CN108623598A - A kind of preparation method of Imipenem intermediate and Imipenem - Google Patents
A kind of preparation method of Imipenem intermediate and Imipenem Download PDFInfo
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- CN108623598A CN108623598A CN201810486886.3A CN201810486886A CN108623598A CN 108623598 A CN108623598 A CN 108623598A CN 201810486886 A CN201810486886 A CN 201810486886A CN 108623598 A CN108623598 A CN 108623598A
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- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
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Abstract
The present invention provides the preparation method of a kind of Imipenem intermediate and Imipenem, the preparation methods of Imipenem intermediate：At organic base A, compound III and diphenyl phosphate chloride are added in organic solvent A, intermediate IV is obtained by the reaction；At organic base B, Mercaptamine is added in intermediate IV and obtains Imipenem intermediate I through stirring, suction filtration, washing and drying after reaction；The preparation method of the Imipenem：At organic base C, Imipenem intermediate I and imines side chain are added in organic solvent D, intermediate V is obtained by the reaction；V separating-purifying of intermediate, organic solvent E and organic base D is then added, hydrogenation is carried out after adjusting pH, then through filtering, stirs, filters, washing is dried to obtain Imipenem II；The method overcomes in existing Imipenem preparation process, because impurity, by-product and the raw material accumulation in hydrogenation stage seriously lead to the defect that the conversion ratio of reactant is low and crystallinity is poor.
Description
Technical field
The present invention relates to pharmaceutical chemistry and the field of chemical synthesis, and in particular to a kind of Imipenem intermediate and Imipenem
Preparation method.
Background technology
Imipenem, also referred to as：6- (1- hydroxyethyls) -3- [[2- [(iminomethyl) amino] ethyl] sulphur] -7- oxos -
1- azabicyclos [3.2.0] hept-2-ene" -2- formic acid belongs to Carbapenems beta-lactam antibiotic, with a variety of penicillin knots
The generation of bacteria cell wall can be inhibited by closing, and parasitize bacterium in host cell to achieve the purpose that eliminate, and blue to leather
Family name positive and negative aerobe and anaerobic organism show extremely strong activity, are shown to beta-lactamase highly stable
Property, therefore great market potential, Clinical practice rate are high.
Currently, in the prior art, the synthetic method of Imipenem is summed up, mainly there are following several synthetic routes：
Synthetic route 1：US4292436 discloses a kind of method that Imipenem is prepared in situ, and is the bicyclic ketone of activation first
The carbonyl of the positions ester acid C3, then be condensed with shielded imines side chain, then make catalyst hydrogenation using platinum oxide and sloughs
Protecting group on C2 carboxylic acids and side chain imines.Process route is as follows：
Wherein R is hydrogen or blocking group；X is leaving group.
The advantages of this method is, does not have to detach any intermediate, directly obtains Imipenem.Disadvantage it is also obvious that from
Bicyclic ketone ester prepares the yield of Imipenem down to 35%, while the preparation of side chain N- formimino group -2- aminoothyl mercaptans includes
Four steps, and a large amount of water is needed to be extracted and washed, it is unfavorable on economical and environmentally friendly to result in.
Synthetic route 2：US4845261 and US4894450 discloses one kind using bicyclic ketone ester as parent nucleus, via four-step reaction
The new method in continuous synthesizing imine training south.Process route is as follows：
Wherein, R is to nitrobenzyl or to methoxy-benzyl.
This method continuously synthesizes the method synthesizing imine training south treated different things alike using four steps, and which results in final products to keep away
That exempts from has brought a large amount of impurity into so that product is difficult to detach and purify.Meanwhile in order to activate bicyclic ketone ester, use is at high price
Double dichlorophenyl phosphoryl chloride phosphorus oxychlorides as initiator, be not suitable for industrial-scale production, limit the development of the technique.
Synthetic route 3：US4374772, which is proposed, uses the thiomycin separated from Ka Teli streptomysins former as starting
The Imipenem semisynthesis of material.Process route is as follows：
The method seems simple, is difficult to operate actually.Since raw material thiomycin is obtained on a small quantity from microorganism, at the later stage
It is big to manage difficulty, economic inefficiencies, and it is quite stringent to the monitoring of PH (8.5) in the process, be not suitable for industrialized production.
Synthetic route 4：CN200610111831 is reported using bicyclic ketone ester parent nucleus as starting material, using phosphoryl chloride phosphorus oxychloride as
Activator is condensed to yield the Imipenem of double protections with the side chain with protecting group later, most obtains imines training through catalytic hydrogenation afterwards
South.
This method is since shielded side chain is unstable, and double protection imipenem easily sloughs imines first in hydrogenation process
Base group and develop into thiomycin, limit its application.
Synthetic route 5：WO2005056553 has made improvement in Imipenem chemical synthesis, is adsorbed using with ketogenesis
The mode of alkali protects the amino of thiomycin, obtains the sulfomycin derivant protected with lower band, then pass through hydrolysis, formimino group
Change, three step of catalytic hydrogenation obtains Imipenem
Wherein, R is to nitrobenzyl or to methoxy-benzyl.
The shortcomings that technique, is that the preparation process for adsorbing alkali is more complicated, and yield is not high, and pH value in hydrolytic process
It is difficult to control.In addition, subsequent catalytic hydrogenation agent and objective condition control is not disclosed in the patent.
By the typical itineraries in above five synthesizing imines training south it is found that synthetic route is generally using bicyclic ketone ester as parent nucleus, with
Phosphoryl chloride phosphorus oxychloride makees activator, so that the carbonyl on C2 is obtained reactivity, then be condensed with the imines side chain with protection, finally hydrogenation obtains
Imipenem.In synthesis technology, main to prepare Imipenem using the method for " treating different things alike ", centre is without reference to any point
The intermediate of high-purity is prepared from, purification operations, causes last hydrogenation stage because raw material, impurity and by-product largely accumulate,
So that the conversion ratio of reactant is low and crystallinity is poor, and the color of Imipenem crystal is deep, and stability is bad.
Invention content
In order to overcome the deficiencies of existing technologies, the present invention provides a kind of preparation method of Imipenem intermediate, with described
Intermediate prepares Imipenem, and impurity, by-product and the raw material accumulation because of the hydrogenation stage is overcome seriously to lead to reactant
The low defect with crystallinity difference of conversion ratio.
In order to achieve the above object, the technical solution adopted by the present invention is as follows：
A kind of preparation method of Imipenem intermediate, described method includes following steps：
(1) under -70-0 degrees Celsius, in the presence of organic base A, compound III and chlorine phosphorus are added in organic solvent A
Intermediate IV is obtained by the reaction in diphenyl phthalate；
The chemical structural formula of the compound III and intermediate IV is：
R1 is to nitrobenzyl or to methoxy-benzyl；
(2) under -50-0 degrees Celsius, in the presence of organic base B, Mercaptamine is added in the intermediate IV,
Agitated crystallization, suction filtration, mashing washing and drying successively, obtains the Imipenem intermediate I after insulation reaction 1-2.5h；
The chemical structural formula of the Imipenem intermediate I is：
Preferably, the organic solvent A is selected from one kind of pyrrolidinone compounds, amides, alkyl chloride hydro carbons, nitrile and alcohols
Or it is a variety of；Further, the organic solvent A is preferably N-Methyl pyrrolidone.
The organic base A and organic base B is selected from N, N- diisopropyl ethyl amines, diisopropylamine, pyridine, N, N- diformazan ammonia
It is one or more in yl pyridines, triethylamine and 2,6- lutidines；Further, the organic base A and organic base B is N,
N- diisopropyl ethyl amines and N, N- dimethylamino naphthyridines；
Ratio between the volume of the organic solvent A and the weight of compound III is 3-15ml：1g, preferably 7-
10ml:1g；The molar ratio of the organic base A and compound III is 1-4:1, preferably 1.5-2:1；The diphenyl phosphate chloride with
The molar ratio 1-2 of compound III:1, preferably 1-1.2:1.
Preferably, crystallization is stirred in solvent B, the solvent B is selected from one kind of nitrile, ethers, hydro carbons and esters
Or it is a variety of, further, solvent B is preferably acetonitrile；Carry out mashing washing with solvent C, the solvent C be selected from nitrile, ketone and
Esters it is one or more, further, solvent C is preferably ethyl acetate.
Preferably, the ratio between the volume and the weight of compound III of the solvent B is 8-20ml：1g, preferably 10-
12ml:1g；Ratio between the volume of the solvent C and the weight of compound III is 1-10ml：1g, preferably 1-10ml:1g；
The molar ratio of the Mercaptamine and compound III is 1-3:1, preferably 1.2-1.5:1, the organic base B and compound
III molar ratio is 1-4:1, preferably 1.5-2:1.
Another object of the present invention is to provide a kind of preparation method of the Imipenem using the Imipenem intermediate,
Described method includes following steps：
(1) it under -60-10 degrees Celsius, in the presence of organic base C, is added in organic solvent D in the Imipenem
Mesosome I and imines side chain, are obtained by the reaction intermediate V；
The chemical structural formula of the intermediate V is：
The chemical structural formula of the imines side chain is：
R2 is benzyl, to nitrobenzyl or to methoxy-benzyl；
(2) intermediate V after separating-purifying, is then added organic solvent E and organic base D, with acid in extractant
It adjusts pH to 7.0-7.5 (inhibit impurity to generate, while ensureing the normal suction filtration of hydrogenant agent palladium carbon or platinum carbon) and hydrogenation is added afterwards
Agent carries out catalytic hydrogenation, and successively through filtering after the completion of reaction, organic solvent F stirring and crystallizings filter, and washing is dried to obtain
Imipenem monohydrate II；
The chemical structural formula of the Imipenem monohydrate II is：
Preferably, the organic solvent D is selected from the one or more of alkyl chloride hydro carbons, nitrile and alcohols, further, institute
It is preferably dichloromethane and methanol to state solvent D；The organic base C is selected from N, N- diisopropyl ethyl amines, diisopropylamine, three
One or more in ethamine and pyridine, further, the organic base C is preferably N, N- diisopropyl ethyl amines.
Preferably, the ratio between the volume and the weight of the Imipenem intermediate I of the organic solvent D is 6-
20ml：1g, preferably 12-15ml:1g；The molar ratio of the organic base C and the Imipenem intermediate I is 1-4:1, preferably
For 1.5-2:1；The molar ratio 1-3 of the imines side chain and the Imipenem intermediate I:1, preferably 1.5-2:1；The extraction
It is 1 to take the molar ratio between agent and intermediate:15~20ml/g.
Preferably, the organic base D is selected from N, N- diisopropyl ethyl amines, diisopropylamine, triethylamine, pyridine, N, N-
One or more in dimethylaniline and N-methylmorpholine, further, the organic base D is preferably N-methylmorpholine；
The organic solvent E is selected from the one or more of ethyl alcohol, isopropanol, acetone, ethyl acetate and tetrahydrofuran, preferably
For isopropanol；
The organic solvent F is selected from the one or more of acetone, ethyl acetate, isopropanol, n-butanol and tetrahydrofuran, excellent
It is selected as acetone；
The acid is one or more in propionic acid, benzoic acid, acetic acid, formic acid and citric acid, preferably citric acid, makees
For buffer, C2 carboxylic acids exist with molecular forms after ensureing hydrogenation, inhibit free, to ensure to crystallize.
The hydrogenant agent is palladium carbon or platinum carbon, preferably palladium carbon, and the content of palladium or platinum is 0.5~35% in palladium carbon or platinum carbon
Content 0.5~35%.
Preferably, the temperature of the catalytic hydrogenation is 0-45 DEG C, time 10min-6h；Pressure is 1-2.5kg/
cm2。
Preferably, the ratio between the volume and the weight of Imipenem intermediate I of the solvent E is 5-20ml：1g, it is excellent
It is selected as 10-15ml:1g；Ratio between the volume and the weight of Imipenem intermediate I of the organic solvent F is 30-80ml：
1g, preferably 50-60ml:1g；The molar ratio of the organic base D and Imipenem intermediate I is 1-4:1, preferably 3-3.5:
1；The molar ratio of the acid and Imipenem intermediate I is 1-4:1, preferably 2-2.5:1.
With immediate prior art ratio, technical scheme of the present invention has following advantageous effect：
1, the present invention provides a kind of preparation method of Imipenem intermediate, and the sub- ampere south prepared in this way is intermediate
Body prepares Imipenem, overcomes in existing " treating different things alike " technique, because the impurity, by-product and raw material of last hydrogenation stage accumulate
It is serious to cause the conversion ratio of reactant low and the defect of crystallinity difference.
2, the present invention provides a kind of preparation method of Imipenem, is trained with the Imipenem intermediate to prepare imines
The content in crude product in south, the Imipenem of preparation is high, high income.
3, in a kind of preparation method of Imipenem of present invention offer, the intermediate V is detached in extractant and is carried
It is pure, avoid remaining raw material and the by-product of generation in reaction from having an adverse effect subsequent hydrogenation reaction.
4, the present invention provides a kind of preparation method of Imipenem, at low cost, is suitble to industrial-scale production.
Specific implementation mode
Technical scheme of the present invention is described further with reference to specific embodiment, it is involved each in embodiment
Class chemicals and reagent are unless otherwise specified commercially available.
Embodiment 1
A kind of preparation method of Imipenem intermediate, described method includes following steps：
(1) under -70 degrees Celsius, in organic base N, under N- diisopropyl ethyl amines with nitrogen atmosphere in the presence of protecting, in anti-
It answers and adds compound III and diphenyl phosphate chloride in the organic solvent N-Methyl pyrrolidone of kettle, detected through thin-layer chromatography (TLC)
Intermediate IV is obtained after the reaction was complete；
Ratio between the volume and the weight of compound III of the organic solvent N-Methyl pyrrolidone is 3ml：1g；Institute
The molar ratio for stating organic base N, N- diisopropyl ethyl amine and compound III is 1:1；The diphenyl phosphate chloride and compound III
Molar ratio 1：1；
The chemical structural formula of the compound III and intermediate IV is：
R1 is to nitrobenzyl or to methoxy-benzyl；
(2) under -50 degrees Celsius, in the presence of organic base N, N- diisopropyl ethyl amines, add in the intermediate IV
Enter Mercaptamine, is filtered successively through solvent acetonitrile stirring and crystallizing after insulation reaction 1h, solvent ethyl acetate mashing washing,
Then dry the Imipenem intermediate I；
The chemical structural formula of the Imipenem intermediate I is：
Ratio between the volume of the solvent acetonitrile and the weight of compound III is 8ml：1g；The solvent ethyl acetate
Volume and the weight of compound III between ratio be 1ml：1g；The molar ratio of the Mercaptamine and compound III is
1:1；The molar ratio of the organic base N, N- diisopropyl ethyl amines and compound III is 1:1.
In the method that the Imipenem intermediate prepares Imipenem, include the following steps：
(1) under -60 degrees Celsius, in organic base N, under N- diisopropyl ethyl amines with nitrogen atmosphere in the presence of protecting, in anti-
It answers and adds the Imipenem intermediate I and imines side chain in the organic solvent dichloromethane of kettle, intermediate V is obtained by the reaction；
Ratio between the volume of the organic solvent dichloromethane and the weight of the Imipenem intermediate I is 6ml：
1g；The molar ratio of the organic base N, N- diisopropyl ethyl amines and the Imipenem intermediate I is 1:1；The imines side
The molar ratio 1 of chain and the Imipenem intermediate I:1.
The chemical structural formula of the intermediate V is：
The chemical structural formula of the imines side chain is：
R2 is benzyl, to nitrobenzyl or to methoxy-benzyl；
(2) hydrogenation reaction cauldron is added in the intermediate V in purified water after separating-purifying, adds organic solvent isopropyl
Alcohol and organic base N-methylmorpholine, hydrogenant agent palladium carbon to be added after sour lime acid for adjusting pH to 7.0, in 0 DEG C of temperature and pressure
1kg/cm2Lower progress catalytic hydrogenation 10min is filtered to remove palladium carbon after the completion of reaction, and filtrate is transferred to crystallizing tank and is cooled to 0
DEG C, stirring and crystallizing in organic solvent-acetone is added, then through filtering, washing is dried to obtain Imipenem monohydrate II；
Palladium content 0.5% in the palladium carbon；
Ratio between the volume and the weight of Imipenem intermediate I of the organic solvent isopropanol is 5ml：1g；Institute
It is 30ml to state the ratio between the volume of organic solvent-acetone and the weight of Imipenem intermediate I：1g；The organic base N- first
The molar ratio of base morpholine and Imipenem intermediate I is 1:1；The molar ratio of the sour lime acid and Imipenem intermediate I is
1:1；
The purified water separating-purifying specifically includes：
The intermediate V is stirred phase inversion layering in purified water, obtains water phase one and organic phase one；
Organic phase one washed once with purified water, obtain water phase two；
Merge water phase one and two, obtains mixing water phase；
It is stripped the mixing water phase, obtains purifying water phase.
The chemical structural formula of the Imipenem monohydrate II is：
Embodiment 2
(1) under 0 degree Celsius, in organic base N, under N- dimethylamino naphthyridines with nitrogen atmosphere in the presence of protecting, in reaction kettle
Organic solvent N-Methyl pyrrolidone in addition compound III and diphenyl phosphate chloride, detect and react through thin-layer chromatography (TLC)
Intermediate IV is obtained after completely；
Ratio between the volume and the weight of compound III of the organic solvent N-Methyl pyrrolidone is 15ml：1g；
The molar ratio of the organic base N, N- dimethylamino naphthyridines and compound III is 4:1；The diphenyl phosphate chloride and compound III
Molar ratio 2：1；
The chemical structural formula of the compound III and intermediate IV is：
R1 is to nitrobenzyl or to methoxy-benzyl；
(2) under 0 degree Celsius, in the presence of organic base N, N- dimethylamino naphthyridines, half is added in the intermediate IV
Cystamine hydrochloride filters successively through solvent acetonitrile stirring and crystallizing after insulation reaction 2.5h, solvent ethyl acetate mashing washing, so
Dry the Imipenem intermediate I afterwards；
The chemical structural formula of the Imipenem intermediate I is：
Ratio between the volume of the solvent acetonitrile and the weight of compound III is 20ml：1g；The solvent acetic acid second
Ratio between the volume of ester and the weight of compound III is 10ml：1g；Mole of the Mercaptamine and compound III
Than being 3:1；The molar ratio of the organic base N, N- dimethylamino naphthyridines and compound III is 4:1.
The method for preparing Imipenem using the Imipenem intermediate, includes the following steps：
(1) under 10 degrees Celsius, in the case where organic base diisopropylamine exists and nitrogen atmosphere is protected, in the organic of reaction kettle
The Imipenem intermediate I and imines side chain are added in solvent methanol, and intermediate V is obtained by the reaction；
Ratio between the volume and the weight of the Imipenem intermediate I of the organic solvent methanol is 20ml：1g；
The molar ratio of the organic base diisopropylamine and the Imipenem intermediate I is 4:1；The imines side chain and the imines
The molar ratio 3 of the southern intermediate I of training:1.
The chemical structural formula of the intermediate V is：
The chemical structural formula of the imines side chain is：
R2 is benzyl, to nitrobenzyl or to methoxy-benzyl；
(2) hydrogenation reaction cauldron is added in the intermediate V in purified water after separating-purifying, adds organic solvent ethyl alcohol
With organic base N, N- diisopropyl ethyl amines, hydrogenant agent platinum carbon to be added after vinegar acid for adjusting pH to 7.5, in temperature 45 C and pressure
Power 2.5kg/cm2Lower progress catalytic hydrogenation 6h is filtered to remove platinum carbon after the completion of reaction, and filtrate is transferred to crystallizing tank and is cooled to 0
DEG C, stirring and crystallizing in organic solvent ethyl acetate is added, then through filtering, washing is dried to obtain Imipenem monohydrate II；
Platinum content 35% in the platinum carbon；
Ratio between the volume and the weight of Imipenem intermediate I of the organic solvent ethyl alcohol is 20ml：1g；It is described
Ratio between the volume and the weight of Imipenem intermediate I of organic solvent ethyl acetate is 80ml：1g；The organic base N,
The molar ratio of N- diisopropyl ethyl amines and Imipenem intermediate I is 4:1；The vinegar acid and Imipenem intermediate I
Molar ratio is 4:1；
The purified water separating-purifying specifically includes：
The intermediate V is stirred phase inversion layering in purified water, obtains water phase one and organic phase one；
Organic phase one washed once with purified water, obtain water phase two；
Merge water phase one and two, obtains mixing water phase；
It is stripped the mixing water phase, obtains purifying water phase.
The chemical structural formula of the Imipenem monohydrate II is：
Embodiment 3
A kind of preparation method of Imipenem intermediate, described method includes following steps：
(1) under -35 degrees Celsius, in organic base N, N- diisopropyl ethyl amines and N, N- dimethylamino naphthyridine exist and nitrogen
Under gas atmosphere protection, compound III and diphenyl phosphate chloride, warp are added in the organic solvent N-Methyl pyrrolidone of reaction kettle
Thin-layer chromatography (TLC) detection obtains intermediate IV after the reaction was complete；
Ratio between the volume and the weight of compound III of the organic solvent N-Methyl pyrrolidone is 8ml：1g；Institute
It is 2 to state organic base N, N- diisopropyl ethyl amine and the molar ratio of N, N- dimethylamino naphthyridine and compound III:1；The chlorine phosphorus
The molar ratio 1.2 of diphenyl phthalate and compound III：1；
The chemical structural formula of the compound III and intermediate IV is：
R1 is to nitrobenzyl or to methoxy-benzyl；
(2) under -25 degrees Celsius, in organic base N, the presence of N- diisopropyl ethyl amines and N, N- dimethylamino naphthyridine
Under, Mercaptamine is added in the intermediate IV, after insulation reaction 1.5h successively through solvent acetonitrile stirring and crystallizing, suction filtration,
Solvent ethyl acetate mashing washing, then dry the Imipenem intermediate I；
The chemical structural formula of the Imipenem intermediate I is：
Ratio between the volume of the solvent acetonitrile and the weight of compound III is 11ml：1g；The solvent acetic acid second
Ratio between the volume of ester and the weight of compound III is 5ml：1g；The molar ratio of the Mercaptamine and compound III
It is 1.5:1；The organic base N, N- diisopropyl ethyl amines and the molar ratio of N, N- dimethylamino naphthyridine and compound III are 2:
1。
The method for preparing Imipenem using the Imipenem intermediate, includes the following steps：
(1) under -30 degrees Celsius, in the case where organic bases triethylamine exists and nitrogen atmosphere is protected, in the organic molten of reaction kettle
The Imipenem intermediate I and imines side chain are added in agent dichloromethane and methanol, and intermediate V is obtained by the reaction；
Ratio between the organic solvent dichloromethane and the volume and the weight of the Imipenem intermediate I of methanol
For 13ml：1g；The molar ratio of the organic bases triethylamine and the Imipenem intermediate I is 2:1；The imines side chain and institute
State the molar ratio 1.5 of Imipenem intermediate I:1.
The chemical structural formula of the intermediate V is：
The chemical structural formula of the imines side chain is：
R2 is benzyl, to nitrobenzyl or to methoxy-benzyl；
(2) hydrogenation reaction cauldron is added in the intermediate V in purified water after separating-purifying, adds organic solvent tetrahydrochysene
Furans and organic base pyridine, hydrogenant agent palladium carbon is added after sour third acid for adjusting pH to 7.2, in 25 DEG C of temperature and pressure 1.5kg/
cm2Lower progress catalytic hydrogenation 3h is filtered to remove palladium carbon after the completion of reaction, and filtrate is transferred to crystallizing tank and is cooled to 0 DEG C, and addition has
Stirring and crystallizing in solvent isopropanol, then through filtering, washing is dried to obtain Imipenem monohydrate II；
Palladium content 10% in the palladium carbon；
Ratio between the volume and the weight of Imipenem intermediate I of the organic solvent tetrahydrofuran is 10ml：1g；
Ratio between the volume and the weight of Imipenem intermediate I of the organic solvent isopropanol is 50ml：1g；The organic base
The molar ratio of pyridine and Imipenem intermediate I is 3:1；The molar ratio of the acid propionic acid and Imipenem intermediate I is 2:1；
The purified water separating-purifying specifically includes：
The intermediate V is stirred phase inversion layering in purified water, obtains water phase one and organic phase one；
Organic phase one washed once with purified water, obtain water phase two；
Merge water phase one and two, obtains mixing water phase；
It is stripped the mixing water phase, obtains purifying water phase.
The chemical structural formula of the Imipenem monohydrate II is：
The preparation method of Imipenem described in 1-3 of the embodiment of the present invention is compared with existing Imipenem preparation method
Compared with as a result such as following table：
The above embodiments are merely illustrative of the technical scheme of the present invention and are not intended to be limiting thereof, although with reference to above-described embodiment pair
The present invention is described in detail, those of ordinary skill in the art still can to the present invention specific implementation mode into
Row modification either equivalent replacement these without departing from any modification of spirit and scope of the invention or equivalent replacement, applying
Within the claims of the pending present invention.
Claims (10)
1. a kind of preparation method of Imipenem intermediate, which is characterized in that described method includes following steps：
(1) under -70-0 degrees Celsius, in the presence of organic base A, compound III and chlorine di(2-ethylhexyl)phosphate are added in organic solvent A
Intermediate IV is obtained by the reaction in phenyl ester；
The chemical structural formula of the compound III and intermediate IV is：
R1 is to nitrobenzyl or to methoxy-benzyl；
(2) under -50-0 degrees Celsius, in the presence of organic base B, Mercaptamine, heat preservation is added in the intermediate IV
1-2.5h agitated crystallization, suction filtration, mashing washing and drying successively are reacted, the Imipenem intermediate I is obtained；
The chemical structural formula of the Imipenem intermediate I is：
2. a kind of preparation method of Imipenem intermediate as described in claim 1, which is characterized in that the organic solvent A
Selected from the one or more of pyrrolidinone compounds, amides, alkyl chloride hydro carbons, nitrile and alcohols；
The organic base A and organic base B is selected from N, N- diisopropyl ethyl amines, diisopropylamine, pyridine, N, N- dimethylamino pyrroles
It is one or more in pyridine, triethylamine and 2,6- lutidines；
Ratio between the volume of the organic solvent A and the weight of compound III is 3-15ml：1g；The organic base A and change
The molar ratio for closing object III is 1-4:1；The molar ratio 1-2 of the diphenyl phosphate chloride and compound III:1.
3. a kind of preparation method of Imipenem intermediate as described in claim 1, which is characterized in that carried out in solvent B
Stirring and crystallizing, the solvent B are selected from the one or more of nitrile, ethers, hydro carbons and esters；Mashing washing, institute are carried out with solvent C
It states solvent C and is selected from the one or more of nitrile, ketone and esters.
4. a kind of preparation method of Imipenem intermediate as claimed in claim 3, which is characterized in that the body of the solvent B
Ratio between product and the weight of compound III is 8-20ml：1g；Between the volume of the solvent C and the weight of compound III
Ratio is 1-10ml：1g；The molar ratio of the Mercaptamine and compound III is 1-3:1, the organic base B and compound
III molar ratio is 1-4:1.
5. a kind of preparation method of Imipenem using Imipenem intermediate as described in claim 1, which is characterized in that
Include the following steps：
(1) under -60-10 degrees Celsius, in the presence of organic base C, the Imipenem intermediate is added in organic solvent D
I and imines side chain, intermediate V is obtained by the reaction；
The chemical structural formula of the intermediate V is：
The chemical structural formula of the imines side chain is：
R2 is benzyl, to nitrobenzyl or to methoxy-benzyl；
(2) the intermediate V in extractant separating-purifying, then add organic solvent E and organic base D, with acid for adjusting pH
To 7.0-7.5, hydrogenant agent is added and carries out catalytic hydrogenation, successively through filtering, organic solvent F stirring analysis after the completion of reaction
Crystalline substance filters, and washing is dried to obtain Imipenem monohydrate II；
The chemical structural formula of the Imipenem monohydrate II is：
6. the preparation method of Imipenem as claimed in claim 5, which is characterized in that the organic solvent D is selected from alkyl chloride
Hydro carbons, nitrile and alcohols it is one or more；The organic base C is selected from N, N- diisopropyl ethyl amines, diisopropylamine, three second
It is one or more in amine and pyridine.
7. the preparation method of Imipenem as claimed in claim 5, which is characterized in that the volume of the organic solvent D and institute
It is 6-20ml to state the ratio between the weight of Imipenem intermediate I：1g；The organic base C and the Imipenem intermediate I
Molar ratio be 1-4:1；The molar ratio 1-3 of the imines side chain and the Imipenem intermediate I:1.
8. the preparation method of Imipenem as claimed in claim 5, which is characterized in that the organic base D is selected from N, and N- bis- is different
Ethylamine, diisopropylamine, triethylamine, pyridine, N, it is one or more in accelerine and N-methylmorpholine；
The organic solvent E is selected from the one or more of ethyl alcohol, isopropanol, acetone, ethyl acetate and tetrahydrofuran；
The organic solvent F is selected from the one or more of acetone, ethyl acetate, isopropanol, n-butanol and tetrahydrofuran；
The acid is one or more in propionic acid, benzoic acid, acetic acid, formic acid and citric acid；
The hydrogenant agent be palladium carbon or platinum carbon,：The content of palladium or platinum is 0.5~35% in palladium carbon or platinum carbon.
9. the preparation method of Imipenem as claimed in claim 5, which is characterized in that the temperature of the catalytic hydrogenation is
0-45 DEG C, time 10min-6h, pressure 1-2.5kg/cm2。
10. the preparation method of Imipenem as claimed in claim 5, which is characterized in that the volume of the solvent E is trained with imines
Ratio between the weight of southern intermediate I is 5-20ml：1g, the weight of the volume and Imipenem intermediate I of the organic solvent F
Ratio between amount is 30-80ml：The molar ratio of 1g, the organic base D and Imipenem intermediate I is 1-4:1；It is described acid with
The molar ratio of Imipenem intermediate I is 1-4:1.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109988168A (en) * | 2019-05-07 | 2019-07-09 | 重庆天地药业有限责任公司 | A method of southern crude product is trained using micro passage reaction synthesizing imine |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0429726A1 (en) * | 1987-05-11 | 1991-06-05 | Merck & Co. Inc. | Process for 2-(aminoalkylthio)carbapenems |
| JP2000044587A (en) * | 1998-07-30 | 2000-02-15 | Kanegafuchi Chem Ind Co Ltd | Production of carbapenem antibiotic intermediate |
| CN1481384A (en) * | 2000-11-03 | 2004-03-10 | ʵ | Process for prepn. of crystalline N-forminidoyl thienamycin monohydrate (imipenem monohydrate) |
| CN1522255A (en) * | 2001-05-18 | 2004-08-18 | ʵ | Process for the isolation of crystalline imipenem |
| CN1829716A (en) * | 2003-12-09 | 2006-09-06 | (株)中外制药 | A new process for preparation of imipenem |
| CN101735219A (en) * | 2009-12-29 | 2010-06-16 | 浙江海正药业股份有限公司 | Imipenem intermediate and preparation method thereof |
| CN101747334A (en) * | 2008-12-16 | 2010-06-23 | 上海医药工业研究院 | Method for preparing double protection imipenem |
| CN101891743A (en) * | 2010-07-20 | 2010-11-24 | 深圳市海滨制药有限公司 | Method for synthesizing meropenem intermediate |
| CN101921274A (en) * | 2010-07-16 | 2010-12-22 | 深圳市海滨制药有限公司 | Method for preparing imipenem |
| CN101955482A (en) * | 2010-09-18 | 2011-01-26 | 景德镇市富祥药业有限公司 | Method for preparing protected meropenem |
-
2018
- 2018-05-21 CN CN201810486886.3A patent/CN108623598A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0429726A1 (en) * | 1987-05-11 | 1991-06-05 | Merck & Co. Inc. | Process for 2-(aminoalkylthio)carbapenems |
| JP2000044587A (en) * | 1998-07-30 | 2000-02-15 | Kanegafuchi Chem Ind Co Ltd | Production of carbapenem antibiotic intermediate |
| CN1481384A (en) * | 2000-11-03 | 2004-03-10 | ʵ | Process for prepn. of crystalline N-forminidoyl thienamycin monohydrate (imipenem monohydrate) |
| CN1522255A (en) * | 2001-05-18 | 2004-08-18 | ʵ | Process for the isolation of crystalline imipenem |
| CN1829716A (en) * | 2003-12-09 | 2006-09-06 | (株)中外制药 | A new process for preparation of imipenem |
| CN101747334A (en) * | 2008-12-16 | 2010-06-23 | 上海医药工业研究院 | Method for preparing double protection imipenem |
| CN101735219A (en) * | 2009-12-29 | 2010-06-16 | 浙江海正药业股份有限公司 | Imipenem intermediate and preparation method thereof |
| CN101921274A (en) * | 2010-07-16 | 2010-12-22 | 深圳市海滨制药有限公司 | Method for preparing imipenem |
| CN101891743A (en) * | 2010-07-20 | 2010-11-24 | 深圳市海滨制药有限公司 | Method for synthesizing meropenem intermediate |
| CN101955482A (en) * | 2010-09-18 | 2011-01-26 | 景德镇市富祥药业有限公司 | Method for preparing protected meropenem |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109988168A (en) * | 2019-05-07 | 2019-07-09 | 重庆天地药业有限责任公司 | A method of southern crude product is trained using micro passage reaction synthesizing imine |
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