CN104650119B - A kind of preparation method of beta lactam compounds - Google Patents
A kind of preparation method of beta lactam compounds Download PDFInfo
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- CN104650119B CN104650119B CN201510067470.4A CN201510067470A CN104650119B CN 104650119 B CN104650119 B CN 104650119B CN 201510067470 A CN201510067470 A CN 201510067470A CN 104650119 B CN104650119 B CN 104650119B
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- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/06—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 containing at least one condensed beta-lactam ring system, provided for by groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00, e.g. a penem or a cepham system
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Abstract
A kind of preparation method of beta lactam compounds of the present invention, belongs to medicinal chemistry art.The method is with Utimox and 6 Aminopenicillin alkanoic acids as raw material, successfully synthesize beta lactam compounds (2S, 5R, 6R) 6 ((2S, 5R, 6R) 6 ((R) 2 amino 2 (4 hydroxy phenyl) acetylamino) 3,3 dimethyl, 7 oxo, 4 thia, 1 azabicyclo [3.2.0] heptane, 2 formamide) 3,3 dimethyl, 7 oxo, 4 thia, 1 azabicyclo [3.2.0] heptane, 2 formic acid, the preparation method mild condition, preparation method is simple, can realize high-volume synthesis.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to a kind of preparation method of 'beta '-lactam compounds.
Background technology
Beta-lactam antibiotic clinically applies quite varied due to its efficient, low toxicity, but its allergic reaction
Occupy first of various kinds of drug.Wherein, the anaphylactogen for causing beta-lactam antibiotic type Ⅰ hypersensitivity reaction is not beta-lactam
Class antibiotic itself, but macromolecule impurity present in which.Macromolecule impurity in antibiotic medicine is generally divided by its source
For Adventitious impurities and endogenous impurity：Adventitious impurities include the class impurity such as albumen, polypeptide, polysaccharide, or antibiotic and albumen,
The conjugate of polypeptide, polysaccharide etc., Adventitious impurities are typically derived from zymotechnique；Endogenous impurity means antibiotic medicine itself
Polymerizate, polymer may be from production process, can be formed again in storage, or even also can be produced by improper use in medication
It is raw.
Existing prepare compound Amoxicillin impurity L is obtained using chromatographic separation technology, its separating effect and
Efficiency is all very limited, it is impossible to which the product for obtaining q.s carries out follow-up research.
The content of the invention
It is an object of the invention to provide a kind of preparation method of 'beta '-lactam compounds, the preparation method reaction condition temperature
With, and 'beta '-lactam compounds can be synthesized in batches.
The present invention provides a kind of preparation method of 'beta '-lactam compounds, and the preparation method includes：
Step one：The synthesis of compound III
Utimox and sodium hydrate aqueous solution are mixed, mixed solution is obtained, then in mixed solution
Benzyl chloroformate reaction is added, acid is added and is adjusted to acidity, obtain compound III (2S, 5R, 6R) -3,3- dimethyl -6-
[(R) -2- (benzyloxycarbonyl amino) -2- (4- benzyloxycarbonyl group oxygen phenyl) acetamido] -7- oxygen band -4- thia -1- azabicyclos
[3.2.0] heptane -2- formic acid；
Step 2：The synthesis of compound VII
6-aminopenicillanic acid and triethylamine are mixed, and are obtained mixed solution, then acetyl are added in mixed solution
Ethyl acetate, obtains oily compound, and oily compound is dissolved in solvent, is subsequently adding benzyl chloride stirring, obtains compound VII
(2S, 5R, 6R)-benzyl 6- (((Z) butenoic acid ethyl -2- bases) amino) -3,3- dimethyl -7- oxo -4- thia -1- azepines are double
Ring [3.2.0] heptane -2- formic acid esters；
Step 3：The synthesis of compound IV
Compound VII is dissolved in solvent, the stirring of p-methyl benzenesulfonic acid monohydrate is subsequently adding, is added ether, obtain
Compound IV (2S, 5R, 6R) -2- (benzyloxycarbonyl group) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos [3.2.0] heptan
Alkane -6- amino tosilate；
Step 4：The synthesis of compound II
Compound III is dissolved in organic solvent, is added organic amine, condensation reagent is added under ice bath, obtain mixed solution
Ⅰ；Compound IV is dissolved in solvent, organic amine is added, is obtained mixed solution II；Mixed solution II is added into above-mentioned mixed solution
In I, compound II (2S, 5R, 6R)-benzyl 6- ((2S, 5R, 6R) -6- ((R) -2- (benzyloxycarbonyl amino) -2- (4- (benzyls are obtained
Oxygen carbonyl oxygen phenyl) acetylamino) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos [3.2.0] heptane -2- formyls
Amine) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos [3.2.0] heptane -2- formic acid esters；
Step 5：The synthesis of compound I
Compound II is dissolved in solvent, palladium catalyst is subsequently adding, and is passed through hydrogen reaction, obtain compound I (2S,
5R, 6R) -6- ((2S, 5R, 6R) -6- ((R) -2- amino -2- (4- hydroxy phenyls) acetylaminos) -3,3- dimethyl -7- oxos -
4 thia -1- azabicyclos [3.2.0] heptane -2- formamides) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos
[3.2.0] heptane -2- formic acid.
Preferably, the mol ratio of step one Utimox and benzyl chloroformate is 1：2.
Preferably, the mol ratio of the step 2 6-aminopenicillanic acid, triethylamine, ethyl acetoacetate and benzyl chloride
For 10：20：10：11.
Preferably, the mol ratio of the step 3 compound VII and p-methyl benzenesulfonic acid monohydrate is 1：1.
Preferably, the step 4 compound III and BTA -1- bases-epoxide tripyrrole alkyl hexafluorophosphate
Mol ratio be 10：12.
Preferably, the organic amine of the step 4 is triethylamine, N, N- diisopropyl ethyl amine or N, N- dimethyl
Aniline.
Preferably, the condensation reagent of the step 4 be N, N '-dicyclohexylcarbodiimide, 1- ethyls-(3- dimethyl
Aminopropyl) carbodiimide, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, 1- ethyls-(3- dimethylaminos
Base propyl group) carbodiimide mixed with hydroxy benzo triazole, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride with
Hydroxy benzo triazole mixes, hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl phosphorus, hexafluorophosphoric acid (7- azepine benzos
Triazole -1- epoxides) tripyrrole alkane phosphorus, BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester or O- (7- azepines
BTA -1- bases)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester.
Preferably, the palladium catalyst of the step 5 is Pd/C or Pd (OH)2/C。
Preferably, the pressure of the hydrogen of the step 5 is 0.1～10MPa.
Beneficial effects of the present invention
A kind of preparation method of 'beta '-lactam compounds of the present invention, the method are blue or green with Utimox and 6- amino
Mycin alkanoic acid is raw material, by selective hydroxyl, amino and carboxy protective, amide condensed and protective reaction, is successfully synthesized
Amoxicillin impurity L (compound I), i.e. 'beta '-lactam compounds (2S, 5R, 6R) -6- ((2S, 5R, 6R) -6- ((R) -2- ammonia
Base -2- (4- hydroxy phenyls) acetylamino) -4 thia -1- azabicyclos [3.2.0] heptane -2- first of -3,3- dimethyl -7- oxos
Acid amides) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos [3.2.0] heptane -2- formic acid, the preparation method condition temperature
With preparation method is simple, can realize high-volume synthesis, so as to be used for Amoxicillin antiallergy research and novel ss-lactam chemical combination
The exploitation of thing and study on mechanism etc..
Description of the drawings
Fig. 1 is the nucleus magnetic hydrogen spectrum figure that the embodiment of the present invention 1 prepares compound I.
Specific embodiment
The present invention provides a kind of preparation method of 'beta '-lactam compounds, and the preparation method includes：
Step one：The synthesis of compound III
In reaction vessel, Utimox, sodium hydrate aqueous solution and solvent are mixed, preferably at room temperature
Stirring 10-15min, obtains mixed solution, then in mixed solution adds benzyl chloroformate to react, and described reaction condition is excellent
It is selected under ice bath, it is complete to raw material conversion by TLC monitorings reaction, add acid and be adjusted to acidity, adjustment pH value is to 4～5, described
Acid be preferably hydrochloric acid, concentration is preferably 1M, and finally preferably through ethyl acetate point liquid, organic layer washing, saturated sodium-chloride are washed,
Anhydrous magnesium sulfate is dried, and suction filtration, organic phase are spin-dried for, and obtain compound III (2S, 5R, 6R) -3,3- bis- through column chromatography for separation
Methyl -6- [(R) -2- (benzyloxycarbonyl amino) -2- (4- benzyloxycarbonyl group oxygen phenyl) acetamido] -7- oxygen band -4- thia -1- nitrogen
Miscellaneous bicyclic [3.2.0] heptane -2- formic acid；The mol ratio of the Utimox and benzyl chloroformate is preferably 1：2, institute
The solvent stated is preferably tetrahydrofuran, Utimox quality (g)：The volume (ml) of sodium hydrate aqueous solution is
3.65：30；The concentration of sodium hydrate aqueous solution is 1M.
Step 2：The synthesis of compound VII
In reaction vessel, 6-aminopenicillanic acid is dissolved in solvent, preferably triethylamine is added under condition of ice bath
Stirring mixing, stirs to raw material and is completely dissolved, obtain mixed solution, and described solvent is preferably dichloromethane, then to mixing
Ethyl acetoacetate is added dropwise in solution, preferably reaction TLC monitorings at room temperature, vacuum distillation after completion of the reaction removes solvent,
Obtain oily compound；Oily compound is dissolved in solvent, described solvent is not particularly limited, preferably dimethyl formyl
Amine, is subsequently adding benzyl chloride, and 2-4h is preferably stirred at room temperature, reactant is obtained, by reactant Jing extractions, washing, dry filter,
Obtain compound VII (2S, 5R, 6R)-benzyl 6- (((Z) butenoic acid ethyl -2- bases) amino) -3,3- dimethyl -7- oxo -4-
Thia -1- azabicyclos [3.2.0] heptane -2- formic acid esters；The 6-aminopenicillanic acid, triethylamine, ethyl acetoacetate
10 are preferably with the mol ratio of benzyl chloride：20：10：11.
Step 3：The synthesis of compound IV
Compound VII is dissolved in solvent, described solvent is not particularly limited, energy dissolved compound VII, preferably
For acetone, the stirring of p-methyl benzenesulfonic acid monohydrate is subsequently adding, described mixing time is preferably 10-15min, adds second
Ether, the reactant Jing suction filtrations for obtaining, washing, obtains compound IV (2S, 5R, 6R) -2- (benzyloxycarbonyl group) -3,3- dimethyl -7-
Oxo -4- thia -1- azabicyclos [3.2.0] heptane -6- amino tosilate；The compound VII and to toluene sulphur
The mol ratio of sour monohydrate is preferably 1：1；
Step 4：The synthesis of compound II
Compound III is dissolved in organic solvent, described organic solvent is preferably dichloromethane, tetrahydrofuran, acetonitrile,
One or more in ethyl acetate, toluene or DMF, are subsequently adding organic amine, and described organic amine is excellent
Elect triethylamine, N, N- diisopropyl ethyl amines or DMA as, under ice bath, add condensation reagent stirring, it is described
Mixing time is 1-3min, obtains mixed solution I；Compound IV is dissolved in solvent, described solvent is not particularly limited, energy
Dissolved compound IV, preferably dichloromethane, are subsequently adding the stirring of organic amine ice bath, and described organic amine is preferably three second
Amine, N, N- diisopropyl ethyl amines or DMA, described mixing time is 1-3min, obtains mixed solution
Ⅱ；Mixed solution II is added in above-mentioned mixed solution I, stirring monitoring, after raw material reaction is complete, Jing separates washing, is dried, subtracts
Pressure obtains compound II (2S, 5R, 6R)-benzyl 6- ((2S, 5R, 6R) -6- ((R) -2- (benzyloxycarbonyl amino) -2- (4- (benzyloxies
Ketonic oxygen phenyl) acetylamino) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos [3.2.0] heptane -2- formyls
Amine) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos [3.2.0] heptane -2- formic acid esters；The compound III and contracting
The mol ratio for closing reagent is 10：The quality (mg) of 12, described compound III:The volume (ml) of organic amine is 633：0.37；Change
The quality (mg) of compound IV:The volume (ml) of organic amine is 480：0.37；The mass ratio of compound III and compound IV is 633：
480；Described condensation reagent be N, N '-dicyclohexylcarbodiimide (DCC), 1- ethyls-(3- dimethylaminopropyls) carbon two
Imines (EDC), 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride (EDCI), 1- ethyls-(3- dimethylaminos
Propyl group) carbodiimide (EDC) mixed with hydroxy benzo triazole (HOBt), 1- ethyls-(3- dimethylaminopropyls) carbon two is sub-
Amine hydrochlorate (EDCI) is mixed with hydroxy benzo triazole (HOBt), hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl
Phosphorus (PyBOP), hexafluorophosphoric acid (7- azepine BTA -1- epoxides) tripyrrole alkane phosphorus (PyAOP), BTA-N, N, N ',
N '-tetramethylurea hexafluorophosphoric acid ester (HBTU) or O- (7- azepine benzo triazol-1-yls)-N, N, N ', N '-tetramethylurea hexafluoro
Phosphate (HATU).
The course of reaction of step 4 is as follows：
Step 5：The synthesis of compound I
Compound II is dissolved in solvent, described solvent is not particularly limited, energy dissolved compound II, preferably
Tetrahydrofuran, is subsequently adding palladium catalyst, and is passed through hydrogen reaction, and described reaction temperature is preferably room temperature, and the reaction time is excellent
Elect 1-3 hours as, the reactant Jing for obtaining after completion of the reaction is filtered, washing vacuum distillation obtains compound I (2S, 5R, 6R) -6-
((2S, 5R, 6R) -6- ((R) -2- amino -2- (4- hydroxy phenyls) acetylaminos) -4 thia -1- of -3,3- dimethyl -7- oxos
Azabicyclo [3.2.0] heptane -2- formamides) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos [3.2.0] heptane -
2- formic acid.The palladium catalyst is preferably Pd/C or Pd (OH)2/C；The addition of described palladium catalyst is preferably compound
The 5%～500% of II；The pressure of hydrogen is preferably 0.1～10MPa.
The course of reaction of step 5 is as follows：
With reference to embodiments further illustrating the present invention, its objective is to be better understood when that present disclosure carrys out body
The substantive distinguishing features of the existing present invention, therefore the cited case is not construed as limiting the scope of the invention.
Embodiment 1
1st, the preparation method of compound III：
Prepare (2S, 5R, 6R) -3,3- dimethyl -6- [(R) -2- (benzyloxycarbonyl amino) -2- (4- benzyloxycarbonyl group oxygen benzene
Base) acetamido] -7- oxygen band -4- thias -1- azabicyclos [3.2.0] heptane -2- formic acid (compound III)
In 100mL round-bottomed flasks, add Utimox 3.65g (10mmol) and sodium hydrate aqueous solution (1M,
30mL) and THF 30mL, mixture is stirred at room temperature 15min, and benzyl chloroformate 20mmol, TLC monitorings is added dropwise under ice bath thereto
React complete to raw material conversion, add hydrochloric acid (1M) acid to mixture, adjustment pH value to 4～5 adds ethyl acetate point liquid,
Organic layer is washed, and saturated sodium-chloride is washed, and anhydrous magnesium sulfate is dried, and suction filtration, organic phase are spin-dried for, and through column chromatography for separation
(CH2Cl2/ MeOH=20:1) white solid product 4.81g, yield 76% are obtained.1H NMR(500MHz,DMSO)δ9.07(d,J
=7.5Hz, 1H), 8.08 (d, J=8.5Hz, 1H), 7.51 (d, J=8.5Hz, 2H), 7.48-7.34 (m, 9H), 7.32 (dd, J
=8.3,4.1Hz, 1H), 7.21 (d, J=8.5Hz, 2H), 5.76 (s, 1H), 5.53 (d, J=8.6Hz, 1H), 5.49 (dd, J
=7.2,4.0Hz, 1H), 5.39 (d, J=3.9Hz, 1H), 5.27 (s, 2H), 5.14-5.00 (m, 2H), 4.20 (s, 1H),
1.52(s,3H),1.40(s,3H).
2nd, the preparation method of compound VII：
Prepare (2S, 5R, 6R)-benzyl 6- (((Z) butenoic acid ethyl -2- bases) amino) -3,3- dimethyl -7- oxo -4-
Thia -1- azabicyclos [3.2.0] heptane -2- formic acid esters (compound VII)
In 100mL round-bottomed flasks, raw material 6-aminopenicillanic acid 2.16g (10mmol) and CH are added2Cl220mL, ice bath
Lower dropwise addition triethylamine 2.02g (20mmol), stirs to raw material and is completely dissolved, and ethyl acetoacetate 1.30g is added dropwise thereto
(10mmol), room temperature reaction TLC monitorings, after completion of the reaction vacuum distillation remove solvent, the oily compound for obtaining；To obtain
Oily compound be dissolved in the DMF of 25mL dryings, benzyl chloride 1.39g is added dropwise thereto and (11mmol) 3h is stirred at room temperature, obtain
Mixture diluted with 40mL water, and the ether/ethyl acetate (40X 4mL) with 5/1 is extracted, and is merged organic phase and is simultaneously washed, satisfies
Water magnesium sulfate drying is had no with salt washing, the organic phase removal of solvent under reduced pressure being filtrated to get obtains colourless viscous liquid (chemical combination
Thing VII) 2.95g, yield 70%.1H NMR(300MHz,CDCl3) δ 9.03 (d, J=8.9Hz, 1H), 7.37 (s, 5H), 5.60
(d, J=4.4Hz, 1H), 5.19 (d, J=1.2Hz, 2H), 5.12 (dd, J=9.1,4.4Hz, 1H), 4.64 (s, 1H), 4.51
(s, 1H), 4.11 (q, J=7.1Hz, 2H), 2.01 (s, 3H), 1.63 (s, 4H), 1.43 (s, 3H), 1.24 (t, J=7.1Hz,
3H).
3rd, the preparation method of compound IV：
Prepare (2S, 5R, 6R) -2- (benzyloxycarbonyl group) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos
[3.2.0] heptane -6- amino tosilate (compound IV)
2.95g (7mmol) raw material VII is dissolved in the acetone of 7mL dryings, p-methyl benzenesulfonic acid monohydrate is added thereto to
There are a large amount of white solids in 1.34g (7mmol), stirring, are added thereto to 30mL ether, suction filtration, solid second after reaction 10min
Ether is washed, and obtains white solid product 2.5g, yield 74%.1H NMR (300MHz, MeOD) δ 7.72 (d, J=8.2Hz, 2H),
7.48-7.31 (m, 5H), 7.25 (d, J=8.0Hz, 2H), 5.62 (d, J=4.3Hz, 1H), 5.25 (q, J=12.0Hz, 2H),
5.03 (d, J=4.2Hz, 1H), 4.63 (s, 1H), 2.38 (s, 3H), 1.68 (s, 3H), 1.43 (s, 3H).
4th, the preparation method of compound II：
Prepare (2S, 5R, 6R)-benzyl 6- ((2S, 5R, 6R) -6- ((R) -2- (benzyloxycarbonyl amino) -2- (4- (benzyloxy carbonyls
Base oxygen phenyl) acetylamino) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos [3.2.0] heptane -2- formamides) -
3,3- dimethyl -7- oxos -4- thias -1- azabicyclos [3.2.0] heptane -2- formic acid esters (compound II)
633mg raw material IIs I are dissolved in 3mL dichloromethane, 0.37mL diisopropyl ethyl amines are added, are added under ice bath
624mg PyBOP (BTA -1- bases-epoxide tripyrrole alkyl hexafluorophosphate), stir 2min, obtain mixed solution I；Will
480mg raw material IV are dissolved in 3mL dichloromethane, add 0.37mL N ' N- diisopropyl ethyl amines, are stirred 2min, are mixed
Solution II；Mixed solution II is added in above-mentioned mixed solution I, stirring monitoring, raw material reaction finish after add 10mL water and
10mL dichloromethane, separates organic layer and washes, and anhydrous magnesium sulfate is dried, removal of solvent under reduced pressure, the residue column chromatography for obtaining
(CH2Cl2：MeOH=100:1) white solid product 703mg, yield 76% are obtained.1H NMR(500MHz,DMSO)δ9.04
(dd, J=14.6,7.4Hz, 2H), 8.09 (d, J=8.6Hz, 1H), 7.51 (d, J=8.6Hz, 3H), 7.48-7.40 (m,
9H), 7.37 (q, J=7.4Hz, 6H), 7.34-7.29 (m, 1H), 7.21 (d, J=8.6Hz, 2H), 5.63-5.57 (m, 1H),
5.54 (dd, J=11.3,6.5Hz, 2H), 5.47-5.43 (m, 1H), 5.40 (d, J=3.9Hz, 1H), 5.26 (s, 2H), 5.21
(q, J=12.2Hz, 2H), 5.06 (q, J=12.6Hz, 2H), 4.54 (s, 1H), 4.48-4.42 (m, 1H), 1.59 (s, 3H),
1.46(s,3H),1.36(s,3H),1.31(s,3H).
5th, the preparation method of compound I：
Preparation (2S, 5R, 6R) -6- ((2S, 5R, 6R) -6- ((R) -2- amino -2- (4- hydroxy phenyls) acetylaminos) -3,
- 4 thia -1- azabicyclos [3.2.0] heptane -2- formamides of 3- dimethyl -7- oxos) -3,3- dimethyl -7- oxo -4- sulphur
Miscellaneous -1- azabicyclos [3.2.0] heptane -2- formic acid (compound I)
92.1mg raw material IIs are dissolved in 1.5mL tetrahydrofuran solutions, 310mg Pd/C are added, is passed through hydrogen (2MPa) room
Temperature reaction 2h, is filtered to remove Pd/C after completion of the reaction, and simultaneously vacuum distillation removing solvent obtains white solid product 48mg for washing, produces
Rate 86%.Fig. 1 is the nucleus magnetic hydrogen spectrum figure that the embodiment of the present invention 1 prepares compound I,1H NMR(300MHz,D2O)δ7.23
(d, J=8.5Hz, 2H), 6.84 (d, J=8.5Hz, 3H), 5.42 (ddd, J=10.7,6.8,3.8Hz, 4H), 5.02 (s,
1H),4.28(s,1H),4.12(s,1H),1.49(s,3H),1.37(s,3H),1.27(s,6H).
Embodiment 2
1st, the preparation method of compound III：
Prepare (2S, 5R, 6R) -3,3- dimethyl -6- [(R) -2- (benzyloxycarbonyl amino) -2- (4- benzyloxycarbonyl group oxygen benzene
Base) acetamido] -7- oxygen band -4- thias -1- azabicyclos [3.2.0] heptane -2- formic acid (compound III)
In 100mL round-bottomed flasks, add Utimox 3.65g (10mmol) and sodium hydrate aqueous solution (1M,
30mL) and THF 30mL, mixture is stirred at room temperature 10min, and benzyl chloroformate 20mmol, TLC monitorings is added dropwise under ice bath thereto
React complete to raw material conversion, add hydrochloric acid (1M) acid to mixture, adjustment pH value to 4～5 adds ethyl acetate point liquid,
Organic layer is washed, and saturated sodium-chloride is washed, and anhydrous magnesium sulfate is dried, and suction filtration, organic phase are spin-dried for, and through column chromatography for separation
(CH2Cl2/ MeOH=20:1) white solid product 4.81g, yield 77% are obtained.1H NMR(500MHz,DMSO)δ9.07(d,J
=7.5Hz, 1H), 8.08 (d, J=8.5Hz, 1H), 7.51 (d, J=8.5Hz, 2H), 7.48-7.34 (m, 9H), 7.32 (dd, J
=8.3,4.1Hz, 1H), 7.21 (d, J=8.5Hz, 2H), 5.76 (s, 1H), 5.53 (d, J=8.6Hz, 1H), 5.49 (dd, J
=7.2,4.0Hz, 1H), 5.39 (d, J=3.9Hz, 1H), 5.27 (s, 2H), 5.14-5.00 (m, 2H), 4.20 (s, 1H),
1.52(s,3H),1.40(s,3H).
2nd, the preparation method of compound VII：
Prepare (2S, 5R, 6R)-benzyl 6- (((Z) butenoic acid ethyl -2- bases) amino) -3,3- dimethyl -7- oxo -4-
Thia -1- azabicyclos [3.2.0] heptane -2- formic acid esters (compound VII)
In 100mL round-bottomed flasks, raw material 6-aminopenicillanic acid 2.16g (10mmol) and CH are added2Cl220mL, ice bath
Lower dropwise addition triethylamine 2.02g (20mmol), stirs to raw material and is completely dissolved, and 1.30g (10mmol) acetoacetate is added dropwise thereto
Ethyl ester, room temperature reaction TLC monitorings, after completion of the reaction vacuum distillation remove solvent, the oily compound for obtaining；By the oil for obtaining
Shape compound is dissolved in the DMF of 25mL dryings, benzyl chloride 1.39g (11mmol) is added dropwise thereto and 2h is stirred at room temperature, and what is obtained is mixed
Compound is diluted with 40mL water, and the ether/ethyl acetate (40*4mL) with 5/1 is extracted, and is merged organic phase and is washed, saturated common salt
Washing anhydrous magnesium sulfate drying, the organic phase removal of solvent under reduced pressure being filtrated to get obtain colourless viscous liquid (compound VII)
2.95g, yield 72%.1H NMR(300MHz,CDCl3) δ 9.03 (d, J=8.9Hz, 1H), 7.37 (s, 5H), 5.60 (d, J=
4.4Hz, 1H), 5.19 (d, J=1.2Hz, 2H), 5.12 (dd, J=9.1,4.4Hz, 1H), 4.64 (s, 1H), 4.51 (s, 1H),
4.11 (q, J=7.1Hz, 2H), 2.01 (s, 3H), 1.63 (s, 4H), 1.43 (s, 3H), 1.24 (t, J=7.1Hz, 3H).
3rd, the preparation method of compound IV：
Prepare (2S, 5R, 6R) -2- (benzyloxycarbonyl group) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos
[3.2.0] heptane -6- amino tosilate (compound IV)
2.95g (7mmol) raw material VII is dissolved in the acetone of 7mL dryings, p-methyl benzenesulfonic acid monohydrate is added thereto to
There are a large amount of white solids in 1.34g (7mmol), stirring, are added thereto to 30mL ether, suction filtration, solid second after reaction 15min
Ether is washed, and obtains white solid product 2.5g, yield 75%.1H NMR (300MHz, MeOD) δ 7.72 (d, J=8.2Hz, 2H),
7.48-7.31 (m, 5H), 7.25 (d, J=8.0Hz, 2H), 5.62 (d, J=4.3Hz, 1H), 5.25 (q, J=12.0Hz, 2H),
5.03 (d, J=4.2Hz, 1H), 4.63 (s, 1H), 2.38 (s, 3H), 1.68 (s, 3H), 1.43 (s, 3H).
4th, the preparation method of compound II：
Prepare (2S, 5R, 6R)-benzyl 6- ((2S, 5R, 6R) -6- ((R) -2- (benzyloxycarbonyl amino) -2- (4- (benzyloxy carbonyls
Base oxygen phenyl) acetylamino) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos [3.2.0] heptane -2- formamides) -
3,3- dimethyl -7- oxos -4- thias -1- azabicyclos [3.2.0] heptane -2- formic acid esters (compound II)
633mg raw material IIs I are dissolved in 3mL dichloromethane, 0.37mL triethylamines are added, 480mg EDCI under ice bath, are added
(1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride) and 60mg HOBt (hydroxy benzo triazole), stirring
3min, obtains mixed solution I；480mg raw material IV are dissolved in 3mL dichloromethane, 0.37mL triethylamines, stirring is added
3min, obtains mixed solution II；Mixed solution II is added in above-mentioned mixed solution I, stirring monitoring, raw material reaction add after finishing
Enter 10mL water and 10mL dichloromethane, separate organic layer and wash, anhydrous magnesium sulfate is dried, and removal of solvent under reduced pressure, what is obtained are residual
Excess column chromatography (CH2Cl2：MeOH=100:1) white solid product 703mg, yield 78% are obtained.1HNMR(500MHz,
DMSO) δ 9.04 (dd, J=14.6,7.4Hz, 2H), 8.09 (d, J=8.6Hz, 1H), 7.51 (d, J=8.6Hz, 3H), 7.48-
7.40 (m, 9H), 7.37 (q, J=7.4Hz, 6H), 7.34-7.29 (m, 1H), 7.21 (d, J=8.6Hz, 2H), 5.63-5.57
(m, 1H), 5.54 (dd, J=11.3,6.5Hz, 2H), 5.47-5.43 (m, 1H), 5.40 (d, J=3.9Hz, 1H), 5.26 (s,
2H), 5.21 (q, J=12.2Hz, 2H), 5.06 (q, J=12.6Hz, 2H), 4.54 (s, 1H), 4.48-4.42 (m, 1H), 1.59
(s,3H),1.46(s,3H),1.36(s,3H),1.31(s,3H).
5th, the preparation method of compound I：
Preparation (2S, 5R, 6R) -6- ((2S, 5R, 6R) -6- ((R) -2- amino -2- (4- hydroxy phenyls) acetylaminos) -3,
- 4 thia -1- azabicyclos [3.2.0] heptane -2- formamides of 3- dimethyl -7- oxos) -3,3- dimethyl -7- oxo -4- sulphur
Miscellaneous -1- azabicyclos [3.2.0] heptane -2- formic acid (compound I)
92.1mg raw material IIs are dissolved in 1.5mL tetrahydrofuran solutions, 325mg Pd (OH) are added2/ C, is passed through hydrogen
(0.1MPa) room temperature reaction 3h, is filtered to remove Pd (OH) after completion of the reaction2/ C, washing vacuum distillation remove solvent and obtain white
Solid product 48mg, yield 84%.1H NMR(300MHz,D2O) δ 7.23 (d, J=8.5Hz, 2H), 6.84 (d, J=8.5Hz,
3H), 5.42 (ddd, J=10.7,6.8,3.8Hz, 4H), 5.02 (s, 1H), 4.28 (s, 1H), 4.12 (s, 1H), 1.49 (s,
3H),1.37(s,3H),1.27(s,6H).
Embodiment 3
1st, the preparation method of compound III：
Prepare (2S, 5R, 6R) -3,3- dimethyl -6- [(R) -2- (benzyloxycarbonyl amino) -2- (4- benzyloxycarbonyl group oxygen benzene
Base) acetamido] -7- oxygen band -4- thias -1- azabicyclos [3.2.0] heptane -2- formic acid (compound III)
In 100mL round-bottomed flasks, add Utimox 3.65g (10mmol) and sodium hydrate aqueous solution (1M,
30mL) and THF 30mL, mixture is stirred at room temperature 12min, and benzyl chloroformate 20mmol, TLC monitorings is added dropwise under ice bath thereto
React complete to raw material conversion, add hydrochloric acid (1M) acid to mixture, adjustment pH value to 4～5 adds ethyl acetate point liquid,
Organic layer is washed, and saturated sodium-chloride is washed, and anhydrous magnesium sulfate is dried, and suction filtration, organic phase are spin-dried for, and through column chromatography for separation
(CH2Cl2/ MeOH=20:1) white solid product 4.81g, yield 75% are obtained.1H NMR(500MHz,DMSO)δ9.07(d,J
=7.5Hz, 1H), 8.08 (d, J=8.5Hz, 1H), 7.51 (d, J=8.5Hz, 2H), 7.48-7.34 (m, 9H), 7.32 (dd, J
=8.3,4.1Hz, 1H), 7.21 (d, J=8.5Hz, 2H), 5.76 (s, 1H), 5.53 (d, J=8.6Hz, 1H), 5.49 (dd, J
=7.2,4.0Hz, 1H), 5.39 (d, J=3.9Hz, 1H), 5.27 (s, 2H), 5.14-5.00 (m, 2H), 4.20 (s, 1H),
1.52(s,3H),1.40(s,3H).
2nd, the preparation method of compound VII：
Prepare (2S, 5R, 6R)-benzyl 6- (((Z) butenoic acid ethyl -2- bases) amino) -3,3- dimethyl -7- oxo -4-
Thia -1- azabicyclos [3.2.0] heptane -2- formic acid esters (compound VII)
In 100mL round-bottomed flasks, raw material 6-aminopenicillanic acid 2.16g (10mmol) and CH are added2Cl220mL, ice bath
Lower dropwise addition triethylamine 2.02g (20mmol), stirs to raw material and is completely dissolved, and 1.30g (10mmol) acetoacetate is added dropwise thereto
Ethyl ester, room temperature reaction TLC monitorings, after completion of the reaction vacuum distillation remove solvent, the oily compound for obtaining；By the oil for obtaining
Shape compound is dissolved in the DMF of 25mL dryings, benzyl chloride 1.39g (11mmol) is added dropwise thereto and 4h is stirred at room temperature, and what is obtained is mixed
Compound is diluted with 40mL water, and the ether/ethyl acetate (40*4mL) with 5/1 is extracted, and is merged organic phase and is washed, saturated common salt
Washing anhydrous magnesium sulfate drying, the organic phase removal of solvent under reduced pressure being filtrated to get obtain colourless viscous liquid (compound VII)
2.95g, yield 71%.1H NMR(300MHz,CDCl3) δ 9.03 (d, J=8.9Hz, 1H), 7.37 (s, 5H), 5.60 (d, J=
4.4Hz, 1H), 5.19 (d, J=1.2Hz, 2H), 5.12 (dd, J=9.1,4.4Hz, 1H), 4.64 (s, 1H), 4.51 (s, 1H),
4.11 (q, J=7.1Hz, 2H), 2.01 (s, 3H), 1.63 (s, 4H), 1.43 (s, 3H), 1.24 (t, J=7.1Hz, 3H).
3rd, the preparation method of compound IV：
Prepare (2S, 5R, 6R) -2- (benzyloxycarbonyl group) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos
[3.2.0] heptane -6- amino tosilate (compound IV)
2.95g (7mmol) raw material VII is dissolved in the acetone of 7mL dryings, p-methyl benzenesulfonic acid monohydrate is added thereto to
There are a large amount of white solids in 1.34g (7mmol), stirring, are added thereto to 30mL ether, suction filtration, solid second after reaction 12min
Ether is washed, and obtains white solid product 2.5g, yield 75%.1H NMR (300MHz, MeOD) δ 7.72 (d, J=8.2Hz, 2H),
7.48-7.31 (m, 5H), 7.25 (d, J=8.0Hz, 2H), 5.62 (d, J=4.3Hz, 1H), 5.25 (q, J=12.0Hz, 2H),
5.03 (d, J=4.2Hz, 1H), 4.63 (s, 1H), 2.38 (s, 3H), 1.68 (s, 3H), 1.43 (s, 3H).
4th, the preparation method of compound II：
Prepare (2S, 5R, 6R)-benzyl 6- ((2S, 5R, 6R) -6- ((R) -2- (benzyloxycarbonyl amino) -2- (4- (benzyloxy carbonyls
Base oxygen phenyl) acetylamino) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos [3.2.0] heptane -2- formamides) -
3,3- dimethyl -7- oxos -4- thias -1- azabicyclos [3.2.0] heptane -2- formic acid esters (compound II)
633mg raw material IIs I are dissolved in 3mL toluene, add 0.37mL N, N- diisopropyl ethyl amines to add under ice bath
624mg PyBOP (BTA -1- bases-epoxide tripyrrole alkyl hexafluorophosphate), stir 1min, obtain mixed solution I；Will
480mg raw material IV are dissolved in 3mL dichloromethane, add 0.37mL DMAs, are stirred 1min, are obtained mixed solution
Ⅱ；Mixed solution II is added in above-mentioned mixed solution I, stirring monitoring, raw material reaction add 10mL water and 10mL bis- after finishing
Chloromethanes, separates organic layer and washes, and anhydrous magnesium sulfate is dried, removal of solvent under reduced pressure, the residue column chromatography (CH for obtaining2Cl2：
MeOH=100:1) white solid product 703mg, yield 75% are obtained.1H NMR (500MHz, DMSO) δ 9.04 (dd, J=
14.6,7.4Hz, 2H), 8.09 (d, J=8.6Hz, 1H), 7.51 (d, J=8.6Hz, 3H), 7.48-7.40 (m, 9H), 7.37
(q, J=7.4Hz, 6H), 7.34-7.29 (m, 1H), 7.21 (d, J=8.6Hz, 2H), 5.63-5.57 (m, 1H), 5.54 (dd, J
=11.3,6.5Hz, 2H), 5.47-5.43 (m, 1H), 5.40 (d, J=3.9Hz, 1H), 5.26 (s, 2H), 5.21 (q, J=
12.2Hz, 2H), 5.06 (q, J=12.6Hz, 2H), 4.54 (s, 1H), 4.48-4.42 (m, 1H), 1.59 (s, 3H), 1.46 (s,
3H),1.36(s,3H),1.31(s,3H).
5th, the preparation method of compound I：
Preparation (2S, 5R, 6R) -6- ((2S, 5R, 6R) -6- ((R) -2- amino -2- (4- hydroxy phenyls) acetylaminos) -3,
- 4 thia -1- azabicyclos [3.2.0] heptane -2- formamides of 3- dimethyl -7- oxos) -3,3- dimethyl -7- oxo -4- sulphur
Miscellaneous -1- azabicyclos [3.2.0] heptane -2- formic acid (compound I)
92.1mg raw material IIs are dissolved in 1.5mL tetrahydrofuran solutions, 92.1mg Pd (OH) are added2/ C, is passed through hydrogen
(10MPa) room temperature reaction 1h, is filtered to remove Pd (OH) after completion of the reaction2/ C, washing vacuum distillation remove solvent and obtain white
Solid product 48mg, yield 87%.1H NMR(300MHz,D2O) δ 7.23 (d, J=8.5Hz, 2H), 6.84 (d, J=8.5Hz,
3H), 5.42 (ddd, J=10.7,6.8,3.8Hz, 4H), 5.02 (s, 1H), 4.28 (s, 1H), 4.12 (s, 1H), 1.49 (s,
3H),1.37(s,3H),1.27(s,6H).
The explanation of above example is only intended to help and understands the method for the present invention and its core concept.It should be pointed out that right
For those skilled in the art, under the premise without departing from the principles of the invention, the present invention can also be carried out
Some improvement and modification, these improve and modification is also fallen in the protection domain of the claims in the present invention.
The foregoing description of the disclosed embodiments, enables professional and technical personnel in the field to realize or using the present invention.
Various modifications to these embodiments will be apparent 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
The embodiments shown herein is not intended to be limited to, and is to fit to and principles disclosed herein and features of novelty phase one
The most wide scope for causing.
Claims (8)
1. a kind of preparation method of 'beta '-lactam compounds, it is characterised in that the preparation method includes：
Step one：The synthesis of compound III
Utimox and sodium hydrate aqueous solution are mixed, mixed solution is obtained, is then added in mixed solution
Benzyl chloroformate reacts, and adds acid and is adjusted to acidity, obtains compound III (2S, 5R, 6R) -3,3- dimethyl -6- [(R) -2-
(benzyloxycarbonyl amino) -2- (4- benzyloxycarbonyl group oxygen phenyl) acetamido] -7- oxygen band -4- thias -1- azabicyclos [3.2.0]
Heptane -2- formic acid；
Step 2：The synthesis of compound VII
6-aminopenicillanic acid and triethylamine are mixed, and are obtained mixed solution, then acetoacetate are added in mixed solution
Ethyl ester, obtains oily compound, and oily compound is dissolved in solvent, be subsequently adding benzyl chloride stirring, obtain compound VII (2S,
5R, 6R)-benzyl 6- (((Z) butenoic acid ethyl -2- bases) amino) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos
[3.2.0] heptane -2- formic acid esters；
Step 3：The synthesis of compound IV
Compound VII is dissolved in solvent, the stirring of p-methyl benzenesulfonic acid monohydrate is subsequently adding, is added ether, obtain chemical combination
Thing IV (2S, 5R, 6R) -2- (benzyloxycarbonyl group) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos [3.2.0] heptane -6-
Amino tosilate；
Step 4：The synthesis of compound II
Compound III is dissolved in organic solvent, add organic amine, under ice bath add condensation reagent hexafluorophosphoric acid BTA-
1- bases-epoxide tripyrrole alkyl phosphorus, obtain mixed solution I；Compound IV is dissolved in solvent, organic amine is added, is mixed
Solution II；Mixed solution II is added in above-mentioned mixed solution I, obtain compound II (2S, 5R, 6R)-benzyl 6- ((2S, 5R,
6R) -6- ((R) -2- (benzyloxycarbonyl amino) -2- (4- (benzyloxycarbonyl group oxygen phenyl) acetylamino) -3,3- dimethyl -7- oxos -
4- thia -1- azabicyclos [3.2.0] heptane -2- formamides) -3,3- dimethyl -7- oxo -4- thia -1- azabicyclos
[3.2.0] heptane -2- formic acid esters；
Step 5：The synthesis of compound I
Compound II is dissolved in solvent, palladium catalyst is subsequently adding, and is passed through hydrogen reaction, obtain compound I (2S, 5R,
6R) -6- ((2S, 5R, 6R) -6- ((R) -2- amino -2- (4- hydroxy phenyls) acetylaminos) -4 sulphur of -3,3- dimethyl -7- oxos
Miscellaneous -1- azabicyclos [3.2.0] heptane -2- formamides) -3,3- dimethyl -7- oxos -4- thias -1- azabicyclos [3.2.0]
Heptane -2- formic acid.
2. a kind of preparation method of 'beta '-lactam compounds according to claim 1, it is characterised in that step one Ah
The mol ratio of Amdinocillin trihydrate and benzyl chloroformate is 1：2.
3. a kind of preparation method of 'beta '-lactam compounds according to claim 1, it is characterised in that step 2 6-
The mol ratio of Aminopenicillin alkanoic acid, triethylamine, ethyl acetoacetate and benzyl chloride is 10：20：10：11.
4. a kind of preparation method of 'beta '-lactam compounds according to claim 1, it is characterised in that the step 3
The mol ratio of compound VII and p-methyl benzenesulfonic acid monohydrate is 1：1.
5. a kind of preparation method of 'beta '-lactam compounds according to claim 1, it is characterised in that the step 4
The mol ratio of compound III and BTA -1- bases-epoxide tripyrrole alkyl hexafluorophosphate is 10：12.
6. the preparation method of a kind of 'beta '-lactam compounds according to claim 1, it is characterised in that the step 4
Organic amine is triethylamine, N, N- diisopropyl ethyl amine or DMA.
7. the preparation method of a kind of 'beta '-lactam compounds according to claim 1, it is characterised in that the step 5
Palladium catalyst is Pd/C or Pd (OH)2/C。
8. the preparation method of a kind of 'beta '-lactam compounds according to claim 1, it is characterised in that the step 5
The pressure of hydrogen is 0.1～10MPa.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1241844A (en) * | 1968-08-23 | 1971-08-04 | Beecham Group Ltd | Penicillins |
| US4364957A (en) * | 1979-09-26 | 1982-12-21 | Pfizer Inc. | Bis-esters of alkanediols as antibacterial agents |
| EP0074783A1 (en) * | 1981-09-14 | 1983-03-23 | Pfizer Inc. | Beta-lactamase inhibiting 2-beta-substituted-2-alpha-methyl-(5R) penam-3-alpha-carboxylic acid 1,1-dioxides and intermediates therefor |
| EP0170192A1 (en) * | 1984-07-30 | 1986-02-05 | Merck & Co. Inc. | Penicillin derivatives as anti-inflammatory and antidegenerative agents |
| US6569847B1 (en) * | 1999-04-06 | 2003-05-27 | Naeja Pharmaceuticals Inc. | Substituted azetidin-2-ones as cysteine protease inhibitors |
-
2015
- 2015-02-10 CN CN201510067470.4A patent/CN104650119B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1241844A (en) * | 1968-08-23 | 1971-08-04 | Beecham Group Ltd | Penicillins |
| US4364957A (en) * | 1979-09-26 | 1982-12-21 | Pfizer Inc. | Bis-esters of alkanediols as antibacterial agents |
| EP0074783A1 (en) * | 1981-09-14 | 1983-03-23 | Pfizer Inc. | Beta-lactamase inhibiting 2-beta-substituted-2-alpha-methyl-(5R) penam-3-alpha-carboxylic acid 1,1-dioxides and intermediates therefor |
| EP0170192A1 (en) * | 1984-07-30 | 1986-02-05 | Merck & Co. Inc. | Penicillin derivatives as anti-inflammatory and antidegenerative agents |
| US6569847B1 (en) * | 1999-04-06 | 2003-05-27 | Naeja Pharmaceuticals Inc. | Substituted azetidin-2-ones as cysteine protease inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| In vivo antibacterial activity of dipeptides of penicillins;G. Beskid, 等;《Medicina Experimentalis》;19681231;第18卷(第4-6期);327-330 * |
| Penicillin Dipeptides;A rthur M. Felix, 等;《Journal of Medicinal Chemistry》;19680930;第11卷(第5期);929-932 * |
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