CN105061425A - 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 the synthetic method of diazabicyclo octanone sulfuric acid monoester and analogue thereof.
Background technology
Since the forties in last century uses first β-lactam antibitics-penicillin, the antibiotic drug resistance problems of bacterium to widespread use has clinically become 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 from many aspects, wherein the mechanism of action of beta-lactamase inhibitor is combined with bacteriogenic β-lactamase, makes it deactivation, thus make bacterium lose resistance to β-lactam antibitics.This Inhibitors and the β-lactam antibitics combined utilization of not resistance to enzyme, given full play to original antibiotic anti-microbial effect, and this is the important means improving β-lactam antibitics curative effect.
Diazabicyclo octanone sulfuric acid monoester is novel ss-lactam enzyme inhibitors, it press down zymogram than Tazobactam Sodium, Sulbactam and clavulanic acid wide.Arstwyth and the AstraZeneca cooperative research and development compound preparation of ceftazime and A Wei Batan, for injection, within 2015, go on the market in the U.S. first, A Wei Batan belongs to diazabicyclo octanone compound, chemical name is [(1R, 2S, 5R) pungent-6-base of-2-(aminocarboxyl)-7-oxo-1,6-diazabicyclo [3.2.1]] sulfuric acid monoester.It is the novel ss-lactam enzyme inhibitors be expected most at present, all germicidal action is had addicted to the gram-positive microorganism (G+) of oxygen and anaerobism and Gram-negative bacteria (G-) to majority, be applicable to complicated intra-abdominal infection and complicated urinary tract infections (cUTI), comprise pyelonephritis.
AstraZeneca discloses the synthetic method of this compound in its patent WO2012172368, sees synthetic route 1.They for raw material, synthesize diazabicyclo octanone sulfuric acid monoesters 1 by ten single step reactions with the a-carbonyl proline(Pro) of full guard.This route can produce two isomer when synthetic intermediate 18, more difficult separation, and affects ultimate yield.
WO2012086241 discloses with compound 21 for raw material, and by the method for ten single step reaction synthesis diazabicyclo octanone sulfuric acid monoesters 1, see synthetic route 2, this route can produce two isomer when synthetic intermediate 22, more difficult separation, and affects ultimate yield.
WO2014135930 also discloses the synthetic method of diazabicyclo octanone sulfuric acid monoester 1, sees synthetic route 3, and the method adopts the method synthetic compound 28 identical with patent WO2012086241, and the synthesis of compound 20 adopts ammoniacal liquor mixture, reduces costs.The previous section of this route is identical with patent WO2012086241, therefore, can produce two isomer, more difficult separation, and affect ultimate yield when synthetic intermediate 22.
Summary of the invention
Based on this, the object of the present invention is to provide a kind of synthetic method of diazabicyclo octanone sulfuric acid monoester.
For achieving the above object, concrete technical scheme is as follows:
A synthetic method for diazabicyclo octanone sulfuric acid monoester, synthetic route is as follows:
Described synthetic method comprises the following steps:
(1) in organic solvent, L-glutamic acid lactan 2 obtains compound 3 in 2-10 hour with amine reaction under the effect of condensing agent, and temperature of reaction is 0 DEG C-50 DEG C, and the mol ratio of L-glutamic acid lactan 2 and amine is 1.0:1.0-5;
(2) in organic solvent, compound 3 and amido protecting agent reaction 1-20 hour, obtain compound 4, temperature of reaction 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, compound 4 reacts 1-30 hour with Trimethylsulfoxonium Iodide under the effect of alkali, obtains compound 5, and temperature of reaction is 0 DEG C-50, and the mol ratio of compound 4, Trimethylsulfoxonium Iodide and alkali 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, and react and obtain compound 6 in 1-20 hour, temperature of reaction 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 reductive agent reaction 1-10 hour, obtain reduzate compound 7, temperature of reaction is-20-30 DEG C, and the mol ratio of compound 6 and reductive agent is 1.0:1.0-5;
(6) in organic solvent, compound 7 and SULPHURYL CHLORIDE reaction 1-15 hour, obtain compound 8, temperature of reaction is-20 DEG C-50 DEG C, and the mol ratio of compound 7 and SULPHURYL CHLORIDE is 1.0:1.0-5;
(7) in organic solvent, the benzyloxy amine reaction 1-20 hour of compound 8 and benzyloxy amine or Boc protection, obtain compound 9, temperature of reaction is 0 DEG C-50 DEG C, and the mol ratio of the benzyloxy amine of compound 8 and benzyloxy amine or Boc protection is 1.0:1.0-5;
(8) in organic solvent, compound 9 reacts 1-10 hour under acid effect, removes Boc protecting group and obtains compound 10, and temperature of reaction 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 reaction 1-8 hour, obtain compound 11, temperature of reaction 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 is under catalyst action and hydrogen reaction 1-30 hour, and obtain compound 12, temperature of reaction is 0 DEG C-60 DEG C, and the mol ratio of compound 11 and catalyzer is 1.0:0.01-1;
(11) in organic solvent, compound 12 and sulfur trioxide pyridine reaction 10-48 hour, obtain compound 13, temperature of reaction 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 diazabicyclo octanone sulfuric acid monoester, temperature of reaction 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 reaction times of reaction is 2-4 hour, and temperature of reaction is 20 DEG C-30 DEG C, and the mol ratio of L-glutamic acid lactan and amine is 1:1-2; Described in step 2, the reaction times of reaction is 10-15 hour, and temperature of reaction is 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 reaction times of reaction is 10-15 hour, and temperature of reaction is 20 DEG C-30 DEG C, and the mol ratio of compound 4, Trimethylsulfoxonium Iodide and alkali is 1:1.5-2.5:1.5-2.5; Described in step 4, the reaction times of reaction is 10-15 hour, and temperature of reaction 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, the reaction times of reaction is 1-2 hour, and temperature of reaction is-20 DEG C-0 DEG C, and the mol ratio of compound 6 and reductive agent is 1:1-2; Described in step 6, the reaction times of reaction is 3-8 hour, and temperature of reaction is 20 DEG C-30 DEG C, and the mol ratio of compound 7 and SULPHURYL CHLORIDE is 1:1-2; Described in step 7, the reaction times of reaction is 8-12 hour, and temperature of reaction 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 reaction times of reaction is 6-10 hour, and temperature of reaction is 30 DEG C-40 DEG C, and the mol ratio of compound 9 and acid is 1:1-2; Described in step 9, the reaction times of reaction is 1-3 hour, and temperature of reaction is 20 DEG C-30 DEG C, and the mol ratio of compound 10 and triphosgene is 1:1-2; Described in step 10, the reaction times of reaction is 8-12 hour, and temperature of reaction is 40 DEG C-60 DEG C, and the mol ratio of compound 11 and catalyzer is 1:0.01-1; Described in step 11, the reaction times of reaction is 22-26 hour, and temperature of reaction is 20 DEG C-30 DEG C, and the mol ratio of compound 12 and sulfur trioxide pyridine is 1:3-4; Described in step 12, the reaction times of reaction is 1-3 hour, and temperature of reaction 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 methylene dichloride, tetrahydrofuran (THF), dimethyl formamide, N,N-DIMETHYLACETAMIDE, glycol dimethyl ether, 1,2-ethylene dichloride, dimethyl sulfoxide (DMSO), toluene, methyl alcohol, ethanol, acetonitrile, sherwood oil, 2,2,2-trifluoroethanol, normal hexane or ether.
Wherein in some embodiments, step (1), (6), (8) and organic solvent described in (9) be methylene dichloride, described in step (2), organic solvent is acetonitrile, described in step (3), organic solvent is dimethyl formamide or dimethyl sulfoxide (DMSO), described in step (4) and (5), organic solvent is toluene, described in step (7), organic solvent is N,N-DIMETHYLACETAMIDE, described in step (10), organic solvent is methyl alcohol, described in step (11), organic solvent is tetrahydrofuran (THF), described in step (12), organic solvent is 2, 2, 2-trifluoroethanol.
Wherein in some embodiments, described in step (1), amine is TERTIARY BUTYL AMINE or benzylamine, and described condensing agent is 2-(7-azo benzotriazole)-tetramethyl-urea phosphofluoric acid ester (HATU), 2-(7-azo benzotriazole)-tetramethyl-urea phosphofluoric acid (HBTU) or carbodiimide (EDCI).
Wherein in some embodiments, described in step (2), amido protecting agent is bromobenzyl, benzoyl bromide or tert-Butyl dicarbonate.
Wherein in some embodiments, step (3) described reaction is carried out under the condition of protection of inert gas, and described alkali is sodium hydrogen; potassium tert.-butoxide, tert-butyl lithium, imidazoles; triethylamine, diisopropylethylamine, piperidines; lutidine; 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 dipolymer, trifluoroacetic acid, aluminum chloride, hydrochloric acid, tosic acid, sulfuric acid or nitric acid; Reductive agent described in step (5) is lithium borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE, di-isopropyl aluminum hydride, Lithium Aluminium Hydride.
Wherein in some embodiments, SULPHURYL CHLORIDE described in step (6) is benzene sulfonyl chloride, to trifluoromethyl benzene sulfonyl chloride or methylsulfonyl chloride; Described in step 8, acid is iridium chloride dipolymer, tosic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or nitric acid.
Wherein in some embodiments, step (10) described catalyzer is palladium/carbon.
Wherein in some embodiments, step (12) described alkali is sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate.
The synthetic method of diazabicyclo octanone sulfuric acid monoester of the present invention, easy and simple to handle, intermediate is stablized, environmental protection and economy, and reaction easily controls, and described method can be used for synthesizing the related analogs of diazabicyclo octanone sulfuric acid monoester.Compared with prior art, the method for the invention is when synthetic intermediate 7, and can not produce isomer, product is easily separated, and the yield of final product is high.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.
In following embodiment, conventional post-treating method is: after having reacted, in reaction solution, add suitable quantity of water, is separated organic phase and aqueous phase, merges organic phase.If needed, organic phase uses saturated common salt water washing successively, then uses anhydrous Na SO
4drying, after filtration, decompression is spin-dried for, and obtains crude product, then obtain final product after column chromatographic isolation and purification.
To L-Glutimic acid (20g, EDCI (35.7g is added in methylene dichloride (300ml) solution 155mmol), 186mmol, 1.2eq), HOBT (1.1g, 7.8mmol, 0.05eq) with TERTIARY BUTYL AMINE (16.3ml, 155mmol, 1eq), room temperature reaction 2h, react with saturated ammonium chloride solution (100ml) cancellation, concentrated, add propyl carbinol (200ml) and water (100ml), stratification, aqueous phase propyl carbinol (200ml*2) extracts, saturated aqueous common salt (100ml) washs, anhydrous sodium sulfate drying, filter, concentrated, compound as white solid 3 (26.3g is obtained with ethyl acetate (100ml) recrystallization, 92%).
1HNMR(400MHz,CDCl
3):δ5.23(d,J＝12.2Hz,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)。
Be under the condition of 0 DEG C in temperature, to compound 3 (20g, N is added in acetonitrile (300ml) solution 108.6mmol), N-diisopropylethylamine (19.7ml, 119.5mmol, 1.1eq), tert-Butyl dicarbonate (26.1g, 119.5mmol, 1.1eq) with DMAP (663mg, 5.4mmol, 0.05eq), room temperature reaction spends the night, react with saturated ammonium chloride solution (100ml) cancellation, concentrated, add propyl carbinol (200ml) and water (100ml), stratification, aqueous phase propyl carbinol (200ml*2) extracts, saturated aqueous common salt (100ml) washs, anhydrous sodium sulfate drying, filtering and concentrating, compound as white solid 4 (30.3g is obtained with ethyl acetate (100ml) recrystallization, 98%).
1HNMR(400MHz,CDCl
3):δ5.26(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, Trimethylsulfoxonium Iodide (17.0g is added successively in anhydrous DMSO (100ml), 59.8mmol, 1.7eq) with potassium tert.-butoxide (5.9g, 52.8mmol, 1.5eq) room temperature reaction 1h, then compound 4 (10g is instilled, 35.2mmol, DMSO (75ml) solution 1eq), room temperature reaction spends the night, concentrated, add ethyl acetate (100ml) and water (50ml), stratification, aqueous phase ethyl acetate (100ml*2) extracts, saturated aqueous common salt (50ml) washs, anhydrous sodium sulfate drying, concentrate to obtain compound as white solid 5 (12.3g, 93%).
1HNMR(400MHz,CDCl
3):δ5.71(d,J＝7.8Hz,1H),5.11(d,J＝12.0Hz,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 C
3(100mg, 0.75mmol, compound 5 (8g is dripped in toluene (40ml) solution 0.035eq), 21.3mmol, toluene (60ml) solution 1.0eq), at 80 DEG C of reaction 12h after dropwising, be cooled to room temperature, react with saturated ammonium chloride solution (50ml) cancellation, concentrated, add ethyl acetate (100ml) and water (50ml), stratification, aqueous phase ethyl acetate (100ml*2) extracts, saturated aqueous common salt (50ml) washs, anhydrous sodium sulfate drying, concentrates to obtain compound 6 (5.85g, 93%).
1HNMR(400MHz,CDCl
3):δ5.02-5.18(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, in toluene (70ml) solution of compound 6 (4g, 13.4mmol, 1.0eq), add LiBH
4(4MsolutioninTHF, 3.6ml, 1.07eq), reaction 1h, with saturated ammonium chloride solution (50ml) cancellation reaction, concentrated, add ethyl acetate (100ml) and water (50ml), stratification, aqueous phase ethyl acetate (100ml*2) extraction, saturated aqueous common salt (50ml) washs, anhydrous sodium sulfate drying, concentrate to obtain compound 7 (3.85g, 96%).
1HNMR(400MHz,CDCl
3):δ5.20(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)。
To compound 7 (3.0g, triethylamine (1.9ml is added successively in methylene dichloride (50ml) solution 10.0mmol), 14.0mmol), to trifluoromethyl benzene sulfonyl chloride (1.3ml, 12.0mmol, 1.2eq) with DMAP (61.1mg, 0.5mmol), room temperature reaction 5h, react with saturated ammonium chloride solution (20ml) cancellation, concentrated, add ethyl acetate (50ml) and water (20ml), stratification, aqueous phase ethyl acetate (50ml*2) extracts, saturated aqueous common salt (20ml) washs, anhydrous sodium sulfate drying, concentrate to obtain compound 8 (5.03g, 99%).
1HNMR(400MHz,CDCl
3):δ8.01(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＝5.0Hz,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)。
To N-Boc-benzyloxy amine (2.1g, 9.44mmol, potassium tert.-butoxide (1.06g is added in DMAC (20ml) solution 1.2eq), 9.44mmol, 1.2eq), after 30min, add compound 8 (4.0g, DMAC (20ml) solution 7.87mmol), room temperature reaction 10h, react with saturated ammonium chloride solution (30ml) cancellation, concentrated, add ethyl acetate (50ml) and water (20ml), stratification, aqueous phase ethyl acetate (50ml*2) extracts, saturated aqueous common salt (20ml) washs, anhydrous sodium sulfate drying, concentrate to obtain compound 9 (3.78g, 95%).
1HNMR(400MHz,CDCl
3):δ8.01(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＝5.0Hz,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, to compound 9 (3.0g, tosic acid (3.9ml59.4mmol) is added in methylene dichloride (20ml) solution 5.94mmol), be heated to 35 DEG C of reaction 8h, react with saturated ammonium chloride solution (20ml) cancellation, stratification, aqueous phase methylene dichloride (20ml*2) extracts, merge organic phase saturated aqueous common salt (20ml) to wash, anhydrous sodium sulfate drying, concentrated rear acetonitrile (20ml) dissolves, add tosic acid (1.02g, 5.94mmol), room temperature reaction 1h, filter to obtain compound 10 (2.5g, 100%).
1HNMR(400MHz,CDCl
3):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%NaHCO is added in methylene dichloride (20ml) solution of compound 10 (2.0g, 4.75mmol)
3solution (16.0mL, 9.5mmol), stir 30min, layering, aqueous phase methylene dichloride (20ml*2) extracts, merge organic phase saturated aqueous common salt (20ml) to wash, anhydrous sodium sulfate drying, filter, filtrate is cooled to-10 DEG C, add N, N-diisopropylethylamine (2.4ml, 14.25mmol, 3.0eq) He two (trichloromethyl) carbonic ether (4.75mmol, 1eq), reaction 30min, add 10% phosphoric acid solution (10ml), be warming up to room temperature, reaction 2h, layering, aqueous phase methylene dichloride (20ml*2) extracts, merge organic phase, saturated sodium bicarbonate solution (20ml) washs, saturated aqueous common salt (20ml) washs, anhydrous sodium sulfate drying, concentrate to obtain compound 11 (1.22g, 93%).
1HNMR(400MHz,CDCl
3):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) is added, replacing hydrogen three times in methyl alcohol (15ml) solution of compound 11 (800mg, 2.91mmol), be heated to 50 DEG C of reaction 10h, cross and filter Pd/C, concentrate to obtain compound 12 (516mg, 96%).
1HNMR(400MHz,CDCl
3):δ3.84(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 compound 12 (40mg; 0.216mmol; 2-picoline (0.043ml) and sulfur trioxide pyridine (0.12g, 0.756mmol, 3.5eq) is added in THF (1.5ml) solution 1.0eq); room temperature reaction 24h; concentrated, add methylene dichloride (1.5ml), add 0.5MK
2hPO
4(0.65mL, 0.32mmol) then adds Bu
4nHSO
4(80.8mg, 0.24mmol) with water (0.2ml), stratification, aqueous phase methylene dichloride (10ml*2) extracts, merge the washing of organic phase saturated aqueous common salt (10ml), anhydrous sodium sulfate drying, concentrated, with methyl alcohol: ethyl acetate (1:5) (3ml) recrystallization obtains compound 13 (101mg, 92%).
1HNMR(400MHz,D
2O):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)。
To compound 13 (50mg, 0.099mmol, Tetrafluoroboric acid (0.01mL is added in 2,2,2 tfifluoroethyl alcohol (1.5ml) solution 1.0eq), 0.139mmol, 1.4eq), reaction is spent the night, concentrated, add methylene dichloride (2ml), add water (1ml), NaHCO
3(10mg, 0.119mmol, 1.2eq), 0 DEG C of reaction 1h, concentrates to obtain compound 1 (28mg, 100%).
1HNMR(400MHz,D
2O):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 the above embodiment can combine arbitrarily, for making description succinct, the all possible combination of each technical characteristic in above-described embodiment is not all described, but, as long as the combination of these technical characteristics does not exist contradiction, be all considered to be the scope that this specification sheets is recorded.
The above embodiment only have expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but can not therefore be construed as limiting the scope of the patent.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (10)
1. a synthetic method for diazabicyclo octanone sulfuric acid monoester, is characterized in that, comprises the following steps:
(1) in organic solvent, raw material 2 L-glutamic acid lactan obtains compound 3 in 1-10 hour with amine reaction under the effect of condensing agent, and temperature of reaction is 0 DEG C-50 DEG C, and the mol ratio of L-glutamic acid lactan and amine is 1:1-5;
(2) in organic solvent, compound 3 and amido protecting agent reaction 1-20 hour, obtain compound 4, temperature of reaction 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, compound 4 reacts 1-30 hour with Trimethylsulfoxonium Iodide under the effect of alkali, obtains compound 5, and temperature of reaction is 0 DEG C-50 DEG C, and the mol ratio of compound 4, Trimethylsulfoxonium Iodide and alkali is 1:1-5:1-5;
(4) in organic solvent, there is ring closure reaction in compound 5 under the action of an acid, and react and obtain compound 6 in 1-20 hour, temperature of reaction 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 reductive agent reaction 1-10 hour, obtain reduzate compound 7, temperature of reaction is-20 DEG C-30 DEG C, and the mol ratio of compound 6 and reductive agent is 1:1-5;
(6) in organic solvent, compound 7 and SULPHURYL CHLORIDE reaction 1-15 hour, obtain compound 8, temperature of reaction is-20 DEG C-50 DEG C, and the mol ratio of compound 7 and SULPHURYL CHLORIDE is 1:1-5;
(7) in organic solvent, the benzyloxy amine reaction 1-20 hour of compound 8 and benzyloxy amine or Boc protection, obtain compound 9, temperature of reaction is 0 DEG C-50 DEG C, and the mol ratio of the benzyloxy amine of compound 8 and benzyloxy amine or Boc protection is 1:1-5;
(8) in organic solvent, compound 9 reacts 1-10 hour under acid effect, removes Boc protecting group and obtains compound 10, and temperature of reaction 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 reaction 1-8 hour, obtain compound 11, temperature of reaction 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 is under catalyst action and hydrogen reaction 1-30 hour, and obtain compound 12, temperature of reaction is 0 DEG C-60 DEG C, and the mol ratio of compound 11 and catalyzer is 1:0.01-1;
(11) in organic solvent, compound 12 and sulfur trioxide pyridine reaction 10-48 hour, obtain compound 13, temperature of reaction is 0 DEG C-50 DEG C, and the mol ratio of compound 12 and sulfur trioxide pyridine is 1:1-10;
(12) in organic solvent, compound 13 and alkali reaction 1-10 hour, obtain product 1 diazabicyclo octanone sulfuric acid monoester, temperature of reaction 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 have following structure respectively:
2. the synthetic method of diazabicyclo octanone sulfuric acid monoester according to claim 1, is characterized in that, described in step 1, the reaction times of reaction is 2-4 hour, and temperature of reaction is 20 DEG C-30 DEG C, and the mol ratio of L-glutamic acid lactan and amine is 1:1-2; Described in step 2, the reaction times of reaction is 10-15 hour, and temperature of reaction is 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 reaction times of reaction is 10-15 hour, and temperature of reaction is 20 DEG C-30 DEG C, and the mol ratio of compound 4, Trimethylsulfoxonium Iodide and alkali is 1:1.5-2.5:1.5-2.5; Described in step 4, the reaction times of reaction is 10-15 hour, and temperature of reaction 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, the reaction times of reaction is 1-2 hour, and temperature of reaction is-20 DEG C-0 DEG C, and the mol ratio of compound 6 and reductive agent is 1:1-2; Described in step 6, the reaction times of reaction is 3-8 hour, and temperature of reaction is 20 DEG C-30 DEG C, and the mol ratio of compound 7 and SULPHURYL CHLORIDE is 1:1-2; Described in step 7, the reaction times of reaction is 8-12 hour, and temperature of reaction 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 reaction times of reaction is 6-10 hour, and temperature of reaction is 30 DEG C-40 DEG C, and the mol ratio of compound 9 and acid is 1:1-2; Described in step 9, the reaction times of reaction is 1-3 hour, and temperature of reaction is 20 DEG C-30 DEG C, and the mol ratio of compound 10 and triphosgene is 1:1-2; Described in step 10, the reaction times of reaction is 8-12 hour, and temperature of reaction is 40 DEG C-60 DEG C, and the mol ratio of compound 11 and catalyzer is 1:0.01-1; Described in step 11, the reaction times of reaction is 22-26 hour, and temperature of reaction is 20 DEG C-30 DEG C, and the mol ratio of compound 12 and sulfur trioxide pyridine is 1:3-4; Described in step 12, the reaction times of reaction is 1-3 hour, and temperature of reaction is 0 DEG C-10 DEG C, and the mol ratio of compound 13 and alkali is 1:1-2.
3. the synthetic method of diazabicyclo octanone sulfuric acid monoester according to claim 1, it is characterized in that, described organic solvent is methylene dichloride, tetrahydrofuran (THF), dimethyl formamide, N,N-DIMETHYLACETAMIDE, glycol dimethyl ether, 1,2-ethylene dichloride, dimethyl sulfoxide (DMSO), toluene, methyl alcohol, ethanol, acetonitrile, sherwood oil, 2,2,2-trifluoroethanol, normal hexane or ether.
4. the synthetic method of diazabicyclo octanone sulfuric acid monoester according to claim 3, it is characterized in that, step (1), (6), (8) and organic solvent described in (9) be methylene dichloride, described in step (2), organic solvent is acetonitrile, described in step (3), organic solvent is dimethyl formamide or dimethyl sulfoxide (DMSO), described in step (4) and (5), organic solvent is toluene, described in step (7), organic solvent is N,N-DIMETHYLACETAMIDE, described in step (10), organic solvent is methyl alcohol, described in step (11), organic solvent is tetrahydrofuran (THF), described in step (12), organic solvent is 2, 2, 2-trifluoroethanol.
5. the synthetic method of the diazabicyclo octanone sulfuric acid monoester according to any one of claim 1-4, it is characterized in that, described in step (1), amine is TERTIARY BUTYL AMINE or benzylamine, and described condensing agent is 2-(7-azo benzotriazole)-tetramethyl-urea phosphofluoric acid ester, 2-(7-azo benzotriazole)-tetramethyl-urea phosphofluoric acid or carbodiimide class condensing agent.
6. the synthetic method of the diazabicyclo octanone sulfuric acid monoester according to any one of claim 1-4, is characterized in that, described in step (2), amido protecting agent is bromobenzyl, benzoyl bromide or tert-Butyl dicarbonate.
7. the synthetic method of the diazabicyclo octanone sulfuric acid monoester according to any one of claim 1-4, is characterized in that, step (3) described reaction is carried out under the condition of protection of inert gas; described alkali is sodium hydrogen, potassium tert.-butoxide, tert-butyl lithium; imidazoles, triethylamine, diisopropylethylamine; piperidines, lutidine, sodium hexamethyldisilazide; potassium hexamethyldisilazide; N-methylmorpholine, Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane or pyridine.
8. the synthetic method of the diazabicyclo octanone sulfuric acid monoester according to any one of claim 1-4, is characterized in that, step (4) described acid is: iridium chloride dipolymer, tosic acid, trifluoroacetic acid, hydrochloric acid, aluminum chloride, sulfuric acid or nitric acid; Reductive agent described in step (5) is lithium borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE, di-isopropyl aluminum hydride or Lithium Aluminium Hydride.
9. the synthetic method of the diazabicyclo octanone sulfuric acid monoester according to any one of claim 1-4, is characterized in that, SULPHURYL CHLORIDE described in step (6) is benzene sulfonyl chloride, to trifluoromethyl benzene sulfonyl chloride or methylsulfonyl chloride; Described in step (8), acid is iridium chloride dipolymer, trifluoroacetic acid, hydrochloric acid, tosic acid, sulfuric acid or nitric acid.
10. the synthetic method of the diazabicyclo octanone sulfuric acid monoester according to any one of claim 1-4, is characterized in that, step (10) described catalyzer is palladium/carbon; Step (12) described alkali is sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate.
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