CN104693216B - 1-N-substituted benzyl-6-N'-substituent-2,3,6,9-tetralin-1H-[1,4] benzoxazine [3,2-g] quinolone-9-ketone-8-formic acid compound and preparation method and application thereof - Google Patents
1-N-substituted benzyl-6-N'-substituent-2,3,6,9-tetralin-1H-[1,4] benzoxazine [3,2-g] quinolone-9-ketone-8-formic acid compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicine compounds, and discloses a 1-N-substituted benzyl-6-N'-substituent-2,3,6,9-tetralin-1H-[1,4] benzoxazine [3,2-g] quinolone-9-ketone-8-formic acid compound and a preparation method and application thereof. According to the formula (I) of the 1-N-substituted benzyl-6-N'-substituent-2,3,6,9-tetralin-1H-[1,4] benzoxazine [3,2-g] quinolone-9-ketone-8-formic acid compound, R1 represents a benzyl or a substituted benzyl, and R2 represents hydrogen or an alkyl or a hydroxyalkyl or a substituted benzyl or a carboxyalkyl. The method comprises the steps that firstly, 2-amino-5-nitrophenol is used as a raw material, acetylation protection, affinity substitute ring closure and deprotection are performed, affinity substitute is introduced into substituted benzyl, nitro reduction is performed through stannous chloride, condensation is performed, Gould-Jacobs reaction ring closure is performed, affinity substitute is introduced into different substituent groups, and finally hydrolysis is performed to obtain the compound of the formula (I). The compound has the inhibiting effect on the HIV-1 integrase.
Description
Technical field
The present invention relates to 1-N- substituted benzyl -6-N '-substituent -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine is simultaneously [3,2-g]
Quinoline -9- ketone -8- formic acid compound and preparation method thereof and the application as HIV-1 integrase inhibitor, belong to medicine
Compound technical field.
Background technology
The HIV-1 (human immunodeficiency virus-I type) belonging to retrovirus is the virus causing AIDS.
HIV-1 virocyte invasion host cell can substantially divide following 4 stages：First stage, the gp120 albumen of HIV-1 adventitia is special
Recognize the CD4 molecule on T cell film different in naturely, high affinely in combination, so that target cell is in close contact with virion.
Subsequently merge between gp41 mediation HIV-1 outer layer adipose membrane and target cell, and viral core particle is discharged into target cell
Endochylema in.Second stage, after entering born of the same parents, the geneome RNA of HIV-1, under viral reverse transcriptase effect, is inversely transcribed into double-strand
Proviral DNA is simultaneously proceeded in nucleus in the form of nucleic acid-protein complex, then insertion host is thin under viral integrase enzyme effect
In the chromosomal DNA of born of the same parents.Phase III, viral DNA is become mRNA by the rna transcription of host cell, and it is required to translate synthesis virus
Structural proteins.4th section, RNA and structural proteins ressemble new virion on cell membrane, are discharged by bud life.
Therefore it is directed to 4 stage different characteristics of HIV cell, following several anti-HIV-1 medicines can be designed：1) virus
Be combined inhibitor and fusion inhibitor with target cell；2) viral reverse transcriptase inhibitor；3) HIV-1 integrase inhibitor；4)
HIV-1 protease inhibitors；5) HIV-1 maturation inhibitor.
So far, existing 25 kinds of single anti-HIV-1 medicines and 5 kinds of compound preparations being made up of these medicines are by the U.S.
FDA ratifies for clinic.According to mechanism of action, this 25 kinds of medicines can be divided into 4 classes.The first kind is that RTI (includes
Ucleosides and totally 12 kinds of non-nucleoside, e.g., Zidovudine (Retrovir, AZT), Lamivudine (Epivir, 3TC), take charge of its husband
Fixed (Zerit, d4T), Didanosine (Videx) etc.)；Equations of The Second Kind be protease inhibitors (totally 10 kinds, e.g., indinavir
(Crixivan, IDV), Ritonavir (Norvir) etc.)；3rd class is the inhibitor stoping HIV-1 from invading, and such medicine is current
Only two kinds, a kind of is the medicine T-20 for gp41 target that FDA approval in 2003 lists, and another kind is that in August, 2007 FDA is criticized
The new drug Selzentry for CCR5 target of quasi- listing；4th class is integrase inhibitor, ends to the end of the year 2013, the U.S.
Food and FAD (FDA) have been approved by three integrase inhibitor listings.It is on October 12nd, 2007 approval respectively
Raltegravir, the Dolutegravir of Elvitegravir and 2013 on August approval in 12, of August in 2012 approval on the 27th.
The HAART cure (highly efficient anti-virus therapy) clinically commonly used at present, that is, using 2 kinds or 3 kinds of RTIs and extremely
Few a kind of protease inhibitors, can effectively reduce plasma viral load, extend the asymptomatic stage of the infected.However, HIV-1 gene
Variation result in the appearance of drug-resistant virus, existing some patients use this conventional therapeutic scheme invalid.In addition, it is antiviral
Some toxic and side effects of medicine also limit the application of HAART.Because front two class medicines easily induce HIV resistance, and human body is had
Stronger toxic and side effect etc., increasing patient cannot constantly accept the treatment of these inverases.And HIV-1 integrates
Enzyme is that HIV-1 proviral DNA is integrated into requisite a kind of enzyme during host cell gene group, and does not have in human body
Find that the enzyme analog of identical function exists, the medicine being therefore directed to integrase design will not destroy the cell of health, significantly drops
The low toxicity of medicine.
At present it has been reported that integrase inhibitor mainly have peptides, hydroxylated aro compound, ucleotides, diketone
Acids and other inhibitor.Wherein diketone acid (including Quinolone acid derivative) is to study a most successful class, acts on machine
System is probably the avtive spot with Substrate DNA competitive binding to integrase, the chain transfer reaction of suppression integration process.
EP2161258 (A2) (publication date：2010.03.10) disclose a series of Quinolone acid derivative synthesizing process and
Integrase inhibiting activities.
WO 2009/089263 (A2) (publication date：2009.07.16) disclose a series of integrase inhibitor, wherein
Just include quinoline keto-acid compound.
In " Investigations on the 4-Quinolone-3-carboxylic Acid
Motif.1.Synthesis and Structure-Activity Relationship of a Class of Human
Immunodeficiency Virus type 1Integrase Inhibitors”(J.Med.Chem.,2008,51:5125–
5129) structure of HIV-1 integrase inhibitor quinoline keto-acid compound and the relation of activity are reported in a literary composition.
Content of the invention
It is an object of the invention to provide 1-N- substituted benzyl -6-N '-substituent -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine
And [3,2-g] quinoline -9- ketone -8- formic acid compound and preparation method thereof and the application as HIV-1 integrase inhibitor.
The invention provides 1-N- substituted benzyl -6-N '-substituent -2,3,6,9- tetrahydrochysene -1H- [1,4] that formula (I) represents
Piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid compound and preparation method thereof and answering as HIV-1 integrase inhibitor
With.
Wherein, R1Represent benzyl or substituted benzyl, R2Represent hydrogen, alkyl, hydroxyalkyl, substituted benzyl or carboxyalkyl.
The compounds of this invention is respectively provided with the inhibitory action to HIV-1 integrase, and the suppression effect of wherein part of compounds is notable.
1-N- substituted benzyl -6-N ' provided by the present invention-substituent -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,
2-g] preparation method of quinoline -9- ketone -8- formic acid compound comprises the following steps：
A 2- Amino-5-nitrophenol and acetic acid, acetic anhydride are reacted in toluene by (), 80 DEG C of preferable reaction temperature, reaction
After 3～4 hours, insoluble matter is collected by filtration, obtains the 2- acetylaminohydroxyphenylarsonic acid 5- nitrophenol that formula (II) represents,
B () formula (II) compound is dissolved in DMF, add 1,2- Bromofume, in potassium carbonate effect
Lower reaction, the preferably amount of the material of formula (II) compound and 1,2- Bromofume are than for 1:1.2～1.5, reaction temperature 70～80
DEG C, in 3～5 hours reaction time, obtain N- acetyl group -7- nitro benzo [Isosorbide-5-Nitrae] piperazine that formula (III) represents,
C formula (III) compound is reacted in ethanol by () with concentrated hydrochloric acid, concentrated hydrochloric acid and the volume ratio of ethanol are preferably wherein
1:1.5,80～90 DEG C of reaction temperature, in 2～3 hours reaction time, obtain 7- nitro benzo [Isosorbide-5-Nitrae] piperazine that formula (IV) represents,
D () formula (IV) compound is dissolved in DMF, add potassium carbonate and substituted benzyl bromides, preferably instead
Answer 70～80 DEG C of temperature, 3～5 hours reaction time, obtain N- substituted benzyl -7- nitro benzo [Isosorbide-5-Nitrae] that formula (V) represents
Piperazine,
Wherein, R1Represent benzyl or substituted benzyl；
E formula (V) compound and two hydrated stannous chlorides, concentrated hydrochloric acid are reacted by () in ethanol, preferably formula (V) compound,
The amount of two hydrated stannous chlorides and the material of concentrated hydrochloric acid is than for 1:2～4:10,70～80 DEG C of reaction temperature, react 1～3 hour
Afterwards, plus saturated sodium bicarbonate solution neutralization, obtain N- substituted benzyl -3 that formula (VI) represents, 4- dihydrobenzo [Isosorbide-5-Nitrae] piperazine -7-
Amine,
Wherein, R1The group representing is same as above；
F ethyoxyl that N- substituted benzyl -6- amino benzo [1,4] piperazine that formula (VI) represents is represented by () with formula (VII)
Diethyl methylenemalonate reacts in dioxane, preferably the amount of the material of formula (VI) compound and formula (VII) compound
Than for 1:1～1.2,70～80 DEG C of reaction temperature, in 2～5 hours reaction time, obtain ((the N- replacement benzyl that formula (VIII) represents
Base -3,4- dihydrobenzo [Isosorbide-5-Nitrae] piperazine -7- amino) methylene) diethyl malonate,
Wherein, R1The group representing is same as above；
G formula (VIII) compound is reacted in diphenyl ether by (), 245～250 DEG C of preferable reaction temperature, the reaction time 0.5
～1.5 hours, obtain 1-N- substituted benzyl -2 that formula (IX) represents, 3,6,9- tetrahydrochysene -1H- [Isosorbide-5-Nitrae] piperazine simultaneously [3,2-g] quinolines
Quinoline -9- ketone -8- Ethyl formate,
Wherein, R1The group representing is same as above；
H () will be anti-in N,N-dimethylformamide in the presence of potassium carbonate with N- replacement reagent for formula (IX) compound
Should, preferably formula (IX) compound and N- replace the amount of the material of reagent ratio for 1:1.5～4,50～90 DEG C of reaction temperature, during reaction
Between 4～16 hours, obtain 1-N- substituted benzyl -6-N '-substituent -2 that formula (X) represents, 3,6,9- tetrahydrochysene -1H- [Isosorbide-5-Nitrae] piperazines
And [3,2-g] quinoline -9- ketone -8- Ethyl formate,
Wherein, R1The group representing is same as above, R2Replace reagent from N-, represent hydrogen, alkyl, hydroxyalkyl, substituted benzyl
Or carboxyalkyl；
I formula (X) compound and 20% potassium hydroxide aqueous solution are reacted by () in ethanol, 20% potassium hydroxide preferably wherein
The aqueous solution is 1 with the volume ratio of ethanol:1～1.5,2～8 hours reaction time, 80～90 DEG C of reaction temperature.Obtain formula (I) table
1-N- substituted benzyl-the 6-N ' showing-substituent -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- first
Acid.
Wherein, R1、R2The group representing is same as above.
The inventive method uses industrial common reagent and conventional working condition, and reaction condition is gentle, and step is simple.
Chemical equation in above-mentioned building-up process is as follows：
Wherein, R1Represent benzyl or substituted benzyl, further indicate thatR2Table
Show hydrogen, alkyl, hydroxyalkyl, substituted benzyl or carboxyalkyl, further indicate that-H,
The inventive method is first with 2- Amino-5-nitrophenol as raw material, protects through acetylation, affine replacement cyclization,
Deprotection, affine replacement introduces substituted benzyl, Reduction with Stannous Chloride nitro, condensation, and Gould-Jacobs reacts cyclization, affine takes
In generation, introduces different substituents, and finally hydrolysis generates formula (I) compound.The compounds of this invention has suppression and makees to HIV-1 integrase
With.
Specific embodiment
With reference to embodiment, the present invention will be further described, but the present invention is not limited to following examples.
Embodiment 1
1-N- benzyl 6-N '-methyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid
Preparation
The preparation of (a) 2- acetylaminohydroxyphenylarsonic acid 5- nitrophenol
2- Amino-5-nitrophenol (20g, 0.130mol) is added in 250mL toluene with 50mL acetic acid, system rises to 80
Drip 15mL acetic anhydride after DEG C, after finishing 80 DEG C of reactions 3～4 hours, insoluble matter, insoluble matter 100mL × 3 oil are collected by filtration
Ether washs, and obtains 2- acetylaminohydroxyphenylarsonic acid 5- nitrophenol after drying.
Sterling is khaki solid 24.7g, yield 97%
1H NMR (400MHz, DMSO) δ 11.01 (s, 1H), 9.55 (s, 1H), 8.31 (d, J=9.0Hz, 1H), 7.82
7.59(m,2H),2.19(s,3H).
The preparation of (b) N- acetyl group -7- nitro benzo [1,4] piperazine
2- acetylaminohydroxyphenylarsonic acid 5- nitrophenol (24.7g, 0.126mol) is dissolved in 200mL DMF,
Add potassium carbonate (52g, 0.378mol), dropping 1,2- Bromofume (47g, 0.25mol) after system rises to 80 DEG C finishes 80 DEG C
Reaction 2-5h (TLC monitoring reaction finishes), suction filtration, it is poured into after filtrate decompression precipitation in 1L frozen water, filter after ice melts completely
Collect insoluble matter, insoluble matter 150ml × 3 water washings, after drying, obtain N- acetyl group -6- nitro benzo [Isosorbide-5-Nitrae] piperazine.
Sterling is yellow solid 15.7g, yield 56%
1H NMR (400MHz, DMSO) δ 7.78 (dd, J=9.2,2.7Hz, 1H), 7.70 (d, J=2.7Hz, 1H),
4.42–4.33(m,2H),3.99–3.87(m,2H),2.31(s,3H).
The preparation of (c) 7- nitro benzo [1,4] piperazine
N- acetyl group -6- nitro benzo [Isosorbide-5-Nitrae] piperazine (15.6g, 0.070mol) is dissolved in 100mL ethanol, adds
40mL concentrated hydrochloric acid, is heated to reflux 1-4h, and TLC monitoring reaction finishes.System vacuum distillation precipitation, remaining liq is poured into 500mL water
In, insoluble matter is collected by filtration, insoluble matter is with 50ml × 3 water washing, obtaining 6- nitro benzo [Isosorbide-5-Nitrae] piperazine after drying.
Sterling is red crystals 11.9g, yield 94%
1H NMR (400MHz, DMSO) δ 7.69 (dd, J=8.9,2.5Hz, 1H), 7.56 (s, 1H), 7.48 (d, J=
2.5Hz, 1H), 6.63 (d, J=8.9Hz, 1H), 4.15 (t, J=4.5Hz, 2H), 3.43 (dd, J=6.8,4.3Hz, 2H).
The preparation of (d) N- benzyl -7- nitro benzo [1,4] piperazine
6- nitro benzo [Isosorbide-5-Nitrae] piperazine (10g, 55mmol) is dissolved in 100mL DMF, adds carbon
Sour potassium (26g, 0.189mol), system rises to 80 DEG C, dropping benzyl bromide a-bromotoluene (18.8g, 110mmol), finishes 80 DEG C of reactions 4h, TLC
Monitoring raw material point disappears, and suction filtration is poured into after filtrate decompression precipitation in 500mL frozen water, is collected by filtration insoluble after ice melts completely
Thing, insoluble matter 50mL × 3 water washings, obtain N- benzyl -6- nitro benzo [Isosorbide-5-Nitrae] piperazine after drying.
Sterling is yellow solid 12.1g, yield 82%
1H NMR (400MHz, DMSO) δ 7.70 (dd, J=9.0,2.5Hz, 1H), 7.52 (d, J=2.4Hz, 1H),
7.39 7.33 (m, 2H), 7.28 (d, J=5.4Hz, 3H), 6.76 (d, J=9.1Hz, 1H), 4.72 (s, 2H), 4.35 4.21
(m,2H),3.68–3.53(m,2H).
The preparation of (e) N- benzyl -3,4- dihydrobenzo [1,4] piperazine -7- amine
By N- benzyl -6- nitro benzo [1,4] piperazine (10g, 37mmol), two hydrated stannous chlorides (33.4g,
148mmol), during 30mL concentrated hydrochloric acid is added in 150mL ethanol, it is heated to reflux, TLC monitoring raw material point disappears, cooling, precipitation,
Add saturated sodium bicarbonate solution to neutral in system, filter after adding the shaking of 200ml ethyl acetate, filtrate is divided water
Phase, filter residue is washed with 50mL × 3 ethyl acetate, merges organic phase, after precipitation, obtains N- benzyl -3,4- dihydrobenzo [Isosorbide-5-Nitrae]
Piperazine -7- amine crude product, this crude product reacts without being further purified i.e. input next step.
The preparation of (f) ((N- benzyl -3,4- dihydrobenzo [1,4] piperazine -7- amino) methylene) diethyl malonate
Step (e) gained N- substituted benzyl -3,4- dihydrobenzo [1,4] piperazine -7- amine crude product is dissolved in 50mL 1,4-
In dioxane, add ethoxy methylene diethyl malonate (7.9g 37mmol), be heated to reflux 1-4h, TLC monitoring reaction
Finish, cool down precipitation, column chromatography (silica gel, petrol ether/ethyl acetate=10:1～5:1) separate and obtain ((N- benzyl -3,4- two
Hydrogen benzo [1,4] piperazine -7- amino) methylene) diethyl malonate.
Sterling is light yellow solid 7.5g, two step joint yields 49%
1H NMR (400MHz, DMSO) δ 10.62 (d, J=14.1Hz, 1H), 8.23 (d, J=14.1Hz, 1H), 7.38
7.23 (m, 5H), 6.80 (d, J=2.5Hz, 1H), 6.72 (dd, J=8.7,2.5Hz, 1H), 6.66 (d, J=8.7Hz, 1H),
4.47 (s, 2H), 4.27 4.22 (m, 2H), 4.17 (q, J=7.1Hz, 2H), 4.08 (q, J=7.1Hz, 2H), 3.40 3.36
(m,2H),1.25–1.20(m,6H).
(g) 1-N- benzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate
Preparation
50mL diphenyl ether is heated to 240 DEG C about, is dividedly in some parts ((N- benzyl -3,4- dihydrobenzo [Isosorbide-5-Nitrae] piperazine -7-
Amino) methylene) diethyl malonate (4.1g, 10mmol), finish, continue to keep 240 DEG C of high temperature above to stir 0.5h.Cooling
To room temperature, add 50mL n-hexane, be filtrated to get native brown solid, DMF recrystallizes, obtain 1-N- benzyl -2,3,6,9- tetrahydrochysenes -
1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate.
Sterling is khaki solid 1.15g, yield 32%
1H NMR (400MHz, DMSO) δ 11.91 (s, 1H), 8.31 (s, 1H), 7.38 7.31 (m, 4H), 7.27 (d, J=
7.0Hz, 1H), 7.21 (s, 1H), 6.92 (s, 1H), 4.57 (s, 2H), 4.37 (d, J=3.8Hz, 2H), 4.15 (q, J=
7.0Hz, 2H), 3.51 (d, J=4.1Hz, 2H), 1.25 (d, J=7.1Hz, 3H).
(h) 1-N- benzyl -6-N '-methyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
The preparation of Ethyl formate
By 1-N- benzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate
(364mg, 1mmol) is dissolved in 15mLN, in dinethylformamide, adds potassium carbonate (1.3g, 9.5mmol) system to be warming up to 70
DEG C, dropping iodomethane (284mg, 2mmol), finish 70 DEG C of reaction 4h, TLC monitoring raw material point disappears, suction filtration, and filtrate is poured into 50mL
In frozen water, insoluble matter be collected by filtration after ice melts completely, insoluble matter 10mL × 3 water washings, column chromatography (neutral alumina,
Methylene chloride/methanol=100:1～10:1) separate and obtain 1-N- benzyl -6-N '-methyl -2,3,6,9- tetrahydrochysene -1H- [1,4]
Piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product, this crude product direct plunges into next step reaction.
(i) 1-N- benzyl -6-N '-methyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
The preparation of formic acid
By step (h) gained 1-N- benzyl -6-N '-methyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline
Quinoline -9- ketone -8- Ethyl formate crude product is added in 10mL ethanol and 10mL 20% potassium hydroxide solution, is heated to reflux 4h.Cold
But, add 1M hydrochloric acid to be adjusted to pH=1～2, filter, insoluble matter is washed with water, 50% ethanol water successively, is dried to obtain 1-N-
Benzyl -6-N '-methyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid.
Sterling is light yellow solid 175mg, two step joint yields 50%
1H NMR(400MHz,DMSO)δ15.80(s,1H),8.74(s,1H),7.38–7.25(m,7H),4.67(s,
2H),4.45(s,2H),3.97(s,3H),3.60(s,2H).
MS(ESI)m/z,351.1339[M+H]+
Embodiment 2
The preparation of 1-N- benzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid
Step (a) (b) (c) (d) (e) (f) (g) is with embodiment 1
The preparation of (h) 1-N- benzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid
By 1-N- benzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate
(182mg, 0.5mmol) is added in 10mL ethanol and 10mL 20% potassium hydroxide solution, is heated to reflux 4h.Cooling, adds 1M
Hydrochloric acid is adjusted to pH=1～2, filters, insoluble matter washs with water, 50% ethanol water successively, is dried to obtain 1-N- benzyl -2, and 3,
6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid.
Sterling is light yellow solid 134mg, yield 80%
1H NMR (400MHz, DMSO) δ 15.89 (s, 1H), 13.02 (s, 1H), 8.63 (d, J=6.6Hz, 1H), 7.38
7.27 (m, 5H), 7.21 (s, 1H), 7.12 (s, 1H), 4.65 (s, 2H), 4.43 (d, J=3.8Hz, 2H), 3.59 (d, J=
4.1Hz,2H).
MS(ESI)m/z,337.1185[M+H]+
Embodiment 3
1-N- benzyl -6-N '-ethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid
Preparation
Step (a) (b) (c) (d) (e) (f) (g) is with embodiment 1.
(h) 1-N- benzyl -6-N '-ethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
The preparation of Ethyl formate
By 1-N- benzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate
(364mg, 1mmol) is dissolved in 15mL DMF, adds potassium carbonate (1.3g, 9.5mmol) system to be warming up to 70
DEG C, dropping bromoethane (218mg, 2mmol), finish 70 DEG C of reaction 4h, TLC monitoring raw material point disappears, suction filtration, and filtrate is poured into 50mL
In frozen water, insoluble matter be collected by filtration after ice melts completely, insoluble matter 10mL × 3 water washings, column chromatography (neutral alumina,
Methylene chloride/methanol=100:1～10:1) separate and obtain 1-N- benzyl -6-N '-ethyl -2,3,6,9- tetrahydrochysene -1H- [1,4]
Piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product, this crude product direct plunges into next step reaction.
(i) 1-N- benzyl -6-N '-ethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
The preparation of formic acid
By step (h) gained 1-N- benzyl -6-N '-ethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline
Quinoline -9- ketone -8- Ethyl formate crude product is added in 10mL ethanol and 10mL 20% potassium hydroxide solution, is heated to reflux 4h.Cold
But, add 1M hydrochloric acid to be adjusted to pH=1～2, filter, insoluble matter is washed with water, 50% ethanol water successively, is dried to obtain 1-N-
Benzyl -6-N '-ethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid.
Sterling is light yellow solid 182mg, two step joint yields 50%
1H NMR(400MHz,DMSO)δ15.80(s,1H),8.77(s,1H),7.37–7.26(m,7H),4.66(s,
2H), 4.53 4.42 (m, 4H), 3.60 (s, 2H), 1.36 (t, J=6.9Hz, 3H).
MS(ESI)m/z,365.1494[M+H]+
Embodiment 4
1-N- benzyl -6-N '-propyl group -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid
Preparation
Step (a) (b) (c) (d) (e) (f) (g) is with embodiment 1.
(h) 1-N- benzyl -6-N '-propyl group -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
The preparation of Ethyl formate
By 1-N- benzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate
(364mg, 1mmol) is dissolved in 15mL DMF, adds potassium carbonate (1.3g, 9.5mmol) system to be warming up to 70
DEG C, dropping 1- N-Propyl Bromide (246mg, 2mmol), finish 70 DEG C of reaction 4h, TLC monitoring raw material point disappears, suction filtration, and filtrate is poured into
In 50mL frozen water, insoluble matter, insoluble matter 10mL × 3 water washings, column chromatography (neutral alumina are collected by filtration after ice melts completely
Aluminium, methylene chloride/methanol=100:1～10:1) separate obtain 1-N- benzyl -6-N '-propyl group -2,3,6,9- tetrahydrochysene -1H- [1,
4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product, this crude product direct plunges into next step reaction.
(i) 1-N- benzyl -6-N '-propyl group -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
The preparation of formic acid
By step (h) gained 1-N- benzyl -6-N '-propyl group -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline
Quinoline -9- ketone -8- Ethyl formate crude product is added in 10mL ethanol and 10mL 20% potassium hydroxide solution, is heated to reflux 4h.Cold
But, add 1M hydrochloric acid to be adjusted to pH=1～2, filter, insoluble matter is washed with water, 50% ethanol water successively, is dried to obtain 1-N-
Benzyl -6-N '-propyl group -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid.
Sterling is light yellow solid 166mg, two step joint yields 44%
1H NMR (400MHz, DMSO) δ 15.80 (s, 1H), 8.75 (s, 1H), 7.34 (t, J=9.8Hz, 7H), 4.66
(s, 2H), 4.44 (d, J=15.2Hz, 4H), 3.60 (s, 2H), 1.76 (d, J=7.0Hz, 2H), 0.87 (t, J=7.1Hz,
3H).
MS(ESI)m/z,379.1656[M+H]+
Embodiment 5
1-N- benzyl -6-N '-butyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid
Preparation
Step (a) (b) (c) (d) (e) (f) (g) is with embodiment 1.
(h) 1-N- benzyl -6-N '-butyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
The preparation of Ethyl formate
By 1-N- benzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate
(364mg, 1mmol) is dissolved in 15mL DMF, adds potassium carbonate (1.3g, 9.5mmol) system to be warming up to 70
DEG C, dropping 1- NBB (274mg, 2mmol), finish 70 DEG C of reaction 4h, TLC monitoring raw material point disappears, suction filtration, and filtrate is poured into
In 50mL frozen water, insoluble matter, insoluble matter 10mL × 3 water washings, column chromatography (neutral alumina are collected by filtration after ice melts completely
Aluminium, methylene chloride/methanol=100:1～10:1) separate obtain 1-N- benzyl -6-N '-butyl -2,3,6,9- tetrahydrochysene -1H- [1,
4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product, this crude product direct plunges into next step reaction.
(i) 1-N- benzyl -6-N '-butyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
The preparation of formic acid
By step (h) gained 1-N- benzyl -6-N '-butyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline
Quinoline -9- ketone -8- Ethyl formate crude product is added in 10mL ethanol and 10mL 20% potassium hydroxide solution, is heated to reflux 4h.Cold
But, add 1M hydrochloric acid to be adjusted to pH=1～2, filter, insoluble matter is washed with water, 50% ethanol water successively, is dried to obtain 1-N-
Benzyl -6-N '-butyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid.
Sterling is light yellow solid 165mg, two step joint yields 42%
1H NMR (400MHz, DMSO) δ 15.79 (s, 1H), 8.75 (s, 1H), 7.34 (t, J=10.6Hz, 7H), 4.66
(s, 2H), 4.45 (s, 4H), 3.60 (s, 2H), 1.72 (s, 2H), 1.30 (dd, J=15.1,7.4Hz, 2H), 0.89 (t, J=
7.3Hz,3H).
MS(ESI)m/z,393.1815[M+H]+
Embodiment 6
1-N- benzyl -6-N '-to luorobenzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
The preparation of formic acid
Step (a) (b) (c) (d) (e) (f) (g) is with embodiment 1.
(h) 1-N- benzyl -6-N '-to luorobenzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9-
The preparation of ketone -8- Ethyl formate
By 1-N- benzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate
(364mg, 1mmol) is dissolved in 15mL DMF, adds potassium carbonate (1.3g, 9.5mmol) system to be warming up to 70
DEG C, dropping, to fluoro benzyl bromide (378mg, 2mmol), finishes 70 DEG C of reaction 4h, and TLC monitoring raw material point disappears, suction filtration, and filtrate is poured into
In 50mL frozen water, insoluble matter, insoluble matter 10mL × 3 water washings, column chromatography (neutral alumina are collected by filtration after ice melts completely
Aluminium, methylene chloride/methanol=100:1～10:1) separate and obtain 1-N- benzyl -6-N '-to luorobenzyl -2,3,6,9- tetrahydrochysene -1H-
[Isosorbide-5-Nitrae] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product, this crude product direct plunges into next step reaction.
(i) 1-N- benzyl -6-N '-to luorobenzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9-
The preparation of ketone -8- formic acid
By step (h) gained 1-N- benzyl -6-N '-to luorobenzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-
G] quinoline -9- ketone -8- Ethyl formate crude product is added in 10mL ethanol and 10mL 20% potassium hydroxide solution, is heated to reflux
4h.Cooling, adds 1M hydrochloric acid to be adjusted to pH=1～2, filters, insoluble matter is washed with water, 50% ethanol water successively, dry
To 1-N- benzyl -6-N '-to luorobenzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid.
Sterling is light yellow solid 190mg, two step joint yields 43%
1H NMR(400MHz,DMSO)δ15.70(s,1H),9.01(s,1H),7.38–7.28(m,8H),7.22–7.16
(m,3H),5.73(s,2H),4.63(s,2H),4.38(s,2H),3.55(s,2H).
MS(ESI)m/z,445.1558[M+H]+
Embodiment 7
1-N- benzyl -6-N '-to nitrobenzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -
The preparation of 8- formic acid
Step (a) (b) (c) (d) (e) (f) (g) is with embodiment 1.
(h) 1-N- benzyl -6-N '-to nitrobenzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9-
The preparation of ketone -8- Ethyl formate
By 1-N- benzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate
(364mg, 1mmol) is dissolved in 15mLN, in dinethylformamide, adds potassium carbonate (1.3g, 9.5mmol) system to be warming up to 70
DEG C, dropping P-nitrobenzyl bromide (432mg, 2mmol), finish 70 DEG C of reaction 4h, TLC monitoring raw material point disappears, suction filtration, and filtrate is inclined
Enter in 50mL frozen water, insoluble matter, insoluble matter 10mL × 3 water washings, column chromatography (neutral oxygen are collected by filtration after ice melts completely
Change aluminium, methylene chloride/methanol=100:1～10:1) separate and obtain 1-N- benzyl -6-N '-to nitrobenzyl -2,3,6,9- four
Hydrogen -1H- [Isosorbide-5-Nitrae] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product, this crude product direct plunges into next step reaction
(i) 1-N- benzyl -6-N '-to nitrobenzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9-
The preparation of ketone -8- formic acid
By step (h) gained 1-N- benzyl -6-N '-to nitrobenzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,
2-g] quinoline -9- ketone -8- Ethyl formate crude product is added in 10mL ethanol and 10mL 20% potassium hydroxide solution, heats back
Stream 4h.Cooling, adds 1M hydrochloric acid to be adjusted to pH=1～2, filters, insoluble matter is washed with water, 50% ethanol water successively, be dried
Obtain 1-N- benzyl -6-N '-to nitrobenzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- first
Acid.
1H NMR (400MHz, DMSO) δ 15.62 (s, 1H), 8.98 (s, 1H), 7.57 (t, J=7.0Hz, 1H), 7.35
(dd, J=12.4,5.1Hz, 5H), 7.31 (s, 1H), 7.26 (t, J=6.7Hz, 1H), 7.19 (t, J=7.9Hz, 1H), 7.15
(s, 1H), 7.05 (t, J=7.1Hz, 1H), 5.85 (s, 2H), 4.64 (s, 2H), 4.40 (s, 2H), 3.56 (s, 2H).
Sterling is light yellow solid 183mg, two step joint yields 39%
Embodiment 8
1-N- benzyl -6-N '-ethoxy -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- first
The preparation of acid
Step (a) (b) (c) (d) (e) (f) (g) is with embodiment 1.
(h) 1-N- benzyl -6-N '-Acetoxyethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9-
The preparation of ketone -8- Ethyl formate
By 1-N- benzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate
(364mg, 1mmol) is dissolved in 15mL DMF, adds potassium carbonate (1.3g, 9.5mmol) system to be warming up to 70
DEG C, dropping ethylene bromohyrin acetic acid esters (334mg, 2mmol), finish 70 DEG C of reaction 4h, TLC monitoring raw material point disappears, suction filtration, filtrate
It is poured in 50mL frozen water, insoluble matter, insoluble matter 10mL × 3 water washings are collected by filtration after ice melts completely, column chromatography is (neutral
Aluminum oxide, methylene chloride/methanol=100:1～10:1) separate and obtain 1-N- benzyl -6-N '-Acetoxyethyl -2,3,6,9- four
Hydrogen -1H- [Isosorbide-5-Nitrae] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product, this crude product direct plunges into next step reaction
(i) 1-N- benzyl -6-N '-ethoxy -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -
The preparation of 8- formic acid
By step (h) gained 1-N- benzyl -6-N ' Acetoxyethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-
G] quinoline -9- ketone -8- Ethyl formate crude product is added in 10mL ethanol and 10mL 20% potassium hydroxide solution, is heated to reflux
4h.Cooling, adds 1M hydrochloric acid to be adjusted to pH=1～2, filters, insoluble matter is washed with water, 50% ethanol water successively, dry
To 1-N- benzyl -6-N '-ethoxy -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid.
Sterling is light yellow solid 152mg, two step joint yields 40%
1H NMR (400MHz, DMSO) δ 15.79 (s, 1H), 8.61 (s, 1H), 7.49 7.21 (m, 7H), 4.98 (t, J=
5.6Hz, 1H), 4.66 (s, 2H), 4.49 (s, 2H), 4.44 (s, 2H), 3.71 (d, J=4.6Hz, 2H), 3.59 (s, 2H).
MS(ESI)m/z,381.1449[M+H]+
Embodiment 9
1-N- benzyl -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- first
The preparation of acid
Step (a) (b) (c) (d) (e) (f) (g) is with embodiment 1.
(h) 1-N- benzyl -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -
The preparation of 8- Ethyl formate
By 1-N- benzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate
(364mg, 1mmol) is dissolved in 15mL DMF, adds potassium carbonate (1.3g, 9.5mmol) system to be warming up to 70
DEG C, dropping 3- bromo- 1- propyl alcohol (334mg, 2mmol), finish 70 DEG C of reaction 4h, TLC monitoring raw material point disappears, suction filtration, and filtrate is inclined
Enter in 50mL frozen water, insoluble matter, insoluble matter 10mL × 3 water washings, column chromatography (neutral oxygen are collected by filtration after ice melts completely
Change aluminium, methylene chloride/methanol=100:1～10:1) separate and obtain 1-N- benzyl -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H-
[Isosorbide-5-Nitrae] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product, this crude product direct plunges into next step reaction
(i) 1-N- benzyl -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -
The preparation of 8- formic acid
By step (h) gained 1-N- benzyl -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g]
Quinoline -9- ketone -8- Ethyl formate crude product is added in 10mL ethanol and 10mL 20% potassium hydroxide solution, is heated to reflux 4h.
Cooling, adds 1M hydrochloric acid to be adjusted to pH=1～2, filters, insoluble matter is washed with water, 50% ethanol water successively, is dried to obtain 1-
N- benzyl -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid.
Sterling is light yellow solid 130mg, two step joint yields 33%
1H NMR(400MHz,DMSO)δ15.79(s,1H),8.71(s,1H),7.39–7.26(m,7H),4.76(s,
1H), 4.66 (s, 2H), 4.53 4.40 (m, 4H), 3.60 (s, 2H), 3.43 (s, 2H), 1.91 (d, J=5.6Hz, 2H).
MS(ESI)m/z,395.1606[M+H]+
Embodiment 10
1-N- benzyl -6-N '-carboxymethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- first
The preparation of acid
Step (a) (b) (c) (d) (e) (f) (g) is with embodiment 1.
(h) 1-N- benzyl -6-N '-ethoxy acyl methyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9-
The preparation of ketone -8- Ethyl formate
By 1-N- benzyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate
(364mg, 1mmol) is dissolved in 15mL DMF, adds potassium carbonate (1.3g, 9.5mmol) system to be warming up to 70
DEG C, dropping bromoacetate (334mg, 2mmol), finish 70 DEG C of reaction 4h, TLC monitoring raw material point disappears, suction filtration, and filtrate is poured into
In 50mL frozen water, insoluble matter, insoluble matter 10mL × 3 water washings, column chromatography (neutral alumina are collected by filtration after ice melts completely
Aluminium, methylene chloride/methanol=100:1～10:1) separate obtain 1-N- benzyl -6-N '-ethoxy acyl methyl -2,3,6,9- tetrahydrochysene -
1H- [Isosorbide-5-Nitrae] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product, this crude product direct plunges into next step reaction
(i) 1-N- benzyl -6-N '-carboxymethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -
The preparation of 8- formic acid
By step (h) gained 1-N- benzyl -6-N '-ethoxy acyl methyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,
2-g] quinoline -9- ketone -8- Ethyl formate crude product is added in 10mL ethanol and 10mL 20% potassium hydroxide solution, heats back
Stream 4h.Cooling, adds 1M hydrochloric acid to be adjusted to pH=1～2, filters, insoluble matter is washed with water, 50% ethanol water successively, be dried
Obtain 1-N- benzyl -6-N '-ethoxy acyl methyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- first
Acid.
Sterling is light yellow solid 202mg, two step joint yields 48%
1H NMR(400MHz,DMSO)δ15.63(s,1H),13.60(s,1H),8.81(s,1H),7.39–7.26(m,
6H), 7.09 (s, 1H), 5.35 (s, 2H), 4.66 (s, 2H), 4.45 (d, J=3.8Hz, 2H), 3.60 (d, J=4.0Hz, 2H).
MS(ESI)m/z,395.1239[M+H]+
Embodiment 11
The system of 1-N- (2- luorobenzyl) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid
Standby
Step (a) (b) (c) is with embodiment 1.
The preparation of (d) N- (2- luorobenzyl) -7- nitro benzo [1,4] piperazine
6- nitro benzo [Isosorbide-5-Nitrae] piperazine (10g, 55mmol) is dissolved in 100mL DMF, adds carbon
Sour potassium (26g, 0.189mol), system rises to 80 DEG C, dropping 2- fluoro benzyl bromide (20.8g, 110mmol), finishes 80 DEG C of reaction 4h,
TLC monitoring raw material point disappears, and suction filtration is poured into after filtrate decompression precipitation in 500mL frozen water, is collected by filtration not after ice melts completely
Molten thing, insoluble matter 50mL × 3 water washings, obtain N- (2- luorobenzyl) -6- nitro benzo [Isosorbide-5-Nitrae] piperazine after drying.
Sterling is yellow solid 12.6g, yield 80%
1H NMR(400MHz,CDCl3) δ 7.82 7.67 (m, 2H), 7.30 (d, J=6.8Hz, 1H), 7.17 (s, 1H),
7.12 (dd, J=16.4,8.4Hz, 2H), 6.60 (d, J=9.1Hz, 1H), 4.64 (s, 2H), 4.35 4.24 (m, 2H),
3.63–3.53(m,2H).
The preparation of (e) N- (2- luorobenzyl) -3,4- dihydrobenzo [1,4] piperazine -7- amine
By N- (2- luorobenzyl) -6- nitro benzo [1,4] piperazine (10.6g, 37mmol), two hydrated stannous chlorides
During (33.4g, 148mmol), 30mL concentrated hydrochloric acid are added in 150mL ethanol, it is heated to reflux, TLC monitoring raw material point disappears, cold
But, precipitation, adds saturated sodium bicarbonate solution to neutral in system, filters, by filtrate after adding the shaking of 200ml ethyl acetate
Divide and remove aqueous phase, filter residue is washed with 50mL × 3 ethyl acetate, merge organic phase, after precipitation, obtain N- (2- luorobenzyl) -3,4- bis-
Hydrogen benzo [Isosorbide-5-Nitrae] piperazine -7- amine crude product, this crude product reacts without being further purified i.e. input next step.
(f) ((N- (2- luorobenzyl) -3,4- dihydrobenzo [1,4] piperazine -7- amino) methylene) diethyl malonate
Preparation
Step (e) gained N- (2- luorobenzyl) -3,4- dihydrobenzo [1,4] piperazine -7- amine crude product is dissolved in 50mL 1,
In 4- dioxane, add ethoxy methylene diethyl malonate (7.9g 37mmol), be heated to reflux 1-4h, TLC monitoring is anti-
Should finish, cool down precipitation, column chromatography (silica gel, petrol ether/ethyl acetate=10:1～5:1) separate and obtain ((N- (2- fluorine benzyl
Base) -3,4- dihydrobenzo [1,4] piperazine -7- amino) methylene) diethyl malonate.
Sterling is light yellow liquid 6.6g, two step joint yields 42%
1H NMR(400MHz,CDCl3) δ 10.90 (d, J=13.9Hz, 1H), 8.39 (d, J=13.9Hz, 1H), 7.32
7.22 (m, 2H), 7.13 7.04 (m, 2H), 6.66 (d, J=2.3Hz, 1H), 6.58 (dt, J=8.7,5.5Hz, 2H), 4.46
(s, 2H), 4.32 4.25 (m, 4H), 4.22 (q, J=7.1Hz, 2H), 3.44 3.36 (m, 2H), 1.37 (t, J=7.1Hz,
3H), 1.31 (t, J=7.1Hz, 3H).
(g) 1-N- (2- luorobenzyl) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid
The preparation of ethyl ester
50mL diphenyl ether is heated to 240 DEG C about, is dividedly in some parts ((N- (2- luorobenzyl) -3,4- dihydrobenzo [Isosorbide-5-Nitrae]
Piperazine -7- amino) methylene) diethyl malonate (4.3g, 10mmol), finish, continue to keep 240 DEG C of high temperature above stirrings
0.5h.It is cooled to room temperature, adds 50mL n-hexane, be filtrated to get native brown solid, DMF recrystallizes, and obtains 1-N- (2- fluorine benzyl
Base) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate.
Sterling is khaki solid 1.14g, yield 30%
1H NMR (400MHz, DMSO) δ 11.95 (s, 1H), 8.34 (s, 1H), 7.29 (dt, J=19.3,8.3Hz, 4H),
7.17 (s, 1H), 6.94 (s, 1H), 4.61 (s, 2H), 4.36 (s, 2H), 4.15 (q, J=7.0Hz, 2H), 3.53 (s, 2H),
1.24 (t, J=7.0Hz, 3H).
(h) 1-N- (2- luorobenzyl) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid
Preparation
By 1-N- (2- luorobenzyl) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid second
Ester (191mg, 0.5mmol) is added in 10mL ethanol and 10mL 20% potassium hydroxide solution, is heated to reflux 4h.Cooling, adds
1M hydrochloric acid is adjusted to pH=1～2, filters, insoluble matter is washed with water, 50% ethanol water successively, is dried to obtain 1-N- (2- fluorine benzyl
Base) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid.
Sterling is light yellow solid 145mg, yield 82%
1H NMR (400MHz, DMSO) δ 15.89 (s, 1H), 13.04 (d, J=6.6Hz, 1H), 8.64 (d, J=6.8Hz,
1H), 7.31 (dt, J=19.0,7.7Hz, 3H), 7.21 (s, 1H), 7.16 (t, J=7.4Hz, 1H), 7.12 (s, 1H), 4.69
(s, 2H), 4.41 (t, J=4.2Hz, 2H), 3.61 3.55 (m, 2H).
MS(ESI)m/z,355.1093[M+H]+
Embodiment 12
1-N- (2- luorobenzyl) -6-N '-ethoxy -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9-
The preparation of ketone -8- formic acid
Step (a) (b) (c) (d) (e) (f) (g) is with embodiment 1.
H () 1-N- (2- luorobenzyl) -6-N '-Acetoxyethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine is simultaneously [3,2-g]
The preparation of quinoline -9- ketone -8- Ethyl formate
By 1-N- (2- luorobenzyl) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid second
Ester (382mg, 1mmol) is dissolved in 15mL DMF, adds potassium carbonate (1.3g, 9.5mmol) system to be warming up to
70 DEG C, dropping ethylene bromohyrin acetic acid esters (334mg, 2mmol), finish 70 DEG C of reaction 4h, TLC monitoring raw material point disappears, suction filtration, filter
Liquid is poured in 50mL frozen water, and insoluble matter be collected by filtration after ice melts completely, insoluble matter 10mL × 3 water washings, column chromatography (in
Property aluminum oxide, methylene chloride/methanol=100:1～10:1) separate and obtain 1-N- (2- luorobenzyl) -6-N '-Acetoxyethyl -2,
3,6,9- tetrahydrochysene -1H- [Isosorbide-5-Nitrae] piperazines simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product, this crude product direct plunges into next
Step reaction.
(i) 1-N- (2- luorobenzyl) -6-N '-ethoxy -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -
The preparation of 9- ketone -8- formic acid
By step (h) gained 1-N- (2- luorobenzyl) -6-N ' Acetoxyethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine
And [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product is added in 10mL ethanol and 10mL 20% potassium hydroxide solution, plus
Heat backflow 4h.Cooling, adds 1M hydrochloric acid to be adjusted to pH=1～2, filters, insoluble matter is washed with water, 50% ethanol water successively,
It is dried to obtain 1-N- (2- luorobenzyl) -6-N '-ethoxy -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9-
Ketone -8- formic acid.
Sterling is light yellow solid 159mg, two step joint yields 40%
1H NMR(400MHz,DMSO)δ15.79(s,1H),8.62(s,1H),7.45–7.11(m,6H),4.70(s,
2H),4.50(s,2H),4.44(s,2H),3.71(s,2H),3.60(s,2H).
MS(ESI)m/z,399.1353[M+H]+
Embodiment 13
1-N- (2- luorobenzyl) -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9-
The preparation of ketone -8- formic acid
Step (a) (b) (c) (d) (e) (f) (g) is with embodiment 1.
(h) 1-N- (2- luorobenzyl) -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -
The preparation of 9- ketone -8- Ethyl formate
By 1-N- (2- luorobenzyl) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid second
Ester (382mg, 1mmol) is dissolved in 15mL DMF, adds potassium carbonate (1.3g, 9.5mmol) system to be warming up to
70 DEG C, dropping 3- bromo- 1- propyl alcohol (334mg, 2mmol), finish 70 DEG C of reaction 4h, TLC monitoring raw material point disappears, suction filtration, filtrate
It is poured in 50mL frozen water, insoluble matter, insoluble matter 10mL × 3 water washings are collected by filtration after ice melts completely, column chromatography is (neutral
Aluminum oxide, methylene chloride/methanol=100:1～10:1) separate and obtain 1-N- (2- luorobenzyl) -6-N '-hydroxypropyl -2,3,6,9-
Tetrahydrochysene -1H- [Isosorbide-5-Nitrae] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product, it is anti-that this crude product direct plunges into next step
Should.
(i) 1-N- (2- luorobenzyl) -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -
The preparation of 9- ketone -8- formic acid
By step (h) gained 1-N- (2- luorobenzyl) -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously
[3,2-g] quinoline -9- ketone -8- Ethyl formate crude product is added in 10mL ethanol and 10mL 20% potassium hydroxide solution, heating
Backflow 4h.Cooling, adds 1M hydrochloric acid to be adjusted to pH=1～2, filters, insoluble matter is washed with water, 50% ethanol water successively, do
Dry obtain 1-N- (2- luorobenzyl) -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -
8- formic acid.
Sterling is light yellow solid 128mg, two step joint yields 31%
1H NMR (400MHz, DMSO) δ 15.77 (s, 1H), 8.72 (s, 1H), 7.38 (s, 1H), 7.35 (d, J=
7.5Hz, 2H), 7.32 (s, 1H), 7.29 (d, J=10.2Hz, 1H), 7.18 (d, J=7.4Hz, 1H), 4.76 (s, 1H), 4.70
(s, 2H), 4.53 4.41 (m, 4H), 3.61 (s, 2H), 3.42 (d, J=5.2Hz, 2H), 1.90 (s, 2H).
MS(ESI)m/z,413.1513[M+H]+
Embodiment 14
1-N- (2- luorobenzyl) -6-N '-carboxymethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9-
The preparation of ketone -8- formic acid
Step (a) (b) (c) (d) (e) (f) (g) is with embodiment 1.
H () 1-N- (2- luorobenzyl) -6-N '-ethoxy acyl methyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine is simultaneously [3,2-g]
The preparation of quinoline -9- ketone -8- Ethyl formate
By 1-N- (2- luorobenzyl) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid second
Ester (382mg, 1mmol) is dissolved in 15mL DMF, adds potassium carbonate (1.3g, 9.5mmol) system to be warming up to
70 DEG C, dropping bromoacetate (334mg, 2mmol), finish 70 DEG C of reaction 4h, TLC monitoring raw material point disappears, suction filtration, and filtrate is inclined
Enter in 50mL frozen water, insoluble matter, insoluble matter 10mL × 3 water washings, column chromatography (neutral oxygen are collected by filtration after ice melts completely
Change aluminium, methylene chloride/methanol=100:1～10:1) separate and obtain 1-N- (2- luorobenzyl) -6-N '-ethoxy acyl methyl -2,3,6,
9- tetrahydrochysene -1H- [Isosorbide-5-Nitrae] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product, it is anti-that this crude product direct plunges into next step
Should.
(i) 1-N- (2- luorobenzyl) -6-N '-carboxymethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -
The preparation of 9- ketone -8- formic acid
By step (h) gained 1-N- (2- luorobenzyl) -6-N '-ethoxy acyl methyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine
And [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product is added in 10mL ethanol and 10mL 20% potassium hydroxide solution, plus
Heat backflow 4h.Cooling, adds 1M hydrochloric acid to be adjusted to pH=1～2, filters, insoluble matter is washed with water, 50% ethanol water successively,
It is dried to obtain 1-N- (2- luorobenzyl) -6-N '-ethoxy acyl methyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline
Quinoline -9- ketone -8- formic acid.
Sterling is light yellow solid 181mg, two step joint yields 44%
1H NMR(400MHz,DMSO)δ15.61(s,1H),13.56(s,1H),8.82(s,1H),7.41–7.02(m,
6H),5.35(s,2H),4.70(s,2H),4.43(s,2H),3.59(s,2H).
MS(ESI)m/z,413.1143[M+H]+
Embodiment 15
1-N- (3- chloro- 2- luorobenzyl) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- first
The preparation of acid
Step (a) (b) (c) is with embodiment 1.
The preparation of (d) N- (3- chloro- 2- luorobenzyl) -7- nitro benzo [1,4] piperazine
6- nitro benzo [Isosorbide-5-Nitrae] piperazine (10g, 55mmol) is dissolved in 100mL DMF, adds carbon
Sour potassium (26g, 0.189mol), system rises to 80 DEG C, dropping 3- chloro- 2- fluoro benzyl bromide (24.6g, 110mmol), finishes 80 DEG C instead
Answer 4h, TLC monitoring raw material point disappears, suction filtration is poured into after filtrate decompression precipitation in 500mL frozen water, filters after ice melts completely
Collect insoluble matter, insoluble matter 50mL × 3 water washings, after drying, obtain N- (3- chloro- 2- luorobenzyl) -6- nitro benzo [Isosorbide-5-Nitrae]
Piperazine.
Sterling is yellow solid 13.6g, yield 77%
1H NMR(400MHz,CDCl3)δ7.82–7.67(m,2H),7.43–7.31(m,1H),7.14–6.98(m,2H),
6.56 (d, J=9.0Hz, 1H), 4.65 (s, 2H), 4.35 4.25 (m, 2H), 3.64 3.52 (m, 2H).
The preparation of (e) N- (3- chloro- 2- luorobenzyl) -3,4- dihydrobenzo [1,4] piperazine -7- amine
By N- (3- chloro- 2- luorobenzyl) -6- nitro benzo [1,4] piperazine (11.9g, 37mmol), two hydrated stannous chlorides
During (33.4g, 148mmol), 30mL concentrated hydrochloric acid are added in 150mL ethanol, it is heated to reflux, TLC monitoring raw material point disappears, cold
But, precipitation, adds saturated sodium bicarbonate solution to neutral in system, filters, by filtrate after adding the shaking of 200ml ethyl acetate
Divide and remove aqueous phase, filter residue is washed with 50mL × 3 ethyl acetate, merge organic phase, after precipitation, obtain N- (3- chloro- 2- luorobenzyl) -3,
4- dihydrobenzo [Isosorbide-5-Nitrae] piperazine -7- amine crude product, this crude product reacts without being further purified i.e. input next step.
(f) ((N- (3- chloro- 2- luorobenzyl) -3,4- dihydrobenzo [1,4] piperazine -7- amino) methylene) malonic acid diethyl
The preparation of ester
Step (e) gained N- (3- chloro- 2- luorobenzyl) -3,4- dihydrobenzo [1,4] piperazine -7- amine crude product is dissolved in
In 50mL Isosorbide-5-Nitrae-dioxane, add ethoxy methylene diethyl malonate (7.9g 37mmol), be heated to reflux 1-4h,
TLC monitoring reaction finishes, and cools down precipitation, column chromatography (silica gel, petrol ether/ethyl acetate=10:1～5:1) separate and obtain ((N-
(3- chloro- 2- luorobenzyl) -3,4- dihydrobenzo [1,4] piperazine -7- amino) methylene) diethyl malonate.
Sterling is light yellow liquid 6.8g, two step joint yields 40%
(g) 1-N- (3- chloro- 2- luorobenzyl) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
The preparation of Ethyl formate
50mL diphenyl ether is heated to 240 DEG C about, is dividedly in some parts ((N- (3- chloro- 2- luorobenzyl) -3,4- dihydrobenzo
[Isosorbide-5-Nitrae] piperazine -7- amino) methylene) diethyl malonate (4.6g, 10mmol), finish, continue to keep 240 DEG C of high temperature above
Stirring 0.5h.It is cooled to room temperature, adds 50mL n-hexane, be filtrated to get native brown solid, DMF recrystallizes, and obtains 1-N- (3-
Chloro- 2- luorobenzyl)) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate.
Sterling is khaki solid 1.25g, yield 30%
1H NMR (400MHz, DMSO) δ 11.95 (s, 1H), 8.33 (d, J=8.4Hz, 1H), 7.51 (d, J=7.4Hz,
1H), 7.26 (d, J=7.2Hz, 1H), 7.18 (t, J=8.0Hz, 1H), 7.13 (s, 1H), 6.94 (s, 1H), 4.66 (s, 2H),
4.37 (s, 2H), 4.15 (q, J=7.1Hz, 2H), 3.54 (s, 2H), 1.25 (d, J=7.0Hz, 3H).
(h) 1-N- (3- chloro- 2- luorobenzyl) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
The preparation of formic acid
By 1-N- (3- chloro- 2- luorobenzyl) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
Ethyl formate (208mg, 0.5mmol) is added in 10mL ethanol and 10mL 20% potassium hydroxide solution, is heated to reflux 4h.Cold
But, add 1M hydrochloric acid to be adjusted to pH=1～2, filter, insoluble matter is washed with water, 50% ethanol water successively, is dried to obtain 1-N-
(3- chloro- 2- luorobenzyl) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- formic acid.
Sterling is light yellow solid 157mg, yield 81%
1H NMR (400MHz, DMSO) δ 13.19 (d, J=6.0Hz, 1H), 8.63 (d, J=6.8Hz, 1H), 7.53 (t, J
=7.5Hz, 1H), 7.28 (d, J=6.2Hz, 1H), 7.22 7.15 (m, 3H), 4.74 (s, 2H), 4.41 (d, J=4.1Hz,
2H), 3.58 (d, J=4.0Hz, 2H).
MS(ESI)m/z,389.0699[M+H]+
Embodiment 16
1-N- (3- chloro- 2- luorobenzyl) -6-N '-ethoxy -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline
The preparation of quinoline -9- ketone -8- formic acid
Step (a) (b) (c) (d) (e) (f) (g) is with embodiment 1.
(h) 1-N- (3- chloro- 2- luorobenzyl) -6-N '-Acetoxyethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,
2-g] quinoline -9- ketone -8- Ethyl formate preparation
By 1-N- (3- chloro- 2- luorobenzyl) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
Ethyl formate (416mg, 1mmol) is dissolved in 15mL DMF, adds potassium carbonate (1.3g, 9.5mmol) system
It is warming up to 70 DEG C, dropping ethylene bromohyrin acetic acid esters (334mg, 2mmol), finish 70 DEG C of reaction 4h, TLC monitoring raw material point disappears,
Suction filtration, filtrate is poured in 50mL frozen water, and insoluble matter, insoluble matter 10mL × 3 water washings, post are collected by filtration after ice melts completely
Chromatography (neutral alumina, methylene chloride/methanol=100:1～10:1) separate obtain 1-N- (3- chloro- 2- luorobenzyl) -6-N ' -
Acetoxyethyl -2,3,6,9- tetrahydrochysene -1H- [Isosorbide-5-Nitrae] piperazines simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product, this is thick
Product direct plunge into next step reaction.
I () 1-N- (3- chloro- 2- luorobenzyl) -6-N '-ethoxy -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine is simultaneously [3,2-g]
The preparation of quinoline -9- ketone -8- formic acid
By step (h) gained 1-N- (3- chloro- 2- luorobenzyl) -6-N ' Acetoxyethyl -2,3,6,9- tetrahydrochysene -1H- [1,4]
Simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product is added to 10mL ethanol and 10mL 20% potassium hydroxide solution to piperazine
In, it is heated to reflux 4h.Cooling, adds 1M hydrochloric acid to be adjusted to pH=1～2, filters, and insoluble matter uses water, 50% ethanol water successively
Washing, is dried to obtain 1-N- (3- chloro- 2- luorobenzyl) -6-N '-ethoxy -2,3,6,9- tetrahydrochysene -1H- [Isosorbide-5-Nitrae] piperazines simultaneously [3,2-
G] quinoline -9- ketone -8- formic acid.
Sterling is light yellow solid 168mg, two step joint yields 39%
1H NMR (400MHz, DMSO) δ 15.77 (s, 1H), 8.63 (s, 1H), 7.53 (t, J=8.0Hz, 1H), 7.42
(s, 1H), 7.31 (s, 1H), 7.28 (d, J=7.4Hz, 1H), 7.19 (t, J=8.0Hz, 1H), 4.76 (s, 2H), 4.50 (t, J
=4.3Hz, 2H), 4.48 4.39 (m, 2H), 3.71 (t, J=4.0Hz, 2H), 3.60 (t, J=4.3Hz, 2H).
MS(ESI)m/z,433.0969[M+H]+
Embodiment 17
1-N- (2- luorobenzyl) -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9-
The preparation of ketone -8- formic acid
Step (a) (b) (c) (d) (e) (f) (g) is with embodiment 1.
(h) 1-N- (2- luorobenzyl) -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -
The preparation of 9- ketone -8- Ethyl formate
By 1-N- (3- chloro- 2- luorobenzyl) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
Ethyl formate (416mg, 1mmol) is dissolved in 15mL DMF, adds potassium carbonate (1.3g, 9.5mmol) system
It is warming up to 70 DEG C, dropping 3- bromo- 1- propyl alcohol (334mg, 2mmol), finish 70 DEG C of reaction 4h, TLC monitoring raw material point disappears, and takes out
Filter, filtrate is poured in 50mL frozen water, and insoluble matter, insoluble matter 10mL × 3 water washings, post layer are collected by filtration after ice melts completely
Analysis (neutral alumina, methylene chloride/methanol=100:1～10:1) separate and obtain 1-N- (3- chloro- 2- luorobenzyl) -6-N '-hydroxyl
Propyl group -2,3,6,9- tetrahydrochysene -1H- [Isosorbide-5-Nitrae] piperazines simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product, this crude product is direct
Put into next step reaction.
I () 1-N- (3- chloro- 2- luorobenzyl) -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine is simultaneously [3,2-g]
The preparation of quinoline -9- ketone -8- formic acid
By step (h) gained 1-N- (3- chloro- 2- luorobenzyl) -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H- [1,4]
Simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product is added in 10mL ethanol and 10mL 20% potassium hydroxide solution piperazine,
It is heated to reflux 4h.Cooling, adds 1M hydrochloric acid to be adjusted to pH=1～2, filters, and insoluble matter uses water, 50% ethanol aqueous wash successively
Wash, be dried to obtain 1-N- (3- chloro- 2- luorobenzyl) -6-N '-hydroxypropyl -2,3,6,9- tetrahydrochysene -1H- [Isosorbide-5-Nitrae] piperazines are simultaneously [3,2-g]
Quinoline -9- ketone -8- formic acid.
Sterling is light yellow solid 134mg, two step joint yields 30%
1H NMR (400MHz, DMSO) δ 15.75 (s, 1H), 8.73 (s, 1H), 7.53 (t, J=7.2Hz, 1H), 7.39
(s, 1H), 7.33 7.27 (m, 2H), 7.20 (t, J=7.8Hz, 1H), 4.77 (s, 1H), 4.75 (s, 2H), 4.53 4.42 (m,
4H), 3.60 (s, 2H), 3.43 (d, J=5.1Hz, 2H), 1.95 1.86 (m, 2H).
MS(ESI)m/z,447.1121[M+H]+
Embodiment 18
1-N- (3- chloro- 2- luorobenzyl) -6-N '-carboxymethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline
The preparation of quinoline -9- ketone -8- formic acid
Step (a) (b) (c) (d) (e) (f) (g) is with embodiment 1.
(h) 1-N- (3- chloro- 2- luorobenzyl) -6-N '-ethoxy acyl methyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,
2-g] quinoline -9- ketone -8- Ethyl formate preparation
By 1-N- (3- chloro- 2- luorobenzyl) -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
Ethyl formate (416mg, 1mmol) is dissolved in 15mL DMF, adds potassium carbonate (1.3g, 9.5mmol) system
It is warming up to 70 DEG C, dropping bromoacetate (334mg, 2mmol), finish 70 DEG C of reaction 4h, TLC monitoring raw material point disappears, suction filtration,
Filtrate is poured in 50mL frozen water, and insoluble matter, insoluble matter 10mL × 3 water washings, column chromatography are collected by filtration after ice melts completely
(neutral alumina, methylene chloride/methanol=100:1～10:1) separate and obtain 1-N- (3- chloro- 2- luorobenzyl) -6-N '-ethoxy
Acyl methyl -2,3,6,9- tetrahydrochysene -1H- [Isosorbide-5-Nitrae] piperazines simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product, this crude product is straight
Connect input next step reaction.
I () 1-N- (3- chloro- 2- luorobenzyl) -6-N '-carboxymethyl -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine is simultaneously [3,2-g]
The preparation of quinoline -9- ketone -8- formic acid
By step (h) gained 1-N- (3- chloro- 2- luorobenzyl) -6-N '-ethoxy acyl methyl -2,3,6,9- tetrahydrochysene -1H- [1,
4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate crude product to be added to 10mL ethanol molten with 10mL 20% potassium hydroxide
In liquid, it is heated to reflux 4h.Cooling, adds 1M hydrochloric acid to be adjusted to pH=1～2, filters, and insoluble matter uses water, 50% ethanol water-soluble successively
Liquid washs, and is dried to obtain 1-N- (3- chloro- 2- luorobenzyl) -6-N '-ethoxy acyl methyl -2,3,6,9- tetrahydrochysene -1H- [Isosorbide-5-Nitrae] piperazines
And [3,2-g] quinoline -9- ketone -8- formic acid.
Sterling is light yellow solid 182mg, two step joint yields 41%
1H NMR (400MHz, DMSO) δ 15.60 (s, 1H), 13.57 (s, 1H), 8.83 (s, 1H), 7.53 (t, J=
7.0Hz,1H),7.35–7.03(m,4H),5.36(s,2H),4.76(s,2H),4.44(s,2H),3.59(s,2H).
MS(ESI)m/z,447.0758[M+H]+
Embodiment 19
Integrase chain transfer reaction inhibitory activity continuous mode is as follows：
Reaction is carried out in 96 orifice plates, and cumulative volume is 50 μ L, and reaction buffer is：25mmol/L PIPES,pH 7.0,
5%glycerol, 0.1g/L BSA.37 DEG C of incubation 20min in reaction buffer system by testing sample and 800ng integrase,
Subsequently, add the MnCl of final concentration of 10mmol/L2, 1.5pmol donor dna and 15pmol target DNA, react 1h at 37 DEG C.Plus
Enter 51.5 μ L combination buffer (10mmol/L Tris-HCl, pH 7.6,2mol/L NaCl, 20mmol/L EDTA, 0.1%
Tween 20) and 1.5mL magnetic bead, mix rear 20 DEG C of incubation 15min.Microwell plate is placed in 90s on magnetic bead collector, abandons supernatant.
PBST washes plate 3 times.Add 100 μ L with PBS 1:The DigiTAb of the alkali phosphatase enzyme mark of 5000 dilutions, 37 DEG C of incubations
30min, PBST wash plate 3 times, and magnetic bead is transferred in new microwell plate, add 100mL chromogenic substrate (0.1mol/L Na2CO3,
pH 9.5,6.7mmol/L PNPP,2mmol/L MgCl2), measure OD value at 405nm.Setting is added without sample in an experiment
DMSO is negative control, and with the S-1360 of 25 μm of ol/L for measurement result positive control, ELIASA measures A value (absorbance), leads to
(method detailed is shown in H.Q.He et al.A novel to calculate inhibiting rate to cross formula 100 × (1- dosing group A value/control group A value)
high-throughput format assay for HIV-1 integrase strand transfer reaction
using magnetic beads.Acta.Pharma-cologica.Sinica.,2008,29(3):397–404).Its activity
Measurement result is shown in Table 1.
Table 1：Enzyme assay result is integrated in compound suppression
Claims (4)
1.1-N- substituted benzyl -6-N '-substituent -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -9- ketone -8-
Formic acid compound is it is characterised in that structural formula is as follows
R1Represent benzyl or substituted benzyl, described substituted benzyl is 2- luorobenzyl or 3- chloro- 2- luorobenzyl；R2Represent hydrogen, alkyl,
Hydroxyalkyl, substituted benzyl or carboxyalkyl, described substituted benzyl is 4- luorobenzyl or 4- nitrobenzyl.
2. the 1-N- substituted benzyl-6-N ' described in claim 1-substituent-2,3,6,9- tetrahydrochysene-1H- [1,4] piperazine simultaneously [3,
2-g] quinoline -9- ketone -8- formic acid compound preparation method it is characterised in that comprising the following steps：
A 2- Amino-5-nitrophenol and formic acid, formic anhydride are reacted in toluene by (), insoluble matter is collected by filtration, obtains formula (II)
The 2- acetylaminohydroxyphenylarsonic acid 5- compounds p-nitrophenol representing；
B () formula (II) compound is dissolved in DMF, add 1,2- Bromofume, anti-under potassium carbonate effect
Should, obtain N- acetyl group -7- nitro benzo [Isosorbide-5-Nitrae] the piperazine compound that formula (III) represents,
C formula (III) compound is reacted in ethanol by () with concentrated hydrochloric acid, obtain 7- nitro benzo [Isosorbide-5-Nitrae] that formula (IV) represents
Piperazine compound；
D () formula (IV) compound is dissolved in DMF, add potassium carbonate and substituted benzyl bromides, obtain formula (V)
N- substituted benzyl -7- nitro benzo [Isosorbide-5-Nitrae] the piperazine compound representing,
Wherein, R1Represent benzyl or substituted benzyl, described substituted benzyl is 2- luorobenzyl or 3- chloro- 2- luorobenzyl；
E formula (V) compound and two hydrated stannous chlorides, concentrated hydrochloric acid are reacted by () in ethanol, after reacting 1～3 hour, plus saturation
Sodium bicarbonate solution neutralizes, and obtains N- substituted benzyl -3 that formula (VI) represents, 4- dihydrobenzo [Isosorbide-5-Nitrae] piperazine -7- amines,
Wherein, R1The same step (d) of group representing is described；
F () is with formula (VI) N- substituted benzyl -3,4- dihydrobenzo [1,4] piperazine -7- amine representing and the second being represented with formula (VII)
Epoxide diethyl methylenemalonate reacts in dioxane, obtains ((N- substituted benzyl -3,4- bis- that formula (VIII) represents
Hydrogen benzo [Isosorbide-5-Nitrae] piperazine -7- amino) methylene) diethyl malonate compound,
Wherein, R1The same step (d) of group representing is described；
G formula (VIII) compound is reacted in diphenyl ether by (), obtain 1-N- substituted benzyl -2 that formula (IX) represents, and 3,6,9- tetra-
Hydrogen -1H- [Isosorbide-5-Nitrae] piperazine simultaneously [3,2-g] quinoline -9- ketone -8- Ethyl formate compound,
Wherein, R1The same step (d) of group representing is described；
H formula (IX) compound is replaced reagent with N- and reacts in DMF in the presence of potassium carbonate by (), obtain
1-N- substituted benzyl-the 6-N ' representing to formula (X)-substituent -2,3,6,9- tetrahydrochysene -1H- [1,4] piperazine simultaneously [3,2-g] quinoline -
9- ketone -8- Ethyl formate compound,
Wherein, R1The same step (d) of group representing is described；
R2Replace reagent from N-, represent hydrogen, alkyl, hydroxyalkyl, substituted benzyl or carboxyalkyl, described substituted benzyl is 4- fluorine benzyl
Base, 4- nitrobenzyl；
I formula (X) compound and 20% potassium hydroxide aqueous solution are reacted by () in ethanol, obtain the 1-N- replacement that formula (I) represents
Benzyl -6-N '-substituent -2,3,6,9- tetrahydrochysene -1H- [Isosorbide-5-Nitrae] piperazines simultaneously [3,2-g] quinoline -9- ketone -8- carboxylic acid compounds,
3. method according to claim 2, it is characterised in that 80 DEG C of step (a) reaction temperature, is reacted 3～4 hours；Step (b)
The amount of formula (II) compound and the material of glycol dibromide is than for 1:(1.2～1.5), 70～80 DEG C of reaction temperature, during reaction
Between 3～5 hours；Step (c) wherein concentrated hydrochloric acid is 1 with the volume ratio of ethanol:1.5,80～90 DEG C of reaction temperature, the reaction time 2
～3 hours；70～80 DEG C of reaction temperature, 3～5 hours reaction time, 70～80 DEG C of step (d) reaction temperature, reaction time 3～
5 hours；The amount of the material of step (e) formula (V) compound, two hydrated stannous chlorides and concentrated hydrochloric acid is than for 1:(2～4):10, reaction
70～80 DEG C of temperature, after reacting 1～3 hour, plus saturated sodium bicarbonate solution neutralization；Step (f) formula (VI) compound and formula
(VII) amount of the material of compound is than for 1:(1～1.2), 70～80 DEG C of reaction temperature, 2～5 hours reaction time；G () is reacted
245～250 DEG C of temperature, 0.5～1.5 hour reaction time；H amount ratio that () formula (IX) compound and N- replace the material of reagent is
1:(1.5～4), 50～90 DEG C of reaction temperature, 4～16 hours reaction time；(i) wherein 20% potassium hydroxide aqueous solution and ethanol
Volume ratio be 1:(1～1.5), 2～8 hours reaction time, 80～90 DEG C of reaction temperature.
4. the 1-N- substituted benzyl-6-N ' described in claim 1-substituent-2,3,6,9- tetrahydrochysene-1H- [1,4] piperazine simultaneously [3,
2-g] application in preparing HIV-1 integrase inhibitor for the quinoline -9- ketone -8- formic acid compound.
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| CN102503900A (en) * | 2011-09-30 | 2012-06-20 | 北京工业大学 | (Z)-1-(1-substituted benzyl-5-methyl-1H-1,2,3-triazole-4-yl)-3-substituted benzyl-3-hydroxy-2-propylene-1-ketone compound and preparation method and application thereof |
| CN102617487A (en) * | 2012-03-02 | 2012-08-01 | 北京工业大学 | Multi-substituted pyrimidinones compounds as well as preparation method and application thereof |
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| CN102503900A (en) * | 2011-09-30 | 2012-06-20 | 北京工业大学 | (Z)-1-(1-substituted benzyl-5-methyl-1H-1,2,3-triazole-4-yl)-3-substituted benzyl-3-hydroxy-2-propylene-1-ketone compound and preparation method and application thereof |
| CN102617487A (en) * | 2012-03-02 | 2012-08-01 | 北京工业大学 | Multi-substituted pyrimidinones compounds as well as preparation method and application thereof |
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| 喹啉酮酸类HIV-1整合酶抑制剂的研究进展;罗再刚等;《药学进展》;20131231;第37卷(第3期);第97-104页 * |
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