CN108822101B - Method for synthesizing benzhydrylquinuclidinone by Michael addition - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 17
- LCHVZSFLSFTBHH-UHFFFAOYSA-N 3-benzhydryl-1-azabicyclo[2.2.2]octan-2-one Chemical compound C(C1=CC=CC=C1)(C1=CC=CC=C1)C1C(N2CCC1CC2)=O LCHVZSFLSFTBHH-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 238000006845 Michael addition reaction Methods 0.000 title claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 239000002994 raw material Substances 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- PQSXXBSNZJLXMQ-UHFFFAOYSA-N 2-benzhydryl-1-azabicyclo[2.2.2]octan-3-one Chemical compound O=C1C(CC2)CCN2C1C(C=1C=CC=CC=1)C1=CC=CC=C1 PQSXXBSNZJLXMQ-UHFFFAOYSA-N 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 14
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 13
- 239000012043 crude product Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
- 239000012074 organic phase Substances 0.000 claims description 11
- 239000007818 Grignard reagent Substances 0.000 claims description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims description 10
- 150000004795 grignard reagents Chemical class 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- UYNAFHNUGOEVFE-UHFFFAOYSA-M [Cl-].C1CCOC1.[Mg+]C1=CC=CC=C1 Chemical compound [Cl-].C1CCOC1.[Mg+]C1=CC=CC=C1 UYNAFHNUGOEVFE-UHFFFAOYSA-M 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- RBGFDYWXBIXLSF-RAXLEYEMSA-N (2z)-2-benzylidene-1-azabicyclo[2.2.2]octan-3-one Chemical compound O=C1C(CC2)CCN2\C1=C/C1=CC=CC=C1 RBGFDYWXBIXLSF-RAXLEYEMSA-N 0.000 claims description 8
- 239000008346 aqueous phase Substances 0.000 claims description 8
- 238000001308 synthesis method Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 6
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 5
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 5
- 229940045803 cuprous chloride Drugs 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- SNIYGPDAYLBEMK-UHFFFAOYSA-M [I-].[Mg+]C1=CC=CC=C1 Chemical compound [I-].[Mg+]C1=CC=CC=C1 SNIYGPDAYLBEMK-UHFFFAOYSA-M 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 claims description 4
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 2
- 230000007613 environmental effect Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- QMMFVYPAHWMCMS-UHFFFAOYSA-N dimethyl monosulfide Natural products CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 1
- PGVSXRHFXJOMGW-YBZGWEFGSA-N (2s,3s)-2-benzhydryl-n-[(5-tert-butyl-2-methoxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine;2-hydroxypropane-1,2,3-tricarboxylic acid;hydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O.COC1=CC=C(C(C)(C)C)C=C1CN[C@@H]1[C@H](C(C=2C=CC=CC=2)C=2C=CC=CC=2)N2CCC1CC2 PGVSXRHFXJOMGW-YBZGWEFGSA-N 0.000 description 1
- ZKMZPXWMMSBLNO-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-one Chemical compound C1CC2C(=O)CN1CC2 ZKMZPXWMMSBLNO-UHFFFAOYSA-N 0.000 description 1
- RFDPHKHXPMDJJD-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-one;hydron;chloride Chemical compound Cl.C1CC2C(=O)CN1CC2 RFDPHKHXPMDJJD-UHFFFAOYSA-N 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 102100024304 Protachykinin-1 Human genes 0.000 description 1
- 101800003906 Substance P Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229940069233 cerenia Drugs 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- GEOWCLRLLWTHDN-UHFFFAOYSA-N phenyl formate Chemical compound O=COC1=CC=CC=C1 GEOWCLRLLWTHDN-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing benzhydryl quinuclidinone by Michael addition, belonging to the field of organic synthesis. The invention takes (Z) -2-benzylidene quinine-3-ketone as a raw material, and obtains a 2- (diphenylmethyl) quinuclidine-3-ketone product through Michael addition reaction in the presence of a cuprous catalyst. Under the optimized reaction condition, the yield can reach 85%, and the purity is higher than 99%. The preparation method of the benzhydryl quinuclidinone solves the problems of low yield, low selectivity, environmental friendliness and the like in the existing method.
Description
Technical Field
The invention relates to a synthesis method of benzhydryl quinuclidinone, wherein a synthesis method of Michael addition is adopted, and belongs to the technical field of organic synthesis.
Background
The benzhydrylquinuclidinone system is named as 2- (benzhydryl) quinuclidin-3-one, the English name is 2-benzathine-3-one, the benzhydrylquinuclidin-3-one is a key intermediate of veterinary drug maririptan, and the structural formula is as follows:
currently, cerini (Cerenia) on the market contains malupitan citrate as an active ingredient, and is a large animal antiemetic produced and sold by feverre corporation in the united states. Marropin is an anti-receptor agent of neurokinin type 1 (NK1), acts on central nervous system by inhibiting substance P (key neurotransmitter causing emesis), and can inhibit peripheral and central emesis.
The following methods are reported for the synthesis of benzhydrylquinuclidinone:
the first method is that the US3560510 discloses a method, under the condition of not adding catalyst, benzene with carcinogenicity is used as solvent, and the yield is only 51.8%.
The second method is a document of European Journal of Medicinal Chemistry 119(2016)231-249, cuprous iodide is used as a catalyst, benzene is used as a solvent, the yield is only 3%, the main product is byproduct alcohol (shown in a structure below), and the purification adopts a column, so that the operation is not easy.
Method three, US2005075473 discloses another production method, using cuprous bromide dimethyl sulfide as catalyst, but does not disclose yield. The catalyst has strong odor and is not friendly to the environment due to the sulfur-containing compound, and the environment-friendly pressure is provided for the scale-up production.
Therefore, a method for synthesizing 2- (benzhydryl) quinuclidin-3-one with high yield and environmental friendliness, which is suitable for industrial production, is needed in the field.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a method for preparing benzhydrylquinuclidinone by Michael addition, which has the advantages of simple and convenient operation, high yield and low pollution and is suitable for large-scale commercial production.
The invention provides a method for synthesizing benzhydryl quinuclidinone by Michael addition, which comprises the steps of mixing a raw material (Z) -2-benzylidene quinuclidin-3-one, a Grignard reagent and a catalyst in a reaction solvent, and carrying out Michael addition reaction to generate 2- (benzhydryl) quinuclidin-3-one, wherein the catalyst is one of cuprous iodide, cuprous bromide or cuprous chloride, and the molar ratio of the raw material (Z) -2-benzylidene quinuclidin-3-one to the catalyst is 1: 0.01-0.30. The reaction formula is as follows:
further, the molar ratio of the starting material (Z) -2-benzylidene quinin-3-one to the catalyst was 1: 0.10.
Further, the reaction solvent is one of toluene, diethyl ether, methyl tert-butyl ether, tetrahydrofuran or methyl tetrahydrofuran.
Further, the Grignard reagent is one of phenylmagnesium chloride, phenylmagnesium bromide, or phenylmagnesium iodide.
Furthermore, the molar ratio of the raw material (Z) -2-benzylidene quinine-3-one to the format reagent is 1: 1.2-3.0, and preferably 1: 1.7.
Further, the mass-to-volume ratio (g/mL) of the raw material (Z) -2-benzylidene quinine-3-one to the reaction solvent is 1: 8-20.
Further, the reaction temperature is between room temperature and 50 ℃, and the reaction time is 8-24 hours.
Further, the synthesis method comprises the following steps: mixing (Z) -2-benzylidene quinine-3-one, a Grignard reagent and a catalyst in a reaction solvent, reacting for 8-24 hours at room temperature to 50 ℃, then adding an ammonium chloride aqueous solution, stirring, separating liquid, carrying out back extraction on an aqueous phase by using an organic solvent, combining organic phases, washing by using water and a saturated sodium chloride solution, drying and concentrating to obtain a crude product, and crystallizing by using absolute ethyl alcohol to obtain the 2- (benzhydryl) quinuclidine-3-one, wherein the reaction solvent is one of toluene, diethyl ether, methyl tert-butyl ether, tetrahydrofuran or methyl tetrahydrofuran, the Grignard reagent is one of phenyl magnesium chloride, phenyl magnesium bromide or phenyl magnesium iodide, the catalyst is one of cuprous iodide, cuprous bromide or cuprous chloride, the molar ratio of the raw material (Z) -2-benzylidene quinine-3-one to the Grignard reagent is 1: 1.2-3.0, the molar ratio of the raw material (Z) -2-benzylidene quinine-3-ketone to the catalyst is 1: 0.01-0.30.
Further, the synthesis method comprises the following steps: weighing (Z) -2-benzylidene quinine-3-one (9.0g), adding tetrahydrofuran (110mL), and stirring to dissolve to obtain a solution A; 2.0M phenylmagnesium chloride tetrahydrofuran solution (36mL), cuprous bromide (602mg) is added, the temperature is reduced to-5 ℃ under the protection of nitrogen, solution A is dropwise added into the mixture, the mixture naturally returns to room temperature after the addition, the reaction is carried out for 15 hours, the reaction solution is slowly poured into saturated ammonium chloride aqueous solution (40mL), the mixture is stirred for 10 minutes, liquid separation is carried out, the aqueous phase is extracted twice by ethyl acetate, the organic phase is combined, washed by water and saturated sodium chloride solution, dried by anhydrous sodium sulfate and concentrated in vacuum, a crude product is obtained, and the crude product is crystallized by anhydrous ethanol, so that 2- (benzhydryl) quinuclidin-3-one (10.1g) is obtained.
The invention also provides application of the synthesis method in preparation of the maleopiptan or the derivative thereof.
The invention has the beneficial effects that:
(1) under the participation of the catalyst, the by-product of the Grignard reaction is less than 10 percent, the purity after crystallization is more than 99 percent, and the yield is as high as 85 percent.
(2) The catalyst used in the invention has the advantages of small dosage, low price, no dimethyl sulfide complex, environmental protection and no environmental protection pressure of amplified production.
(3) The raw material (Z) -2-benzylidene quinine-3-ketone used in the invention can be synthesized from 3-quinuclidinone and benzaldehyde in the presence of sodium hydroxide and ethanol, the yield is more than 90%, and 3-quinuclidinone hydrochloride is a common industrial product, can be purchased in large quantities on the market and has low price.
(4) The phenyl format reagent used in the invention is a common industrialized product, can be purchased in large quantities in the market, and has low price. In summary, the invention has the advantages of cheap and easily available chemical raw materials, mild reaction conditions, high yield, good purity, simple operation, little influence on environment and no environmental protection pressure.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention.
The structure of the compound is nuclear magnetic resonance (1H NMR、13C NMR) or MS.
The term "room temperature" according to the present invention means a temperature between 10 and 25 ℃.
Example 1
(Z) -2-Benzylidenequinin-3-one (9.0g) was weighed into a 250mL beaker, tetrahydrofuran (110mL) was added, and the mixture was dissolved with stirring to give solution A, which was transferred to a dropping funnel. 2.0M phenylmagnesium chloride tetrahydrofuran solution (36mL) was added to a 250mL three-necked flask, cuprous bromide (602mg) was added, the temperature was reduced to-5 ℃ under nitrogen protection, solution A was added dropwise, the addition was naturally restored to 25 ℃, reaction was carried out for 15 hours, the reaction solution was slowly poured into saturated ammonium chloride solution (40mL), stirring was carried out for 10 minutes, liquid separation was carried out, the aqueous phase was extracted twice with ethyl acetate, the organic phase was combined, washed with water, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, vacuum-concentrated to obtain a crude product, which was crystallized with anhydrous ethanol to obtain 2- (benzhydryl) quinuclidin-3-one (10.5g), yield: 85 percent and 99.6 percent of HPLC.1HNMR(400MHz,CDCl3)：δ(ppm)＝7.394-7.133，(m，10H,Ar-H)，4.524-4.503(d,1H,J＝8.4Hz),3.986-3.966(d,1H,J＝8Hz),3.101-3.022(m,2H),2.649-2.505(m,2H),2.427-2.397(m,1H),2.035-1.896(m,4H)；13CNMR(400MHz,CDCl3):δ(ppm)＝206.0,142.0,141.1,127.4,125.5,71.5,49.3,48.6,40.8,39.8,25.6,24.7；ESI-MS:m/z＝292(M+H)+。
Example 2
(Z) -2-benzylidene-quinin-3-one (10.0g) was weighed into a 250mL beaker, tetrahydrofuran (80mL) was added, and the mixture was dissolved with stirring to give solution A, which was transferred to the dropping funnel. 2.0M phenylmagnesium chloride tetrahydrofuran solution (28mL) was added to a 250mL three-necked flask, cuprous bromide (674mg) was added, the temperature was reduced to-5 ℃ under nitrogen protection, solution A was added dropwise, the addition was naturally restored to 25 ℃, reaction was carried out for 12 hours, the reaction solution was slowly poured into saturated ammonium chloride solution (45mL), stirring was carried out for 10 minutes, liquid separation was carried out, the aqueous phase was extracted twice with ethyl acetate, the organic phase was combined, washed with water, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, vacuum-concentrated to give a crude product, which was crystallized with anhydrous ethanol to give 2- (benzhydryl) quinuclidin-3-one (10.9g), yield: 80%, HPLC: 99.2%, NMR and MS data as in example 1.
Example 3
(Z) -2-benzylidene-quinin-3-one (10.0g) was weighed into a 500mL beaker, tetrahydrofuran (200mL) was added, and the mixture was dissolved with stirring to give solution A, which was transferred to a dropping funnel. 2.0M phenylmagnesium chloride tetrahydrofuran solution (70mL) was added to a 500mL three-necked flask, cuprous bromide (674mg) was added, the temperature was reduced to-5 ℃ under nitrogen protection, solution A was added dropwise, the addition was naturally restored to 25 ℃, reaction was carried out for 24 hours, the reaction solution was slowly poured into saturated ammonium chloride solution (55mL), stirring was carried out for 10 minutes, liquid separation was carried out, the aqueous phase was extracted twice with ethyl acetate, the organic phase was combined, washed with water, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, vacuum-concentrated to give a crude product, which was crystallized with anhydrous ethanol to give 2- (benzhydryl) quinuclidin-3-one (11.2g), yield: 82%, HPLC: 99.2%, NMR and MS data as in example 1.
Example 4
(Z) -2-benzylidene-quinin-3-one (10.0g) was weighed into a 250mL beaker, methyltetrahydrofuran (120mL) was added, and the mixture was dissolved with stirring to give solution A, which was transferred to a dropping funnel. Adding 2.0M phenylmagnesium chloride tetrahydrofuran solution (40mL) into a 250mL three-necked flask, adding cuprous bromide (67mg), cooling to-5 ℃ under the protection of nitrogen, dropwise adding solution A, heating to 50 ℃ after adding, reacting for 8 hours, slowly pouring reaction liquid into saturated ammonium chloride solution (45mL), stirring for 10 minutes, separating liquid, extracting the water phase twice with ethyl acetate, combining organic phases, washing with water, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, concentrating in vacuum to obtain a crude product, crystallizing with anhydrous ethanol to obtain 2- (benzhydryl) quinuclidin-3-one (10.9g), and obtaining the yield: 80%, HPLC: 99.1%, NMR and MS data as in example 1.
Example 5
(Z) -2-benzylidene-quinin-3-one (10.0g) was weighed into a 250mL beaker, diethyl ether (120mL) was added, and the solution A was dissolved with stirring and transferred to the dropping funnel. Adding 2.0M phenylmagnesium chloride tetrahydrofuran solution (40mL) into a 250mL three-necked flask, adding cuprous bromide (2.0g), cooling to-5 ℃ under the protection of nitrogen, dropwise adding the solution A, naturally recovering to 25 ℃ after adding, reacting for 15 hours, slowly pouring the reaction solution into saturated ammonium chloride solution (45mL), stirring for 10 minutes, separating, extracting the aqueous phase twice with ethyl acetate, combining the organic phases, washing with water, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, concentrating in vacuum to obtain a crude product, crystallizing with anhydrous ethanol to obtain 2- (benzhydryl) quinuclidin-3-one (11.1g), and obtaining the yield: 81%, HPLC: 99.5%, NMR and MS data as in example 1.
Example 6
The same procedure of example 1 was repeated except for using (Z) -2-benzylidene-quinuclidin-3-one (9.0g) as a solvent methyl tert-butyl ether (120mL) and cuprous chloride as a catalyst (418mg) to give 2- (benzhydryl) quinuclidin-3-one (9.0g) in yield: 73%, HPLC: 99.2%, NMR and MS data as in example 1.
Example 7
The same procedure as in example 1 was repeated except for using (Z) -2-benzylidene-quinuclidin-3-one (9.0g) and cuprous iodide as a catalyst to give 2- (benzhydryl) quinuclidin-3-one (9.5g) in yield: 77%, HPLC: 99.3%, NMR and MS data as in example 1.
Example 8
(Z) -2-benzylidene-quinin-3-one (10.0g) was weighed into a 250mL beaker, toluene (130mL) was added, and dissolved with stirring to give solution A, which was transferred to the addition funnel. 2.0M phenylmagnesium chloride tetrahydrofuran solution (40mL) was added into a 250mL three-necked flask, cuprous bromide (674mg) was added, the temperature was reduced to-5 ℃ under the protection of nitrogen, solution A was added dropwise, the addition was naturally restored to 25 ℃, reaction was carried out for 15 hours, the reaction solution was slowly poured into saturated ammonium chloride solution (45mL), stirring was carried out for 10 minutes, liquid separation was carried out, the aqueous phase was extracted twice with toluene, the organic phase was combined, washed with water, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, vacuum-concentrated to obtain a crude product, which was crystallized with anhydrous ethanol to obtain 2- (benzhydryl) quinuclidin-3-one (10.9g), yield: 80%, HPLC: 99.3%, NMR and MS data as in example 1.
Example 9
(Z) -2-benzylidene-quinin-3-one (1kg) was weighed into a 2.5L beaker, tetrahydrofuran (1.2L) was added, stirred and dissolved to give solution A, which was transferred to the dropping funnel. Adding 2.0M phenylmagnesium chloride tetrahydrofuran solution (4L) into a 10L reaction kettle, adding cuprous bromide (67g), cooling to-5 ℃ under the protection of nitrogen, dropwise adding solution A, naturally recovering to 25 ℃ after adding, reacting for 15 hours, slowly pouring the reaction solution into saturated ammonium chloride solution (4.5L), stirring for 10 minutes, separating liquid, extracting the water phase twice with ethyl acetate, combining the organic phase, washing with water, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, concentrating in vacuum to obtain a crude product, crystallizing with anhydrous ethanol to obtain 2- (benzhydryl) quinuclidin-3-one (1.16kg), and obtaining the yield: 85%, HPLC: 99.5%, NMR and MS data as in example 1.
In conclusion, the method for synthesizing 2- (benzhydryl) quinuclidin-3-one provided by the invention has the advantages that the yield is up to 85%, the purity is higher than 99%, and the method is suitable for mass production and industrialization.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. A method for synthesizing benzhydryl quinuclidinone through Michael addition is characterized in that a raw material (Z) -2-benzylidene quinuclidin-3-one, a Grignard reagent and a catalyst are mixed in a reaction solvent to generate Michael addition reaction to generate 2- (benzhydryl) quinuclidin-3-one, wherein the catalyst is one of cuprous iodide, cuprous bromide or cuprous chloride, the molar ratio of the raw material (Z) -2-benzylidene quinuclidin-3-one to the catalyst is 1: 0.01-0.30, the reaction solvent is one of toluene, diethyl ether, methyl tert-butyl ether, tetrahydrofuran or methyl tetrahydrofuran, the Grignard reagent is one of phenylmagnesium chloride, phenylmagnesium bromide or phenylmagnesium iodide, the molar ratio of the raw material (Z) -2-benzylidene quinuclidin-3-one to the Grignard reagent is 1: 1.2-3.0, the mass-volume ratio of the raw material (Z) -2-benzylidene quinine-3-one to the reaction solvent is 1: 8-20 g/mL, the reaction temperature is from room temperature to 50 ℃, and the reaction time is 8-24 hours.
2. The synthesis method according to claim 1, wherein the molar ratio of the raw material (Z) -2-benzylidene quinin-3-one to the catalyst is 1: 0.10.
3. The synthesis method according to claim 1, wherein the molar ratio of the raw material (Z) -2-benzylidene quinin-3-one to the format reagent is 1: 1.7.
4. The synthetic method according to claim 1, wherein (Z) -2-benzylidene quinuclidin-3-one, Grignard reagent and catalyst are mixed in a reaction solvent, after the reaction is carried out for 8-24 hours at room temperature to 50 ℃, ammonium chloride aqueous solution is added, the mixture is stirred and separated, the aqueous phase is subjected to back extraction by an organic solvent, organic phases are combined, the mixture is washed by water and saturated sodium chloride solution, dried and concentrated to obtain a crude product, the crude product is crystallized by absolute ethyl alcohol to obtain the 2- (benzhydryl) quinuclidin-3-one, wherein the reaction solvent is one of toluene, diethyl ether, methyl tert-butyl ether, tetrahydrofuran or methyl tetrahydrofuran, the Grignard reagent is one of phenylmagnesium chloride, phenylmagnesium bromide or phenylmagnesium iodide, and the catalyst is one of cuprous iodide, cuprous bromide or cuprous chloride, the molar ratio of the raw material (Z) -2-benzylidene quinine-3-one to the format reagent is 1: 1.2-3.0, and the molar ratio of the raw material (Z) -2-benzylidene quinine-3-one to the catalyst is 1: 0.01-0.30.
5. The synthesis method according to claim 1, wherein 9.0g of (Z) -2-benzylidene-quinin-3-one is weighed, 110mL of tetrahydrofuran is added, and the solution A is obtained after stirring and dissolving; 36mL of 2.0M phenylmagnesium chloride tetrahydrofuran solution is added with 602mg of cuprous bromide, the temperature is reduced to-5 ℃ under the protection of nitrogen, the solution A is dropwise added, the solution is naturally recovered to the room temperature after the addition, the reaction is carried out for 15 hours, the reaction solution is slowly poured into 40mL of saturated ammonium chloride aqueous solution, the stirring is carried out for 10 minutes, liquid separation is carried out, the water phase is extracted twice by ethyl acetate, the organic phase is combined, the washing is carried out by saturated sodium chloride solution, the drying is carried out by anhydrous sodium sulfate, the vacuum concentration is carried out, the crude product is obtained, and the anhydrous ethanol is used for crystallization, so that 10.1g of 2- (.
6. Use of the synthetic method according to any one of claims 1 to 5 for the preparation of maropiptan or a derivative thereof.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US3560510A (en) * | 1969-03-05 | 1971-02-02 | Aldrich Chem Co Inc | 2-benzhydrylquinuclidines |
| US5716965A (en) * | 1991-05-22 | 1998-02-10 | Pfizer Inc. | Substituted 3-aminoquinuclidines |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US3560510A (en) * | 1969-03-05 | 1971-02-02 | Aldrich Chem Co Inc | 2-benzhydrylquinuclidines |
| US5716965A (en) * | 1991-05-22 | 1998-02-10 | Pfizer Inc. | Substituted 3-aminoquinuclidines |
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