CN105061425B - Synthesis method of diazabicyclo octanone sulfuric acid monoester - Google Patents
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Abstract
The invention relates to a synthesis method of a compound diazabicyclo octanone sulfuric acid monoester for preventing and treating bacterial infection diseases. According to the synthesis method, cheap and available glutamate lactam is taken as a raw material and reacts for twelve steps, and chemical synthesis of diazabicyclo octanone sulfuric acid monoester is completed with higher total yield. According to the novel synthesis method of diazabicyclo octanone sulfuric acid monoester, the preparation method is simple and convenient, an intermediate is stable, environmental protection and economy are achieved, and the reaction is easy to control.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, particularly relate to diazabicyclo octanone sulphuric acid list
The synthetic method of ester and the like.
Background technology
Since the forties in last century uses first beta-lactam antibiotic penicillin, antibacterial is to clinic
The drug resistance problems of upper wide variety of antibiotic has become the one of clinical treatment to be threatened greatly.For many years, people
Attempt to find the scheme solving Production by Bacteria enzyme drug resistance problems, the wherein work of beta-lactamase inhibitor from many aspects
It is to be combined with bacteriogenic beta-lactamase by mechanism, is allowed to inactivate, so that antibacterial loses beta-lactam
The drug resistance of class antibiotic.This Inhibitors and the beta-lactam antibiotic use in conjunction being weak to enzyme, fully
Having played the antibacterial action of original antibiotic, this is the important means improving beta-lactam antibiotic curative effect.
Diazabicyclo octanone sulfuric acid monoester is novel ss-lactam enzyme inhibitor, it press down zymogram than his azoles bar
Smooth, sulbactam and clavulanic acid are wide.Arstwyth and AstraZeneca cooperative research and development ceftazidime and A Weiba
Smooth compound preparation, for injection, lists for 2015 first in the U.S., and it is double that A Wei Batan belongs to diaza
Cyclooctanone compound, chemical name is [(1R, 2S, 5R)-2-(amino carbonyl)-7-oxo-1,6-diazabicyclo
[3.2.1] octyl-6-yl] sulfuric acid monoester.It is the novel ss-lactam enzyme inhibitor being expected at present most, to majority
Gram positive bacteria (G+) and gram negative bacteria (G-) addicted to oxygen and anaerobism all have bactericidal action, it is adaptable to multiple
Miscellaneous intra-abdominal infection and complicated urinary tract infection (cUTI), including pyelonephritis.
AstraZeneca discloses the synthetic method of this compound in its patent WO2012172368, sees synthesis
Route 1.They are with the a-carbonyl proline of full guard as raw material, by ten single step reactions synthesis diazabicyclos
Octanone sulfuric acid monoester 1.This route can produce two isomers when synthetic intermediate 18, it is more difficult to separates, and
Affect ultimate yield.
WO2012086241 discloses with compound 21 as raw material, double by ten single step reaction synthesis diazas
The method of cyclooctanone sulfuric acid monoester 1, is shown in synthetic route 2, and this route can produce two when synthetic intermediate 22
Individual isomer, it is more difficult to separate, and affect ultimate yield.
WO2014135930 also discloses that the synthetic method of diazabicyclo octanone sulfuric acid monoester 1, sees synthesis road
Line 3, the method uses the method synthesis compound 28 identical with patent WO2012086241, compound 20
Synthesis use ammonia complex, reduce cost.The previous section of this route and patent WO2012086241
Identical, therefore, two isomers can be produced when synthetic intermediate 22, it is more difficult to separate, and affect final receipts
Rate.
Summary of the invention
Based on this, it is an object of the invention to provide the synthetic method of a kind of diazabicyclo octanone sulfuric acid monoester.
For achieving the above object, concrete technical scheme is as follows:
A kind of synthetic method of diazabicyclo octanone sulfuric acid monoester, synthetic route is as follows:
Described synthetic method comprises the following steps:
(1) in organic solvent, glutamic acid lactams 2 reacts 2-10 hour with amine under the effect of condensing agent
Obtaining compound 3, reaction temperature is 0 DEG C-50 DEG C, and the mol ratio of glutamic acid lactams 2 and amine is 1.0:1.0-5；
(2) in organic solvent, compound 3 and amido protecting agent react 1-20 hour, obtain compound 4,
Reaction temperature is 0 DEG C-50 DEG C, and the mol ratio of compound 3 and amido protecting agent is 1.0:1-5；
(3) in organic solvent, to react 1-30 with Trimethylsulfoxonium Iodide under the effect of alkali little for compound 4
Time, obtain compound 5, reaction temperature is 0 DEG C-50, compound 4, Trimethylsulfoxonium Iodide and alkali mole
Ratio is 1.0:1.0-5:1.0-5；
(4) in organic solvent, there is ring closure reaction in compound 5 under the action of an acid, reacts 1-20 hour
Obtaining compound 6, reaction temperature is room temperature-50 DEG C, and the mol ratio of compound 5 and acid is 1.0:0.01-1；
(5) in organic solvent, compound 6 and reducing agent react 1-10 hour, obtain reduzate chemical combination
Thing 7, reaction temperature is-20-30 DEG C, and the mol ratio of compound 6 and reducing agent is 1.0:1.0-5；
(6) in organic solvent, compound 7 and sulfonic acid chloride react 1-15 hour, obtain compound 8, reaction
Temperature is-20 DEG C-50 DEG C, and the mol ratio of compound 7 and sulfonic acid chloride is 1.0:1.0-5；
(7) in organic solvent, the benzyloxy amine reaction 1-20 of compound 8 and benzyloxy amine or Boc protection
Hour, obtaining compound 9, reaction temperature is 0 DEG C-50 DEG C, compound 8 and benzyloxy amine or Boc protection
The mol ratio of benzyloxy amine be 1.0:1.0-5；
(8) in organic solvent, compound 9 reacts 1-10 hour under acid effect, removes Boc protection group
Obtaining compound 10, reaction temperature is 0 DEG C-40 DEG C, and the mol ratio of compound 9 and acid is 1.0:1.0-5；
(9) in organic solvent, compound 10 and triphosgene are reacted 1-8 hour, obtain compound 11,
Reaction temperature is 0 DEG C-50 DEG C, and the mol ratio of compound 10 and triphosgene is 1.0:1.0-5；
(10) in mixed solvent, compound 11 reacts 1-30 hour with hydrogen under catalyst action,
To compound 12, reaction temperature is 0 DEG C-60 DEG C, and the mol ratio of compound 11 and catalyst is 1.0:0.01-1；
(11) in organic solvent, compound 12 and sulfur trioxide pyridine react 10-48 hour, obtain chemical combination
Thing 13, reaction temperature is 0 DEG C-50 DEG C, and the mol ratio of compound 12 and sulfur trioxide pyridine is 1.0:1.0-10；
(12) in organic solvent, compound 13 and alkali reaction 1-10 hour, obtain compound 1 diaza
Dicyclo octanone sulfuric acid monoester, reaction temperature is 0 DEG C-30 DEG C, and the mol ratio of compound 13 and alkali is 1.0:1.0-2.
Wherein in some embodiments, described in step 1, the response time of reaction is 2-4 hour, and reaction temperature is
20 DEG C-30 DEG C, the mol ratio of glutamic acid lactams and amine is 1:1-2；Described in step 2 reaction response time be
10-15 hour, reaction temperature was 20 DEG C-30 DEG C, and the mol ratio of compound 3 and amido protecting agent is 1:1-2；
Described in step 3, the response time of reaction is 10-15 hour, and reaction temperature is 20 DEG C-30 DEG C, compound 4,
The mol ratio of Trimethylsulfoxonium Iodide and alkali is 1:1.5-2.5:1.5-2.5；The response time of reaction described in step 4
For 10-15 hour, reaction temperature was 70 DEG C-90 DEG C, and the mol ratio of compound 5 and acid is 1:0.03-0.05；
Described in step 5, the response time of reaction is 1-2 hour, and reaction temperature be-20 DEG C-0 DEG C, compound 6 and and also
The mol ratio of former dose is 1:1-2；Described in step 6, the response time of reaction is 3-8 hour, and reaction temperature is
20 DEG C-30 DEG C, the mol ratio of compound 7 and sulfonic acid chloride is 1:1-2；Described in step 7 reaction response time be
8-12 hour, reaction temperature was 20 DEG C-30 DEG C, compound 8 and benzyloxy amine or the benzyloxy amine of Boc protection
Mol ratio be 1:1-2；Described in step 8, the response time of reaction is 6-10 hour, and reaction temperature is
30 DEG C-40 DEG C, the mol ratio of compound 9 and acid is 1:1-2；Described in step 9, the response time of reaction is 1-3
Hour, reaction temperature is 20 DEG C-30 DEG C, and the mol ratio of compound 10 and triphosgene is 1:1-2；Step 10
The response time of described reaction is 8-12 hour, and reaction temperature is 40 DEG C-60 DEG C, compound 11 and catalyst
Mol ratio be 1:0.01-1；Described in step 11, the response time of reaction is 22-26 hour, and reaction temperature is
20 DEG C-30 DEG C, the mol ratio of compound 12 and sulfur trioxide pyridine is 1:3-4；Described in step 12, reaction is anti-
Being 1-3 hour between Ying Shi, reaction temperature is 0 DEG C-10 DEG C, and the mol ratio of compound 13 and alkali is 1:1-2.
Wherein in some embodiments, described organic solvent is dichloromethane, oxolane, dimethyl formyl
Amine, dimethyl acetylamide, glycol dimethyl ether, 1,2-dichloroethanes, dimethyl sulfoxide, toluene, methanol,
Ethanol, acetonitrile, petroleum ether, 2,2,2 tfifluoroethyl alcohol, normal hexane or ether.
Wherein in some embodiments, described in step (1), (6), (8) and (9), organic solvent is dichloromethane,
Described in step (2), organic solvent is acetonitrile, and described in step (3), organic solvent is dimethylformamide or diformazan
Base sulfoxide, described in step (4) and (5), organic solvent is toluene, and described in step (7), organic solvent is diformazan
Yl acetamide, described in step (10), organic solvent is methanol, and described in step (11), organic solvent is tetrahydrochysene furan
Muttering, organic solvent described in step (12) is 2,2,2-trifluoroethanols.
Wherein in some embodiments, described in step (1), amine is tert-butylamine or benzylamine, and described condensing agent is 2-(7-
Azo BTA)-tetramethylurea hexafluorophosphoric acid ester (HATU), 2-(7-azo BTA)-tetramethyl
Base urea hexafluorophosphoric acid (HBTU) or carbodiimides (EDCI).
Wherein in some embodiments, described in step (2), amido protecting agent is bromobenzyl, benzoyl bromide or two
Dimethyl dicarbonate butyl ester.
Wherein in some embodiments, step (3) described reaction is carried out under conditions of inert gas shielding, institute
Stating alkali is sodium hydrogen, potassium tert-butoxide, tert-butyl lithium, imidazoles, triethylamine, diisopropylethylamine, piperidines, two
Picoline, sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS),
N-methylmorpholine, Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane (DABCO) or pyridine.
Wherein in some embodiments, step (4) described acid is: iridium chloride dimer, trifluoroacetic acid, trichlorine
Change aluminum, hydrochloric acid, p-methyl benzenesulfonic acid, sulphuric acid or nitric acid；Described in step (5), reducing agent is lithium borohydride, boron
Sodium hydride, potassium borohydride, diisopropyl aluminum hydride, Lithium Aluminium Hydride.
Wherein in some embodiments, sulfonic acid chloride described in step (6) is benzene sulfonyl chloride, to trifluoromethylbenzene sulphur
Acyl chlorides or mesyl chloride；Described in step 8, acid is iridium chloride dimer, p-methyl benzenesulfonic acid, trifluoroacetic acid, salt
Acid, sulphuric acid or nitric acid.
Wherein in some embodiments, step (10) described catalyst is palladium/carbon.
Wherein in some embodiments, step (12) described alkali is sodium hydroxide, Lithium hydrate, hydroxide
Potassium, sodium carbonate, potassium carbonate, sodium bicarbonate.
The synthetic method of diazabicyclo octanone sulfuric acid monoester of the present invention, easy and simple to handle, intermediate is steady
Fixed, environmental protection and economy, reaction is easily controlled, and described method can be used to synthesize diazabicyclo octanone sulphuric acid list
The related analogs of ester.Compared with prior art, the method for the invention, will not when synthetic intermediate 7
Producing isomer, product can be easily separated, and the yield of end product is high.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further elaborated.
In following embodiment, conventional post-processing approach is: after having reacted, and adds suitable quantity of water in reactant liquor,
Separate organic facies and aqueous phase, merge organic facies.If it is desired, organic facies uses saturated aqueous common salt to wash successively,
Then anhydrous Na SO is used4Being dried, after filtration, decompression is spin-dried for, and obtains crude product, then through column chromatography for separation
End product is obtained after purification.
EDCI (35.7 is added in dichloromethane (300ml) solution of L-Glutimic acid (20g, 155mmol)
G, 186mmol, 1.2eq), HOBT (1.1g, 7.8mmol, 0.05eq) and tert-butylamine (16.3ml, 155
Mmol, 1eq), room temperature reaction 2h, reacts with saturated ammonium chloride solution (100ml) cancellation, concentrates, add
N-butyl alcohol (200ml) and water (100ml), stratification, aqueous phase n-butyl alcohol (200ml*2) extracts, saturated common salt
Water (100ml) washs, and anhydrous sodium sulfate is dried, and filters, and concentrates, obtains with ethyl acetate (100ml) recrystallization
Compound as white solid 3 (26.3g, 92%).1HNMR(400MHz,CDCl3): δ 5.23 (d, J=12.2
Hz, 1H), 5.18 (d, J=12.2Hz, 1H), 4.46 (dd, J=9.3Hz, J=2.4Hz, 1H), 2.55 (m,
1H),2.43(m,1H),2.21(m,1H),2.01(m,1H),1.29(s,9H)ppm.MS(m/z):185
(M++1)。
Under conditions of temperature is 0 DEG C, to the acetonitrile (300ml) of compound 3 (20g, 108.6mmol)
Solution adds N, N-diisopropylethylamine (19.7ml, 119.5mmol, 1.1eq), Bis(tert-butoxycarbonyl)oxide
(26.1g, 119.5mmol, 1.1eq) and DMAP (663mg, 5.4mmol, 0.05eq),
Room temperature reaction overnight, reacts with saturated ammonium chloride solution (100ml) cancellation, concentrates, and adds n-butyl alcohol (200ml)
With water (100ml), stratification, aqueous phase n-butyl alcohol (200ml*2) extracts, and saturated aqueous common salt (100ml) is washed
Washing, anhydrous sodium sulfate is dried, filtering and concentrating, obtains white solid chemical combination with ethyl acetate (100ml) recrystallization
Thing 4 (30.3g, 98%).1HNMR(400MHz,CDCl3): δ 5.26 (d, J=12.2Hz, 1H), 5.21
(d, J=12.2Hz, 1H), 4.51 (dd, J=9.2Hz, J=2.3Hz, 1H), 2.56 (m, 1H), 2.43 (m,
1H),2.27(m,1H),2.01(m,1H),1.41(s,9H),1.32(s,9H)ppm.MS(m/z):285
(M++1)。
Under argon shield, be sequentially added in anhydrous DMSO (100ml) Trimethylsulfoxonium Iodide (17.0g,
59.8mmol, 1.7eq) and potassium tert-butoxide (5.9g, 52.8mmol, 1.5eq) room temperature reaction 1h, then drip
Entering DMSO (75ml) solution of compound 4 (10g, 35.2mmol, 1eq), room temperature reaction is overnight, dense
Contracting, adds ethyl acetate (100ml) and water (50ml), stratification, and aqueous phase ethyl acetate (100ml*2) extracts
Taking, saturated aqueous common salt (50ml) washs, and anhydrous sodium sulfate is dried, and is concentrated to give compound as white solid 5 (12.3
G, 93%).1HNMR(400MHz,CDCl3): δ 5.71 (d, J=7.8Hz, 1H), 5.11 (d, J=12.0
Hz, 1H), 5.01 (d, J=12.0Hz, 1H), 4.28 (s, 1H), 4.15 (m, 1H), 3.25 (s, 3H), 3.21 (s,
3H),2.21-2.31(m,2H),2.01(m,1H),1.89(m,1H),1.49(s,9H)1.38(s,9H)ppm.
MS(m/z):377(M++1)。
Under argon shield, to the AlCl being heated to 80 DEG C3The toluene of (100mg, 0.75mmol, 0.035eq)
(40ml) solution drips toluene (60ml) solution of compound 5 (8g, 21.3mmol, 1.0eq), dropping
After 80 DEG C react 12h, be cooled to room temperature, with saturated ammonium chloride solution (50ml) cancellation react, dense
Contracting, adds ethyl acetate (100ml) and water (50ml), stratification, and aqueous phase ethyl acetate (100ml*2) extracts
Taking, saturated aqueous common salt (50ml) washs, and anhydrous sodium sulfate is dried, and is concentrated to give compound 6 (5.85g, 93%).1H NMR(400MHz,CDCl3): δ 5.02-5.18 (m, 2H), 4.66 (dd, J=6.4Hz, J=58Hz,
0.5H), 4.58 (dd, J=7.1Hz, J=6.4Hz, 0.5H), 4.38 (d, J=18.8Hz, 0.5H), 4.31 (d, J
=18.8Hz, 0.5H), 3.95 (d, J=18.8Hz, 0.5H), 3.91 (d, J=18.6Hz, 0.5H), 2.10-2.39
(m,4H),1.46(s,4.5H),1.39(s,4.5H),1.32(s,9H)ppm.MS(m/z):299(M++1)。
At-20 DEG C, under argon shield, to the toluene (70ml) of compound 6 (4g, 13.4mmol, 1.0eq)
Solution adds LiBH4(4M solution inTHF, 3.6ml, 1.07eq), reacts 1h, uses saturated ammonium chloride
Solution (50ml) cancellation is reacted, and concentrates, and adds ethyl acetate (100ml) and water (50ml), stratification, aqueous phase
Extracting by ethyl acetate (100ml*2), saturated aqueous common salt (50ml) washs, and anhydrous sodium sulfate is dried, and is concentrated to give
Compound 7 (3.85g, 96%).1HNMR(400MHz,CDCl3): δ 5.20 (d, J=12.0Hz, 1H),
5.01 (d, J=12.2Hz, 1H), 4.65 (d, J=4.8Hz, 0.5H), 4.61 (d, J=5.0Hz, 0.5H),
4.21-4.24(m,0.5H),4.11-4.25(m,0.5H),3.60(s,1H),2.81-2.96(m,0.5H),
2.71-2.75(m,0.5H),2.21-2.31(m,1H),1.90-2.01(m,2H),1.60-1.70(m,2H),1.48
(s,4.5H),1.43(s,4.5H),1.39(s,9H)ppm.MS(m/z):301(M++1)。
It is sequentially added into triethylamine (1.9 in dichloromethane (50ml) solution of compound 7 (3.0g, 10.0mmol)
Ml, 14.0mmol), to trifluoromethyl benzene sulfonyl chloride (1.3ml, 12.0mmol, 1.2eq) and 4-dimethylamino pyrrole
Pyridine (61.1mg, 0.5mmol), room temperature reaction 5h, react with saturated ammonium chloride solution (20ml) cancellation, concentrate,
Adding ethyl acetate (50ml) and water (20ml), stratification, aqueous phase ethyl acetate (50ml*2) extracts, full
Washing with saline solution (20ml), anhydrous sodium sulfate is dried, and is concentrated to give compound 8 (5.03g, 99%).1H NMR
(400MHz,CDCl3): δ 8.01 (d, J=8.0Hz, 2H), 7.81 (d, J=8.2Hz, 2H), 5.15 (d, J=
12.0Hz, 1H), 4.93 (d, J=11.8Hz, 1H), 4.52 (d, J=4.8Hz, 0.5H), 4.45 (d, J=5.0
Hz,0.5H),4.01-4.16(m,0.5H),3.87-3.92(m,0.5H),3.55(s,1H),2.77-2.81(m,
0.5H),2.66-2.71(m,0.5H),2.01-2.19(m,1H),1.87-1.91(m,2H),1.55-1.61(m,
2H),1.41(s,4.5H),1.33(s,4.5H),1.41(s,9H)ppm.MS(m/z):301(M++1)。
Tertiary fourth is added in DMAC (20ml) solution of N-Boc-benzyloxy amine (2.1g, 9.44mmol, 1.2eq)
Potassium alcoholate (1.06g, 9.44mmol, 1.2eq), after 30min, adds compound 8 (4.0g, 7.87mmol)
DMAC (20ml) solution, room temperature reaction 10h, react with saturated ammonium chloride solution (30ml) cancellation, concentrate,
Adding ethyl acetate (50ml) and water (20ml), stratification, aqueous phase ethyl acetate (50ml*2) extracts, full
Washing with saline solution (20ml), anhydrous sodium sulfate is dried, and is concentrated to give compound 9 (3.78g, 95%).1H NMR
(400MHz,CDCl3): δ 8.01 (d, J=8.0Hz, 2H), 7.81 (d, J=8.2Hz, 2H), 5.15 (d, J=
12.0Hz, 1H), 4.93 (d, J=11.8Hz, 1H), 4.52 (d, J=4.8Hz, 0.5H), 4.45 (d, J=5.0
Hz,0.5H),4.01-4.16(m,0.5H),3.87-3.92(m,0.5H),3.55(s,1H),2.77-2.81(m,
0.5H),2.66-2.71(m,0.5H),2.01-2.19(m,1H),1.87-1.91(m,2H),1.55-1.61(m,
2H),1.41(s,4.5H),1.33(s,4.5H),1.41(s,9H)ppm.MS(m/z):506(M++1)。
Under argon shield, in dichloromethane (20ml) solution of compound 9 (3.0g, 5.94mmol)
Add p-methyl benzenesulfonic acid (3.9ml 59.4mmol), be heated to 35 DEG C of reaction 8h, use saturated ammonium chloride solution
(20ml) cancellation reaction, stratification, aqueous phase dichloromethane (20ml*2) extracts, and merges organic facies with full
Washing with saline solution (20ml), anhydrous sodium sulfate is dried, and dissolves with acetonitrile (20ml) after concentration, and it is right to add
Toluenesulfonic acid (1.02g, 5.94mmol), room temperature reaction 1h, filters to obtain compound 10 (2.5g, 100%).1H NMR(400MHz,CDCl3):δ7.38-7.43(m,5H),4.71(s,2H),3.66(m,1H),3.21
(m,1H),3.06(m,1H),2.51(m,1H),2.14(m,1H),1.99(m,1H),1.49-1.51(m,
10H),1.29(m,1H)ppm.MS(m/z):422(M++1)。
5wt% is added in dichloromethane (20ml) solution of compound 10 (2.0g, 4.75mmol)
NaHCO3Solution (16.0mL, 9.5mmol), stirs 30min, layering, and aqueous phase is with dichloromethane (20ml*2)
Extraction, merges organic facies saturated aqueous common salt (20ml) and washs, and anhydrous sodium sulfate is dried, and filters, and filtrate is cold
But to-10 DEG C, DIPEA (2.4ml, 14.25mmol, 3.0eq) and two (trichloromethyls) are added
Carbonic ester (4.75mmol, 1eq), reacts 30min, adds 10% phosphoric acid solution (10ml), be warming up to room
Temperature, reacts 2h, layering, and aqueous phase dichloromethane (20ml*2) extracts, and merges organic facies, unsaturated carbonate hydrogen
Sodium solution (20ml) washs, and saturated aqueous common salt (20ml) washs, and anhydrous sodium sulfate is dried, and is concentrated to give chemical combination
Thing 11 (1.22g, 93%).1HNMR(400MHz,CDCl3):δ7.20-7.39(m,5H),6.50(s,1H),
5.41 (s, 1H), 5.01 (d, J=11.0Hz, 1H), 4.88 (d, J=11.2Hz, 1H), 3.90 (d, J=7.8Hz,
1H), 3.28 (s, 1H), 3.01 (d, J=11.0Hz, 1H), 2.71 (d, J=11.0Hz, 1H), 2.31 (m,
1H),1.83-1.96(m,2H),1.58(m,1H)ppm.MS(m/z):276(M++1)。
Pd/C (80mg), displacement is added in methanol (15ml) solution of compound 11 (800mg, 2.91mmol)
Hydrogen three times, is heated to 50 DEG C of reaction 10h, is filtered to remove Pd/C, is concentrated to give compound 12 (516mg, 96%).1H NMR(400MHz,CDCl3): δ 3.84 (d, J=8.0Hz, 1H), 3.69 (s, 1H), 3.15 (m, 1H),
2.96 (d, J=11.6Hz, 1H), 2.26 (m, 1H), 2.04 (m, 1H), 1.89 (m, 1H), 1.74 (m, 1H)
ppm.MS(m/z):186(M++1)。
Under argon shield, to THF (1.5ml) solution of compound 12 (40mg, 0.216mmol, 1.0eq)
Middle addition 2-picoline (0.043ml) and sulfur trioxide pyridine (0.12g, 0.756mmol, 3.5eq), room temperature
Reaction 24h, concentrates, and adds dichloromethane (1.5ml), adds 0.5M K2HPO4(0.65mL,0.32mmol)
It is subsequently adding Bu4NHSO4(80.8mg, 0.24mmol) and water (0.2ml), stratification, aqueous phase is with two
Chloromethanes (10ml*2) extracts, and merges organic facies saturated aqueous common salt (10ml) and washs, and anhydrous sodium sulfate is dried,
Concentrate, with methanol: ethyl acetate (1:5) (3ml) recrystallization obtains compound 13 (101mg, 92%).1H NMR(400MHz,D2O):δ4.06(s,1H),3.72(m,2H),3.62(m,3H),3.58-3.55(m,
3H), 3.09 (t, J=9.6Hz, 1H), 2.39 (t, J=8.6Hz, 8H), 1.96-1.75 (m, 16H), 1.52 (m,
12H)ppm.MS(m/z):288(M++1)。
In 2,2,2 tfifluoroethyl alcohol (1.5ml) solution of compound 13 (50mg, 0.099mmol, 1.0eq)
Adding Tetrafluoroboric acid (0.01mL, 0.139mmol, 1.4eq), reaction overnight, concentrates, and adds dichloromethane (2
Ml), water (1ml), NaHCO are added3(10mg, 0.119mmol, 1.2eq), 0 DEG C of reaction 1h is dense
Contract to obtain compound 1 (28mg, 100%).1H NMR(400MHz,D2O):δ4.06(s,1H),3.72(m,
2H), 3.62 (m, 3H), 3.58-3.55 (m, 3H), 3.09 (t, J=9.6Hz, 1H) ppm.MS (m/z): 288
(M++1)。
Each technical characteristic of embodiment described above can combine arbitrarily, for making description succinct, the most right
The all possible combination of each technical characteristic in above-described embodiment is all described, but, if these skills
There is not contradiction in the combination of art feature, is all considered to be the scope that this specification is recorded.
Embodiment described above only have expressed the several embodiments of the present invention, and it describes more concrete and detailed,
But can not therefore be construed as limiting the scope of the patent.It should be pointed out that, for this area
For those of ordinary skill, without departing from the inventive concept of the premise, it is also possible to make some deformation and change
Entering, these broadly fall into protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be with appended power
Profit requires to be as the criterion.
Claims (8)
1. the synthetic method of a diazabicyclo octanone sulfuric acid monoester, it is characterised in that comprise the following steps:
(1) in organic solvent, under the effect of condensing agent and amine reacts 1-10 to raw material 2 glutamic acid lactams
Hour obtaining compound 3, reaction temperature is 0 DEG C-50 DEG C, and the mol ratio of glutamic acid lactams and amine is 1:1-5；
(2) in organic solvent, compound 3 and amido protecting agent react 1-20 hour, obtain compound 4,
Reaction temperature is 0 DEG C-50 DEG C, and the mol ratio of compound 3 and amido protecting agent is 1:1-5；
(3) in organic solvent, to react 1-30 with Trimethylsulfoxonium Iodide under the effect of alkali little for compound 4
Time, obtaining compound 5, reaction temperature is 0 DEG C-50 DEG C, rubbing of compound 4, Trimethylsulfoxonium Iodide and alkali
That ratio is 1:1-5:1-5；
(4) in organic solvent, there is ring closure reaction in compound 5 under the action of an acid, reacts 1-20 hour
Obtaining compound 6, reaction temperature is 50-100 DEG C, and the mol ratio of compound 5 and acid is 1:0.01-1；
(5) in organic solvent, compound 6 and reducing agent react 1-10 hour, obtain reduzate chemical combination
Thing 7, reaction temperature is-20 DEG C-30 DEG C, and the mol ratio of compound 6 and reducing agent is 1:1-5；
(6) in organic solvent, compound 7 and sulfonylation agent react 1-15 hour, obtain compound 8,
Reaction temperature is-20 DEG C-50 DEG C, and the mol ratio of compound 7 and sulfonylation agent is 1:1-5；
(7) in organic solvent, the benzyloxy amine reaction 1-20 of compound 8 and benzyloxy amine or Boc protection
Hour, obtaining compound 9, reaction temperature is 0 DEG C-50 DEG C, compound 8 and benzyloxy amine or Boc protection
The mol ratio of benzyloxy amine be 1:1-5；
(8) in organic solvent, compound 9 reacts 1-10 hour under acid effect, removes Boc protection group
Obtaining compound 10, reaction temperature is 0 DEG C-40 DEG C, and the mol ratio of compound 9 and acid is 1:1-5；
(9) in organic solvent, compound 10 and triphosgene are reacted 1-8 hour, obtain compound 11, instead
Answering temperature is 0 DEG C-50 DEG C, and the mol ratio of compound 10 and triphosgene is 1:1-5；
(10) in mixed solvent, compound 11 reacts 1-30 hour with hydrogen under catalyst action,
To compound 12, reaction temperature is 0 DEG C-60 DEG C, and the mol ratio of compound 11 and catalyst is 1:0.01-1；
(11) in organic solvent, compound 12 and sulfur trioxide pyridine react 10-48 hour, then with
Bu4NHSO4Reaction, obtains compound 13, and reaction temperature is 0 DEG C-50 DEG C, compound 12 and sulfur trioxide
The mol ratio of pyridine is 1:1-10；
(12) in organic solvent, compound 13 and alkali reaction 1-10 hour, obtain product 1 diaza double
Cyclooctanone sulfuric acid monoester, reaction temperature is 0 DEG C-30 DEG C, and the mol ratio of compound 13 and alkali is 1:1-5；
Described product 1, raw material 2 and compound 3-13 are respectively provided with following structure:
Described in step (1), amine is tert-butylamine or benzylamine, and described condensing agent is 2-(7-azo BTA)-four
MU hexafluorophosphoric acid ester, 2-(7-azo BTA)-tetramethylurea hexafluorophosphoric acid or the condensation of carbodiimide class
Agent；
Sulfonylation agent described in step (6) is benzene sulfonyl chloride, to trifluoromethyl benzene sulfonyl chloride or mesyl chloride；
Described in step (8), acid is iridium chloride dimer, trifluoroacetic acid, hydrochloric acid, p-methyl benzenesulfonic acid, sulphuric acid or nitric acid；
B in product 1 structural formula is selected from Na+、Li+Or K+。
The synthetic method of diazabicyclo octanone sulfuric acid monoester the most according to claim 1, its feature exists
In, described in step 1, the response time of reaction is 2-4 hour, and reaction temperature is 20 DEG C-30 DEG C, in glutamic acid
The mol ratio of amide and amine is 1:1-2；Described in step 2, the response time of reaction is 10-15 hour, reaction temperature
Degree is 20 DEG C-30 DEG C, and the mol ratio of compound 3 and amido protecting agent is 1:1-2；React described in step 3
Response time be 10-15 hour, reaction temperature is 20 DEG C-30 DEG C, compound 4, Trimethylsulfoxonium Iodide
It is 1:1.5-2.5:1.5-2.5 with the mol ratio of alkali；Described in step 4, the response time of reaction is 10-15 hour,
Reaction temperature is 70 DEG C-90 DEG C, and the mol ratio of compound 5 and acid is 1:0.03-0.05；Described in step 5 instead
The response time answered is 1-2 hour, and reaction temperature is-20 DEG C-0 DEG C, compound 6 and the mol ratio of reducing agent
For 1:1-2；Described in step 6, the response time of reaction is 3-8 hour, and reaction temperature is 20 DEG C-30 DEG C, chemical combination
The mol ratio of thing 7 and sulfonylation agent is 1:1-2；Described in step 7, the response time of reaction is 8-12 hour,
Reaction temperature is 20 DEG C-30 DEG C, and the mol ratio of the benzyloxy amine of compound 8 and benzyloxy amine or Boc protection is
1:1-2；Described in step 8, the response time of reaction is 6-10 hour, and reaction temperature is 30 DEG C-40 DEG C, chemical combination
The mol ratio of thing 9 and acid is 1:1-2；Described in step 9, the response time of reaction is 1-3 hour, reaction temperature
Being 20 DEG C-30 DEG C, the mol ratio of compound 10 and triphosgene is 1:1-2；The reaction of reaction described in step 10
Time is 8-12 hour, and reaction temperature is 40 DEG C-60 DEG C, and the mol ratio of compound 11 and catalyst is
1:0.01-1；Described in step 11, the response time of reaction is 22-26 hour, and reaction temperature is 20 DEG C-30 DEG C, changes
The mol ratio of compound 12 and sulfur trioxide pyridine is 1:3-4；Described in step 12, the response time of reaction is 1-3
Hour, reaction temperature is 0 DEG C-10 DEG C, and the mol ratio of compound 13 and alkali is 1:1-2.
The synthetic method of diazabicyclo octanone sulfuric acid monoester the most according to claim 1, its feature exists
In, described organic solvent is dichloromethane, oxolane, dimethylformamide, dimethyl acetylamide, second
Glycol dimethyl ether, 1,2-dichloroethanes, dimethyl sulfoxide, toluene, methanol, ethanol, acetonitrile, petroleum ether,
2,2,2 tfifluoroethyl alcohol, normal hexane or ether.
The synthetic method of diazabicyclo octanone sulfuric acid monoester the most according to claim 3, its feature exists
In, described in step (1), (6), (8) and (9), organic solvent is dichloromethane, organic solvent described in step (2)
For acetonitrile, described in step (3), organic solvent is dimethylformamide or dimethyl sulfoxide, step (4) and (5)
Described in organic solvent be toluene, described in step (7), organic solvent is dimethyl acetylamide, institute in step (10)
Stating organic solvent is methanol, and described in step (11), organic solvent is oxolane, organic described in step (12)
Solvent is 2,2,2 tfifluoroethyl alcohol.
5. according to the synthetic method of the diazabicyclo octanone sulfuric acid monoester described in any one of claim 1-4,
It is characterized in that, described in step (2), amido protecting agent is bromobenzyl, benzoyl bromide or Bis(tert-butoxycarbonyl)oxide.
6. according to the synthetic method of the diazabicyclo octanone sulfuric acid monoester described in any one of claim 1-4,
It is characterized in that, step (3) described reaction is carried out under conditions of inert gas shielding, and described alkali is sodium hydrogen,
Potassium tert-butoxide, tert-butyl lithium, imidazoles, triethylamine, diisopropylethylamine, piperidines, lutidines,
Sodium hexamethyldisilazide, potassium hexamethyldisilazide, N-methylmorpholine, Isosorbide-5-Nitrae-diazabicylo [2.2.2]
Octane or pyridine.
7. according to the synthetic method of the diazabicyclo octanone sulfuric acid monoester described in any one of claim 1-4,
It is characterized in that, step (4) described acid is: iridium chloride dimer, p-methyl benzenesulfonic acid, trifluoroacetic acid, hydrochloric acid,
Aluminum chloride, sulphuric acid or nitric acid；Described in step (5), reducing agent is lithium borohydride, sodium borohydride, hydroboration
Potassium, diisopropyl aluminum hydride or Lithium Aluminium Hydride.
8. according to the synthetic method of the diazabicyclo octanone sulfuric acid monoester described in any one of claim 1-4,
It is characterized in that, step (10) described catalyst is palladium/carbon；Step (12) described alkali is sodium hydroxide, hydroxide
Lithium, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate.
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|---|---|---|---|---|
| WO2019075984A1 (en) * | 2017-10-18 | 2019-04-25 | 新发药业有限公司 | Method for preparing avibactam intermediate |
| KR102238179B1 (en) | 2017-12-25 | 2021-04-09 | 신파 파머슈티컬 컴퍼니 리미티드 | Simple manufacturing method of abibactam |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014135930A1 (en) * | 2013-03-08 | 2014-09-12 | Wockhardt Limited | A process for sodium salt of (2s, 5r)-2-carboxamido-7-oxo-6-sulfooxy -1,6-diaza-bicyclo[3.2.1]octane |
| WO2014141132A1 (en) * | 2013-03-14 | 2014-09-18 | Naeja Pharmaceutical Inc. | NEW HETEROCYCLIC COMPOUNDS AND THEIR USE AS ANTIBACTERIAL AGENTS AND β-LACTAMASE INHIBITORS |
| WO2015110963A1 (en) * | 2014-01-21 | 2015-07-30 | Wockhardt Limited | 2-(1,3,4-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1 ]octane derivatives and their use as antibacterial agents |
-
2015
- 2015-08-13 CN CN201510496134.1A patent/CN105061425B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014135930A1 (en) * | 2013-03-08 | 2014-09-12 | Wockhardt Limited | A process for sodium salt of (2s, 5r)-2-carboxamido-7-oxo-6-sulfooxy -1,6-diaza-bicyclo[3.2.1]octane |
| WO2014141132A1 (en) * | 2013-03-14 | 2014-09-18 | Naeja Pharmaceutical Inc. | NEW HETEROCYCLIC COMPOUNDS AND THEIR USE AS ANTIBACTERIAL AGENTS AND β-LACTAMASE INHIBITORS |
| WO2015110963A1 (en) * | 2014-01-21 | 2015-07-30 | Wockhardt Limited | 2-(1,3,4-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1 ]octane derivatives and their use as antibacterial agents |
Non-Patent Citations (1)
| Title |
|---|
| "Enantioselective Synthesis and Profiling of Two Novel Diazabicyclooctanone β-Lactamase Inhibitors";Hui Xiong et al.;《ACS Medicinal Chemistry Letters》;20140812;第5卷(第10期);第1143-1147页 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019075984A1 (en) * | 2017-10-18 | 2019-04-25 | 新发药业有限公司 | Method for preparing avibactam intermediate |
| EP3543236A4 (en) * | 2017-10-18 | 2020-05-27 | Xinfa Pharmaceutical Co., Ltd | Method for preparing avibactam intermediate |
| KR102238179B1 (en) | 2017-12-25 | 2021-04-09 | 신파 파머슈티컬 컴퍼니 리미티드 | Simple manufacturing method of abibactam |
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