CN106432122A - Preparation method of 3-(2-chloro-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one as meropenem intermediate - Google Patents
Preparation method of 3-(2-chloro-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one as meropenem intermediate Download PDFInfo
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- CN106432122A CN106432122A CN201610812510.8A CN201610812510A CN106432122A CN 106432122 A CN106432122 A CN 106432122A CN 201610812510 A CN201610812510 A CN 201610812510A CN 106432122 A CN106432122 A CN 106432122A
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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 invention provides a preparation method of 3-(2-chloro-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one as a meropenem intermediate. According to the preparation method, alpha-chloropropionyl chloride with lower reaction activity is adopted and cooperates with specific raw materials to play a role together, so that the reaction yield is greatly increased instead of being reduced; meanwhile, due to the lower activity of alpha-chloropropionyl chloride, fewer side reactions participate in the reaction, an obtained product contains fewer impurities, and 3-(2-chloro-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one with higher yield and purity is obtained and can replace 3-(2-bromo-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one for preparing meropenem. Besides, a synthetic process of 3-(2-chloro-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one requires no magnetic solid base catalysts, so that the reaction conditions are safer, the reaction path is simple, aftertreatment is convenient, the raw materials and the catalyst are inexpensive and available, and the preparation method is safe, environment-friendly, lower in preparation cost and more suitable for industrial 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 benzimidazole dihydrochloride
The preparation method of hexamethylene.
Background technology
Meropenem, also known as Meropenem, English name：Meropenem, chemical name：(4R,5S,6S)-3-[[(3S,5S)-
5- (dimethylcarbamoyl) -3- pyrrolidine] sulfur] -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 in nineteen ninety-five first in Italy's listing, subsequently gradually in whole world application listing, there is wide market prospect.As second
For carbapenem antibiotic, compared to other similar antibiotic, there is has a broad antifungal spectrum, antibacterial action is strong, stable to DHP-1 enzyme
The advantages of, it is mainly used in treating the serious bacterial infections such as respiratory tract infection, abdominal cavity infection, urinary tract infection, excellent.
, as one of key intermediate synthesizing meropenem, the quality of its quality is straight for Spirobromin benzimidazole dihydrochloride hexamethylene
Connect the yield having influence on meropenem and quality.The structure of Spirobromin benzimidazole dihydrochloride hexamethylene is as shown in formula II.However, adopting
The yield of the meropenem being obtained with Spirobromin benzimidazole dihydrochloride hexamethylene is not high.Meanwhile, prepare Spirobromin benzimidazole dihydrochloride
Raw material α-bromopropionyl bromide required for hexamethylene is expensive, abnormal smells from the patient is larger, and toxicity is higher.
Number of patent application be 201110203766.6 Chinese patent disclose a kind of 3- (2- bromine propiono)-spiral shell [2H-1,
3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4 (3H) -one preparation method, this method is initial former with salicylamide and Ketohexamethylene
Material, in the presence of solid acid catalyst, obtains spiral shell [2H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene in reflux in toluene reaction
Alkane] -4 (3H) -one；Then, in the presence of magnetic solid base catalyst, react with halogen acyl halide in toluene and obtain 3- (2- bromine
Propiono)-spiral shell [2H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4 (3H) -one, wherein, halogen acyl halide is α-bromopropionyl bromide.
The Spirobromin benzimidazole dihydrochloride hexamethylene yield that this method is obtained and purity are relatively low, meanwhile, need to adopt in preparation
With the complicated and expensive magnetic solid base catalyst of production process, course of reaction complexity, the dangerous system of reaction is higher, after
Process complicated, environmental pollution is serious, relatively costly.
Content of the invention
In view of this, the technical problem to be solved in the present invention is to provide a kind of meropenem intermediate chlorine propionyl spiral shell benzo
The preparation method of piperazine hexamethylene, the chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene prepared by this method can substitute Spirobromin benzene
And meropenem prepared by piperazine hexamethylene, and the yield of chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene and purity all higher.
The invention provides a kind of preparation method of meropenem intermediate chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene, including with
Lower step：By spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone and α-chlorpromazine chloride acid binding agent work
With under carry out condensation reaction in aprotic solvent, obtain chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene.
Preferably, described spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and tie up
The mol ratio of sour agent is 1：1.0～2.5：0.5～3.0.
Preferably, described spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone and aprotic solvent
Mass ratio is 1：1.0～5.0.
Preferably, described acid binding agent includes one or more of organic base and inorganic base.
Preferably, described organic base includes triethylamine, pyridine, DIPEA, DMAP, three second
One or more of hydramine and quaternary ammonium salt.
Preferably, described inorganic base includes one or more of potassium carbonate, ammonium carbonate and sodium carbonate.
Preferably, described aprotic solvent be toluene, dimethylbenzene, benzene, chlorobenzene, Nitrobenzol, acetone, dimethylformamide,
One or more of oxolane, dichloromethane, chloroform and carbon tetrachloride.
Preferably, the temperature of described condensation reaction be room temperature to reflux temperature, time of described condensation reaction is 0.5～
20h.
Preferably, described condensation reaction is carried out under conditions of shielding gas presence.
Preferably, after described condensation reaction, it is additionally included in cooling crystallize in proton solvent.
The invention provides a kind of preparation method of meropenem intermediate chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene, including with
Lower step：By spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone and α-chlorpromazine chloride acid binding agent work
With under carry out condensation reaction in aprotic solvent, obtain chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene.Disclosed in prior art
Prepare Spirobromin benzimidazole dihydrochloride hexamethylene using α-bromopropionyl bromide to compare, the present invention adopts the lower α-chlorine propionyl of reactivity
Chlorine, coordinates specific raw material one to work, not only will not reduce reaction yield, so that reaction yield is greatly improved on the contrary；
Simultaneously as the activity of α-chlorpromazine chloride lower so that participate in reaction side reaction less, enter obtained from impurity in products relatively
Few, thus yield and purity higher chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene have been obtained, and this yield and the higher chlorine of purity
Propionyl spiral shell benzimidazole dihydrochloride hexamethylene can replace Spirobromin benzimidazole dihydrochloride hexamethylene and prepare meropenem.In addition, the present invention carries
For chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene synthesis technique in, magnetic solid base catalyst need not be adopted, reaction condition is more
Safety, reaction scheme is simple, convenient post-treatment, and raw material and catalyst are cheap and easy to get, safety and environmental protection, and preparation cost is relatively low, more suitable
Close industrialized production.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical scheme is clearly and completely described it is clear that institute
The embodiment of description is only a part of embodiment of the present invention, rather than whole embodiments.Based on the embodiment in the present invention,
The every other embodiment that those of ordinary skill in the art are obtained under the premise of not making creative work, broadly falls into this
The scope of bright protection.
The invention provides a kind of preparation method of meropenem intermediate chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene, including with
Lower step：
By spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone and α-chlorpromazine chloride acid binding agent work
With under carry out condensation reaction in aprotic solvent, obtain chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene.
Preferably, specially：Under conditions of shielding gas exists, by spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'-
Hexamethylene] -4- ketone, α-chlorpromazine chloride, acid binding agent and aprotic solvent mixing, carry out condensation reaction, obtain chlorine propionyl spiral shell benzo
Piperazine hexamethylene.
The present invention has no special restriction to described protective gas, using protective gas well known to those skilled in the art is
Can, present invention preferably employs nitrogen.
Described spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone has the knot as shown in formula III
Structure：
Described α-chlorpromazine chloride has the structure as shown in formula (IV)：
Described acid binding agent includes one or more of organic base and inorganic base.Described organic base preferably include triethylamine,
Pyridine, N, one or more of N- diisopropylethylamine, DMAP, triethanolamine and quaternary ammonium salt.Described quaternary ammonium
Salt is preferably tetrabutyl ammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, cetyl trimethylammonium bromide, chlorination
In the double octadecyldimethyl ammonium of dodecyl dimethyl hexadecyldimethyl benzyl ammonium, bromination, octadecyldimethyl hydroxyethyl ammonium nitrate
One or more.Described inorganic base preferably includes one or more of potassium carbonate, ammonium carbonate and sodium carbonate.
Described aprotic solvent is preferably toluene, dimethylbenzene, benzene, chlorobenzene, Nitrobenzol, acetone, dimethylformamide, tetrahydrochysene
One or more of furan, dichloromethane, chloroform and carbon tetrachloride.
In the present invention, described spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride
It is preferably 1 with the mol ratio of acid binding agent：1.0～2.5：0.5～3.0；More preferably 1：1.4～1.6：0.8～1.4.At this
In bright some embodiments, described spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride with
The mol 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, described spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone is molten with non-proton
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, described spiral shell
[2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone is 1 with the mass ratio of aprotic solvent：3.1；Or 1：3.7；
Or 1：4.4；Or 1：5.
The present invention has no special restriction to the device of described condensation reaction, and the present invention is preferably four-hole boiling flask.
The temperature of described condensation reaction is preferably room temperature to reflux temperature, more preferably 50～90 DEG C；The present invention certain
In a little embodiments, the temperature of described condensation reaction is 50 DEG C, 55 DEG C, 60 DEG C, 70 DEG C, 80 DEG C, 90 DEG C.
The time of described condensation reaction is preferably 0.5～20h, more preferably 4.5～8h；In certain embodiments of the present invention
In, the time of described condensation reaction is 3.5h, 5h, 6h, 7h or 8h.
After described condensation reaction, it is preferably also included in cooling crystallize in proton solvent.Preferably, described cooling crystallize is concrete
For：After being cooled to recrystallization temperature, crystallize in stirring.
Described proton solvent is preferably one or more of alcohols solvent, more preferably methanol, ethanol, isopropanol, just
One or more of butanol and the tert-butyl alcohol.In the present invention, described proton solvent and spiral shell [2,3- dihydro -4H-1,3- benzo
Piperazine -2,1'- hexamethylene] -4- ketone mass ratio be preferably 0.5～5.0：1, more preferably 1～2：1.Some realities in the present invention
Apply in example, described proton solvent is 1 with the mass ratio of spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone：
1、1.5：1 or 4：1.
The present invention has no special restriction to the mode of above-mentioned cooling, using cooling method well known to those skilled in the art
?.The present invention has no special restriction to the mode of described stirring, using alr mode well known to those skilled in the art is
Can.The temperature of described crystallize is preferably -20～10 DEG C；In certain embodiments of the present invention, the temperature of described crystallize is -5 DEG C.
The time of described crystallize is preferably 1～3h；In certain embodiments of the present invention, the time of described crystallize is 2h.
Before described cooling crystallize in proton solvent, preferably also include being cooled to room temperature, cleaning, concentrating under reduced pressure；Described
After cooling crystallize in proton solvent, preferably also include filtering and drying.
In the present invention, it is preferred to, described cleaning is specially：First washed three times with the first clear water, then wash three times with alkali liquor,
Wash three times with the second clear water afterwards.The present invention has no special restriction to described first clear water and the second clear water, using this area skill
Clear water known to art personnel, the present invention is preferably：First clear water and the second clear water are deionized water.The present invention is to described
Alkali liquor and its mass percent have no special restriction, using alkaline solution well known to those skilled in the art and its percent mass
Number, the present invention is 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 described alkaline solution is preferably 0.5%～20%.Described
The mass ratio of the first clear water, alkali liquor and the second clear water is preferably 1.5～4：2～4：1.5～4.Described alkali liquor and described spiral shell [2,3-
Dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone mass ratio be preferably 2～4：1～1.5.
The present invention has no special restriction to the Apparatus and method for of described concentrating under reduced pressure, is known using those skilled in the art
Concentrating under reduced pressure equipment and method, the pressure to concentrating under reduced pressure and time have no special restriction to the present invention simultaneously, and decompression is dense
It is reduced to no liquid to flow out.The present invention has no special restriction to the described Apparatus and method for filtering and drying, using ability
Filtration known to field technique personnel and the Apparatus and method for of drying.
The present invention has no special restriction to the source of above-mentioned adopted raw material, the product that market is bought.
The product meropenem intermediate chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene being finally obtained has the knot as shown in formula I
Structure：
The invention provides a kind of preparation method of meropenem intermediate chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene, including with
Lower step：By spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone and α-chlorpromazine chloride acid binding agent work
With under carry out condensation reaction in aprotic solvent, obtain chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene.The present invention adopts reactivity
Lower α-chlorpromazine chloride, cooperation acid binding agent works with other raw materials one, not only will not reduce reaction yield, on the contrary so that instead
Yield is answered to be greatly improved；Simultaneously as the activity of α-chlorpromazine chloride is lower so that the side reaction participating in reaction is less, enter
Obtained from impurity in products less.The present invention, by further controlling reaction temperature and material proportion, obtains yield and purity
Higher chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene, and this yield and the higher chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene of purity are permissible
Replace Spirobromin benzimidazole dihydrochloride hexamethylene and prepare meropenem.In addition, the chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene that the present invention provides
In the synthesis technique of alkane, reaction condition is safer, and reaction scheme is simple, convenient post-treatment, and raw material and catalyst are cheap and easy to get,
Safety and environmental protection, preparation cost is relatively low, is more suitable for industrialized production.
In order to further illustrate the present invention, a kind of meropenem intermediate chlorine to present invention offer with reference to embodiments
The preparation method of propionyl spiral shell benzimidazole dihydrochloride hexamethylene is described in detail, but can not be understood as to the scope of the present invention
Limit.
Embodiment 1
According to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and triethylamine
Mol ratio is 1：1.4：1.2, weigh respectively 80g spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone,
α-the chlorpromazine chloride of 65g and the triethylamine of 45g；According to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone
Mass ratio with toluene is 1：3.1, weigh 250g toluene；According to [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -
4- ketone is 1 with the mass ratio of isopropanol：1, weigh 80g isopropanol.
Under nitrogen protection, by toluene, spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorine
Reacted in propionyl chloride and triethylamine addition four-hole boiling flask, the temperature of described reaction is 80 DEG C, the time of reaction is 5h.Reaction
After end, it is down to room temperature, washed three times with 200g respectively, washed three times with the sodium hydroxide solution of 200g8%, wash three with 200g
Secondary, merge organic faciess, be evaporated to no liquid and flow out.It is subsequently adding isopropanol, be cooled to -5 DEG C, stirring and crystallizing 2h, filter,
Dry, obtain chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene 106.5g.Its molar yield is 94.1%, and purity is 99.6%.
Embodiment 2
According to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and 4- diformazan ammonia
The mol ratio of yl pyridines is 1：1.5：0.8, weigh spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2, the 1'- hexamethylene of 80g respectively
Alkane] -4- ketone, the α-chlorpromazine chloride of 70g and the DMAP of 38g；According to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -
2,1'- hexamethylene] mass ratio of -4- ketone and dimethylbenzene is 1：3.7, weigh 300g dimethylbenzene；According to [2,3- dihydro -4H-1,3-
Benzimidazole dihydrochloride -2,1'- hexamethylene] mass ratio of -4- ketone and n-butyl alcohol is 1：1, weigh 80g n-butyl alcohol.
Under nitrogen protection, by dimethylbenzene, spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α -
Chlorpromazine chloride and DMAP add in four-hole boiling flask and are reacted, and the temperature of described reaction is 90 DEG C, reaction when
Between be 4.5h.After reaction terminates, it is down to room temperature, washed three times with 200g respectively, wash three with the sodium bicarbonate solution of 250g10%
Secondary, washed three times with 200g, merge organic faciess, be evaporated to no liquid and flow out.It is subsequently adding n-butyl alcohol, be cooled to -5 DEG C,
Stirring and crystallizing 2h, filters, and dries, obtains chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene 104.8g.Its molar yield is 92.5%, purity
For 99.3%.
Embodiment 3
According to rubbing of spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and pyridine
That ratio is 1：1.6：1.4, weigh spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, the 75g of 80g respectively
α-chlorpromazine chloride and 40g pyridine；According to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone and chlorobenzene
Mass ratio be 1：4.4, weigh 350g chlorobenzene；According to [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone with
The mass ratio of ethanol is 1：1, weigh 80g ethanol.
Under nitrogen protection, by chlorobenzene, spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorine
Reacted in propionyl chloride and pyridine addition four-hole boiling flask, the temperature of described reaction is 50 DEG C, the time of reaction is 8h.Reaction knot
Shu Hou, is down to room temperature, is washed three times with 200g respectively, is washed three times with the potassium hydroxide solution of 200g10%, washes three with 200g
Secondary, merge organic faciess, be evaporated to no liquid and flow out.It is subsequently adding ethanol, be cooled to -5 DEG C, stirring and crystallizing 2h, filters, dries
Dry, obtain chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene 107.6g.Its molar yield is 95.0%, and purity is 99.7%.
Embodiment 4
According to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and triethanolamine
Mol ratio be 1：1.5：1.3, weigh respectively 80g spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone,
α-the chlorpromazine chloride of 70g and the triethanolamine of 70g；According to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4-
Ketone is 1 with the mass ratio of benzene：5, weigh 400g benzene；According to [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone
Mass ratio with methanol is 1：1, weigh 80g methanol.
Under nitrogen protection, by benzene, spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorine third
Reacted in acyl chlorides and triethanolamine addition four-hole boiling flask, the temperature of described reaction is 80 DEG C, the time of reaction is 6h.Reaction
After end, it is down to room temperature, washed three times with 200g respectively, washed three times with the potassium bicarbonate solution of 250g10%, washed with 200g
Three times, merge organic faciess, be evaporated to no liquid and flow out.It is subsequently adding methanol, be cooled to -5 DEG C, stirring and crystallizing 2h, filter,
Dry, obtain chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene 104.1g.Its molar yield is 91.9%, and purity is 99.4%.
Embodiment 5
According to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and N, N- bis- is different
The mol ratio of propylethylamine is 1：1.6：1.4, weigh spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2, the 1'- hexamethylene of 80g respectively
Alkane] -4- ketone, the 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
[2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone is 1 with the mass ratio of methanol：1.5, weigh 120g methanol.
Under nitrogen protection, by dimethylformamide, spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4-
Reacted in ketone, α-chlorpromazine chloride and DIPEA addition four-hole boiling flask, the temperature of described reaction is 70 DEG C, instead
The time answered is 6h.After reaction terminates, it is down to room temperature, washed three times with 200g respectively, with the potassium bicarbonate solution of 250g10%
Wash three times, washed three times with 200g, merge organic faciess, be evaporated to no liquid and flow out.It is subsequently adding methanol, be cooled to -5
DEG C, stirring and crystallizing 2h, filters, dries, obtain chlorine propionyl spiral shell benzimidazole dihydrochloride 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- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and tetrabutyl bromine
The mol ratio changing ammonium is 1：1.6：1.3, weigh respectively the spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] of 80g -
4- ketone, the α-chlorpromazine chloride of 75g and the tetrabutyl ammonium bromide of 154g；According to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -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-
Benzimidazole dihydrochloride -2,1'- hexamethylene] mass ratio of -4- ketone and ethanol is 1：1.5, weigh 120g ethanol.
Under nitrogen protection, by carbon tetrachloride, spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone,
α-chlorpromazine chloride and tetrabutyl ammonium bromide add in four-hole boiling flask is reacted, and the temperature of described reaction is 55 DEG C, reaction when
Between be 8h.After reaction terminates, it is down to room temperature, washed three times with 200g respectively, washed three times with the potassium hydroxide solution of 250g9%,
Washed three times with 200g, merge organic faciess, be evaporated to no liquid and flow out.It is subsequently adding ethanol, be cooled to -5 DEG C, stirring analysis
Brilliant 2h, filters, and dries, obtains chlorine propionyl spiral shell benzimidazole dihydrochloride 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- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and sodium carbonate
Mol ratio is 1：1.6：1.1, weigh respectively 80g spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone,
α-the chlorpromazine chloride of 75g and the sodium carbonate of 43g；According to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone
Mass ratio with oxolane is 1：3.1, weigh 250g oxolane；According to [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -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 oxolane, spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone,
Reacted in α-chlorpromazine chloride and sodium carbonate addition four-hole boiling flask, the temperature of described reaction is 60 DEG C, the time of reaction is 7h.
After reaction terminates, it is down to room temperature, washed three times with 200g respectively, washed three times with the sodium carbonate liquor of 250g9%, washed with 200g
Three times, merge organic faciess, be evaporated to no liquid and flow out.It is subsequently adding the tert-butyl alcohol, be cooled to -5 DEG C, stirring and crystallizing 2h, mistake
Filter, dries, obtains chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene 102g.Its molar yield is 90.0%, and purity is 99.2%.
Embodiment 8
According to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and ammonium carbonate
Mol ratio is 1：1.6：1.2, weigh respectively 80g spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone,
α-the chlorpromazine chloride of 75g and the ammonium carbonate of 42g；According to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone
Mass ratio with chloroform is 1：3.1, weigh 250g chloroform；According to [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -
4- ketone is 1 with the mass ratio of n-butyl alcohol：1.5, weigh 120g n-butyl alcohol.
Under nitrogen protection, by chloroform, spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorine
Reacted in propionyl chloride and ammonium carbonate addition four-hole boiling flask, the temperature of described reaction is 55 DEG C, the time of reaction is 8h.Reaction
After end, it is down to room temperature, washed three times with 200g respectively, washed three times with the solution of potassium carbonate of 300g5%, wash three with 200g
Secondary, merge organic faciess, be evaporated to no liquid and flow out.It is subsequently adding n-butyl alcohol, be cooled to -5 DEG C, stirring and crystallizing 2h, filter,
Dry, obtain chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene 103g.Its molar yield is 90.8%, and purity is 99.1%.
Comparative example 1
According to rubbing of spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-bromopropionyl bromide and pyridine
That ratio is 1：1.6：1.4, weigh spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, the 127g of 80g respectively
α-bromopropionyl bromide and 40g pyridine；According to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone and chlorobenzene
Mass ratio be 1：4.4, weigh 350g chlorobenzene；According to [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone with
The mass ratio of ethanol is 1：1, weigh 80g ethanol.
Under nitrogen protection, by chlorobenzene, spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-bromine
Reacted in propionyl bromide and pyridine addition four-hole boiling flask, the temperature of described reaction is 50 DEG C, the time of reaction is 8h.Reaction knot
Shu Hou, is down to room temperature, is washed three times with 200g respectively, is washed three times with the potassium hydroxide solution of 200g10%, washes three with 200g
Secondary, merge organic faciess, be evaporated to no liquid and flow out.It is subsequently adding ethanol, be cooled to -5 DEG C, stirring and crystallizing 2h, filters, dries
Dry, obtain Spirobromin benzimidazole dihydrochloride hexamethylene 109g.Its molar yield is 84.5%, and purity is 97.9%.
Comparative example 2
According to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone with the mol ratio of α-chlorpromazine chloride it is
1：1.6, spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone and magnetic solid catalyst Mg6Al(OH)15CO3·4H2The mol ratio of O (magnetic solid base that magnetic mg_al hydrotalcite is obtained) is 1：1.4, weigh respectively 80g spiral shell [2,
3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, the α-chlorpromazine chloride of 75g and the magnetic solid catalyst of 819g
Mg6Al(OH)15CO3·4H2O；Matter according to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone and chlorobenzene
Amount ratio is 1：4.4, weigh 350g chlorobenzene；According to [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone and ethanol
Mass ratio be 1：1, weigh 80g ethanol.
Under nitrogen protection, by chlorobenzene, spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-chlorine
Propionyl chloride and magnetic solid base catalyst add in four-hole boiling flask and are reacted, and the temperature of described reaction is 50 DEG C, reaction when
Between be 8h.After reaction terminates, it is down to room temperature, washed three times with 200g respectively, washed three times with the potassium hydroxide solution of 200g10%,
Washed three times with 200g, merge organic faciess, be evaporated to no liquid and flow out.It is subsequently adding ethanol, be cooled to -5 DEG C, stirring analysis
Brilliant 2h, filters, and dries, obtains chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene 91g.Its molar yield is 85.5%, and purity is 96.5%.
Comparative example 3
According to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone with the mol ratio of α-bromopropionyl bromide it is
1：1.6, spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone and magnetic solid catalyst Mg6Al(OH)15CO3·4H2The mol ratio of O (magnetic solid base that magnetic mg_al hydrotalcite is obtained) is 1：1.4, weigh respectively 80g spiral shell [2,
3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, the α-bromopropionyl bromide of 127g and 819g magnetic retention base catalysiss
Agent；Mass ratio according to spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone and chlorobenzene is 1：4.4, weigh
350g chlorobenzene；Mass ratio according to [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone and ethanol is 1：1, claim
Take 80g ethanol.
Under nitrogen protection, by chlorobenzene, spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone, α-bromine
Reacted in propionyl bromide and magnetic solid catalyst addition four-hole boiling flask, the temperature of described reaction is 50 DEG C, the time of reaction
For 8h.After reaction terminates, it is down to room temperature, washed three times with 200g respectively, washed three times with the potassium hydroxide solution of 200g10%, use
200g washes three times, merges organic faciess, is evaporated to no liquid and flows out.It is subsequently adding ethanol, be cooled to -5 DEG C, stirring and crystallizing
2h, filters, and dries, obtains Spirobromin benzimidazole dihydrochloride hexamethylene 97g.Its molar yield is 75.0%, and purity is 97.1%.
By above-described embodiment and comparative example it can be seen that the present invention adopts the lower α-chlorpromazine chloride of reactivity
Coordinate other specific raw materials, not only will not reduce reaction yield, so that reaction yield is greatly improved on the contrary；Meanwhile, by
Activity in α-chlorpromazine chloride lower so that participate in reaction side reaction less, enter obtained from impurity in products less.The present invention
By further controlling reaction temperature and material proportion, obtain yield and the higher chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene of purity
Alkane, and this yield and the higher chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene of purity can replace Spirobromin benzimidazole dihydrochloride hexamethylene
Prepare meropenem.In addition, in the synthesis technique of chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene of present invention offer, reaction condition is more
Safety, reaction scheme is simple, convenient post-treatment, and raw material and catalyst are cheap and easy to get, safety and environmental protection, and preparation cost is relatively low, more suitable
Close industrialized production.
Described above to the disclosed embodiments, makes professional and technical personnel in the field be capable of or uses the present invention.
Multiple modifications to these embodiments will be apparent from for those skilled in the art, as defined herein
General Principle can be realized without departing from the spirit or scope of the present invention in other embodiments.Therefore, the present invention
It is not intended to be limited to the embodiments shown herein, and be to fit to and principles disclosed herein and features of novelty phase one
The scope the widest causing.
Claims (10)
1. a kind of preparation method of meropenem intermediate chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene is it is characterised in that include following
Step：
By spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,1'- hexamethylene] -4- ketone and α-chlorpromazine chloride in the presence of acid binding agent
Carry out condensation reaction in aprotic solvent, obtain chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene.
2. preparation method according to claim 1 it is characterised in that described spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,
1'- hexamethylene] -4- ketone, α-chlorpromazine chloride and acid binding agent mol ratio be 1：1.0～2.5：0.5～3.0.
3. preparation method according to claim 1 it is characterised in that described spiral shell [2,3- dihydro -4H-1,3- benzimidazole dihydrochloride -2,
1'- hexamethylene] mass ratio of -4- ketone and aprotic solvent is 1：1.0～5.0.
4. preparation method according to claim 1 is it is characterised in that described acid binding agent is included in organic base and inorganic base
One or more.
5. preparation method according to claim 4 is it is characterised in that described organic base includes triethylamine, pyridine, N, N- bis-
One or more of wopropyl ethyl amine, DMAP, triethanolamine and quaternary ammonium salt.
6. preparation method according to claim 4 is it is characterised in that described inorganic base includes potassium carbonate, ammonium carbonate and carbon
One or more of sour sodium.
7. preparation method according to claim 1 it is characterised in that described aprotic solvent be toluene, dimethylbenzene, benzene,
One or more of chlorobenzene, Nitrobenzol, acetone, dimethylformamide, oxolane, dichloromethane, chloroform and carbon tetrachloride.
8. preparation method according to claim 1 is it is characterised in that the temperature of described condensation reaction is room temperature to the temperature that flows back
Degree, the time of described condensation reaction is 0.5～20h.
9. preparation method according to claim 1 is it is characterised in that described condensation reaction is under conditions of shielding gas presence
Carry out.
10. preparation method according to claim 9 is it is characterised in that after described condensation reaction, be additionally included in proton solvent
Middle cooling crystallize.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108774188A (en) * | 2018-07-23 | 2018-11-09 | 湖北宇阳药业有限公司 | A kind of preparation method of meropenem intermediate |
| CN110025619A (en) * | 2019-04-29 | 2019-07-19 | 江苏汉阔生物有限公司 | Meropenem intermediate is preparing the application in anti-oxidation medicine |
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| CN108774188A (en) * | 2018-07-23 | 2018-11-09 | 湖北宇阳药业有限公司 | A kind of preparation method of meropenem intermediate |
| CN110025619A (en) * | 2019-04-29 | 2019-07-19 | 江苏汉阔生物有限公司 | Meropenem intermediate is preparing the application in anti-oxidation medicine |
| CN110025619B (en) * | 2019-04-29 | 2022-03-22 | 江苏汉阔生物有限公司 | Application of meropenem intermediate in preparation of antioxidant drugs |
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