Na 2 SO 4 Drying, concentration and purification by flash column chromatography gave a white solid, compound 3.
[0027] Furthermore, step S2 is: adding compounds 3, 4 and DIPEA to a sealed tube equipped with a magnetic stirrer, and then reflux for reaction for 3 days, cooling to room temperature, adding dichloromethane for dilution, and purifying by flash column chromatography to obtain a colorless oil, which is compound 5.
[0028] Furthermore, the step S3 is as follows: under a nitrogen atmosphere, 5 is dissolved in tetrahydrofuran, triethylamine and p-toluenesulfonyl chloride are added thereto at 0°C and reacted for 1 hour, MeOH is added to quench, the reaction is concentrated, and rapid column chromatography is performed to purify the compound to obtain a bright yellow solid 6.
[0029] Further, the step S4 is: in a nitrogen atmosphere, 6, 7, Pd 2 dba 3· CHCl 3 , DPPF, cesium carbonate and toluene were added to the reaction bottle and reacted at 80°C for 12 hours. After the reaction was completed, water was added to quench the reaction, and ethyl acetate was used for extraction. 2 SO 4 Drying, concentration and purification by flash column chromatography gave a white solid, compound 8.
[0030] Furthermore, the step S5 is: after dissolving compound 8 in toluene, triethoxysilane and tetraisopropyloxytitanium are added under an inert gas atmosphere, and then refluxed for 12 hours, and the crude product is purified by rapid column chromatography to obtain a yellow solid as the compound of structural formula (I).
[0031] On the other hand, the present invention provides a quinoline imidazole skeleton chiral nitrogen phosphine ligand compound of the present invention, its synthesis and use in catalyzing asymmetric catalytic reactions. Further, the asymmetric catalytic reaction includes: asymmetric hydrogenation, asymmetric transfer hydrogenation, asymmetric hydrosilylation, asymmetric hydroboration, asymmetric hydroamination, asymmetric hydrocyanation, asymmetric coupling, asymmetric cyclization, asymmetric cycloaddition reaction, asymmetric allylic substitution reaction, asymmetric Michael addition reaction, asymmetric epoxidation reaction, and asymmetric kinetic resolution reaction.
[0032] The ligand disclosed in the present invention is a novel chiral nitrogen phosphine ligand with a quinoline imidazole skeleton, and the ligand has the advantages of simple synthesis, easy modification, good stability, etc. The metal complex of the ligand exhibits very excellent catalytic activity and high enantioselectivity in the asymmetric hydrogenation reaction of ketones, and can efficiently reduce the dexmedetomidine precursor to dexmedetomidine through an asymmetric hydrogenation reaction, and further acidify to obtain the product dexmedetomidine hydrochloride, which has very important application value and very good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS
[0033] Figure 1 Dexmedetomidine hydrochloride HPLC chart DETAILED DESCRIPTION
[0034] The present invention is further described in detail below by specific embodiments in conjunction with the accompanying drawings. In the following embodiments, many detailed descriptions are intended to enable the present invention to be better understood. However, those skilled in the art can easily recognize that some of the features can be omitted in different situations, or can be replaced by other materials and methods. In some cases, some operations related to the present invention are not shown or described in the specification, in order to avoid the core part of the present invention being overwhelmed by too much description, and for those skilled in the art, it is not necessary to describe these related operations in detail, and they can fully understand the related operations based on the description in the specification and the general technical knowledge in the art.
[0035] In addition, the features, operations or characteristics described in the specification can be combined in any appropriate manner to form various implementation methods. At the same time, the steps or actions in the method description can also be interchanged or adjusted in a manner that is obvious to those skilled in the art. Therefore, the various sequences in the specification and the drawings are only for the purpose of clearly describing a certain embodiment and are not meant to be a required sequence unless otherwise specified that a certain sequence must be followed.
[0036] The serial numbers assigned to the components in this document, such as "first", "second", etc., are only used to distinguish the objects described and do not have any order or technical meaning.
[0037] The technical problem to be solved by the present invention is to provide a novel chiral nitrogen phosphine ligand with a quinoline imidazole skeleton, a synthesis method and application thereof. The novel chiral nitrogen phosphine ligand with a quinoline imidazole skeleton provided by the present invention forms a catalyst with metal rhodium and is applied to the asymmetric hydrogenation reaction of a dexmedetomidine precursor to obtain dexmedetomidine hydrochloride with good yield and excellent enantioselectivity.
[0038] The use of the catalyst of the present invention in catalyzing the asymmetric hydrogenation reaction of dexmedetomidine precursor, the reaction formula is as follows
[0039] As shown:
[0040]
[0041] In one embodiment, a method for synthesizing a catalyst may include: mixing a transition metal precursor and a ligand in a solvent to obtain a catalyst.
[0042] In one embodiment, the asymmetric hydrogenation reaction can be carried out in an alcohol solvent, toluene, dichloromethane or the like, preferably ethanol as the reaction solvent.
[0043] In one embodiment, the reaction hydrogen pressure may be 2-5 MPa.
[0044] In one embodiment, the amount of the catalyst used may be 0.01 molar equivalent of the structure a.
[0045] In one embodiment, the reaction time may be 12-36 hours.
[0046] In one embodiment, the reaction temperature may be 25-110°C, preferably 50°C.
[0047] The invention discloses dexmedetomidine hydrochloride obtained according to the synthesis method of the invention.
[0048] The invention uses a quinoline imidazole skeleton chiral nitrogen phosphine ligand and metal rhodium to form a catalyst, and utilizes an asymmetric catalytic hydrogenation method to achieve efficient and high-selective synthesis of dexmedetomidine hydrochloride.
[0049] The present invention is further described in detail by specific examples. The following examples are only used to further illustrate the present invention and should not be construed as limiting the present invention.
[0050] Ligand preparation example, taking ligand L21 as an example:
[0051]
[0052] In step S1: under nitrogen atmosphere, 2-chloroquinoline (1.63 g, 10 mmol) and 50 mL of tetrahydrofuran were added to a reaction tube equipped with a magnetic stirrer, and then the temperature was lowered to -78°C and freshly prepared LDA (1.0 eq.) was added dropwise. After the addition was completed, the mixture was stirred for 1 h, and then a tetrahydrofuran solution of iodine (3.4 g, 12 mmol) was added and the mixture was moved to room temperature and stirred overnight. After the reaction was completed, saturated sodium thiosulfate (5 mL) was used for quenching, and ethyl acetate (3×20 mL) was used for extraction. Na 2 SO 4 The residue (10 g) was dried, concentrated and purified by flash column chromatography to give a white solid as compound 3 (2.3 g, 80% yield).
[0053] Furthermore, step S2 is as follows: after adding compound 3 (2.3 g, 8 mmol), 4 (2.2 g, 16 mmol) and DIPEA (3 mL) into a sealed tube equipped with a magnetic stirrer and reacting under reflux for 3 days, 10 mL of dichloromethane is added to dilute the mixture after cooling to room temperature, and the mixture is purified by flash column chromatography to obtain a colorless oil, which is compound 5 (3.4 g, 88% yield).
[0054] Furthermore, the step S3 is as follows: under a nitrogen atmosphere, 5 (3.4 g, 7 mmol) is dissolved in 30 mL of tetrahydrofuran, triethylamine (1.4 g, 14 mmol) and p-toluenesulfonyl chloride (1.1 g, 9.1 mmol) are added thereto at 0°C and reacted for 1 h, MeOH is added to quench, the mixture is concentrated, and purified by rapid column chromatography to obtain a bright yellow solid 6 (2.0 g, 59% yield).
[0055] Further, the step S4 is: under a nitrogen atmosphere, 6 (1.5 g, 4 mmol), 7 (1.7 g, 4 mmol), Pd 2 dba 3· CHCl 3 (112 mg, 0.1 mmol), DPPF (110 mg, 0.2 mmol), cesium carbonate (2.6 g, 8 mmol) and 20 mL of toluene were added to the reaction bottle and reacted at 80 °C for 12 h. After the reaction was completed, 1 mL of water was added to quench, and 3×20 mL of ethyl acetate was used for extraction. 2 SO 4 The residue (20 g) was dried, concentrated and purified by flash column chromatography to give a white solid as compound 8 (1.87 g, 70% yield).
[0056] Furthermore, the step S5 is: after dissolving compound 8 (670 mg, 1 mmol) in 10 mL of toluene, triethoxysilane (320 mg, 2 mmol) and tetraisopropyloxytitanium (570 mg, 2 mmol) are added under an inert gas atmosphere, and the mixture is refluxed for 12 h. The crude product is purified by rapid column chromatography to obtain a yellow solid as a compound of structural formula (I) (580 mg, 90% yield).
[0057] The following are some of the product ligand NMR data:
[0058] The NMR data of product L20 are: 1 H NMR (400 MHz, CDCl 3 )δ7.57(td,J=7.8,5.6Hz,2H),7.44–7.31(m,3H),7.24–7.10(m,8H),7.01–6.96(m,2H),6.93(t,J=7.5Hz,1H) ,6.76–6.67(m,2H),5.45(dd,J=11.5,7.2Hz,1H),4.40(dd,J=11.6,10.0Hz,1H),3.83(dd,J=10.0,7.2Hz,1H). 13 C NMR (100 MHz, CDCl 3)δ163.56,149.44,140.69,139.33,138.04,137.87,129.12,128.94,128.51,1 27.74,127.68,127.62,126.36,124.66,123.44,119.96,116.61,69.94,55.31. 31 P NMR (162 MHz, CDCl 3 )δ-17.98.HRMS(ESI)calculated for[C 29 H 22 F 2 N 2 P] + (M+H + ),requires m / z 467.1483,found m / z 467.1487.
[0059] The NMR data of product L21 are: 1 H NMR (400 MHz, CDCl 3 )δ7.51(d,J=2.2Hz,1H),7.49–7.40(m,3H),7.36–7.22(m,3H),7.17–7.06(m,4H),6.95–6.85(m,3H),6.80(d,J=3.4Hz,1H),6.69 (d,J=8.1Hz,1H),5.47(dd,J=11.5,7.3Hz,1H),4.39(dd,J=11.5,9.9Hz,1H),3.78(dd,J=9.9,7.3Hz,1H),1.28(d,J=4.1Hz,36H). 13 C NMR (100 MHz, CDCl 3 )δ154.02,149.38,140.69,139.33,137.84,135.14,130.95,129.12,128.51,127.74, 127.68,127.62,126.36,124.66,123.44,123.18,119.96,69.94,55.31,34.95,31.28. 31 P NMR (162 MHz, CDCl 3 )δ-12.98.HRMS(ESI)calculated for[C 45 H 56 N 2 P] + (M+H +),requires m / z655.4176,foundm / z655.4177.
[0060] Application Examples
[0061]
[0062] Synthetic b-form dexmedetomidine hydrochloride
[0063] In a hydrogenation bottle, compound a (40 mg, 0.2 mmol), [Rh(cod)Cl] 2 , (1 mg, 0.002 mmol), L21 and 2 mL of ethanol were then transferred to a hydrogenation reactor, nitrogen was replaced three times, hydrogen was replaced three times, the pressure was set to 3 atm, and the reaction was carried out at 50°C for 12 hours. Hydrogen was then slowly released, and an excess of 15% hydrochloric acid ethanol solution was added. After the addition was completed, the mixture was stirred at 25°C for 1 hour, and the solvent was concentrated under reduced pressure at 35°C to obtain the product dexmedetomidine hydrochloride b (40.5 mg, 86% yield, 98% ee).
[0064] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation methods of the present invention. For ordinary technical users in the relevant field, other different forms of changes or modifications can be made on the basis of the above description. It is not necessary and impossible to list all the implementation methods here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the claims of the present invention.
Claims
1. A novel chiral nitrogen phosphine ligand compound with quinoline imidazole skeleton, whose molecular structure formula (I) is as follows: R 1 , R 2 , R 3 Selected from aryl, such as phenyl, naphthyl, 9-anthryl; heteroaryl, such as thiophene, furan; electron-withdrawing substituents, such as trifluoromethyl, cyano, nitro; electron-donating substituents, such as methoxy, ethoxy, benzyloxy, methyl, ethyl, isopropyl, tert-butyl; halogen, such as fluorine, chlorine, bromine; R 4 Selected from alkyl, such as tert-butyl, isopropyl, adamantyl, cycloalkyl, heterocycloalkyl; aryl, such as phenyl, 2,4,6-tri(methyl)phenyl, 2,4,6-tri(isopropyl)phenyl, 3,5-di(trifluoromethyl)phenyl, 3,5-di(tert-butyl)phenyl, 3,5-di(methyl)phenyl, 3,5-di(ethyl)phenyl, naphthyl, 9-anthryl; heteroaryl, such as thiophene, furan; R 5 Selected from alkyl groups such as methyl, ethyl, propyl, isopropyl, tert-butyl, benzyl, cycloalkyl, heterocycloalkyl; aryl groups such as phenyl, o-tolyl, 3-chlorophenyl, 4-fluorophenyl, 4-phenylphenyl, 2-naphthyl.
2. According to claim 1, the chiral nitrogen phosphine ligand compound of quinolinimidazole skeleton is characterized in that: The quinoline imidazole skeleton chiral nitrogen phosphine ligand compound is selected from one of the structural formulas L1-L39; The quinoline imidazole skeleton chiral nitrogen phosphine ligand compound is of R configuration or S configuration.
3. A method for synthesizing the chiral nitrogen phosphine ligand compound with quinolinimidazole skeleton according to any one of claims 1 to 2, comprising the following steps: S1, iodine compound 2 under inert atmosphere and low temperature conditions to obtain compound 3; S2, coupling compound 3 with chiral amine alcohol 4 under inert atmosphere and high temperature to obtain compound 5; S3, reacting compound 5 with methanesulfonyl chloride at low temperature, followed by intramolecular cyclization to generate compound 6; S4, compound 6 undergoes CP bond coupling reaction with a diaryl or dialkylphosphine oxide compound 7 under palladium catalysis, DPPP as a ligand, cesium carbonate as a base, and heating conditions to obtain compound 8; S5. Compound 8 is subjected to silanol reduction under high temperature conditions to generate the target product represented by formula (I). in, Each R 1 , R 2 , R 3 , R 4 , R 5 Has the meaning as defined in claim 1.
4. The use of the chiral nitrogen phosphine ligand compound with quinoline imidazole skeleton according to any one of claims 1 to 3, characterized in that: The quinoline imidazole skeleton chiral nitrogen phosphine ligand compound is used as a ligand for asymmetric hydrogenation reaction to construct a dexmedetomidine hydrochloride drug molecule.
5. The use according to claim 4, characterized in that: Compound a undergoes a reduction reaction with hydrogen under the catalysis of a catalyst and a ligand to obtain dexmedetomidine hydrochloride. The reaction formula is as follows:
6. The method according to claim 5, characterized in that: The catalyst is at least one of (1,5-cyclooctadiene) rhodium chloride (I) dimer, di(ethylene) rhodium chloride dimer, and rhodium trichloride; The molar ratio of the catalyst to the ligand is 1:1 to 1:1.5, and the amount of the catalyst is 0.001-0.05 equivalents; The reaction solvent is at least one of an aromatic hydrocarbon solvent, an ester solvent, and a chlorinated solvent; the aromatic hydrocarbon solvent is preferably at least one of toluene, benzene, and trifluorotoluene; the ester solvent is preferably ethyl acetate; the chlorinated solvent is preferably at least one of dichloromethane and dichloroethane; The reaction hydrogen pressure can be 1-10Mpa; The reaction time can be 1-36h; The reaction temperature may be 25-110°C.