CN101081851B - Preparation method of alpha-aza toroid drug template - Google Patents
Preparation method of alpha-aza toroid drug template Download PDFInfo
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- CN101081851B CN101081851B CN2006100270699A CN200610027069A CN101081851B CN 101081851 B CN101081851 B CN 101081851B CN 2006100270699 A CN2006100270699 A CN 2006100270699A CN 200610027069 A CN200610027069 A CN 200610027069A CN 101081851 B CN101081851 B CN 101081851B
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Abstract
The present invention relates to a process for synthesizing alpha-aza spirocyclic medicine template. The improved technological process prepares the alpha-aza spirocyclic medicine template (target compound I) with proline (m=1) or 2-nipecotic acid (m=2) derivative carrying protecting amido group and through four reaction steps, including amidation, oxidation, alkylation and hydrogenation. The structural formula of the alpha-aza spirocyclic medicine template is as below, wherein m=1 or 2, n=1, 2 or 3, here m and n may be the same or different; PG1 and PG2 are substituent groups on the nitrogen atom, for example hydrogen atom (H), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn) and so on, here the PG1 and the PG2 may be the same or different. The method has less reaction steps, high yield and mild condition and is a synthesizing method of the alpha-aza spirocyclic medicine template having large-scale preparation value.
Description
Technical field:
The present invention relates to a kind of preparation method of spiro drug template, particularly a kind of preparation method of alpha-aza toroid drug template.
Background technology:
Alpha-aza toroid drug template, like [5.5], [5.6]; [6.5], [6.6], [5.7] and [6.7] etc.; Can be used as Type II type β-turn analog; Being had various physiologically actives by extensive proof, below is disclosed in partial monopoly or the document, and the example of the closely-related several compounds of the present invention technology:
In addition; Document J.Med.Chem.1990; (33); Once reported in 2270 that compound 7 was microbiotic of a kind of excellent performance, and, introduced the alpha-aza toroid substituting group and can obviously improve physiologically active as the verivate of quinolone antibiotics such as norfloxicin, sparfloxacin, enoxacin and CIPROFLOXACIN USP 24.
Alpha-aza toroid drug template can combine " combinatorial chemistry " technology platform; Make the researchist be " template " with main structure; Synthesize a large amount of at short notice to the structurally-modified compound library of this type drug template; Through further efficient screening, might obtain having similar active even specificity is stronger, toxicity is littler prodrug, the construction cycle that shortens new drug greatly with reduce cost of development.
About synthesizing of alpha-aza toroid drug template, the main method of bibliographical information comprises:
Method 1 is by (J.Med.Chem.1990,33,2270) report, wherein PG
1=Bn, R
1=Me, R
2=H, overall yield 7%, shown in Scheme 1:
Scheme?1
Reagent and productive rate: (i) diisopropylamine lithium (LDA), bromoacetonitrile, 40%; (ii) hydrogen/Raney's nickel, 90%; (iii) toluene, 36%; (iv) lithium aluminum hydride, 55%
Method 2 is by (J.Med.Chem.2004,47,5587; US5,166,136) report, wherein PG
1=Boc, R
1=H, R
2=dichlorophenyl L-Tyrosine methyl ester base, overall yield 12%, shown in Scheme 2:
Scheme?2
Reagent and productive rate: (i) LDA, allyl bromide 98,40%; (ii) ozone-dimethyl sulfide, 75%; (iii) sodium hydroxide, 85%; (iv) dichlorophenyl L-Tyrosine methyl ester, the acetic acid Peng Qinghuana; (v) room temperature, 42%
Method 3 is by (J.Org.Chem.1993,58,860; J.Am.Chem.Soc.1992,114,8778) report, wherein PG
1=Cbz, R
1=t-Bu, R
2=glycine methyl ester base, overall yield 4%, shown in Scheme 3:
Scheme3
Reagent and productive rate: (i) iso-butylene, 58%; (ii) LDA, allyl bromide 98,74%; (iii) trifluoroacetic acid, 87%; (iv) glycine methyl ester, NSC 57182, I-hydroxybenzotriazole, 83%; (v) perosmic anhydride-Periodic acid 99, Peng Qinghuana, 24%; (vi) triphenylphosphine, diethyl azodiformate, 60%
Method 4 is by (Bio.Med.Chem.Lett.1998,8,3137) report, wherein PG
1=Boc, R
1=Bn, R
2=glycine methyl ester base, overall yield 21%, shown in Scheme 4:
Scheme4
Reagent and productive rate: (i) LDA, allyl bromide 98,65%; (ii) borine-hydrogen peroxide, 70%; (iii) Swem oxidation, 90%; (iv) glycine methyl ester, Peng Qinghuana, 70%; (v) H
2/ Pd (OH)
2, 90%; (vi) 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide, N-methylmorpholine, 82%
Method 5 is by (J.Org.Chem.2002,67,7587) report, wherein PG
1=Boc, R
1=t-Bu, R
2=leucine tert-butyl ester base, overall yield 5%, shown in Scheme 5:
Scheme5
Reagent and productive rate: (i) LDA, allyl bromide 98,65%; (ii) assorted dicyclo [3.3.1] nonane of 9-boron, hydrogen peroxide, 98%; (iii) triphenylphosphine, iodine, 68%; The (iv) leucine tert-butyl ester, 61%; (v) tetrabutyl hydrogenation ammonium, 80%; (vi) DCC, 25%
Related committed step ring closure reaction in the document, or utilize the aminolysis (method 1) of ester, or utilize the condensation (method 3) of alcohol and acid amides; Or utilize the condensation (method 2 of carboxylic acid and amine; 4,5), this several method all need carry out functional group's introducing and conversion of multistep; Increased reactions step, and all there is the low shortcoming of productive rate in ring closure reaction.Thereby in view of whole synthetic route, the whole bag of tricks reactions step that document is reported many (usually need 5~8 step reaction), overall yield low (being generally 4~21%) does not possess the feasibility of mass preparation.
Summary of the invention:
The purpose of this invention is to provide a kind of efficient, mild condition, possess the compound method of a kind of alpha-aza toroid drug template that mass preparation is worth, the technical issues that need to address are: former compound method reactions step is many, and productive rate is low.
In the technical scheme of the present invention: a kind of alpha-aza toroid drug template, its chemical structural formula is as follows:
Compound I
Wherein, m=1 or 2, n=1,2 or 3, m and n can be the same or different here; PG
1And PG
2Be the substituting group on the nitrogen-atoms, be Wasserstoffatoms (H), tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz), benzyl (Bn) etc., PG here
1With PG
2Can be the same or different.
Alpha-aza toroid drug template shown in more related above compound I in the embodiment of the invention, including, but not limited to: (a)-(f) etc.
The present invention will improve the compound method of above-mentioned drug template.Synthesis technique of the present invention is concrete summarizes as follows:
In the above-mentioned technology, when carrying out amidate action, will have amido protection base (PG
1) proline(Pro) (m=1) or Pipecolic Acid (m=2) verivate A be dissolved in methylene dichloride, successively add triethylamine, active ester and ammoniacal liquor, obtain amidated products 2-carbonyl carboxamido-group-pyrroles (B, m=1) or 2-carbonyl carboxamido-group-piperidines (B, m=2); B in the presence of triethylamine, by trifluoroacetic anhydride be oxidized to 2-cyanic acid-pyrroles (C, m=1) or 2-cyanic acid-piperidines (C, m=2); C after the diisopropylamine lithium deprotonation, with the halogenated saturated chain alkane in two ends react alkylate D, the n=1 in the alkylating reagent, 2 or 3 can equate with m or unequal, X
1And X
2Be halogen, be chlorine, bromine or iodine, X
1With X
2Can be the same or different reactive behavior X
1>=X
2D adds catalyzer and ammoniacal liquor in organic solvent, hydrogenation obtains title product aza toroid compd E.
In above-mentioned reaction process, the protection base PG that the present invention adopted
1Tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz) or benzyl (Bn) etc. are arranged; In the amidate action process, the active ester that is adopted is a kind of in methyl-chloroformate, Vinyl chloroformate, isopropyl chlorocarbonate, chloroformic acid n-propyl or the chloroformic acid α-chloroethene ester, and its consumption is 1~4 times of equivalent of A; Be preferably 2~3 times of equivalents, the temperature when adding active ester is-40~10 ℃, is preferably-30~0 ℃; The consumption of triethylamine is 2~8 times of equivalents of A; Be preferably 3~6 times of equivalents, the consumption of ammoniacal liquor is 2~5 times of equivalents of A, is preferably 2.5~4 times of equivalents; In oxidation reaction process, the consumption of trifluoroacetic anhydride is 1~5 times of equivalent of B, is preferably 2~4 times of equivalents, and the consumption of triethylamine is 2~8 times of equivalents of B, is preferably 3~6 times of equivalents; In alkylation process, the consumption of diisopropylamine lithium is 1~2 times of equivalent of C, is preferably 1.2~1.75 times of equivalents, and the consumption of alkylating reagent is 1~3 times of equivalent of C, is preferably 1.5~2 times of equivalents; In reduction ring closure reaction process, it is a kind of in Raney's nickel, palladium charcoal or the platinum dioxide that organic solvent is selected a kind of in methyl alcohol, ethanol, ETHYLE ACETATE or the acetone, catalyzer for use; Its consumption is 5~20% (mass percents) of D, is preferably 8~16% (mass percents), and the consumption of ammoniacal liquor is 2~20% of an organic solvent volume; Be preferably 5~15%, reaction pressure is 30~45psi, is preferably 35~40psi; Temperature of reaction is 40~65 ℃, is preferably 45~55 ℃.
The invention has the beneficial effects as follows: the present invention relates to a kind of improvement of compound method of alpha-aza toroid drug template, provide that a kind of reactions step is few, productive rate is high, mild condition, possess the compound method that mass preparation is worth.This type drug template can combine " combinatorial chemistry " technology platform; Synthesize a large amount of structurally-modified compound libraries of known alpha-aza toroid drug template that are directed against at short notice, further screening can help to obtain biological activity better medicament precursor compound.In the technology according to the invention, reactions step is few, is merely the reaction of 4 steps; Overall yield is high, is generally between 27~35%; Mild condition avoids the use of expensive with dangerous reagent, and technology is simple, and scalable scale is carried out, and is easy to industrial operation.
Embodiment:
Following instance helps to understand content of the present invention, the present invention includes but is not limited to following related content:
Embodiment 1
1.2-formyl radical-pyrroles-1-carboxylic acid tert-butyl ester is synthetic
With pyrroles-1, the 2-dicarboxylicacid-1-tert-butyl ester (10.75g, 0.05mol) and triethylamine (22.5g 0.225mol) is dissolved in methylene dichloride (50ml), is cooled to-30 ℃ and adds Vinyl chloroformates (10.8g 0.1mol), adds NH behind the 30min
3.H
2O (11ml, 0.15mol).System rises to room temperature, and reaction is spent the night.Reaction system is with water washing, and organic phase is with Na
2SO
4Drying, precipitation get 2-formyl radical-pyrroles-1-carboxylic acid tert-butyl ester (6.4g, 60%).
1H-NMR(400MHz,CDCl
3):5.50-7.01(m,2H),4.87(m,1H),4.35(m,1H),3.44(m,2H),1.75-1.99(m,4H),1.43(s,9H);MS(m/z):215(M+1)
2.2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester is synthetic
(10.7g 0.05mol) is dissolved in CH to 2-formyl radical-pyrroles-1-carboxylic acid tert-butyl ester
2Cl
2(300ml) and Et
3N (30.3g, 0.3mol), 0 ℃ add down trifluoroacetic anhydride (20.1g, 0.1mol).System rises to room temperature, and reaction is spent the night.Reaction system is with water washing, and 0.5M HCl washs, NaHCO
3Solution washing, Na
2SO
4Drying removes solvent and gets 2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester (8.3g, 85%).
1H-NMR(400MHz,CDCl
3):4.43(m,1H),3.31-3.55(m,2H),1.96-2.30(m,4H),1.49(s,9H);MS(m/z):197(M+1)
3.2-(2-chloro-ethyl)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester is synthetic
Under-78 ℃, (4.9g, THF 0.025mol) (30ml) solution join in the THF solution of LDA (0.03mol) and go 2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester, continue reaction 45min.Under-78 ℃, and adding 1-bromo-2-chloro-ethane (7.1g, 0.05mol), system rises to room temperature, and reaction is spent the night.System is with NH
4The cancellation of Cl solution, with the EtOAc extraction, organic phase is through drying, and precipitation gets 2-(2-chloro-ethyl)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester (6.4g).Product gets 2-(2-chloro-ethyl)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester (3.5g, 55%) through column chromatography.
1H-NMR(400MHz,CDCl
3):3.41-3.95(m,4H),2.21-2.65(m,2H),1.71-2.35(m,8H),1.50(s,9H);MS(m/z):203(M-23),259(M+1)
4.1,7-phenodiazine-spiral shell [4.4] nonane-1-carboxylic acid tert-butyl ester synthetic
(1.1g 4.4mmol) is dissolved in methyl alcohol (40ml) to 2-(2-chloro-ethyl)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester, adds NH
3.H
2O (3.2ml) and Raney-Ni (1g) at the hydrogen pressure of 30psi in 50 ℃ of following hydrogenations.Filtration catalizer removes solvent and gets 1,7-phenodiazine-spiral shell [4.4] nonane-1-carboxylic acid tert-butyl ester (1.0g, 90%).
1H-NMR(400MHz,CDCl
3):3.20-3.50(m,3H),2.16-2.67(m,6H),1.62-1.89(m,6H),1.49(s,9H);MS(m/z):227(M+1)
Embodiment 2
Synthesizing of 2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester referring to embodiment 1.
1.2-(3-chloro-propyl group)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester is synthetic
Under-78 ℃, (4.9g, THF 0.025mol) (30ml) solution join in the THF solution of LDA (0.0375mol) and go 2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester, continue reaction 45min.Under-78 ℃, add 1, and the 3-propylene dichloride (2.8g, 0.025mol), system rises to room temperature, and reaction is spent the night.System is with NH
4The cancellation of Cl solution, with the EtOAc extraction, organic phase is through drying, and precipitation gets crude product 2-(3-chloro-propyl group)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester (6.9g).Product gets 2-(3-chloro-propyl group)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester (5.1g, 75%) through column chromatography.
1H-NMR(400MHz,CDCl
3):3.31-3.75(m,4H),2.35-2.51(m,2H),1.70-2.25(m,6H),1.51(s,9H);MS(m/z):295(M+23)
2.1,7-phenodiazine-spiral shell [4.5] decane-1-carboxylic acid tert-butyl ester synthetic
(2.8g 10.5mmol) is dissolved in ethanol (100ml) to 2-(3-chloro-propyl group)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester, adds NH
3.H
2O (8ml) and Pd-C (1.5g) under the pressure of 45psi in 65 ℃ of following hydrogenation 16h.Filtration catalizer removes solvent and gets 1,7-phenodiazine-spiral shell [4.5] decane-1-carboxylic acid tert-butyl ester (2.4g, 95%).
1H-NMR(400MHz,CDCl
3):2.80-3.48(m,6H),1.60-2.67(m,8H),1.49(s,9H);MS(m/z):241(M+1)
Embodiment 3
1.2-formyl radical-piperidines-1-carboxylic acid tert-butyl ester is synthetic
With piperidines-1, the 2-dicarboxylicacid 1-tert-butyl ester (11.45g, 0.05mol) and triethylamine (40.4g 0.4mol) is dissolved in methylene dichloride (50ml), is cooled to-20 ℃ and adds isopropyl chlorocarbonates (6.1g 0.05mol), adds NH behind the 30min
3.H
2O (18ml, 0.25mol).System rises to room temperature, and reaction is spent the night.Reaction system is with water washing, and organic phase is with Na
2SO
4Drying, precipitation get 2-formyl radical-piperidines-1-carboxylic acid tert-butyl ester (6.8g, 60%).
1H-NMR(400MHz,CDCl
3):6.12(m,2H),4.70(m,1H),4.11(m,1H),2.70(m,1H),2.25(m,1H),1.46(s,9H),1.38-1.70(m,5H);MS(m/z):229(M+1)
2.2-cyanic acid-piperidines-1-carboxylic acid tert-butyl ester is synthetic
(11.4g 0.05mol) is dissolved in CH to 2-formyl radical-piperidines-1-carboxylic acid tert-butyl ester
2Cl
2(300ml) and Et
3N (25.3g, 0.25mol), 0 ℃ add down trifluoroacetic anhydride (50.0g, 0.25mol).System rises to room temperature, and reaction is spent the night.Reaction system is with water washing, and 0.5M HCl washs, NaHCO
3Solution washing, Na
2SO
4Drying removes solvent and gets 2-cyanic acid-piperidines-1-carboxylic acid tert-butyl ester (11.3g, 89%).
1H-NMR(400MHz,CDCl
3):5.25(m,1H),4.02(m,1H),2.98(m,1H),1.45-1.85(m,6H),1.47(s,9H);MS(m/z):155(M-56),211(M+1),233(M+23)
3.2-(2-chloro-ethyl)-2-cyanic acid-piperidines-1-carboxylic acid tert-butyl ester is synthetic
Under-78 ℃, (5.25g, THF 0.025mol) (30ml) solution join in the THF solution of LDA (0.03mol) and go 2-cyanic acid-piperidines-1-carboxylic acid tert-butyl ester, continue reaction 45min.Under-78 ℃, and adding 1-iodo-2-chloro-ethane (14.3g, 0.075mol), system rises to room temperature, and reaction is spent the night.System is with NH
4The cancellation of Cl solution, with the EtOAc extraction, organic phase is through drying, and precipitation gets 2-(2-chloro-ethyl)-2-cyanic acid-piperidines-1-carboxylic acid tert-butyl ester (6.2g).Product gets 2-(2-chloro-ethyl)-2-cyanic acid-piperidines-1-carboxylic acid tert-butyl ester (3.4g, 50%) through column chromatography.
1H-NMR(400MHz,CDCl
3):3.75(d,1H),3.64(t,2H,J=10Hz),3.10(m,1H),2.50(m,2H),2.05(m,2H),1.45-1.70(m,6H),1.51(s,9H);MS(m/z):217(M-56),295(M+23)
4.2,6-phenodiazine-spiral shell [4.5] nonane-6-carboxylic acid tert-butyl ester synthetic
(1.2g 4.4mmol) is dissolved in methyl alcohol (40ml) to 2-(2-chloro-ethyl)-2-cyanic acid-piperidines-1-carboxylic acid tert-butyl ester, adds NH
3.H
2O (8ml) and Raney-Ni (2.4g) at the hydrogen pressure of 40psi in 65 ℃ of following hydrogenations.Filtration catalizer removes solvent and gets 2,6-phenodiazine-spiral shell [4.5] nonane-6-carboxylic acid tert-butyl ester (1.0g, 92%).
1H-NMR(400MHz,CDCl
3):2.99-3.69(m,6H),1.52-2.18(m,8H),1.43(s,9H);MS(m/z):241(M+1)
Embodiment 4
Synthesizing of 2-cyanic acid-piperidines-1-carboxylic acid tert-butyl ester referring to embodiment 3.
1.2-(3-chloro-propyl group)-2-cyanic acid-piperidines-1-carboxylic acid tert-butyl ester is synthetic
Under-78 ℃, (5.25g, THF 0.025mol) (30ml) solution join in the THF solution of LDA (0.0375mol) and go 2-cyanic acid-piperidines-1-carboxylic acid tert-butyl ester, continue reaction 45min.Under-78 ℃, and adding 1-bromo-3-chloro-propane (5.9g, 0.0375mol), system rises to room temperature, and reaction is spent the night.System is with NH
4The cancellation of Cl solution, with the EtOAc extraction, organic phase is through drying, and precipitation gets crude product 2-(3-chloro-propyl group)-2-cyanic acid-piperidines-1-carboxylic acid tert-butyl ester (6.9g).Product gets 2-(3-chloro-propyl group)-2-cyanic acid-piperidines-1-carboxylic acid tert-butyl ester (4.6g, 65%) through column chromatography.
1H-NMR(400MHz,CDCl
3):3.75(dd,1H,J=4Hz),3.59(tetra,2H,J=6.4Hz),3.10(m,1H),2.14-2.20(m,2H,J=5.2Hz),1.60-2.05(m,8H),1.51(s,9H);MS(m/z):231(M-56),309(M+23)
2.1,8-phenodiazine-spiral shell [5.5] undecane-1-carboxylic acid tert-butyl ester synthetic
(3.0g 10.5mmol) is dissolved in methyl alcohol (100ml) to 2-(3-chloro-propyl group)-2-cyanic acid-piperidines-1-carboxylic acid tert-butyl ester, adds NH
3.H
2O (2ml) and Raney-Ni (2.4g) under the pressure of 35psi in 45 ℃ of following hydrogenation 16h.Filtration catalizer removes solvent and gets 1,8-phenodiazine-spiral shell [5.5] undecane-1-carboxylic acid tert-butyl ester (2.4g, 90%).
1H-NMR(400MHz,CDCl
3):2.44-4.01(m,12H),1.5-1.75(m,4H),1.43(s,9H);MS(m/z):255(M+1)
Embodiment 5
Synthesizing of 2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester referring to embodiment 1.
1.2-(4-bromo-butyl)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester is synthetic
Under-78 ℃, (4.9g, THF 0.025mol) (30ml) solution join in the THF solution of LDA (0.025mol) and go 2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester, continue reaction 45min.Under-78 ℃, add 1, and the 4-dibromobutane (13.4g, 0.0625mol), system rises to room temperature, and reaction is spent the night.System is with NH
4The cancellation of Cl solution, with the EtOAc extraction, organic phase is through drying, and precipitation gets crude product 2-(4-bromo-butyl)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester (6.9g).Product gets 2-(4-bromo-butyl)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester (5.6g, 65%) through column chromatography.
1H-NMR(400MHz,CDCl
3):3.41-3.74(m,4H),2.34-2.55(m,2H),1.70-2.27(m,8H),1.50(s,9H);MS(m/z):331(M+1)
2.1,7-phenodiazine-spiral shell [4.6] undecane-1-carboxylic acid tert-butyl ester synthetic
(3.6g 10.5mmol) is dissolved in acetone (100ml) to 2-(4-bromo-butyl)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester, adds NH
3.H
2O (7ml) and Pd-C (3g) under the pressure of 45psi in 50 ℃ of following hydrogenation 6h.Filtration catalizer removes solvent and gets 1,7-phenodiazine-spiral shell [4.6] undecane-1-carboxylic acid tert-butyl ester (2.4g, 91%).
1H-NMR(400MHz,CDCl
3):2.80-3.48(m,6H),1.60-2.67(m,10H),1.49(s,9H);MS(m/z):255(M+1)
Embodiment 6
Synthesizing of 2-cyanic acid-piperidines-1-carboxylic acid tert-butyl ester referring to embodiment 3.
1.2-(4-chloro-butyl)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester is synthetic
Under-78 ℃, (5.25g, THF 0.025mol) (30ml) solution join in the THF solution of LDA (0.03mol) and go 2-cyanic acid-piperidines-1-carboxylic acid tert-butyl ester, continue reaction 45min.Under-78 ℃, and adding 1-bromo-4-chloro-butane (8.55g, 0.05mol), system rises to room temperature, and reaction is spent the night.System is with NH
4The cancellation of Cl solution, with the EtOAc extraction, organic phase is through drying, and precipitation gets crude product 2-(4-chloro-butyl)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester (6.0g).Product gets 2-(4-chloro-butyl)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester (4.9g, 65%) through column chromatography.
1H-NMR(400MHz,CDCl
3):3.70(dd,1H,J=4.5Hz),3.62(m,2H,J=6.4Hz),3.11(m,1H),2.14-2.20(m,2H,J=5.0Hz),1.60-2.05(m,10H),1.50(s,9H);MS(m/z):301(M+1)
2.1,8-phenodiazine-spiral shell [5.6] dodecyl-1-carboxylic acid tert-butyl ester synthetic
(3.2g 10.5mmol) is dissolved in ethanol (100ml) to 2-(4-chloro-butyl)-2-cyanic acid-pyrroles-1-carboxylic acid tert-butyl ester, adds NH
3.H
2O (15ml) and PtO
2(3g) under the pressure of 40psi in 55 ℃ of following hydrogenation 16h.Filtration catalizer removes solvent and gets 1,8-phenodiazine-spiral shell [5.6] dodecyl-1-carboxylic acid tert-butyl ester (2.6g, 92%).
1H-NMR(400MHz,CDCl
3):2.45-4.03(m,14H),1.50-1.71(m,4H),1.43(s,9H);MS(m/z):269(M+1)。
Claims (9)
1. the compound method of an alpha-aza toroid drug template; It is characterized in that synthesis step is following: compd A is dissolved in methylene dichloride, successively adds triethylamine, active ester and ammoniacal liquor and carry out amidate action; Obtain compd B; Compd B is oxidized to Compound C by trifluoroacetic anhydride in the presence of triethylamine, Compound C is after the diisopropylamine lithium deprotonation;
reacts with alkylating reagent; Get the alkylate Compound D, Compound D adds a kind of and ammoniacal liquor in catalyzer Raney's nickel, palladium charcoal or the platinum dioxide in organic solvent; Hydrogenation obtains compd E, and reaction formula is following:
Wherein, m=1 or 2, n=1,2 or 3, m and n can be the same or different; X
1And X
2A kind of in chlorine, the bromine or iodine, X
1With X
2Can be the same or different reactive behavior X
1>=X
2PG
1A kind of in tertbutyloxycarbonyl, carbobenzoxy-(Cbz), the benzyl.
2. the compound method of a kind of alpha-aza toroid drug template according to claim 1; It is characterized in that; In the amidate action process; The active ester that is adopted is a kind of in methyl-chloroformate, Vinyl chloroformate, isopropyl chlorocarbonate, chloroformic acid n-propyl or the chloroformic acid α-chloroethene ester, and its consumption is 1~4 times of equivalent of compd A; Temperature when adding active ester is-40~10 ℃; The consumption of triethylamine is 2~8 times of equivalents of compd A; The consumption of ammoniacal liquor is 2~5 times of equivalents of compd A.
3. the compound method of a kind of alpha-aza toroid drug template according to claim 1 is characterized in that, in oxidation reaction process, the consumption of trifluoroacetic anhydride is 1~5 times of equivalent of compd B; The consumption of triethylamine is 2~8 times of equivalents of compd B.
4. the compound method of a kind of alpha-aza toroid drug template according to claim 1 is characterized in that, in alkylation process, the consumption of diisopropylamine lithium is 1~2 times of equivalent of Compound C; The consumption of alkylating reagent is 1~3 times of equivalent of Compound C.
5. the compound method of a kind of alpha-aza toroid drug template according to claim 1 is characterized in that, in reduction ring closure reaction process, the catalyst levels mass percent is 5~20% of an alkylate; Organic solvent is selected a kind of in methyl alcohol, ethanol, ETHYLE ACETATE or the acetone for use; The consumption of ammoniacal liquor is 2~20% of an organic solvent volume; Reaction pressure is 30~45psi; Temperature of reaction is 40~65 ℃.
6. the compound method of a kind of alpha-aza toroid drug template according to claim 2; It is characterized in that; The consumption of active ester is 2~3 times of equivalents of compd A; Temperature when adding active ester is-30~0 ℃, and the consumption of triethylamine is 3~6 times of equivalents of compd A, and ammonia volume is 2.5~4 times of equivalents of compd A.
7. the compound method of a kind of alpha-aza toroid drug template according to claim 3 is characterized in that, in oxidation reaction process, the consumption of trifluoroacetic anhydride is 2~4 times of equivalents of compd B; The consumption of triethylamine is 3~6 times of equivalents of compd B.
8. the compound method of a kind of alpha-aza toroid drug template according to claim 4 is characterized in that, in alkylation process, the consumption of diisopropylamine lithium is 1.2~1.75 times of equivalents of Compound C; The consumption of alkylating reagent is 1.5~2 times of equivalents of Compound C.
9. the compound method of a kind of alpha-aza toroid drug template according to claim 5; It is characterized in that; In reduction ring closure reaction process, the catalyst levels mass percent is 8~16% of an alkylate, and the consumption of ammoniacal liquor is 5~15% of an organic solvent volume; Reaction pressure is 35~40psi; Temperature of reaction is 45~55 ℃.
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