CN106432122B - A kind of preparation method of meropenem intermediate chlorine propionyl spiral shell benzoxazine hexamethylene - Google Patents
A kind of preparation method of meropenem intermediate chlorine propionyl spiral shell benzoxazine hexamethylene Download PDFInfo
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- CN106432122B CN106432122B CN201610812510.8A CN201610812510A CN106432122B CN 106432122 B CN106432122 B CN 106432122B CN 201610812510 A CN201610812510 A CN 201610812510A CN 106432122 B CN106432122 B CN 106432122B
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- hexamethylene
- benzoxazine
- spiral shell
- dihydro
- ketone
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- 0 CCCC(CCC)(*C(CC(C)C)=C1C=C)N([C@](*)C(C)*)C1=O Chemical compound CCCC(CCC)(*C(CC(C)C)=C1C=C)N([C@](*)C(C)*)C1=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/20—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 4
- C07D265/22—Oxygen atoms
Abstract
The present invention provides a kind of preparation methods of meropenem intermediate chlorine propionyl spiral shell benzoxazine hexamethylene, use the lower α-chlorpromazine chloride of reactivity, cooperate specific raw material one to work, not but not reduces reaction yield, instead reaction yield is greatly improved；Simultaneously, since α-chlorpromazine chloride activity is lower, so that the side reaction for participating in reaction is less, the impurity in products obtained from is less, to which yield and the higher chlorine propionyl spiral shell benzoxazine hexamethylene of purity be made, and this yield and the higher chlorine propionyl spiral shell benzoxazine hexamethylene of purity can replace Spirobromin benzoxazine hexamethylene to prepare Meropenem.In addition, without magnetic solid base catalyst, reaction condition is safer in the synthesis technology of chlorine propionyl spiral shell benzoxazine hexamethylene provided by the invention, reaction route is simple, convenient post-treatment, and raw material and catalyst are cheap and easy to get, safety and environmental protection, preparation cost is lower, is more suitable for industrialized production.
Description
Technical field
The present invention relates to technical field of medicine synthesis more particularly to a kind of meropenem intermediate chlorine propionyl spiral shell benzoxazines
The preparation method of hexamethylene.
Background technique
Meropenem also known as SM 7338, English name: Meropenem, chemical name: (4R, 5S, 6S) -3- [[(3S, 5S) -
5- (dimethylcarbamoyl) -3- pyrrolidines] sulphur] -6- [(1R) -1- ethoxy] -4- methyl -7- oxygen -1- nitrogen is bicyclic [3.2.0]
Hept-2-ene" -2- carboxylic acid trihydrate is developed by Dainippon Sumitomo Pharma and Astrazeneca AB earliest,
And listed first in Italy in nineteen ninety-five, then gradually had a vast market foreground in whole world application listing.As second
There is has a broad antifungal spectrum compared to other similar antibiotic for carbapenem antibiotic, antibacterial action is strong, stablizes to DHP-1 enzyme
The advantages that, it is mainly used for treating the serious bacterial infections such as respiratory tract infection, abdominal cavity infection, urinary tract infections, excellent.
The quality of key intermediate one of of the Spirobromin benzoxazine hexamethylene as synthesis Meropenem, quality is straight
Connect the yield and quality for influencing Meropenem.Shown in the structure such as formula (II) of Spirobromin benzoxazine hexamethylene.However, adopting
The yield of the Meropenem made from Spirobromin benzoxazine hexamethylene is not high.Meanwhile preparing Spirobromin benzoxazine
The α of raw material required for hexamethylene-bromopropionyl bromide is expensive, smell is larger, and toxicity is higher.
The Chinese patent that number of patent application is 201110203766.6 disclose a kind of 3- (2- bromine propiono)-spiral shell [2H-1,
3- benzoxazine -2,1'- hexamethylene] -4 (3H) -one preparation method, this method is that starting is former with salicylamide and cyclohexanone
Material, under the action of solid acid catalyst, reacts to obtain spiral shell [2H-1,3- benzoxazine -2,1'- hexamethylene in reflux in toluene
Alkane] -4 (3H) -one；Then it under the action of magnetic solid base catalyst, reacts to obtain 3- (2- bromine with halogen acyl halide in toluene
Propiono) -4 (3H) -one of-spiral shell [2H-1,3- benzoxazine -2,1'- hexamethylene], wherein halogen acyl halide is α-bromopropionyl bromide.
Spirobromin benzoxazine hexamethylene yield and purity made from this method are lower, meanwhile, it needs to adopt in preparation
The complicated and expensive magnetic solid base catalyst with production process, reaction process is complicated, and the dangerous system of reaction is higher, after
Processing is complicated, and environmental pollution is serious, higher cost.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is that providing a kind of meropenem intermediate chlorine propionyl spiral shell benzo
The preparation method of oxazines hexamethylene, the chlorine propionyl spiral shell benzoxazine hexamethylene prepared by this method can substitute Spirobromin benzene
And oxazines hexamethylene prepares Meropenem, and the yield of chlorine propionyl spiral shell benzoxazine hexamethylene and purity are higher.
The present invention provides a kind of preparation methods of meropenem intermediate chlorine propionyl spiral shell benzoxazine hexamethylene, including with
Lower step: by spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and α-chlorpromazine chloride acid binding agent work
Condensation reaction is carried out in aprotic solvent under, obtains chlorine propionyl spiral shell benzoxazine hexamethylene.
Preferably, it spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and ties up
The molar ratio of sour agent is 1:1.0~2.5:0.5~3.0.
Preferably, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and aprotic solvent
Mass ratio is 1:1.0~5.0.
Preferably, the acid binding agent includes one or more of organic base and inorganic base.
Preferably, the organic base includes triethylamine, pyridine, n,N-diisopropylethylamine, 4-dimethylaminopyridine, three second
One or more of hydramine and quaternary ammonium salt.
Preferably, the inorganic base includes one or more of potassium carbonate, ammonium carbonate and sodium carbonate.
Preferably, the aprotic solvent be toluene, dimethylbenzene, benzene, chlorobenzene, nitrobenzene, acetone, dimethylformamide,
One or more of tetrahydrofuran, methylene chloride, chloroform and carbon tetrachloride.
Preferably, the temperature of the condensation reaction is room temperature to reflux temperature, the time of the condensation reaction is 0.5~
20h。
Preferably, the condensation reaction carries out under the conditions of protecting existing for gas.
It preferably, further include the crystallization that cools down in proton solvent after the condensation reaction.
The present invention provides a kind of preparation methods of meropenem intermediate chlorine propionyl spiral shell benzoxazine hexamethylene, including with
Lower step: by spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and α-chlorpromazine chloride acid binding agent work
Condensation reaction is carried out in aprotic solvent under, obtains chlorine propionyl spiral shell benzoxazine hexamethylene.With disclosed in the prior art
It prepares Spirobromin benzoxazine hexamethylene using α-bromopropionyl bromide to compare, the present invention uses the lower α of reactivity-chlorine propionyl
Chlorine cooperates specific raw material one to work, and not but not reduces reaction yield, instead reaction yield is greatly improved；
Simultaneously as α-chlorpromazine chloride activity it is lower so that participate in reaction side reaction it is less, the impurity in products obtained from compared with
It is few, so that yield and the higher chlorine propionyl spiral shell benzoxazine hexamethylene of purity has been made, and this yield and the higher chlorine of purity
Propionyl spiral shell benzoxazine hexamethylene can replace Spirobromin benzoxazine hexamethylene to prepare Meropenem.In addition, the present invention mentions
In the synthesis technology of the chlorine propionyl spiral shell benzoxazine hexamethylene of confession, without magnetic solid base catalyst, reaction condition is more
Safety, reaction route is simple, convenient post-treatment, and raw material and catalyst are cheap and easy to get, and safety and environmental protection, preparation cost is lower, more suitable
Close industrialized production.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical solution of the present invention is clearly and completely described, it is clear that institute
The embodiment of description is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention,
Every other embodiment obtained by those of ordinary skill in the art without making creative efforts, belongs to this hair
The range of bright protection.
The present invention provides a kind of preparation methods of meropenem intermediate chlorine propionyl spiral shell benzoxazine hexamethylene, including with
Lower step:
By spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and α-chlorpromazine chloride acid binding agent work
Condensation reaction is carried out in aprotic solvent under, obtains chlorine propionyl spiral shell benzoxazine hexamethylene.
Preferably, specifically: under the conditions of protecting existing for gas, by spiral shell [2,3- dihydro -4H-1,3- Benzoxazines -2,1'-
Hexamethylene] -4- ketone, α-chlorpromazine chloride, acid binding agent and aprotic solvent mixing, condensation reaction is carried out, chlorine propionyl spiral shell benzo is obtained
Oxazines hexamethylene.
The present invention has no special limitation to the protective gas, is using protective gas well known to those skilled in the art
Can, present invention preferably employs nitrogen.
Spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- the hexamethylene] -4- ketone has to be tied as shown in formula (III)
Structure:
α-the chlorpromazine chloride has the structure as shown in formula (IV):
The acid binding agent includes one or more of organic base and inorganic base.The organic base preferably include triethylamine,
Pyridine, N, one or more of N- diisopropylethylamine, 4-dimethylaminopyridine, triethanolamine and quaternary ammonium salt.The quaternary ammonium
Salt is preferably tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, cetyl trimethylammonium bromide, chlorination
In the double octadecyldimethyl ammoniums of dodecyl dimethyl hexadecyldimethyl benzyl ammonium, bromination, octadecyldimethyl hydroxyethyl ammonium nitrate
It is one or more of.The inorganic base preferably includes one or more of potassium carbonate, ammonium carbonate and sodium carbonate.
The aprotic solvent is preferably toluene, dimethylbenzene, benzene, chlorobenzene, nitrobenzene, acetone, dimethylformamide, tetrahydro
One or more of furans, methylene chloride, chloroform and carbon tetrachloride.
In the present invention, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride
Molar ratio with acid binding agent is preferably 1:1.0~2.5:0.5~3.0；More preferably 1:1.4~1.6:0.8~1.4.In this hair
In bright some embodiments, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride with
The molar ratio of acid binding agent is 1:1.4:1.2；Or 1:1.5:0.8；Or 1:1.6:1.4；Or 1:1.5:1.3；Or 1:1.6:1.3；Or
1:1.6:1.1；Or 1:1.6:1.2 or 1:1.0:0.5.
In the present invention, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone with it is non-proton molten
The mass ratio of agent is preferably 1:1.0~5.0；More preferably 1:3.0~5.0.In certain embodiments of the present invention, the spiral shell
The mass ratio of [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and aprotic solvent is 1:3.1；Or 1:3.7；
Or 1:4.4；Or 1:5.
The present invention has no special limitation to the device of the condensation reaction, and the present invention is preferably four-hole boiling flask.
The temperature of the condensation reaction is preferably room temperature to reflux temperature, more preferably 50~90 DEG C；In certain of the invention
In a little embodiments, the temperature of the condensation reaction is 50 DEG C, 55 DEG C, 60 DEG C, 70 DEG C, 80 DEG C, 90 DEG C.
The time of the condensation reaction is preferably 0.5~20h, more preferably 4.5~8h；In certain embodiments of the present invention
In, the time of the condensation reaction is 3.5h, 5h, 6h, 7h or 8h.
After the condensation reaction, the crystallization that cools down is preferably also included in proton solvent.Preferably, the cooling crystallization is specific
Are as follows: after being cooled to crystallization temperature, the crystallization in stirring.
The proton solvent is preferably one or more of alcohols solvent, more preferably methanol, ethyl alcohol, isopropanol, just
One or more of butanol and the tert-butyl alcohol.In the present invention, the proton solvent and spiral shell [2,3- dihydro -4H-1,3- benzos
Piperazine -2,1'- hexamethylene] mass ratio of -4- ketone is preferably 0.5~5.0:1, more preferably 1~2:1.In certain realities of the invention
It applies in example, the mass ratio of the proton solvent and spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone is 1:
1,1.5:1 or 4:1.
The present invention has no special limitation to the mode of above-mentioned cooling, using cooling method well known to those skilled in the art
?.The present invention has no special limitation to the mode of the stirring, is using agitating mode well known to those skilled in the art
It can.The temperature of the crystallization is preferably -20~10 DEG C；In certain embodiments of the present invention, the temperature of the crystallization is -5 DEG C.
The time of the crystallization is preferably 1~3h；In certain embodiments of the present invention, the time of the crystallization is 2h.
Before the crystallization that cools down in proton solvent, it is also preferable to include be cooled to room temperature, clean, be concentrated under reduced pressure；It is described
Cool down after crystallization in proton solvent, it is also preferable to include filterings and drying.
In the present invention, it is preferred to, the cleaning specifically: first washed three times with the first clear water, then washed three times with lye, most
It is washed three times with the second clear water afterwards.The present invention has no special limitation to first clear water and the second clear water, using this field skill
Clear water known to art personnel, the present invention are preferred are as follows: the first clear water and the second clear water are deionized water.The present invention is to described
Lye and its mass percent have no special limitation, using alkaline solution well known to those skilled in the art and its quality percentage
Number, the present invention are preferably sodium hydroxide solution, potassium hydroxide solution, sodium bicarbonate solution, potassium bicarbonate solution, sodium carbonate
One or more of solution, solution of potassium carbonate.The mass percent of the alkaline solution is preferably 0.5%~20%.It is described
The mass ratio of first clear water, lye and the second clear water is preferably 1.5~4:2~4:1.5~4.The lye and the spiral shell [2,3-
Dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] mass ratio of -4- ketone is preferably 2~4:1~1.5.
The present invention has no special limitation to the device and method of the reduced pressure, using known to those skilled in the art
Device and method are concentrated under reduced pressure, the present invention has no special limitation to the pressure of reduced pressure and time simultaneously, depressurizes dense
It is reduced to no liquid outflow.The present invention has no special limitation to the device and method of the filtering and drying, using ability
The device and method of filtering and drying known to field technique personnel.
The present invention has no special limitation to the source of above-mentioned used raw material, the product bought in the market.
Final product meropenem intermediate chlorine propionyl spiral shell benzoxazine hexamethylene obtained has to be tied as shown in formula (I)
Structure:
The present invention provides a kind of preparation methods of meropenem intermediate chlorine propionyl spiral shell benzoxazine hexamethylene, including with
Lower step: by spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and α-chlorpromazine chloride acid binding agent work
Condensation reaction is carried out in aprotic solvent under, obtains chlorine propionyl spiral shell benzoxazine hexamethylene.The present invention uses reactivity
Lower α-chlorpromazine chloride, cooperation acid binding agent work with other raw materials one, not but not reduce reaction yield, make instead anti-
Yield is answered to be greatly improved；Simultaneously as α-chlorpromazine chloride activity is lower, so that the side reaction for participating in reaction is less, into
Obtained from impurity in products it is less.The present invention obtains yield and purity by further controlling reaction temperature and material proportion
Higher chlorine propionyl spiral shell benzoxazine hexamethylene, and this yield and the higher chlorine propionyl spiral shell benzoxazine hexamethylene of purity can be with
Spirobromin benzoxazine hexamethylene is replaced to prepare Meropenem.In addition, chlorine propionyl spiral shell benzoxazine hexamethylene provided by the invention
In the synthesis technology of alkane, reaction condition is safer, and reaction route is simple, convenient post-treatment, and raw material and catalyst are cheap and easy to get,
Safety and environmental protection, preparation cost is lower, is more suitable for industrialized production.
In order to further illustrate the present invention, with reference to embodiments to a kind of meropenem intermediate chlorine provided by the invention
The preparation method of propionyl spiral shell benzoxazine hexamethylene is described in detail, but cannot be understood as to the scope of the present invention
It limits.
Embodiment 1
According to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and triethylamine
Molar ratio is 1:1.4:1.2, weigh respectively 80g spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone,
α-chlorpromazine chloride of 65g and the triethylamine of 45g；According to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone
Mass ratio with toluene is 1:3.1, weighs 250g toluene；According to [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -
The mass ratio of 4- ketone and isopropanol is 1:1, weighs 80g isopropanol.
Under nitrogen protection, by toluene, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorine
Propionyl chloride and triethylamine, which are added in four-hole boiling flask, to be reacted, and the temperature of the reaction is 80 DEG C, and the time of reaction is 5h.Reaction
After, it is down to room temperature, respectively three times with 200g washing, is washed three times with the sodium hydroxide solution of 200g8%, with 200g washing three
It is secondary, merge organic phase, is concentrated under reduced pressure into no liquid outflow.Then isopropanol is added, is cooled to -5 DEG C, stirring and crystallizing 2h, filters,
Drying, obtains chlorine propionyl spiral shell benzoxazine hexamethylene 106.5g.Its molar yield is 94.1%, purity 99.6%.
Embodiment 2
According to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and 4- diformazan ammonia
The molar ratio of yl pyridines is 1:1.5:0.8, weighs spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylenes of 80g respectively
Alkane] -4- ketone, α-chlorpromazine chloride of 70g and the 4-dimethylaminopyridine of 38g；According to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -
2,1'- hexamethylenes] mass ratio of -4- ketone and dimethylbenzene is 1:3.7, weigh 300g dimethylbenzene；According to [2,3- dihydro -4H-1,3-
Benzoxazine -2,1'- hexamethylene] mass ratio of -4- ketone and n-butanol is 1:1, weigh 80g n-butanol.
Under nitrogen protection, by dimethylbenzene, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α -
Chlorpromazine chloride and 4-dimethylaminopyridine, which are added in four-hole boiling flask, is reacted, and the temperature of the reaction is 90 DEG C, reaction when
Between be 4.5h.After reaction, it is down to room temperature, respectively three times with 200g washing, washes three with the sodium bicarbonate solution of 250g10%
It is secondary, three times with 200g washing, merge organic phase, is concentrated under reduced pressure into no liquid outflow.Then n-butanol is added, is cooled to -5 DEG C,
Stirring and crystallizing 2h is filtered, and drying obtains chlorine propionyl spiral shell benzoxazine hexamethylene 104.8g.Its molar yield is 92.5%, purity
It is 99.3%.
Embodiment 3
According to rubbing for spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and pyridine
You weigh spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, 75g of 80g than being 1:1.6:1.4 respectively
α-chlorpromazine chloride and 40g pyridine；According to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and chlorobenzene
Mass ratio be 1:4.4, weigh 350g chlorobenzene；According to [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone with
The mass ratio of ethyl alcohol is 1:1, weighs 80g ethyl alcohol.
Under nitrogen protection, by chlorobenzene, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorine
Propionyl chloride and pyridine, which are added in four-hole boiling flask, to be reacted, and the temperature of the reaction is 50 DEG C, and the time of reaction is 8h.Reaction knot
Shu Hou is down to room temperature, respectively three times with 200g washing, is washed three times with the potassium hydroxide solution of 200g10%, with 200g washing three
It is secondary, merge organic phase, is concentrated under reduced pressure into no liquid outflow.Then ethyl alcohol is added, is cooled to -5 DEG C, stirring and crystallizing 2h, filters, dries
It is dry, obtain chlorine propionyl spiral shell benzoxazine hexamethylene 107.6g.Its molar yield is 95.0%, purity 99.7%.
Embodiment 4
According to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and triethanolamine
Molar ratio be 1:1.5:1.3, weigh respectively 80g spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone,
α-chlorpromazine chloride of 70g and the triethanolamine of 70g；According to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4-
The mass ratio of ketone and benzene is 1:5, weighs 400g benzene；According to [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone
Mass ratio with methanol is 1:1, weighs 80g methanol.
Under nitrogen protection, by benzene, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorine third
Acyl chlorides and triethanolamine, which are added in four-hole boiling flask, to be reacted, and the temperature of the reaction is 80 DEG C, and the time of reaction is 6h.Reaction
After, it is down to room temperature, respectively three times with 200g washing, is washed three times with the potassium bicarbonate solution of 250g10%, is washed with 200g
Three times, merge organic phase, be concentrated under reduced pressure into no liquid outflow.Then methanol is added, is cooled to -5 DEG C, stirring and crystallizing 2h, filters,
Drying, obtains chlorine propionyl spiral shell benzoxazine hexamethylene 104.1g.Its molar yield is 91.9%, purity 99.4%.
Embodiment 5
It is different according to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and N, N- bis-
The molar ratio of propylethylamine is 1:1.6:1.4, weighs spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylenes of 80g respectively
Alkane] -4- ketone, α-chlorpromazine chloride of 75g and the N of 67g, N- diisopropylethylamine；According to spiral shell [2,3- dihydro -4H-1,3- benzo
Piperazine -2,1'- hexamethylene] mass ratio of -4- ketone and dimethylformamide is 1:3.1, weigh 250g dimethylformamide；According to
The mass ratio of [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and methanol is 1:1.5, weighs 120g methanol.
Under nitrogen protection, by dimethylformamide, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4-
Ketone, α-chlorpromazine chloride and n,N-diisopropylethylamine, which are added in four-hole boiling flask, is reacted, and the temperature of the reaction is 70 DEG C, instead
The time answered is 6h.After reaction, it is down to room temperature, respectively three times with 200g washing, with the potassium bicarbonate solution of 250g10%
It washes three times, three times with 200g washing, merges organic phase, be concentrated under reduced pressure into no liquid outflow.Then methanol is added, is cooled to -5
DEG C, stirring and crystallizing 2h is filtered, and drying obtains chlorine propionyl spiral shell benzoxazine hexamethylene 103.0g.Its molar yield is 90.9%,
Purity is 99.1%.
Embodiment 6
According to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and tetrabutyl bromine
The molar ratio for changing ammonium is 1:1.6:1.3, weighs the spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene]-of 80g respectively
4- ketone, α-chlorpromazine chloride of 75g and the tetrabutylammonium bromide of 154g；According to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'-
Hexamethylene] mass ratio of -4- ketone and carbon tetrachloride is 1:3.1, weigh 250g carbon tetrachloride；According to [2,3- dihydro -4H-1,3-
Benzoxazine -2,1'- hexamethylene] mass ratio of -4- ketone and ethyl alcohol is 1:1.5, weigh 120g ethyl alcohol.
Under nitrogen protection, by carbon tetrachloride, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone,
α-chlorpromazine chloride and tetrabutylammonium bromide, which are added in four-hole boiling flask, is reacted, and the temperature of the reaction is 55 DEG C, reaction when
Between be 8h.After reaction, it is down to room temperature, respectively three times with 200g washing, is washed three times with the potassium hydroxide solution of 250g9%,
Three times with 200g washing, merge organic phase, be concentrated under reduced pressure into no liquid outflow.Then ethyl alcohol is added, is cooled to -5 DEG C, stirring analysis
Brilliant 2h is filtered, and drying obtains chlorine propionyl spiral shell benzoxazine hexamethylene 104g.Its molar yield is 91.6%, and purity is
99.3%.
Embodiment 7
According to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and sodium carbonate
Molar ratio is 1:1.6:1.1, weigh respectively 80g spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone,
α-chlorpromazine chloride of 75g and the sodium carbonate of 43g；According to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone
Mass ratio with tetrahydrofuran is 1:3.1, weighs 250g tetrahydrofuran；According to [2,3- dihydro -4H-1,3- Benzoxazine -2,1'-
Hexamethylene] mass ratio of -4- ketone and the tert-butyl alcohol is 1:1.5, weigh the 120g tert-butyl alcohol.
Under nitrogen protection, by tetrahydrofuran, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone,
α-chlorpromazine chloride and sodium carbonate, which are added in four-hole boiling flask, to be reacted, and the temperature of the reaction is 60 DEG C, and the time of reaction is 7h.
After reaction, it is down to room temperature, respectively three times with 200g washing, is washed three times with the sodium carbonate liquor of 250g9%, is washed with 200g
Three times, merge organic phase, be concentrated under reduced pressure into no liquid outflow.Then the tert-butyl alcohol is added, is cooled to -5 DEG C, stirring and crystallizing 2h, mistake
Filter, drying, obtains chlorine propionyl spiral shell benzoxazine hexamethylene 102g.Its molar yield is 90.0%, purity 99.2%.
Embodiment 8
According to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and ammonium carbonate
Molar ratio is 1:1.6:1.2, weigh respectively 80g spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone,
α-chlorpromazine chloride of 75g and the ammonium carbonate of 42g；According to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone
Mass ratio with chloroform is 1:3.1, weighs 250g chloroform；According to [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -
The mass ratio of 4- ketone and n-butanol is 1:1.5, weighs 120g n-butanol.
Under nitrogen protection, by chloroform, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorine
Propionyl chloride and ammonium carbonate, which are added in four-hole boiling flask, to be reacted, and the temperature of the reaction is 55 DEG C, and the time of reaction is 8h.Reaction
After, it is down to room temperature, respectively three times with 200g washing, is washed three times with the solution of potassium carbonate of 300g5%, with 200g washing three
It is secondary, merge organic phase, is concentrated under reduced pressure into no liquid outflow.Then n-butanol is added, is cooled to -5 DEG C, stirring and crystallizing 2h, filters,
Drying, obtains chlorine propionyl spiral shell benzoxazine hexamethylene 103g.Its molar yield is 90.8%, purity 99.1%.
Comparative example 1
According to rubbing for spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-bromopropionyl bromide and pyridine
You weigh spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, 127g of 80g than being 1:1.6:1.4 respectively
α-bromopropionyl bromide and 40g pyridine；According to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and chlorobenzene
Mass ratio be 1:4.4, weigh 350g chlorobenzene；According to [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone with
The mass ratio of ethyl alcohol is 1:1, weighs 80g ethyl alcohol.
Under nitrogen protection, by chlorobenzene, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-bromine
Propionyl bromide and pyridine, which are added in four-hole boiling flask, to be reacted, and the temperature of the reaction is 50 DEG C, and the time of reaction is 8h.Reaction knot
Shu Hou is down to room temperature, respectively three times with 200g washing, is washed three times with the potassium hydroxide solution of 200g10%, with 200g washing three
It is secondary, merge organic phase, is concentrated under reduced pressure into no liquid outflow.Then ethyl alcohol is added, is cooled to -5 DEG C, stirring and crystallizing 2h, filters, dries
It is dry, obtain Spirobromin benzoxazine hexamethylene 109g.Its molar yield is 84.5%, purity 97.9%.
Comparative example 2
It is with α-chlorpromazine chloride molar ratio according to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone
1:1.6, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and magnetic solid catalyst Mg6Al(OH)15CO3·4H2The molar ratio of O (magnetic solid base made from magnetic mg_al hydrotalcite) be 1:1.4, weigh respectively 80g spiral shell [2,
3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride of 75g and the magnetic solid catalyst of 819g
Mg6Al(OH)15CO3·4H2O；According to the matter of spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and chlorobenzene
Amount weighs 350g chlorobenzene than being 1:4.4；According to [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and ethyl alcohol
Mass ratio be 1:1, weigh 80g ethyl alcohol.
Under nitrogen protection, by chlorobenzene, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-chlorine
Propionyl chloride and magnetic solid base catalyst, which are added in four-hole boiling flask, to be reacted, and the temperature of the reaction is 50 DEG C, reaction when
Between be 8h.After reaction, it is down to room temperature, respectively three times with 200g washing, is washed three times with the potassium hydroxide solution of 200g10%,
Three times with 200g washing, merge organic phase, be concentrated under reduced pressure into no liquid outflow.Then ethyl alcohol is added, is cooled to -5 DEG C, stirring analysis
Brilliant 2h is filtered, and drying obtains chlorine propionyl spiral shell benzoxazine hexamethylene 91g.Its molar yield is 85.5%, purity 96.5%.
Comparative example 3
It is with α-bromopropionyl bromide molar ratio according to spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone
1:1.6, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and magnetic solid catalyst Mg6Al(OH)15CO3·4H2The molar ratio of O (magnetic solid base made from magnetic mg_al hydrotalcite) be 1:1.4, weigh respectively 80g spiral shell [2,
3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-bromopropionyl bromide of 127g and 819g magnetic retention base catalysis
Agent；It is 1:4.4 according to the mass ratio of spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and chlorobenzene, weighs
350g chlorobenzene；It is 1:1 according to the mass ratio of [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and ethyl alcohol, claims
Take 80g ethyl alcohol.
Under nitrogen protection, by chlorobenzene, spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone, α-bromine
Propionyl bromide and magnetic solid catalyst, which are added in four-hole boiling flask, to be reacted, and the temperature of the reaction is 50 DEG C, the time of reaction
For 8h.After reaction, it is down to room temperature, respectively three times with 200g washing, is washed three times, is used with the potassium hydroxide solution of 200g10%
200g is washed three times, merges organic phase, is concentrated under reduced pressure into no liquid outflow.Then ethyl alcohol is added, is cooled to -5 DEG C, stirring and crystallizing
2h is filtered, and drying obtains Spirobromin benzoxazine hexamethylene 97g.Its molar yield is 75.0%, purity 97.1%.
Through the foregoing embodiment and comparative example, it can be seen that the present invention uses the lower α-chlorpromazine chloride of reactivity
Cooperate other specific raw materials, not but not reduces reaction yield, instead reaction yield is greatly improved；Meanwhile by
Lower in α-chlorpromazine chloride activity, so that the side reaction for participating in reaction is less, the impurity in products obtained from is less.The present invention
By further controlling reaction temperature and material proportion, yield and the higher chlorine propionyl spiral shell benzoxazine hexamethylene of purity are obtained
Alkane, and this yield and the higher chlorine propionyl spiral shell benzoxazine hexamethylene of purity can replace Spirobromin benzoxazine hexamethylene
Prepare Meropenem.In addition, reaction condition is more in the synthesis technology of chlorine propionyl spiral shell benzoxazine hexamethylene provided by the invention
Safety, reaction route is simple, convenient post-treatment, and raw material and catalyst are cheap and easy to get, and safety and environmental protection, preparation cost is lower, more suitable
Close industrialized production.
The foregoing description of the disclosed embodiments enables those skilled in the art to implement or use the present invention.
Various modifications to these embodiments will be readily apparent to those skilled in the art, as defined herein
General Principle can be realized in other embodiments without departing from the spirit or scope of the present invention.Therefore, of the invention
It is not intended to be limited to the embodiments shown herein, and is to fit to and the principles and novel features disclosed herein phase one
The widest scope of cause.
Claims (2)
1. a kind of preparation method of meropenem intermediate chlorine propionyl spiral shell benzoxazine hexamethylene, which is characterized in that including following
Step:
By spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- hexamethylene] -4- ketone and α-chlorpromazine chloride under the action of acid binding agent
Condensation reaction is carried out in aprotic solvent, obtains chlorine propionyl spiral shell benzoxazine hexamethylene；The condensation reaction is deposited in protection gas
It carries out under the conditions；
The acid binding agent includes triethylamine, pyridine, N, N- diisopropylethylamine, 4-dimethylaminopyridine, triethanolamine, the tetrabutyl
One or more of ammonium bromide, potassium carbonate, ammonium carbonate and sodium carbonate；
Mole of spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- the hexamethylene] -4- ketone, α-chlorpromazine chloride and acid binding agent
Than for 1:1.0~2.5:0.5~3.0；
The mass ratio of spiral shell [2,3- dihydro -4H-1,3- Benzoxazine -2,1'- the hexamethylene] -4- ketone and aprotic solvent is 1:
1.0~5.0；
The aprotic solvent is toluene, dimethylbenzene, benzene, chlorobenzene, nitrobenzene, acetone, dimethylformamide, tetrahydrofuran, two
One or more of chloromethanes, chloroform and carbon tetrachloride；
The temperature of the condensation reaction is 50~90 DEG C, and the time of the condensation reaction is 0.5~20h.
2. preparation method according to claim 1, which is characterized in that further include in proton solvent after the condensation reaction
Middle cooling crystallization.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6011150A (en) * | 1992-11-13 | 2000-01-04 | Tanabe Seiyaku Co., Ltd. | Azetidinone compound and process for preparation thereof |
| CN102321044A (en) * | 2011-07-20 | 2012-01-18 | 江西华邦药业有限公司 | Preparation method of 3-(2-bromo propionyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-one |
| CN106478538A (en) * | 2015-08-28 | 2017-03-08 | 曹子领 | Chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene and its synthesis and application |
-
2016
- 2016-09-08 CN CN201610812510.8A patent/CN106432122B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6011150A (en) * | 1992-11-13 | 2000-01-04 | Tanabe Seiyaku Co., Ltd. | Azetidinone compound and process for preparation thereof |
| CN102321044A (en) * | 2011-07-20 | 2012-01-18 | 江西华邦药业有限公司 | Preparation method of 3-(2-bromo propionyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-one |
| CN106478538A (en) * | 2015-08-28 | 2017-03-08 | 曹子领 | Chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene and its synthesis and application |
Non-Patent Citations (2)
| Title |
|---|
| 2-Substituted 2,3-Dihydro-4H-1,3-benzoxazin-4-ones: A Novel Auxiliary for Stereoselective Synthesis of 1-β-Methylcarbapenems;Kazuhiko Kondo 等;《J. Org. Chem.》;19951231;第60卷(第5期);1096-1097 * |
| 比阿陪南双环母核的合成;宗杰 等;《合成化学》;20081231;第16卷(第5期);596-599 * |
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