CN101869563A - Peptide deformylase inhibitor containing 4-methylene pyrrolidine - Google Patents

Peptide deformylase inhibitor containing 4-methylene pyrrolidine Download PDF

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CN101869563A
CN101869563A CN201010217418A CN201010217418A CN101869563A CN 101869563 A CN101869563 A CN 101869563A CN 201010217418 A CN201010217418 A CN 201010217418A CN 201010217418 A CN201010217418 A CN 201010217418A CN 101869563 A CN101869563 A CN 101869563A
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peptide deformylase
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methylene pyrrolidine
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CN101869563B (en
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胡文浩
石炜
马海坤
段月娇
杨琍苹
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East China Normal University
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Abstract

The invention provides a peptide deformylase inhibitor containing 4-methylene pyrrolidine and relates to a peptide deformylase inhibitor. The peptide deformylase inhibitor has the structural formula shown in the specification, and in the formula, R1 is alkyl, R2 is H or alkyl, and R3 is alkyl or aryl or heterocycle. The peptide deformylase inhibitor can inhibit bacterial to synthesize protein so as to kill the bacterial, has small chance of drug resistance generation, is safe for a human body and can kill strains having antibiotic resistance, such as methicillin-resistant staphylococcus aureus (MRSA) and penicillin resistant streptococcus pneumoniae (PRSP).

Description

The peptide deformylase inhibitor containing 2 that contains the 4-methylene pyrrolidine
Technical field
The peptide deformylase inhibitor containing 2 that contains the 4-methylene pyrrolidine relates to a kind of peptide deformylase (PDF) inhibitor.Belong to antibiosis prime system antibacterials technical field.
Background technology
Antibiotic means under high dilution some special microorganisms such as antibacterial, fungus, rickettsia, mycoplasma, chlamydia and virus etc. is killed or inhibiting microbial product (secondary metabolites).Nineteen twenty-nine Britain scholar Fu Laiming has at first found penicillin in antibiotic.1940, Fu Luoli (Florey) and money grace (Chain) were invented the penicillin that can supply the human injection to use on the basis that Fu Laiming finds.Nineteen forty-four, Waksman isolates streptomycin, make us excited be that this antibiotic has very strong resistant function to tubercule bacillus, making tuberculosis no longer is incurable disease.After this, in chloromycetin (nineteen forty-seven), neomycin (1949), oxytetracycline (nineteen fifty), erythromycin (nineteen fifty-two), tetracycline (nineteen fifty-three) and nineteen fifty-nine-1961 year later semi-synthetic cephalosporin (cephalosporin) and the later stage eighties that occurs, the carbostyril family antibacterial drugs of synthetic (as pipemidic acid, norfloxacin, ofloxacin, ciprofloxacin etc.) develops and is widely used in clinical various infection rapidly.Now, antibiotic has become the fresh combatants of pharmaceutical market, in occupation of the most important part of pharmaceutical market.The present global anti-infectives market sales revenue accounts for about 15% of medicine sales volume, occupies second of global drug market sales volume.But most of antibacterial all produces drug resistance to existing antibiotic.
The process of human body cell and pathogenic bacteria synthetic proteins is similar substantially; both starting materials are methionine; but both have the difference of a maximum: counterpart's somatic cell; the pathogenic bacteria synthetic proteins needs earlier methionine to be carried out formylated; carry out the piptonychia acyl groupization by peptide deformylase again at last; thereby remove the process that N end methionine is finished synthetic protein again, human body cell does not then have the process of formylated-piptonychia acyl group.In view of both this differences; chelation by taking place with Fe (II) in a kind of inhibitor of peptide deformylase (PDF) of the metalloproteases that contains Fe (II); thereby reach the effect that makes the deformylase polypeptide enzyme deactivation; the piptonychia acyl group effect of peptide for inhibiting deformylase; make antibacterial can't remove N end methionine; and then the albumen that has optionally suppressed pathogenic bacteria is synthetic, and does not influence the albumen building-up process of human body cell.
Peptide deformylase inhibitor containing 2 is a kind of class antibacterials that grew up in recent years; this class medicine is different with known antibiotic medicine mechanism of action; thereby can be extremely removing those, existing antibiosis is have chemical sproof antibacterial is that a new road has been opened up in the development of antibacterials, has good development prospect.
The peptide deformylase inhibitor containing 2 that people find the earliest is a kind of natural product actinonin Actinonin (I),
This material is found has good in vitro peptide for inhibiting deformylase activity and antibacterial activity, yet this natural product does not have intravital antibacterial activity, thereby can't be applied as antibacterials.
Peptide deformylase (PDF) is a kind of metalloproteases of piptonychia acyl group; in the process of antibacterial synthetic proteins, play critical effect; peptide deformylase (PDF) inhibitor passes through to suppress the effect of PDF piptonychia acyl group in this course, thereby plays the process that suppresses the antibacterial synthetic proteins.Therefore, the PDF inhibitor of this brand-new mechanism of action provides a kind of brand-new antibiosis treatment possibility, and can not have influence on Eukaryotic metabolism.With regard to present research situation, antibacterial is very little to the probability that the PDF inhibitor produces the drug resistance generation.Up to now, there have been two kinds of PDF inhibitor of BB-83698 and LBM-415 to enter the second stage of clinical.In October calendar year 2001, it is clinical that the peptide deformylase inhibitor containing 2 BB83698 (II) that is developed by British Biotech company enters first phase, and now, this product has entered the second stage of clinical trial.
In October, 2003, it is clinical to enter first phase by the peptide deformylase inhibitor containing 2 LBM415 (III) of Vicuron company exploitation, has also entered the second stage of clinical trial now.
Figure BSA00000169490800031
Summary of the invention
The purpose of this invention is to provide a kind of peptide deformylase inhibitor containing 2, it is a kind of antibacterials, can remove those extremely with it existing antibiosis is have chemical sproof antibacterial.
For reaching above-mentioned purpose, the present invention makes peptide deformylase inhibitor containing 2 contain 4-methylene pyrrole alkyl structure, and this peptide deformylase inhibitor containing 2 that contains the 4-methylene pyrrolidine has following structure,
Figure BSA00000169490800032
R in the formula 1Be alkyl; R 2Be H or alkyl; R 3Be alkyl or aromatic radical or heterocycle.
The molecular weight of the peptide deformylase inhibitor containing 2 of the 4-of containing methylene pyrrolidine of the present invention is between 300～500; Dissolve in dichloromethane, methanol, ethanol, N, dinethylformamide, dimethyl sulfoxide; Room temperature is slightly soluble in toluene, benzene, ether, and heating micro dissolution water is insoluble to petroleum ether.
The peptide deformylase inhibitor containing 2 that contains the 4-methylene pyrrolidine of the present invention, through DRX500 type nuclear magnetic resonance analyser determine hydrogen spectrum ( 1H NMR).The employing deuterochloroform is a solvent, 2 seconds repetition periods, and scanning times 32 times, the result shows that the structure of product is is a kind of peptide deformylase inhibitor containing 2 of formyl hydroxylamine derivative of the 4-of containing methylene pyrrolidine.
Compare with background technology, beneficial effect of the present invention is:
1. because the peptide deformylase (PDF) of the peptide deformylase inhibitor containing 2 of the formyl hydroxylamine derivative of the 4-of containing methylene pyrrolidine of the present invention is a kind of metalloproteases of piptonychia acyl group, can suppress the process of antibacterial synthetic proteins.Therefore, a kind of brand-new antibiosis treatment possibility not only is provided, and can not have had influence on Eukaryotic metabolism, it is very little to studies show that simultaneously antibacterial produces chemical sproof probability to the PDF inhibitor.
2. the peptide deformylase inhibitor containing 2 in-vitro antibacterial experiment of the formyl hydroxylamine derivative of the 4-of containing methylene pyrrolidine of the present invention shows; to staphylococcus aureus; staphylococcus epidermidis; the minimum inhibitory concentration of Resistant strain such as methicillin-resistant staphylococcus aureus, penicillin resistant streptococcus pneumoniae (MIC) is 0.0625～8 μ g/ml; show good to gram positive bacteria; the anti-microbial property of negative bacterium and fastbacteria sees Table 1.
Table 1 Resistant strain minimum inhibitory concentration (MIC) (the μ g/ml of unit)
??ATCC25923??S.aureus ??ATCC29213??MSSA ??ATCC43300??MRSA ??ATCC12228??S.epidermidis Clinical separation PRSP
Embodiment 1 ??2 ??8 ??1 ??2 ??0.125
Embodiment 2 ??0.5 ??1 ??0.0625 ??0.125 ??1
Embodiment 3 ??1 ??2 ??0.125 ??0.5 ??0.25
Embodiment 4 ??2 ??16 ??1 ??2 ??0.25
Embodiment 5 ??1 ??4 ??0.5 ??1 ??0.5
Embodiment 6 ??8 ??＞64 ??8 ??16 ??2
Embodiment 7 ??0.25 ??1 ??0.0625 ??0.25 ??0.25
Penicillin ??0.0625 ??32 ??＞64 ??64 Do not survey
??ATCC25923??S.aureus ??ATCC29213??MSSA ??ATCC43300??MRSA ??ATCC12228??S.epidermidis Clinical separation PRSP
Linezolid ??4 ??4 ??4 ??1 ??1
S.aureus is a staphylococcus aureus, and MSSA is a methicillin-sensitivity gold Portugal bacterium, and MRSA is a methicillin resistance gold Portugal bacterium, and S.epidermidis is a staphylococcus epidermidis, and penicillin and Linezolid are the marketable material medicine, purity＞99%.The Linezolid of contrast usefulness is approval listing in 2000, by the linwzolid of Pfizer's research and development.
The specific embodiment
Embodiment 1: embodiment 2:
Embodiment 3: embodiment 4:
Figure BSA00000169490800042
Embodiment 5: embodiment 6:
Figure BSA00000169490800051
Embodiment 7:
Figure BSA00000169490800052
Obtain embodiment 1 structural formula and be totally 17 steps from a～q,
Wherein each step condition is as follows:
Step a) BuBr, TBAB (tetrabutyl ammonium bromide), K 2CO 3Step b) NaOH, H 2O;
Step c) HCHO (aq), (CH 3CH 2) 2NH, CH 3CH 2OH; Step d) (i) 4, Et 3N, t-BuCOCl (pivaloyl chloride), THF ,-78 ℃ of (ii) BuLi, THF-78 ℃;
Step e) PMBCl (to methoxybenzyl chlorine), Et 3N, DMF (N, dinethylformamide);
Step f) N 2H 4.H 2O, DMF/CH 3OH; 50 ℃ of step g), 24h;
Step h) LiOH, H 2O 2, THF/H 2O; Step I) HCOOH, Ac 2O, THF;
Step j) ClCOCOCl (oxalyl chloride), DMSO (dimethyl sulfoxine), Et 3N, CH 2Cl 2,-78 ℃;
Step k) Ph 3PCH 3Br, t-BuOK, THF; Step l) TFA (trifluoracetic acid), CH 2Cl 2
Step m) HOBT (I-hydroxybenzotriazole), EDCI (1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride), NMM (N-methylmorpholine), CH 2Cl 2, 18h; Step n) LiOH, dioxane/H 2O;
Step o) ClCOOCH 2CH 3, Et 3N, THF; Step p) CO (NH 2) 2H 2O 2(urea hydrogen peroxide), phthalic anhydride;
Step q) TFA/CH 2Cl 2
Each step that obtains embodiment 1 structural formula is as follows:
Figure BSA00000169490800061
Figure BSA00000169490800071
Step a, diethyl butylmalonate (2) synthetic:
With ((((330g, 2.38mol) potassium carbonate joins in the single neck bottle of 1L for 22g, 0.06mol) tetrabutyl ammonium bromide (TBAB) for 324g, 2.38mol) positive n-butyl bromide (BuBr) for 316g, 1.98mol) commercially available diethyl malonate (1).Be heated to backflow, reaction 18h.Stop heating, add 500ml water, solid is all dissolved.Add 200mlEA, separatory.The organic facies anhydrous sodium sulfate drying, sucking filtration is spin-dried for, and reuse oil pump distilling under reduced pressure (installing rectifying column additional) gets product diethyl butylmalonate (2) 200g.Productive rate 47%.
1HNMR(500MHz，CDCl 3)δ4.17-4.22(m，4H)，3.30-3.32(m，1H)，1.87-1.92(m，2H)，1.28-1.40(m，4H)，1.25-1.28(t，J＝7Hz，6H)，0.89-0.92(t，J＝7Hz，3H).
Step b, n-butylmalonic acid (3) synthetic:
With (120g, 3mol) NaOH joins in the single neck bottle of 500mL, adds the 250ml water dissolution.Drip (118g, 0.546mol) product of step a (2).Dropwise, be heated to backflow, stirring reaction is to clarification, no oil reservoir, about 3h.Stop heating, the agitation and dropping concentrated hydrochloric acid is to PH=3～4.(having a large amount of white solids to separate out) sucking filtration, filtrate is with 200ml methyl-n-butyl ether extracting twice.The reuse anhydrous sodium sulfate drying is spin-dried for, and gets grease, adds the 500ml petroleum ether, and vigorous stirring is separated out a large amount of white solids, and sucking filtration merges two batches of solids, amounts to 78g product n-butylmalonic acid (3).Productive rate 90%.
1HNMR(500MHz，CDCl 3)δ7.85～11.87(br.s，2H)，3.42-3.46(t，J＝7Hz，1H)，1.94-1.98(m，2H)，1.35-1.41(m，4H)，0.89-0.94(t，J＝7Hz，3H).
Step c, 2-butylacrylic acid (4) synthetic:
Add in the 2L three-necked bottle (78g, the 0.487mol) product (3) that obtains of step b, diethylamine (75ml, 0.731mol), mass percent concentration be 37% formaldehyde (78ml, 0.974mol), 1.5L ethanol.Be heated to backflow, reaction 16h.Solvent is spin-dried for, and the HCl that adds 4mol/L reconciles PH=3～4.With 400ml methyl-n-butyl ether extracting twice, merge organic facies, use anhydrous sodium sulfate drying, be spin-dried for light yellow oil 2-butylacrylic acid (4) 52g.Productive rate 84%.
1HNMR(500MHz，CDCl 3)δ8.16～11.98(br.s，1H)，6.29(s，1H)，5.65(s，1H)，2.30-2.33(t，J＝8Hz，2H)，1.46-1.52(m，2H)，1.34-1.4(m，2H)，0.92-0.95(t，J＝7Hz，3H).
Steps d, (4S)-3-(2-methylene caproyl)-4-benzyl-2-oxazolidone (5) synthetic:
In the dry three-necked bottle of the 250mL that has cryogenic thermometer and nitrogen protection, add the anhydrous THF of 90mL, add again that (3.9g, 30.5mmol) product (4) that obtains of step c is cooled to-78 degree.Add (5.5mL, 38.0mmol) triethylamine, slowly adding again (3.8mL, 31.7mmo) l pivaloyl chloride, the control rate of addition, the maintenance temperature of reaction system is below-60 degree.Reaction system is reacted 30min under-78 degree, rise to room temperature reaction 2hr, is cooled to-78 degree again, and is stand-by.The single neck bottle of another 250mL, cryogenic thermometer, nitrogen protection.Add the 90mL anhydrous tetrahydro furan, (4.9g, 27.6mmol) (S)-4-benzyl-2-oxazolidone are cooled to-78 degree in adding.Drip the 13.2mL2.5mol/L n-BuLi, the control rate of addition adds and rises to room temperature, reaction 30min.Drips of solution in second reaction bulb is added in the reaction bulb that is cooled to-78 degree, rise to room temperature after dropwising, reaction is spent the night.The KHCO3 solution cancellation reaction that in system, adds 40mL 1mol/L.Revolve to steam and remove most of oxolane, add 100mL ethyl acetate and 100mL water, separatory; organic facies is washed with the 50mL saturated common salt, anhydrous sodium sulfate drying, sucking filtration; be spin-dried for, get orange 7.8g, rapid column chromatography (oil mystery: ethyl acetate=6: 1); get colorless oil; add petroleum ether 15ml, vigorous stirring is separated out white solid; sucking filtration gets white solid (4S)-3-(2-methylene caproyl)-4-benzyl-2-oxazolidone (5) 5.5g, productive rate 63%.
1MR(500MHz，CDCl 3)δ7.29(m，5H)，5.40(d，J＝7Hz，2H)，4.44(m，1H)，4.22(m，2H)，3.37(m，1H)，2.82(m，1H)，2.39(m，2H)，1.43(m，4H)，0.93(m，3H).
Step e, N-((4-methoxyl group) benzyl oxygen) phthalimide (7) synthetic:
In the 500ml three-necked bottle, add (26g, 0.16mol) N-hydroxyphthalimide (6) and (25g is 0.16mol) to methoxybenzyl chlorine (PMBCl).Add (53ml, 0.37mol) triethylamine (Et 3N) and 350mlDMF, dark red solution.Be heated to 90 ℃, reaction 40mins～1h.The TLC monitoring.Reactant liquor is poured in the 1L frozen water, fully stirs 15mins.Sucking filtration, filter cake is washed with the 400ml frozen water.60 ℃ of forced air dryings of gained solid are spent the night, and get light yellow solid N-((4-methoxyl group) benzyl oxygen) phthalimide (7) 30g, productive rate 68%.
1HNMR(CDCl3，500MHz)：δ7.70-7.73(m，4H)，7.44(d，J＝8.7Hz，2H)，6.87(d，J＝8.7Hz，2H)，5.14(s，2H)，3.79(s，3H).
Step f, (4-methoxyl group) benzyl azanol (8) synthetic:
With (30g, the 0.106mol) product of step e (7), 140mlDMF and 300mlMeOH join in the 1L three-necked bottle, get suspension.Be heated to 60 ℃, the complete molten yellow solution that gets drips (16ml, 0.330mol) N2H4.H2O.Behind the 10mins, be chilled to room temperature, solid occurs, add 100mlH2O, get cotton-shaped suspension.Revolve to steam and remove MeOH.With 150ml ethyl acetate extraction four times, anhydrous Na 2SO4 drying, sucking filtration, be spin-dried for the 13g light yellow liquid.Add 10mlMeOH, drip the dense HCl of 6ml, separate out white solid, sucking filtration with the amount of ethyl acetate washing, gets 15gPMBONH2.HCl.The gained solid be dissolved in (8.45g, the 0.08mol) aqueous solution of Na2CO3 and 100ml preparation is with twice of 100ml ethyl acetate extraction, the organic facies anhydrous sodium sulfate drying, sucking filtration, revolve steam to remove desolvate 12.2g colourless viscous liquid (4-methoxyl group) benzyl azanol (8), productive rate 75%.
1HNMR(CDCl3，500MHz)：δ7.29-7.30(d，J＝8.5Hz，2H)，6.89-6.91(d，J＝8.5Hz，2H)，5.34(s，2H)，4.62(s，2H)，3.81(s，3H).
Step g, (4S)-3-((2R)-3-is to methoxyl group benzyloxy amido-2-butyl propiono)-4-benzyl-2-oxazolidone (9) synthetic:
The single neck bottle of 100mL of condensing tube is equipped with, in nitrogen protection.Add (7.8g, 27.1mmol) product (5) that obtains of steps d and (10g, the 64.6mmol) product of step f (8) are warming up to 50 degree, react 24hr.After reacting completely, reduce to room temperature, add the dilution of 32mL ethyl acetate, add again (20.9g, 121.1mmol) p-methyl benzenesulfonic acid is dissolved in the 26mL ethyl acetate solution, stirs 1.5hr, sucking filtration, filter cake is washed with amount of ethyl acetate.Organic facies is spin-dried for, add the 185mL methyl-n-butyl ether, vigorous stirring is spent the night under the room temperature, sucking filtration, and filter cake is washed with a small amount of water saturated methyl-n-butyl ether, dry, get white solid 9.6g, add 33mL ethyl acetate and 10mL water dissolution, add (0.81g, 7.6mmol) sodium carbonate is dissolved in the 15mL water stirring reaction 15min.Separatory, water with the 15mL ethyl acetate extraction once merge organic facies, and with 15mL washing, drying, sucking filtration revolves steaming, gets colorless oil (4S)-3-((2R)-3-is to methoxyl group benzyloxy amido-2-butyl propiono)-4-benzyl-2-oxazolidone (9) 6.4g.Productive rate: 58%.
1HNMR(CDCl 3，500MHz)：δ7.23-7.32(m，5H)，7.17-7.19(d，J＝8.5，2H)，6.80-6.82(d，J＝8.5，2H)，5.75(br，1H)，4.58-4.63(m，3H)，4.07-4.14(m，3H)，3.70(s，3H)，3.32-3.36(m，1H)，3.12-3.20(m，2H)，2.38-2.43(m，1H)，1.63-1.75(m，1H)，1.35-1.55(m，1H)，1.26-1.31(m，4H)，0.87-0.89(t，J＝7Hz，3H).
Step h, (2R)-2-((4-methoxyl group benzyloxy amino) methyl) caproic acid (10) synthetic:
In the single neck bottle of 100mL, will (4.3g, 9.8mmol) product of step g (9) is dissolved in 26mL oxolane and the 6mL water, be cooled to 0 degree, slowly add (6.9mL, 22.6mmol) 30% hydrogen peroxide and 9.5mL1.2mol/l lithium hydroxide solution, stirring reaction 1hr under the ice bath.In system, add the 1mol/l sodium sulfite solution of 35mL, rise to room temperature reaction 30min.Organic solvent is spin-dried for, water 10mL ethyl acetate extraction 6 times, water is regulated pH to 3-4 with the hydrochloric acid of 1mol/l, with twice of 20mL ethyl acetate extraction, the organic facies anhydrous sodium sulfate drying, sucking filtration revolves steaming, gets light yellow oily product (2R)-2-((4-methoxyl group benzyloxy amino) methyl) caproic acid (10) 1g, productive rate: 34%.
1HNMR(CDCl 3，500MHz)：δ7.26-7.28(d，J＝7Hz，2H)，6.87-6.88(d，J＝7Hz，2H)，4.62-4.68(m，2H)，3.80(s，3H)，3.06-3.14(m，2H)，2.71-2.72(m，1H)，1.66-1.70(m，1H)，1.49-1.53(m，1H)，1.26-1.33(m，4H)，0.88-0.91(t，J＝7Hz，3H).
Step I, (2R)-2-(((4-methoxyl group benzyloxy base) formamido group) methyl) caproic acid (11) synthetic:
The single neck bottle of 500mL, nitrogen protection adds the 250mL anhydrous tetrahydro furan down, and (10.4mL, 108mmol) acetic anhydride is with (25mL, 540mmol) formic acid are warming up to 50 degree reaction 2hr, are cooled to 0 degree again in adding again.(the control rate of addition drips off in the 30min, reaction 30min for 1.5g, the 5.3mmol) solution of the product of step h (10) and 25mL oxolane composition in slowly dropping in above-mentioned system.Solvent is spin-dried for, adds 50mL dichloromethane and 50mL moisture liquid, organic facies washes twice with the 50mL saturated common salt, anhydrous sodium sulfate drying, and sucking filtration revolves steaming, gets crude product 1.5g.(the developing solvent: PE: EA=3: 1～2: 1), get light yellow oily product (2R)-2-(((4-methoxyl group benzyloxy base) formamido group) methyl) caproic acid (11) 1.0g of thick product column chromatography purification.Productive rate 60%.
1HNMR(CDCl 3，500MHz)：δ8.09(br，1H)，7.26-7.35(d，J＝8.5Hz，2H)，6.88-6.90(d，J＝8.5Hz，2H)，4.72-4.76(m，2H)，3.81(s，3H)，3.79-3.82(m，2H)，2.73-2.76(m，1H)1.56-1.66(m，1H)1.43-1.53(m，1H)，1.25-1.40(m，4H)，0.87-0.90(t，J＝7Hz，3H).
Step j, (2S)-N-tertbutyloxycarbonyl-4-pidolic acid methyl ester (13) synthetic:
The 250ml three-necked bottle, add (9.5ml, 133.97mmol) the 100ml dichloromethane solution of dimethyl sulfoxine, be chilled to-78 degree, drip (9.0ml, 102.7mmol) oxalyl chloride, stirring reaction 10mins keeps-78 degree, drips (20.0g, 76.2mmol) the 120ml dichloromethane solution (the control temperature is not higher than-60 degree) of the product (12) of step I, dropwise-78 degree reaction 2h ,-78 degree drip (28ml, 194mmol) triethylamine again, dropwise nature and rise to room temperature, add the 60ml shrend reaction of going out.Tell organic facies, water is with 2 * 50ml dichloromethane extraction, merge organic facies, wash once with saturated sodium-chloride, anhydrous sodium sulfate drying, concentrate, (ethyl acetate: petroleum ether=4: 1) separation obtains 18g grease (2S)-N-tertbutyloxycarbonyl-4-pidolic acid methyl ester (13) 18g, productive rate 91% to column chromatography.
1HNMR(CDCl 3，500MHz)：δ4.69-4.81(dd，J＝9.7，9.7Hz，1H，)，3.88-3.90(d，J＝15.4Hz，2H)，3.75(s，1H)，2.88-2.98(m，1H)，2.55-2.59(m，1H)，1.45，1.47(2s，9H).
Step k, (2S)-4-methylene pyrrolidine-1,2-two carbonic acid-1-tert-butyl ester 2-methyl ester (14) synthetic:
In the 50ml three-necked bottle, add (2.1g, 6mmol) first base three phenyl phosphonium bromides, N 2Protection; add the 20ml anhydrous tetrahydrofuran solution, ice bath is chilled to 0 degree, drips (0.71g; 6.3mmol) the 10ml anhydrous tetrahydrofuran solution of potassium tert-butoxide; rise to room temperature reaction 1h, ice bath is chilled to 0 degree, drips (0.73g; 3mmol) step j product (13); rise to room temperature reaction, TLC monitoring to reaction finishes, and needs 3h approximately.Add 30ml water to reaction system, revolve to steam and remove oxolane, with 3 * 20ml ethyl acetate extraction, the organic facies anhydrous sodium sulfate drying, sucking filtration, filtrate concentrates, column chromatography purification (mobile phase ethyl acetate: petroleum ether=5: 1) get 1.3g (2S)-4-methylene pyrrolidine-1,2-two carbonic acid-1-tert-butyl ester 2-methyl ester (14), productive rate 63%.
1HNMR(CDCl 3，500MHz)：δ5.00(m，2H)，4.39-4.52(m，1H)，4.06，4.10(2s，2H)，3.73-3.74(2s，3H)，2.98(m，1H)，2.65(m，1H)，1.43，1.48(2s，9H).
Step l, (2S)-4-methylene pyrrolidine-2-methyl carbonate (15) synthetic:
The single neck bottle of 100ml, add (3.7g, 16.3mmol) product (14) that obtains of step k makes it be dissolved in the 40ml dichloromethane, and ice bath drips that (20ml, 270mmol) trifluoracetic acid (TFA) drips room temperature reaction 30mins.Reactant liquor is spin-dried for, and transfers PH=7～8 with triethylamine.Crude product (2S)-4-methylene pyrrolidine-2-methyl carbonate (15) directly drops into next step, and productive rate is by 100%.
Step m, (2S)-1-((2R)-2-(((4-methoxyl group benzyloxy base) formamido group) methyl) caproyl)-4-methylene pyrrolidine-2-methyl carbonate (16) synthetic:
In the 50ml three-necked bottle, add (0.6g; 4.4mmol) I-hydroxybenzotriazole (HOBT); (0.84g; 4.4mmol) 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI); nitrogen protection; add (1.23g, 3.96mmol) product (11) that obtains of step I and the solution of 10ml anhydrous methylene chloride composition.Add that (0.97ml, 8.8mmol) N-methylmorpholine (NMM) add by (1g, 4.4mmol) crude product of the product (15) that obtains of step l and the solution that the 5ml anhydrous methylene chloride is formed, stirred overnight at room temperature reaction.Reactant liquor is washed once with the saturated aqueous citric acid solution of 10ml; again once with the washing of 10ml saturated sodium carbonate; the organic facies anhydrous sodium sulfate drying; sucking filtration; be spin-dried for; obtain 1.4g product (2S)-1-((2R)-2-(((4-methoxyl group benzyloxy base) formamido group) methyl) caproyl)-4-methylene pyrrolidine-2-methyl carbonate (16), productive rate 85%.
1HNMR(CDCl 3，500MHz)：δ7.86，8.07(s，1H)，7.24-7.25(d，J＝5Hz，2H)，6.88-6.89(d，J＝5Hz，2H)，5.06-5.10(m，2H)，4.86-4.88(m，1H)，4.48-4.50(m，1H)，4.21-4.24(m，1H)，3.83-3.88(m，1H)，3.81(s，5H)，3.72(s，3H)，3.43-3.46(m，1H)，3.16-3.18(m，1H)，2.81-2.93(m，2H)，1.60-1.75(m，1H)，1.42-1.58(m，1H)，1.20-1.42(m，4H)，0.89-0.92(t，J＝7Hz，3H).
Step n, (2S)-1-((2R)-2-(((4-methoxyl group benzyloxy base) formamido group) methyl) caproyl)-4-methylene pyrrolidine-2-carboxylic acid (17) synthetic:
Add in the single neck bottle of 50ml that (the oxolane dissolving with 15ml adds (0.14g, 3.4mmol) the 15ml aqueous solution of a hydronium(ion) oxidation lithium again for 1.4g, the 3.4mmol) product (16) that obtains of step m.Room temperature reaction 1h; reactant liquor with the 20ml ethyl acetate extraction once; water is transferred PH=4～5 with the citric acid saturated aqueous solution; again with twice of 20ml ethyl acetate extraction; the organic facies anhydrous sodium sulfate drying, sucking filtration is spin-dried for; get 1.35g product (2S)-1-((2R)-2-(((4-methoxyl group benzyloxy base) formamido group) methyl) caproyl)-4-methylene pyrrolidine-2-carboxylic acid (17), productive rate 100%.
1HNMR(CDCl 3，500MHz)：δ7.89，7.92(s，1H)，7.23-7.24(d，J＝7Hz，2H)，6.88-6.89(d，J＝7Hz，2H)，5.06-5.10(m，2H)，4.86-4.88(m，1H)，4.48-4.50(m，1H)，4.21-4.24(m，1H)，3.83-3.88(m，1H)，3.81(s，5H)，3.43-3.46(m，1H)，3.16-3.18(m，1H)，2.81-2.93(m，2H)，1.60-1.75(m，1H)，1.48-1.62(m，1H)，1.20-1.30(m，4H)，0.86-0.89(t，J＝7Hz，3H).
Step o, (2S)-N-(5-fluoro-2-pyridine)-1-((2R)-2-(((4-methoxyl group benzyloxy base) formamido group) methyl) caproyl)-4-methylene pyrrolidine-2-amide (18) synthetic:
The 50ml three-necked bottle under the nitrogen protection, adds (1.0g; 2.5mmol) solution formed of the product (17) that obtains of step n and 10ml anhydrous tetrahydro furan, ice bath to 0 ℃ adds (0.36ml; 2.5mmol) anhydrous triethylamine, drip (0.24ml, 2.5mmol) ethyl chloroformate (ClCOOCH 2CH 3), rise to room temperature reaction 1h.Add (0.34g; 3mmol) the 5ml anhydrous tetrahydrofuran solution of 2-amino-5-fluorine pyridine; room temperature reaction spends the night; reactant liquor is spin-dried for; add the dilution of 15ml ethyl acetate; wash once with the saturated aqueous citric acid solution of 10ml; again once with the washing of 10ml saturated sodium carbonate; the organic facies anhydrous sodium sulfate drying; sucking filtration is spin-dried for, and obtains 1.0g product (2S)-N-(5-fluoro-2-pyridine)-1-((2R)-2-(((4-methoxyl group benzyloxy base) formamido group) methyl) caproyl)-2; 5-pyrrolin-2-amide (18), productive rate 81%.
1HNMR(CDCl 3，500MHz)：δ8.36-8.50(m，1H)，8.14-8.17(m，1H)，7.86-8.07(d，1H)，7.37-7.42(m，1H)，7.24-7.25(d，J＝5Hz，2H)，6.88-6.89(d，J＝5Hz，2H)，5.06-5.10(m，2H)，4.86-4.88(m，1H)，4.48-4.50(m，1H)，4.21-4.24(m，1H)，3.83-3.88(m，1H)，3.81(s，5H)，3.43-3.46(m，1H)，3.16-3.18(m，1H)，2.81-2.93(m，2H)，1.60-1.75(m，1H)，1.42-1.58(m，1H)，1.20-1.42(m，4H)，0.89-0.92(t，J＝7Hz，3H).
Step p, (2S)-N-(5-fluoro-1-oxygen-2-pyridine)-1-((2R)-2-(((4-methoxyl group benzyloxy base) formamido group) methyl) caproyl)-4-methylene pyrrolidine-2-amide (19) synthetic:
Add in the single neck bottle of 25ml that (1.0g, 2mmol) product (18) that obtains of step o is dissolved in the 15ml ethyl acetate with it, adds (0.57g, 6mmol) urea hydrogen peroxide complex (CO (NH again 2) 2H 2O 2); add (0.89g in three batches; 6mmol) phthalic anhydride; room temperature reaction spends the night; reactant liquor is with (1.24g; 10mmol) the 10ml aqueous solution cancellation of sodium sulfite; separatory; organic facies again with the solution washing of 10ml saturated sodium carbonate once; the organic facies anhydrous sodium sulfate drying, sucking filtration is spin-dried for; obtain 0.93g product (2S)-N-(5-fluoro-1-oxygen-2-pyridine)-1-((2R)-2-(((4-methoxyl group benzyloxy base) formamido group) methyl) caproyl)-4-methylene pyrrolidine-2-amide (19), productive rate 90%.
1HNMR(CDCl 3，500MHz)：δ8.36-8.50(m，1H)，8.14-8.17(m，1H)，7.86-8.07(d，1H)，7.24-7.25(d，J＝5Hz，2H)，7.10-7.20(m，1H)，6.88-6.89(d，J＝5Hz，2H)，5.06-5.10(m，2H)，4.86-4.88(m，1H)，4.48-4.50(m，1H)，4.21-4.24(m，1H)，3.83-3.88(m，1H)，3.81(s，5H)，3.43-3.46(m，1H)，3.16-3.18(m，1H)，2.81-2.93(m，2H)，1.60-1.75(m，1H)，1.42-1.58(m，1H)，1.20-1.42(m，4H)，0.89-0.92(t，J＝7Hz，3H).
Step q, (2S)-N-(5-fluoro-1-oxygen-2-pyridine)-1-((2R)-2-((formyl hydroxylamino) methyl) caproyl)-4-methylene pyrrolidine-2-amide (20) synthetic:
Add in the single neck bottle of 25ml that ((5ml, 67.5mmol) trifluoracetic acid (TFA) dropwises room temperature reaction 1h in dropping for 0.93g, the 1.8mmol) solution formed of the product (19) that obtains of step p and 10ml dichloromethane.Reactant liquor is spin-dried for, and with the dilution of 10ml dichloromethane, transfers to water PH=8～9 with saturated aqueous sodium carbonate again.Separatory; water again with the 10ml dichloromethane extraction once; merge organic facies; anhydrous sodium sulfate drying; sucking filtration is spin-dried for, crude product column chromatography (dichloromethane: methanol=50: 1); get 0.3g finished product (2S)-N-(5-fluoro-1-oxygen-2-pyridine)-1-((2R)-2-((formyl hydroxylamino) methyl) caproyl)-4-methylene pyrrolidine-2-amide (20), productive rate 42%.
1HNMR(CDCl 3，500MHz)：δ10.6(s，1H)，8.42-8.46(m，1H)，8.22(m，1H)，7.70(s，1H)，7.12-7.14(m，1H)，5.10(m，3H)，4.60-4.63(d，J＝13.5Hz，1H)，4.20-4.23(d，J＝13.5Hz，1H)，3.91-3.96(m，1H)，3.40-3.43(d，J＝11.5Hz，1H)，3.15-3.16(m，1H)，2.83-2.99(m，2H)，1.66-1.68(m，1H)，1.47-1.50(m，1H)，1.25-1.36(m，4H)，0.87-0.89(t，J＝7Hz，3H).
All raw materials that above-mentioned technology is related, solvent is commercially available SILVER REAGENT.
Embodiment 2
Except step o replaces with 2-amino-5 methylthiazol with raw material by 2-amino-5-fluorine pyridine.Other conditions are constant, get product (2S)-N-(5-methyl-2-thiazole)-1-((2R)-2-(((4-methoxyl group benzyloxy base) formamido group) methyl) caproyl)-4-methylene pyrrolidine-2-amide.Directly carry out step q then and obtain finished product (2S)-N-(5-methyl-2-thiazole)-1-((2R)-2-((formyl hydroxylamino) methyl) caproyl)-4-methylene pyrrolidine-2-amide.All the other are identical with embodiment 1.
1HNMR(CDCl 3，500MHz)：δ10.5(brs，1H)，7.68(s，1H)，5.64(brs，1H)，4.97-5.10(m，3H)，4.78(m，1H)，4.23-4.26(m，1H)，4.06-4.11(m，1H)，3.40-3.42(m，1H)，3.12-3.14(m，2H)，2.59-2.62(m，1H)，2.27(s，3H)，1.91(m，1H)，1.27-1.51(m，5H)，0.89-0.99(m，3H).
Embodiment 3
Except after step o obtained (2S)-N-(5-fluoro-2-pyridine)-1-((2R)-2-(((4-methoxyl group benzyloxy base) formamido group) methyl) caproyl)-4-methylene pyrrolidine-2-amide (18); do not carry out step p; directly carry out step q, obtain finished product (2S)-N-(5-fluoro-2-pyridine)-1-((2R)-2-((formyl hydroxylamino) methyl) caproyl)-4-methylene pyrrolidine-2-amide.All the other are identical with embodiment 1.
1HNMR(CDCl 3，500MHz)：δ9.82(s，1H)，8.18-8.20(m，1H)，8.07(m，1H)，7.78(s，1H)，7.39-7.41(m，1H)，5.07-5.09(d，J＝9.2Hz，，2H)，4.96(m，1H)，4.52-4.55(m，1H)，4.23-4.726(m，1H)，3.90-3.95(m，1H)，3.43-3.45(m，1H)，3.19-3.20(m，1H)，2.88-2.90(m，2H)，1.67(m，1H)，1.50(m，1H)，1.29-1.32(m，4H)，0.84-0.87(m，3H).
Embodiment 4
Except step o replaces with aniline with raw material by 2-amino-5-fluorine pyridine.Other conditions are constant, get product (2S)-N-phenyl-1-((2R)-2-(((4-methoxyl group benzyloxy base) formamido group) methyl) caproyl)-4-methylene pyrrolidine-2-amide.Directly carry out step q then and obtain finished product (2S)-N-phenyl-1-((2R)-2-((formyl hydroxylamino) methyl) caproyl)-4-methylene pyrrolidine-2-amide.All the other are identical with embodiment 1.
1HNMR(CDCl 3，500MHz)：δ9.19(s，1H)，7.76(s，1H)，7.47-7.49(m，2H)，7.21-7.24(m，2H)，7.02-7.05(m，1H)，5.08-5.13(m，2H)，4.91-4.93(m，1H)，4.51-4.54(m，1H)，4.20-4.23(m，1H)，3.86-3.91(m，1H)，3.44-3.46(m，1H)，3.18-3.19(m，1H)，2.94-3.00(m，1H)，2.84(m，1H)，1.64-1.67(m，1H)，1.48-1.52(m，1H)，1.23-1.32(m，4H)，0.82-0.85(t，J＝6.7Hz，3H).
Embodiment 5
Except step o replaces with 4-fluoro-aniline with raw material by 2-amino-5-fluorine pyridine.Other conditions are constant, get product (2S)-N-(4-fluoro-phenyl)-1-((2R)-2-(((4-methoxyl group benzyloxy base) formamido group) methyl) caproyl)-4-methylene pyrrolidine-2-amide.Directly carry out step q then and obtain finished product (2S)-N-(4-fluoro-phenyl)-1-((2R)-2-((formyl hydroxylamino) methyl) caproyl)-4-methylene pyrrolidine-2-amide.All the other are identical with embodiment 1.
1HNMR(CDCl 3，500MHz)：δ9.32(s，1H)，7.74(s，1H)，7.36-7.39(m，2H)，6.84-6.87(t，J＝8.4Hz，，2H)，5.06-5.10(d，J＝19Hz，2H)，4.87-4.88(m，1H)，4.48-4.50(m，1H)，4.21-4.24(m，1H)，3.83-3.88(m，1H)，3.43-3.46(m，1H)，3.16-3.18(m，1H)，2.81-2.93(m，2H)，1.63-1.67(m，1H)，1.47-1.51(m，1H)，1.25-1.31(m，4H)，0.82-0.85(t，J＝6.75Hz，3H).
Embodiment 6
Except step o replaces with morpholine with raw material by 2-amino-5-fluorine pyridine.Other conditions are constant, get product (2S)-morpholine-1-((2R)-2-(((4-methoxyl group benzyloxy base) formamido group) methyl) caproyl)-4-methylene pyrrolidine-2-amide.Directly carry out step q then and obtain finished product (2S)-morpholine-1-((2R)-2-((formyl hydroxylamino) methyl) caproyl)-4-methylene pyrrolidine-2-amide.All the other are identical with embodiment 1.
1HNMR(CDCl 3，500MHz)：δ7.70(s，1H)，5.06-5.10(m，3H)，4.43-4.46(m，1H)，4.30-4.32(m，1H)，3.84-3.87(m，1H)，3.42-3.78(m，10H)，3.18(m，1H)，2.92-2.94(m，2H)，1.60-1.75(m，1H)，1.25-1.46(m，5H)，0.90-0.93(t，J＝6.2Hz，3H).
Embodiment 7
Except step a replaces with cyclopentyl bromide methane with the positive n-butyl bromide of raw material.All the other are identical with embodiment 2.
1HNMR(CDCl 3，500MHz)：δ10.5(brs，1H)，7.68(s，1H)，5.68(brs，1H)，4.97-5.10(m，3H)，4.78(m，1H)，4.21-4.24(m，1H)，4.00(m，1H)，3.48-3.51(m，1H)，3.10-3.15(m，2H)，2.59-2.62(m，1H)，2.26(s，3H)，1.43-1.96(m，8H)，0.88-1.30(m，3H).

Claims (1)

1. contain the peptide deformylase inhibitor containing 2 of 4-methylene pyrrolidine, it is characterized in that: this peptide deformylase inhibitor containing 2 has following structure,
Figure FSA00000169490700011
R in the formula 1Be alkyl; R 2Be H or alkyl; R 3Be alkyl or aromatic radical or heterocycle.
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CN103159660A (en) * 2011-12-08 2013-06-19 天津市国际生物医药联合研究院 (2R)-1-(2-methyl-3-(methoxy(methyl)amino)-propionyl)pyrrolidine-2-carboxylic acid and application thereof
CN103159660B (en) * 2011-12-08 2016-07-06 天津市国际生物医药联合研究院 (2R)-1-(2-methyl-3-(methoxyl group (methyl) amino)-propiono) pyrrolidine-2-carboxylic acid and application thereof
WO2017193924A1 (en) 2016-05-11 2017-11-16 如东瑞恩医药科技有限公司 Spiro three-membered ring, spiro five-membered ring peptide deformylase inhibitor and use thereof in antibacteria and anti-tumour.
CN107362162A (en) * 2016-05-11 2017-11-21 如东瑞恩医药科技有限公司 The antitumor application thereof of spiral shell three-membered ring, spiral shell five-membered ring class peptide deformylase inhibitor containing 2
CN107365303A (en) * 2016-05-11 2017-11-21 如东瑞恩医药科技有限公司 The antibacterial applications of spiral shell three-membered ring, spiral shell five-membered ring class peptide deformylase inhibitor containing 2
CN107365302A (en) * 2016-05-11 2017-11-21 如东瑞恩医药科技有限公司 Spiral shell three-membered ring, spiral shell five-membered ring class peptide deformylase inhibitor containing 2
CN107362162B (en) * 2016-05-11 2019-12-13 如东瑞恩医药科技有限公司 Antitumor application of spirotricyclic and spiropentacyclic peptide deformylase inhibitor
CN107365302B (en) * 2016-05-11 2019-12-13 如东瑞恩医药科技有限公司 Spiro three-membered ring, spirofive-membered ring peptoid deformylase inhibitors
CN107365303B (en) * 2016-05-11 2019-12-13 如东瑞恩医药科技有限公司 Antibacterial application of spirotricyclic and spiropentacyclic peptide deformylase inhibitor

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