CN108822101A - A kind of method of Michael's addition synthesis benzhydryl-quinuclidine ketone - Google Patents
A kind of method of Michael's addition synthesis benzhydryl-quinuclidine ketone Download PDFInfo
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- CN108822101A CN108822101A CN201810992880.3A CN201810992880A CN108822101A CN 108822101 A CN108822101 A CN 108822101A CN 201810992880 A CN201810992880 A CN 201810992880A CN 108822101 A CN108822101 A CN 108822101A
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- Prior art keywords
- ketone
- quinine
- benzylidene
- quinuclidine
- solution
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- 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
Abstract
The invention discloses a kind of methods of Michael's addition synthesis benzhydryl-quinuclidine ketone, belong to organic synthesis field.The present invention with（Z）- 2- benzylidene quinine -3- ketone is that raw material obtains 2- (diphenyl methyl) quinuclidine -3- ketone product by mikey addition reaction in the presence of cuprous catalysis agent.Under preferred reaction condition, for yield up to 85%, purity is higher than 99%.Benzhydryl-quinuclidine ketone preparation method of the present invention solves the problems such as yield present in existing method is low, selectivity is low, unfriendly to environment.
Description
Technical field
The present invention relates to a kind of synthetic methods of benzhydryl-quinuclidine ketone, wherein the synthesis side of the Michael's addition used
Method belongs to technical field of organic synthesis.
Background technique
Benzhydryl-quinuclidine ketone systematic naming method is 2- (benzhydryl) quinuclidine -3- ketone, English name 2-
Benzhydrylquinuclidin-3-one, is the smooth key intermediate of veterinary drug horse sieve, and structural formula is as follows：
Sai Ruining on sale (Cerenia) currently on the market, effective component are the smooth citrate of horse sieve, are Pfizers
A kind of larger animal antiemetic of company's production and sales.It is the receptor anticaking agent of 1 type neurokinin (NK1) that horse sieve is smooth, can
By inhibit Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (nauseant key neurotransmitter) act on central nervous system, can inhibit periphery property and in
Pivot vomiting.
There is following several method about the synthesis report of benzhydryl-quinuclidine ketone at present：
Method one is that United States Patent (USP) US3560510 discloses a kind of method, under conditions of catalyst is not added, uses tool
There is the benzene of carcinogenicity to make solvent, yield is only 51.8%.
Method two is 119 (2016) 231-249 of document European Journal of Medicinal Chemistry,
Catalyst is done using cuprous iodide, benzene makees solvent, and yield is only 3%, and primary product is by-product alcohol (structure is as follows), and
Purifying used column, not easy to operate.
Method three is that patent US2005075473 discloses another production method, uses cuprous bromide dimethyl sulphide to urge
Agent, but undisclosed yield.This catalyst has stronger stink, amplification life unfriendly to environment due to being sulfur-containing compound
Production has environmental protection pressure.
Therefore, this field needs a kind of high income, environmental-friendly, is suitble to synthesis 2- (benzhydryl) Kui of industrialized production
The method of Ning Huan -3- ketone.
Summary of the invention
The present invention aiming at the shortcomings in the prior art, proposes the side that a kind of mikey addition prepares benzhydryl-quinuclidine ketone
Method, this method is simple to operate, high income, pollutes low, suitable large-scale commercial production.
The present invention provides a kind of methods of Michael's addition synthesis benzhydryl-quinuclidine ketone, will in reaction dissolvent
Raw material (Z) -2- benzylidene quinine -3- ketone, grignard reagent and catalyst mixing, occur Michael addition reaction and generate 2- (two
Benzyl) quinuclidine -3- ketone, wherein catalyst is one kind of cuprous iodide, cuprous bromide or stannous chloride, raw material (Z) -2- benzene
The molar ratio of methylene quinine -3- ketone and catalyst is 1:0.01~0.30.Reaction equation is as follows：
Further, the molar ratio of raw material (Z) -2- benzylidene quinine -3- ketone and catalyst is 1:0.10.
Further, reaction dissolvent is toluene, ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran or methyltetrahydrofuran
It is a kind of.
Further, grignard reagent is one kind of phenyl-magnesium-chloride, phenyl-magnesium-bromide or phenyl magnesium iodide.
Further, the molar ratio of raw material (Z) -2- benzylidene quinine -3- ketone and grignard reagent is 1:1.2~3.0, it is excellent
It is selected as 1:1.7.
Further, the mass volume ratio (g/mL) of raw material (Z) -2- benzylidene quinine -3- ketone and reaction dissolvent is 1:8
~20.
Further, reaction temperature is room temperature to 50 DEG C, and the reaction time is 8~24 hours.
Further, synthetic method is：In reaction dissolvent by (Z) -2- benzylidene quinine -3- ketone, grignard reagent, urge
Agent mixing, room temperature add aqueous ammonium chloride solution to after react 8~24 hours at 50 DEG C, stirring, liquid separation, and water phase is with organic
Solvent back extraction, merges organic phase, wash with water, saturated sodium chloride solution, dries, is concentrated to get crude product, then with dehydrated alcohol knot
Crystalline substance is to get 2- (benzhydryl) quinuclidine -3- ketone, and wherein reaction dissolvent is toluene, ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran
Or one kind of methyltetrahydrofuran, grignard reagent are one kind of phenyl-magnesium-chloride, phenyl-magnesium-bromide or phenyl magnesium iodide, catalysis
Agent is one kind of cuprous iodide, cuprous bromide or stannous chloride, raw material (Z) -2- benzylidene quinine -3- ketone and grignard reagent
Molar ratio is 1:1.2~3.0, the molar ratio of raw material (Z) -2- benzylidene quinine -3- ketone and catalyst is 1:0.01~0.30.
Further, synthetic method is：(Z) -2- benzylidene quinine -3- ketone (9.0g) is weighed, tetrahydrofuran is added
(110mL), stirring and dissolving obtains solution A；Cuprous bromide is added in 2.0M phenyl-magnesium-chloride tetrahydrofuran solution (36mL)
(602mg) is cooled to -5 DEG C under nitrogen protection, solution A is added dropwise thereto, adds spontaneous recovery to room temperature, reacts 15 hours, will
Reaction solution is poured slowly into saturated aqueous ammonium chloride (40mL), is stirred 10 minutes, and liquid separation, water phase is extracted with ethyl acetate twice,
Merge organic phase, washing, saturated sodium chloride solution is washed, and anhydrous sodium sulfate is dry, and vacuum concentration obtains crude product, uses dehydrated alcohol
Crystallization, obtains 2- (benzhydryl) quinuclidine -3- ketone (10.1g).
The present invention also provides purposes of the above-mentioned synthetic method in preparation horse sieve is smooth or derivatives thereof.
Beneficial effects of the present invention：
(1) in the presence of catalyst, grignard reaction by-product is lower than 10%, and purity is greater than 99% after crystallization, high income
Up to 85%.
(2) catalyst amount that the present invention uses is small, and price is low, does not use dimethylsulfide complex, environmentally friendly,
Environmental protection pressure without amplification production.
(3) raw material (Z) -2- benzylidene quinine -3- ketone that the present invention uses can be by 3- quinuclidone and benzaldehyde in hydrogen
Synthesis obtains in the presence of sodium oxide molybdena and ethyl alcohol, and yield is greater than 90%, and 3- Quinuclidinone hydrochloride is common industrial product, city
It can largely be purchased on face, it is cheap.
(4) the phenyl grignard reagent that the present invention uses is common industrial product, can largely be purchased on the market, price is low
It is honest and clean.To sum up, the advantage of the invention is that various chemical raw materials needed for reacting are all cheap and easy to get, reaction condition is mild, high income, pure
It spends, easy to operate, effect on environment is small, no environmental protection pressure.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.
The structure of compound be nuclear magnetic resonance (1H NMR、13C NMR) or MS determine.
Term " room temperature " of the invention refers to that temperature is between 10-25 DEG C.
Embodiment 1
It weighs (Z) -2- benzylidene quinine -3- ketone (9.0g) and 250mL beaker is added, be added tetrahydrofuran (110mL), stir
It mixes dissolution and obtains solution A, be transferred to dropping funel.2.0M phenyl-magnesium-chloride tetrahydrofuran solution (36mL) is added tri- mouthfuls of 250mL
Bottle is added cuprous bromide (602mg), and -5 DEG C are cooled under nitrogen protection, and solution A is added dropwise, and adds spontaneous recovery to 25 DEG C, reacts
15 hours, reaction solution is poured slowly into saturated ammonium chloride solution (40mL), is stirred 10 minutes, liquid separation, water phase is extracted with ethyl acetate
It takes twice, merges organic phase, washing, saturated sodium chloride solution is washed, and anhydrous sodium sulfate is dry, and vacuum concentration obtains crude product, with nothing
Water-ethanol crystallization, obtains 2- (benzhydryl) quinuclidine -3- ketone (10.5g), yield：85%, HPLC:99.6%.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)+。
Embodiment 2
It weighs (Z) -2- benzylidene quinine -3- ketone (10.0g) and 250mL beaker is added, be added tetrahydrofuran (80mL), stir
It mixes dissolution and obtains solution A, be transferred to dropping funel.2.0M phenyl-magnesium-chloride tetrahydrofuran solution (28mL) is added tri- mouthfuls of 250mL
Bottle is added cuprous bromide (674mg), and -5 DEG C are cooled under nitrogen protection, and solution A is added dropwise, and adds spontaneous recovery to 25 DEG C, reacts
12 hours, reaction solution is poured slowly into saturated ammonium chloride solution (45mL), is stirred 10 minutes, liquid separation, water phase is extracted with ethyl acetate
It takes twice, merges organic phase, washing, saturated sodium chloride solution is washed, and anhydrous sodium sulfate is dry, and vacuum concentration obtains crude product, with nothing
Water-ethanol crystallization, obtains 2- (benzhydryl) quinuclidine -3- ketone (10.9g), yield：80%, HPLC:99.2%, nuclear-magnetism and MS
Data consistent with Example 1.
Embodiment 3
It weighs (Z) -2- benzylidene quinine -3- ketone (10.0g) and 500mL beaker is added, be added tetrahydrofuran (200mL),
Stirring and dissolving obtains solution A, is transferred to dropping funel.500mL tri- is added in 2.0M phenyl-magnesium-chloride tetrahydrofuran solution (70mL)
Mouth bottle, is added cuprous bromide (674mg), and -5 DEG C are cooled under nitrogen protection, and solution A is added dropwise, adds spontaneous recovery to 25 DEG C, instead
It answers 24 hours, reaction solution is poured slowly into saturated ammonium chloride solution (55mL), stir 10 minutes, liquid separation, water phase ethyl acetate
It is extracted twice, merges organic phase, washing, saturated sodium chloride solution is washed, and anhydrous sodium sulfate is dry, and vacuum concentration obtains crude product, is used
Dehydrated alcohol crystallization, obtains 2- (benzhydryl) quinuclidine -3- ketone (11.2g), yield：82%, HPLC:99.2%, nuclear-magnetism and
MS data consistent with Example 1.
Embodiment 4
It weighs (Z) -2- benzylidene quinine -3- ketone (10.0g) and 250mL beaker is added, methyltetrahydrofuran is added
(120mL), stirring and dissolving obtains solution A, is transferred to dropping funel.2.0M phenyl-magnesium-chloride tetrahydrofuran solution (40mL) is added
250mL there-necked flask is added cuprous bromide (67mg), and -5 DEG C are cooled under nitrogen protection, and solution A is added dropwise, adds and is warming up to 50 DEG C,
Reaction 8 hours, reaction solution is poured slowly into saturated ammonium chloride solution (45mL), is stirred 10 minutes, liquid separation, water phase ethyl acetate
It is extracted twice, merges organic phase, washing, saturated sodium chloride solution is washed, and anhydrous sodium sulfate is dry, and vacuum concentration obtains crude product, is used
Dehydrated alcohol crystallization, obtains 2- (benzhydryl) quinuclidine -3- ketone (10.9g), yield：80%, HPLC:99.1%, nuclear-magnetism and
MS data consistent with Example 1.
Embodiment 5
It weighs (Z) -2- benzylidene quinine -3- ketone (10.0g) and 250mL beaker is added, be added ether (120mL), stirring
Dissolution obtains solution A, is transferred to dropping funel.250mL there-necked flask is added in 2.0M phenyl-magnesium-chloride tetrahydrofuran solution (40mL),
It is added cuprous bromide (2.0g), -5 DEG C is cooled under nitrogen protection, solution A is added dropwise, add spontaneous recovery to 25 DEG C, reaction 15 is small
When, reaction solution is poured slowly into saturated ammonium chloride solution (45mL), is stirred 10 minutes, liquid separation, water phase is extracted with ethyl acetate two
It is secondary, merge organic phase, washing, saturated sodium chloride solution is washed, and anhydrous sodium sulfate is dry, and vacuum concentration obtains crude product, with anhydrous second
Alcohol crystallization, obtains 2- (benzhydryl) quinuclidine -3- ketone (11.1g), yield：81%, HPLC:99.5%, nuclear-magnetism and MS data
With embodiment 1.
Embodiment 6
(Z) -2- benzylidene quinine -3- ketone feeds intake (9.0g), and solvent is methyl tertiary butyl ether(MTBE) (120mL), catalyst chlorine
Change cuprous (418mg), operates with embodiment 1, obtain 2- (benzhydryl) quinuclidine -3- ketone (9.0g), yield：73%, HPLC:
99.2%, nuclear-magnetism and MS data consistent with Example 1.
Embodiment 7
(Z) -2- benzylidene quinine -3- ketone feeds intake (9.0g), and catalyst cuprous iodide (805mg) operates same embodiment
1, obtain 2- (benzhydryl) quinuclidine -3- ketone (9.5g), yield：77%, HPLC:99.3%, nuclear-magnetism and MS data are the same as implementation
Example 1.
Embodiment 8
It weighs (Z) -2- benzylidene quinine -3- ketone (10.0g) and 250mL beaker is added, be added toluene (130mL), stirring
Dissolution obtains solution A, is transferred to dropping funel.250mL there-necked flask is added in 2.0M phenyl-magnesium-chloride tetrahydrofuran solution (40mL),
It is added cuprous bromide (674mg), -5 DEG C is cooled under nitrogen protection, solution A is added dropwise, add spontaneous recovery to 25 DEG C, react 15
Hour, reaction solution is poured slowly into saturated ammonium chloride solution (45mL), is stirred 10 minutes, liquid separation, water phase is extracted twice with toluene,
Merge organic phase, washing, saturated sodium chloride solution is washed, and anhydrous sodium sulfate is dry, and vacuum concentration obtains crude product, uses dehydrated alcohol
Crystallization, obtains 2- (benzhydryl) quinuclidine -3- ketone (10.9g), yield：80%, HPLC:99.3%, nuclear-magnetism and MS data are same
Embodiment 1.
Embodiment 9
It weighs (Z) -2- benzylidene quinine -3- ketone (1kg) and 2.5L beaker is added, be added tetrahydrofuran (1.2L), stirring
Dissolution obtains solution A, is transferred to dropping funel.10L reaction kettle is added in 2.0M phenyl-magnesium-chloride tetrahydrofuran solution (4L), is added
Cuprous bromide (67g) is cooled to -5 DEG C under nitrogen protection, and solution A is added dropwise, and adds spontaneous recovery to 25 DEG C, reacts 15 hours, will
Reaction solution is poured slowly into saturated ammonium chloride solution (4.5L), is stirred 10 minutes, liquid separation, and water phase is extracted with ethyl acetate twice, is closed
And organic phase, washing, saturated sodium chloride solution are washed, anhydrous sodium sulfate is dry, and vacuum concentration obtains crude product, with dehydrated alcohol knot
Crystalline substance obtains 2- (benzhydryl) quinuclidine -3- ketone (1.16kg), yield：85%, HPLC:99.5%, nuclear-magnetism and MS data are the same as real
Apply example 1.
To sum up, the method for synthesis 2- (benzhydryl) quinuclidine -3- ketone provided by the invention, yield are up to 85%, purity
Higher than 99%, and it is suitble to produce in enormous quantities, is suitable for industrialization.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of method of Michael's addition synthesis benzhydryl-quinuclidine ketone, which is characterized in that in reaction dissolvent, by raw material
(Z) -2- benzylidene quinine -3- ketone, grignard reagent and catalyst mixing, occur Michael addition reaction and generate 2- (hexichol first
Base) quinuclidine -3- ketone, wherein the catalyst is one kind of cuprous iodide, cuprous bromide or stannous chloride, the raw material
(Z) molar ratio of -2- benzylidene quinine -3- ketone and catalyst is 1:0.01~0.30.
2. synthetic method according to claim 1, which is characterized in that raw material (the Z) -2- benzylidene quinine -3- ketone
Molar ratio with catalyst is 1:0.10.
3. synthetic method according to claim 1, which is characterized in that the reaction dissolvent is toluene, ether, methyl- tert
One kind of butyl ether, tetrahydrofuran or methyltetrahydrofuran.
4. synthetic method according to claim 1, which is characterized in that the grignard reagent is phenyl-magnesium-chloride, phenyl
One kind of magnesium bromide or phenyl magnesium iodide.
5. synthetic method according to claim 1, which is characterized in that raw material (the Z) -2- benzylidene quinine -3- ketone
Molar ratio with grignard reagent is 1:1.2~3.0, preferably 1:1.7.
6. synthetic method according to claim 1, which is characterized in that raw material (the Z) -2- benzylidene quinine -3- ketone
Mass volume ratio (g/mL) with reaction dissolvent is 1:8~20.
7. synthetic method according to claim 1, which is characterized in that reaction temperature is room temperature to 50 DEG C, the reaction time 8
~24 hours.
8. synthetic method according to claim 1, which is characterized in that by (Z) -2- benzylidene Kui in reaction dissolvent
Rather -3- ketone, grignard reagent, catalyst mixing, room temperature add aqueous ammonium chloride solution, stir to after reacting 8~24 hours at 50 DEG C
It mixes, liquid separation, water phase is stripped with organic solvent, is merged organic phase, is washed with water, saturated sodium chloride solution, and it is dry, it is concentrated to get thick
Product, then crystallized with dehydrated alcohol to get 2- (benzhydryl) quinuclidine -3- ketone, wherein the reaction dissolvent is toluene, second
One kind of ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran or methyltetrahydrofuran, the grignard reagent are phenyl-magnesium-chloride, benzene
One kind of base magnesium bromide or phenyl magnesium iodide, the catalyst are one kind of cuprous iodide, cuprous bromide or stannous chloride, institute
The molar ratio for stating raw material (Z) -2- benzylidene quinine -3- ketone and grignard reagent is 1:1.2~3.0, raw material (the Z) -2- benzene
The molar ratio of methylene quinine -3- ketone and catalyst is 1:0.01~0.30.
9. synthetic method according to claim 1, which is characterized in that weigh (Z) -2- benzylidene quinine -3- ketone
(9.0g) is added tetrahydrofuran (110mL), and stirring and dissolving obtains solution A；2.0M phenyl-magnesium-chloride tetrahydrofuran solution
(36mL) is added cuprous bromide (602mg), is cooled to -5 DEG C under nitrogen protection, solution A is added dropwise thereto, adds spontaneous recovery
It to room temperature, reacts 15 hours, reaction solution is poured slowly into saturated aqueous ammonium chloride (40mL), stir 10 minutes, liquid separation, water phase
It being extracted with ethyl acetate twice, merges organic phase, washing, saturated sodium chloride solution is washed, and anhydrous sodium sulfate is dry, vacuum concentration,
Crude product is obtained, is crystallized with dehydrated alcohol, 2- (benzhydryl) quinuclidine -3- ketone (10.1g) is obtained.
10. purposes of the synthetic method described in any one of claim 1-9 in preparation horse sieve is smooth or derivatives thereof.
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| CN201810992880.3A CN108822101B (en) | 2018-08-29 | 2018-08-29 | Method for synthesizing benzhydrylquinuclidinone by Michael addition |
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| CN201810992880.3A CN108822101B (en) | 2018-08-29 | 2018-08-29 | Method for synthesizing benzhydrylquinuclidinone by Michael addition |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2018
- 2018-08-29 CN CN201810992880.3A patent/CN108822101B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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