CN102766083A - 2-amino-3-perfluoro acetoindole compound and its derivative, preparation method and application thereof - Google Patents
2-amino-3-perfluoro acetoindole compound and its derivative, preparation method and application thereof Download PDFInfo
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- CN102766083A CN102766083A CN2011101124402A CN201110112440A CN102766083A CN 102766083 A CN102766083 A CN 102766083A CN 2011101124402 A CN2011101124402 A CN 2011101124402A CN 201110112440 A CN201110112440 A CN 201110112440A CN 102766083 A CN102766083 A CN 102766083A
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Abstract
The invention discloses a 2-amino-3-perfluoro acetoindole compound and its derivative, a preparation method and an application thereof. The compound has the chemical structural general formula defined in the specification, wherein R represents a monosubstituent, a disubstituent, a trisubstituent or a tetrasubstituent on a phenyl ring. The substituent is H, F, Cl, Br, nitro or C1-C3 alkyloxy. The derivative has the chemical structural general formula defined in the specification, wherein R is the same as mentioned above; and R1 is acetonyl, C1-C4 alkyl or C1-C4 nonsaturated alkyl. The compound is prepared by a reaction between the 2-amino-3-perfluoro acetoindole compound and trifluoroactic anhydride. The derivative is prepared by a reaction between the 2-amino-3-perfluoro acetoindole compound and a Grignard reagent or acetone. The 2-amino-3-perfluoro acetoindole compound and its derivative provided by the invention can be applied as an HIV reverse transcriptase inhibitor.
Description
Technical field
The present invention relates to 2-amino-3-perfluor acetyl indole compounds and verivate, preparation method and application, belong to technical field of organic chemistry.
Background technology
AIDS (AIDS) is to infect the serious disease that causes by human immunodeficiency virus (HIV).HIV belongs to the RNA retrovirus, is divided into HIV-1 and HIV-2 type again.The genome of these two types of viruses is having tangible difference aspect the DNA base sequence, thereby the structure of gp is different on corresponding reversed transcriptive enzyme and the coating.The aids patient of most of areas is infected by viral HIV-1 in the world, if existing drug main suppresses duplicating of HIV-1 C-type virus C.The course of infection of HIV pair cell comprises with host cell fused, and DNA transcribes and be integrated into the host cell gene group, carries out protein expression, assembles new virus at last and overflows cell.Anti-hiv drug can reach treatment through any one stage in inhibition or the blocking virus reproduction process and alleviate the purpose of disease.
Developed the compounds for treating AIDS that many viral interferences are duplicated in the world.For example, nucleoside analog, like AZT, ddC, d4T, ddI, 3TC demonstrates good effectiveness in the process that reversed transcriptive enzyme (RT) stage prevention HIV-1 duplicates.
The field of enlivening of current research is the discovery that is the non-nucleoside hiv reverse transcriptase inhibitor.For example: US 5519021 has described the inhibition at hiv reverse transcriptase of a series of benzoxazoles piperazine ketone and quinazolinone, the activity in prevention that HIV infects and the treatment of treatment and AIDS; WO9845276 has described another kind of quinazolinones RTI.This research experiment group has reported one type of new RTI in CN1827605A:
R wherein
7It is alkyl or cycloalkyl; Though this compounds also shows good inhibition activity to hiv reverse transcriptase; But because the limitation of molecular skeleton causes being prone to produce resistance, thereby we need continuous development of new RTI to resist the HIV infection.
Summary of the invention
To problem that exists in the above-mentioned prior art and defective, one of the object of the invention provides a kind of have anti-hiv reverse transcriptase activity and the avirulent basically 2-amino of pair cell-3-perfluor acetyl indole compounds and verivate thereof.
But two of the object of the invention provides the method for the described 2-amino of a kind of scale preparation simple to operate-3-perfluor acetyl indole compounds and verivate thereof.
Three of the object of the invention provides described 2-amino-3-perfluor acetyl indole compounds and the application of verivate in the anti-hiv reverse transcriptase inhibitor of preparation thereof.
For realizing the foregoing invention purpose, the technical scheme that the present invention adopts is following:
2-amino provided by the invention-3-perfluor acetyl indole compounds is to have following chemical structure of general formula:
The verivate of 2-amino provided by the invention-3-perfluor acetyl indole compounds is to have following chemical structure of general formula:
Compound, wherein: R is with the above; R
1Be acetonyl, C
1-C
4Alkyl or C
1-C
4Unsaturated alkyl.
Described R is preferably H, 5-F, 5-Cl, 5-Br, 5-OMe, 5-OEt, 5-OCH (CH
3)
2, 6-Cl, 6-F, 7-NO
2Or 5,7-diCl.
Described R
1Be preferably methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, normal-butyl, the tertiary butyl, allyl group or acetonyl.
The preparation of 2-amino provided by the invention-3-perfluor acetyl indole compounds; Be to react and get by 2-amino-Benzazole compounds and trifluoroacetic anhydride; Concrete preparation process is recommended as follows: with 2-amino-Benzazole compounds and trifluoroacetic anhydride in the organic solvent after no water treatment, under the anhydrous and oxygen-free condition; Under 0～40 ℃, react, wherein: the mol ratio of 2-amino-Benzazole compounds and trifluoroacetic anhydride is 1: 2～1: 5.
Described organic solvent is recommended as ether, 1,4-dioxane, THF, methyltetrahydrofuran or N, dinethylformamide; Be preferably ether or THF.
The preparation of the verivate of 2-amino provided by the invention-3-perfluor acetyl indole compounds is to be reacted and got by 2-amino-3-perfluor acetyl indole compounds and Grignard reagent or acetone.
The reaction process of 2-amino-3-perfluor acetyl indole compounds and Grignard reagent is recommended as follows: in the organic solvent after no water treatment, under the anhydrous and oxygen-free condition; 2-amino-3-perfluor acetyl indole compounds and Grignard reagent are reacted under-20～40 ℃ (preferred 0～40 ℃), and wherein: the mol ratio of 2-amino-3-perfluor acetyl indole compounds and Grignard reagent is 1: 2～1: 5 (preferred 1: 2～1: 3); Described Grignard reagent is R
1MgBr or R
1MgCl, R wherein
1Be C
1-C
4Alkyl or C
1-C
4Unsaturated alkyl.
Described organic solvent is recommended as THF, methyltetrahydrofuran, t-butyl methyl ether, ether or 1,4-dioxane; Be preferably THF, methyltetrahydrofuran or ether.
The reaction process of 2-amino-3-perfluor acetyl indole compounds and acetone is recommended as follows: in organic solvent, 2-amino-3-perfluor acetyl indole compounds, acetone and proline and Potassium ethanoate are reacted under 0～100 ℃ (preferred 0～60 ℃), wherein: the feed ratio of 2-amino-3-perfluor acetyl indole compounds and acetone is 1mmol: 1mL～1mmol: 10mL (preferred 1mmol: 1mL～1mmol: 5mL); The mol ratio of 2-amino-3-perfluor acetyl indole compounds and proline is 1: 0.1～1: 0.5; The mol ratio of proline and Potassium ethanoate is 1: 0.5～1: 2 (being preferably 1: 1).
Described organic solvent is recommended as ether, 1,4-dioxane, THF, methyltetrahydrofuran, N, dinethylformamide or DMSO 99.8MIN. (DMSO); Be preferably ether, THF, N, dinethylformamide or DMSO.
Learn through the external activity experiment: 2-amino of the present invention-3-perfluor acetyl indole compounds and verivate thereof, have anti-hiv reverse transcriptase activity and the basic nontoxicity of pair cell, can be used for preparing hiv reverse transcriptase inhibitor.
Be used to prepare the preferred following chemical structural formula of 2-amino-3-perfluor acetyl indole compounds of hiv reverse transcriptase inhibitor:
Be used to prepare the preferred following chemical structural formula of verivate of hiv reverse transcriptase inhibitor:
Compared with prior art, 2-amino provided by the invention-3-perfluor acetyl indole compounds and verivate thereof has anti-hiv reverse transcriptase activity and the basic nontoxicity of pair cell, is expected as hiv reverse transcriptase inhibitor; And that described preparation method has is simple to operate, implement easily and advantage such as mass-producing; Research to hiv reverse transcriptase inhibitor has important value.
The practical implementation method
Through embodiment the present invention is carried out concrete description below; Be necessary to be pointed out that at this: present embodiment only is used for the present invention is further specified; Can not be interpreted as the restriction to protection domain of the present invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.
Embodiment 1
5-chloro-indoles-2-carbamate (0.659g) is dissolved in exsiccant N, in the dinethylformamide (5mL), the 0.45mL trifluoroacetic anhydride is slowly added in the reaction solution under 0 ℃, TLC follows the tracks of; After reacting completely, add entry, have deposition to separate out; Suction filtration, water washing, bullion is used ethyl alcohol recrystallization; Get title product 511mg, productive rate 55% (mother liquor still has a large amount of products, crystallization once more).
EI-MS?m/z：334([M]+)，288，265，256，237，219，203，193，178，165，158，149，137，129，125，109，97，91，77，69，57，51，43.
1H?NMR(400MHz，Acetone)δ7.69-7.62(m，2H)，7.24(dd，J＝8.6，1.8Hz，1H)，4.37(q，J＝7.1Hz，2H)，1.38(t，J＝7.1Hz，3H).
13C?NMR(101MHz，Acetone)δ173.31(q，J＝36Hz)，152.75，150.12，132.28，128.48，123.22，118.57(q，J＝6Hz)，117.37(q，J＝286Hz)，114.14，94.46，63.09，13.55.
Embodiment 2
7-nitro-indoles-2-carbamate (0.504g) is dissolved in the dry tetrahydrofuran (3mL), under 10 ℃, slowly adds and be dissolved in the trifluoroacetic anhydride (0.7mL) in the dry tetrahydrofuran (5mL), TLC follows the tracks of; After reacting completely, aftertreatment, extraction, washing; After the drying, concentrate, obtain solid crude product; Recrystallization obtains title product 0.524g, productive rate 75% (mother liquor still has product, once more crystallization).
1H?NMR(300MHz，CDCl
3)δ12.26(s，1H)，10.67(s，1H)，8.15(t，J＝7.0Hz，1H)，7.40(t，J＝8.2Hz，1H)，4.43(q，J＝7.1Hz，2H)，1.42(t，J＝7.1Hz，3H).
13C?NMR(101MHz，Acetone)δ174.15(q，J＝38Hz)，153.33，150.47，133.38，126.36(q，J＝5Hz)，125.15，123.27，119.10，117.06(q，J＝286Hz)，94.56，63.77，13.52.
EI?345[M]
+，329，300，284，276，256，248，232，226，214，204，184，158，129，102，90，75，69，51，43.
Embodiment 3
With 5,7-two chloro-indoles-2-carbamate (0.1g) is dissolved in the dry ether (5mL) and under 20 ℃, adds and is dissolved with in the dry ether (5mL) of 0.14mL trifluoroacetic anhydride, and TLC follows the tracks of; Aftertreatment, extraction, washing; After the drying, concentrate, obtain solid crude product; Recrystallization obtains title product 0.11g, productive rate 81% (mother liquor still has product, once more crystallization).
1H?NMR(400MHz，Acetone)δ7.66(d，J＝1.2Hz，1H)，7.45(d，J＝1.7Hz，1H)，4.45(q，J＝7.1Hz，2H)，1.41(t，J＝7.2Hz，3H).
13C?NMR(101MHz，Acetone)δ173.82(1C，q，J＝33Hz)，153.36，150.36，128.87，128.74，124.32，122.58，117.78(1C，q，J＝6Hz)，117.63，117.06(1C，q，J＝286Hz)，95.08，63.64，13.51.
EI?368[M]
+，322，299，271，255，227，220，199，192，171，163，136，127，109，100，95，86，76，69，62，52，43.
Embodiment 4
5-methoxyl group-indoles-2-carbamate (1.58g) is dissolved in drying 1, adds the drying 1 that is dissolved with the 2.4mL trifluoroacetic anhydride down in the 4-dioxane (10mL) and at 40 ℃, in the 4-dioxane (20mL), TLC follows the tracks of; Aftertreatment, extraction, washing; After the drying, concentrate, obtain solid crude product; Recrystallization obtains title product 1.985g, productive rate 89% (mother liquor still has product, once more crystallization).
1H?NMR(400MHz，Acetone)δ11.70(s，1H)，10.85(s，1H)，7.58(d，J＝8.8Hz，1H)，7.27(s，1H)，6.90(dd，J＝8.7，2.4Hz，1H)，4.37(q，J＝7.1Hz，2H)，3.85(s，3H)，1.38(t，J＝7.1Hz，3H).
13C?NMR(101MHz，Acetone)δ174.10(q，J＝36Hz)，157.64，153.78，150.52，129.18，123.82，118.5(q，J＝286Hz)，114.24，111.81，104.52(q，J＝5Hz)，96.11，63.78，55.90，14.48.
ESI[M+H]
+?331.0.
Embodiment 5
6-chloro-indoles-2-carbamate (1.68g) is dissolved in exsiccant N, in the dinethylformamide (5mL), slowly adds the 3.7g trifluoroacetic anhydride in the reaction solution under 5 ℃; TLC follows the tracks of, and after reacting completely, adds entry; There is deposition to separate out suction filtration, water washing; Bullion is used ethyl alcohol recrystallization, final title product 1.63g, the productive rate 69.4% of getting.
1H?NMR(400MHz，Acetone)δ11.88(s，NH)，10.80(s，NH)，7.73(s，1H)，7.72(d，J＝10.3Hz，1H)，7.30(d，J＝7.4Hz，1H)，4.39(q，J＝7.1Hz，2H)，1.39(t，J＝10.3Hz，3H).
13C?NMR(101MHz，Acetone)δ173.46(q，J＝36Hz)，152.84，150.19，134.39，128.35，123.34，120.71，120.29(q，J＝5Hz)，117.42(q，J＝285Hz)，112.75，94.62，63.10，13.55.
EI-MS?m/z：334[M]
+，314，288，261，233，219，201，193，165，137，129，110，102，87，75，64，58，51，43.
Embodiment 6
Add 50mg 5-chloro-2-carbamate-3-trifluoroacetyl indoles in the flask, THF (10mL), 1.2mL acetone, 5.16mg proline(Pro), 4.3mg KAc; 0 ℃ of reaction heats up naturally, and through the reaction solution colour-change, TLC follows the tracks of reaction; Aftertreatment, with petrol ether/ethyl acetate 2/1, aqueous ammonium chloride solution extractive reaction liquid, anhydrous sodium sulfate drying; Drain solvent, column chromatography obtains title product 46mg, productive rate 78%.
1H?NMR(300MHz，CDCl
3)δ10.46(br?s，1H)，9.05(br?s，1H)，7.35(br?s，1H)，7.19(d，J＝7.8Hz，1H)，7.06(dd，J＝7.8，0.9Hz，1H)，6.64(s，1H)，4.26(q，J＝7.2Hz，2H)，3.56(d，J＝16.8Hz，1H)，3.33(d，J＝16.8Hz，1H)，2.28(s，3H)，1.35(t，J＝7.2Hz，3H)；
19F?NMR(300MHz，CDCl
3)：-81.965；
ESI[M+Na]
+415.1，[M+H]
+393.0。
Embodiment 7
Add 200mg 7-nitro-2-carbamate-3-trifluoroacetyl indoles in the flask, DMSO 99.8MIN. (20mL), 2mL acetone, 20mg proline(Pro), 17.2mg KAc; 0 ℃ is reacted to 100 ℃, and through the reaction solution colour-change, TLC follows the tracks of reaction, aftertreatment; With petrol ether/ethyl acetate 2/1, aqueous ammonium chloride solution extractive reaction liquid, anhydrous sodium sulfate drying is drained solvent; Column chromatography obtains title product 147mg, productive rate 62.9%.
1H?NMR(400MHz，Acetone)δ11.94(s，1H)，9.37(s，1H)，8.08(d，J＝8.0Hz，1H)，8.05(d，J＝8.2Hz，1H)，7.29(t，J＝8.1Hz，1H)，7.03(s，1H)，4.35(q，J＝7.1Hz，2H)，3.94(d，J＝17.3Hz，1H)，3.56(d，J＝17.3Hz，1H)，2.21(s，3H)，1.37(t，J＝7.1Hz，3H).
13C?NMR(101MHz，Acetone)δ206.35，153.56，137.52，132.54，128.36，126.17，125.74(q，J＝285Hz)，125.70，120.02，116.67，91.96，76.23(q，J＝31Hz)，62.28，44.55，30.55，13.74.
ESI[M-H]
+402.2，[M+Na]
+426.3，[M+H]
+404.3.
Embodiment 8
Add 500mg 5,7-two chloro-2-carbamates-3-trifluoroacetyl indoles, N, dinethylformamide (40mL), 13mL acetone, 45.6mg proline(Pro) in the flask; 43mg KAc, 0 ℃ is reacted to 40 ℃, and through the reaction solution colour-change, TLC follows the tracks of reaction; Aftertreatment, with petrol ether/ethyl acetate 2/1, aqueous ammonium chloride solution extractive reaction liquid, anhydrous sodium sulfate drying; Drain solvent, column chromatography obtains title product 468mg, productive rate 80.8%.
1H?NMR(400MHz，Acetone)δ10.78(s，1H)，9.29(s，1H)，7.60(s，1H)，7.19(d，J＝1.5Hz，1H)，7.00(s，1H)，4.31(q，J＝7.1Hz，2H)，3.89(d，J＝17.4Hz，1H)，3.54(d，J＝17.4Hz，1H)，1.34(t，J＝7.1Hz，3H).
13C?NMR(101MHz，Acetone)δ206.61，153.70，137.34，127.78，126.78，125.77，125.74(q，J＝285Hz)，119.43(2C)，117.11，116.25，92.59，76.13(q，J＝30Hz)，62.20，44.24，30.54，13.71.
ESI[M-H]
+425.2.
Embodiment 9
Add 50mg 5-bromo-2-carbamate-3-trifluoroacetyl indoles in the flask, THF (15mL), 1mL acetone, 4.56mg proline(Pro), 4.3mg KAc; Room temperature to 60 ℃ reaction, through the reaction solution colour-change, TLC follows the tracks of reaction, aftertreatment; With petrol ether/ethyl acetate 2/1, aqueous ammonium chloride solution extractive reaction liquid, anhydrous sodium sulfate drying is drained solvent; Column chromatography obtains title product 45mg, productive rate 78%.
1H?NMR(300MHz，CDCl
3)δ10.48(br?s，1H)，9.05(br?s，1H)，7.50(br?s，1H)，7.42(d，J＝8.7Hz，1H)，7.19(m，1H)，6.64(s，1H)，4.24(q，J＝7.2Hz，2H)，3.56(d，J＝17.1Hz，1H)，3.33(d，J＝17.1Hz，1H)，2.28(s，3H)，1.35(t，J＝7.2Hz，3H)；
19F?NMR(300MHz，CDCl3)：-81.953；
ESI[M+Na]
+?459.3，[M+H]
+437.1。
Embodiment 10
Add 98mg 6-chloro-2-carbamate-3-trifluoroacetyl indoles in the flask, methyltetrahydrofuran (20mL), 2ml acetone, 10mg proline(Pro), 8.5mg KAc; Room temperature to 80 ℃ reaction, through the reaction solution colour-change, TLC follows the tracks of reaction, aftertreatment; With petrol ether/ethyl acetate 2/1, aqueous ammonium chloride solution extractive reaction liquid, anhydrous sodium sulfate drying is drained solvent; Column chromatography obtains title product 104mg, productive rate 90.4%.
1H?NMR(300MHz，CDCl
3)δ10.44(br?s，1H)，9.00(br?s，1H)，7.28(br?s，1H)，7.28(d，J＝8.7Hz，1H)，7.07(dd，J＝8.7，1.8Hz，1H)，6.54(s，1H)，4.27(q，J＝7.2Hz，2H)，3.60(d，J＝16.8Hz，1H)，3.29(d，J＝16.8Hz，1H)，2.21(s，3H)，1.35(t，J＝7.2Hz，3H)；
19F?NMR(300MHz，CDCl
3)：-82.040；
ESI[M+Na]
+415.2，[M+H]
+393.1。
Embodiment 11
Anhydrous and oxygen-free is dissolved in 96mg 5-bromo-2-carbamate-3-trifluoroacetyl indoles in the 2.5ml anhydrous tetrahydro furan, under-20 ℃, slowly drips 1mol/L allyl group bromination magnesium 1ml; Naturally be warming up to 40 ℃, TLC follows the tracks of reaction, aftertreatment, aqueous ammonium chloride solution cancellation; Tell organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying; Concentrate, column chromatography obtains title product 85mg, productive rate 80.4%.
1H?NMR(400MHz，Acetone)δ11.02(s，1H)，9.34(s，1H)，7.67(s，1H)，7.53(d，J＝8.6Hz，1H)，7.19(dd，J＝8.6，1.7Hz，1H)，6.42(s，1H)，5.75-5.60(m，1H)，5.22(dd，J＝17.1，1.2Hz，1H)，5.04(d，J＝10.2Hz，1H)，4.26(q，J＝7.1Hz，2H)，3.51(dd，J＝15.1，6.4Hz，1H)，2.99(s，1H)，2.89(dd，J＝15.2，7.3Hz，1H)，1.32(t，J＝7.1Hz，3H).
13C?NMR(101MHz，Acetone)δ153.08，136.92，131.57，130.77，126.57，126.52(q，J＝286Hz)，122.59，120.61，119.24，113.17，113.00，89.72，77.63(q，J＝30Hz)，61.68，37.73，13.79.
ESI[M-H]
+419.2.
Embodiment 12
Anhydrous and oxygen-free, with 100mg 5,7-two chloro-2-carbamates-3-trifluoroacetyl indoles is dissolved in the 3.5mL dry tert-butylmethyl ether, under the ice-water bath, slowly drips 22w% methylmagnesium-chloride 0.6mL; Naturally be warming up to room temperature, TLC follows the tracks of reaction, aftertreatment, aqueous ammonium chloride solution cancellation; Tell organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying; Concentrate, column chromatography obtains title product 90mg, productive rate 87%.
1H?NMR(400MHz，Acetone)δ10.71(s，1H)，9.33(s，1H)，7.52(s，1H)，7.18(d，J＝1.4Hz，1H)，6.59(s，1H)，4.31(q，J＝7.1Hz，2H)，2.07(s，3H)，1.34(t，J＝7.1Hz，3H).
13C?NMR(101MHz，Acetone)δ153.65，136.76，127.82，127.20，126.54(q，J＝284Hz)，125.63，119.24，117.21，116.22，94.40，74.70(q，J＝31Hz)，62.16，22.25，13.73.
ESI[M-H]
+383.2.
Embodiment 13
Anhydrous and oxygen-free, with 113mg 5,7-two chloro-2-carbamates-3-trifluoroacetyl indoles is dissolved in the 3.5mL anhydrous tetrahydro furan, under-20 ℃, slowly drips 2mol/L butylmagnesium chloride 0.7mL; Naturally be warming up to room temperature, TLC follows the tracks of reaction, aftertreatment, aqueous ammonium chloride solution cancellation; Tell organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying; Concentrate, column chromatography obtains title product 108mg, productive rate 82%.
1H?NMR(400MHz，Acetone)δ10.75(s，1H)，9.43(s，1H)，7.49(s，1H)，7.18(d，J＝1.6Hz，1H)，6.35(s，1H)，4.31(q，J＝7.1Hz，2H)，2.66(td，J＝14.4，4.5Hz，1H)，2.16-2.03(m，1H)，1.75-1.50(m，1H)，1.47-1.26(m，5H)，1.22-1.08(m，1H)，0.86(t，J＝7.4Hz，3H).
13C?NMR(101MHz，Acetone)δ153.65，138.00，127.82，127.07，126.60(q，J＝285Hz)，125.77，119.30，116.81，116.22，91.72，78.18(q，J＝30Hz)，62.15，32.84，24.54，22.30，13.73，13.25.
ESI[M-H]
+425.2.
Embodiment 14
Anhydrous and oxygen-free, with 112mg 5,7-two chloro-2-carbamates-3-trifluoroacetyl indoles is dissolved in the 3.5mL anhydrous tetrahydro furan, under-10 ℃, slowly drips 2mol/L isopropylmagnesium chloride 0.7mL; Naturally be warming up to 30 ℃, TLC follows the tracks of reaction, aftertreatment, aqueous ammonium chloride solution cancellation; Tell organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying; Concentrate, column chromatography obtains title product 107mg, productive rate 85%.
1HNMR(400MHz，Acetone)δ10.75(s，1H)，9.47(s，1H)，7.53(s，1H)，7.19(s，1H)，6.02(s，1H)，4.31(q，J＝7.1Hz，2H)，3.01(dt，J＝13.7，6.8Hz，1H)，1.35(t，J＝7.1Hz，3H)，1.27(dd，J＝6.8，1.4Hz，3H)，0.91(d，J＝6.9Hz，3H).
13C?NMR(101MHz，Acetone)δ153.65，137.51，127.86，126.62，126.58(q，J＝287Hz)，125.60，119.29，117.27，116.17，93.63，81.15(q，J＝28Hz)，62.13，31.72，16.91，15.13，13.71.
ESI[M-H]
+411.2.
Embodiment 15
Anhydrous and oxygen-free, with 221mg 5,7-two chloro-2-carbamates-3-trifluoroacetyl indoles is dissolved in the 3.5mL anhydrous diethyl ether, under-20 ℃, slowly drips 1mol/L allyl group bromination magnesium 1.5mL; Naturally be warming up to 40 ℃, TLC follows the tracks of reaction, aftertreatment, aqueous ammonium chloride solution cancellation; Tell organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying; Concentrate, column chromatography obtains title product 217mg, productive rate 88%.
1H?NMR(300MHz，CDCl
3)δ10.62(s，1H)，8.91(s，1H)，7.32(s，1H)，7.12(d，J＝1.3Hz，1H)，5.64(dt，J＝16.3，8.3Hz，1H)，5.33(d，J＝11.2Hz，1H)，5.29(d，J＝4.5Hz，1H)，4.28(q，J＝7.1Hz，2H)，3.31(dd，J＝14.6，6.2Hz，1H)，2.96(s，1H)，2.86(dd，J＝14.6，8.4Hz，2H)，1.35(t，J＝7.1Hz，3H).
13C?NMR(101MHz，Acetone)δ153.65，137.94，130.46，127.82，126.92，126.33(q，J＝285Hz)，125.76，119.44，119.33，117.19，116.17，91.69，77.53(q，J＝30Hz)，62.18，37.60，13.71.
ESI[M-H]
+409.2.
Embodiment 16
Anhydrous and oxygen-free, it is anhydrous 1 that 65mg 6-chloro-2-carbamate-3-trifluoroacetyl indoles is dissolved in 2.5mL, in the 4-dioxane, under-10 ℃, slowly drips 2mol/L butylmagnesium chloride 0.45mL; Naturally be warming up to room temperature, TLC follows the tracks of reaction, aftertreatment, aqueous ammonium chloride solution cancellation; Tell organic phase, washing, saturated common salt washing, anhydrous sodium sulfate drying; Concentrate, column chromatography obtains title product 60mg, productive rate 78%.
1HNMR(300MHz，CDCl
3)δ10.83(br?s，1H)，9.20(br?s，1H)，7.49(br?s，1H)，7.32(d，J＝8.4Hz，1H)，6.90(dd，J＝8.4，2.1Hz，1H)，6.14(s，1H)，4.10(q，J＝6.9Hz，2H)，2.53(td，J＝14.1，4.5Hz，1H)，1.92(m，1H)，1.38(m，1H)，1.28-1.14(m，5H)，0.98(m，1H)，0.68(t，J＝7.2Hz，3H)；
19FNMR(300MHz，CDCl
3)：-82.526；
ESI[M-H]
+391.1.
Embodiment 17: the external activity experiment
Compound of the present invention carries out the hiv reverse transcriptase screening active ingredients through Academy of Military Medicine, PLA and AIDS inspection center of the Chinese People's Liberation Army, and concrete experimental technique and result are described below:
Cell and virus:
The MT-2 cell, the human T lymphocyte of going down to posterity is so kind as to give by professor Lu Shan of medical college of Massachusetts, USA university, the RPMI1640 substratum (+10%FBS+Prep/Strep) cultivate, went down to posterity 1 time in 3-4 days.Preceding 1 day of experiment beginning is gone down to posterity at 1: 2, to guarantee the state of cell.
TZM b1 cell is so kind as to give by professor Lu Shan of medical college of Massachusetts, USA university, the DMEM substratum (+10%FBS+Prep/Strep) cultivate, go down to posterity 2 times weekly at 1: 3.
HIV-1 IIIB strain, the HIV-1 B hypotype strain of the long-term adaptation of virus in laboratory, this research department preserves goes down to posterity.
Experimental technique:
1>cell cultures
Preceding 1 day of experiment beginning is gone down to posterity at 1: 2, is in logarithmic phase to guarantee cell.Exclusive method is carried out total cell count and cell viability is quantitative to adopt blood counting chamber and Trypan Blue to dye, and the cell viability that is used to test is greater than 95%.
2>compound preparation
According to the toxic data of the compound that detects, confirm the maximal non-toxic concentration of compound, diluted totally 11 gradients by 1: 2, it is subsequent use that every hole 10 μ l add 384 porocyte culture plates.
3>high throughput testing of the antiviral activity of medicine
1) with behind the centrifugal 10min of MT-2 cell 250 * g, suspend with fresh growth medium, the piping and druming mixing, Trypan Blue dyeing back counting is confirmed cell concn, viable cell percentage ratio is necessary＞95% can be used for next step experiment;
2) get the MT-2 cell of aequum, add HIV-1 IIIB virus, make its infectious multiple (multiplicity of infection) MOI=0.005TCID
50, dilution MT-2 cell suspension is to desired concn, and it is 2 * 10 that adjustment MT-2 cell suspension makes its final concentration
5/ ml;
3) above-mentioned cell suspension 90 μ l are added 384 porocyte culture plates, 37 ℃, 5%CO
2Cultivate 3d;
4) with the new black 384 porocyte culture plates of the culture supernatant to of Precision Power v2 liquid working station transferase 12 0 μ l;
5) with 0.01M PBS cell is washed 1 time after TZM b1 cells and supernatant is abandoned in suction, added cell dissociation method (Cell Disociation Solution) and handle TZM b1 cell;
6) (counting is the generation and the treatment time of recording processing afterwards for+10%FBS+Prep/Strep) suspension again, Trypan Blue dyeing with the DMEM substratum behind the cell dissociation;
7) the adjustment cell concn is 4 * 10
5/ ml, every hole adds 40 μ l, cultivates 24h for 37 ℃, 5%;
8) it is active to detect β-Gal, Wallac 1420 readout instruments detect Umbelliferone (355nm/460nm, 0.1s).
Result treatment:
The antiviral activity %=of medicine (test value-minimum average)/(the highest average-minimum average) * 100, with in follow (Median Equation) method and calculate IC
50Amount effect relation curve adopts Graphpad Prism 5.0 softwares to generate.SPSS 15.0 softwares are adopted in statistical study.Concrete test data is referring to shown in the table 1.
The activity experiment data of the anti-hiv reverse transcriptase of table 1
Visible by table 1: 2-amino of the present invention-3-perfluor acetyl indole compounds and verivate thereof all show obvious inhibiting activity to hiv reverse transcriptase, and the basic nontoxicity of pair cell, are expected as hiv reverse transcriptase inhibitor.
Claims (24)
1. 2-amino-3-perfluor acetyl indole compounds is characterized in that having following chemical structure of general formula:
2. 2-amino according to claim 1-3-perfluor acetyl indole compounds is characterized in that: described R is H, 5-F, 5-Cl, 5-Br, 5-OMe, 5-OEt, 5-OCH (CH
3)
2, 6-Cl, 6-F, 7-NO
2Or 5,7-diCl.
3. the verivate of the described 2-amino of claim 1-3-perfluor acetyl indole compounds is characterized in that having following chemical structure of general formula:
4. the verivate of 2-amino according to claim 3-3-perfluor acetyl indole compounds is characterized in that: described R is H, 5-F, 5-Cl, 5-Br, 5-OMe, 5-OEt, 5-OCH (CH
3)
2, 6-Cl, 6-F, 7-NO
2Or 5,7-diCl; Described R
1Be methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, normal-butyl, the tertiary butyl, allyl group or acetonyl.
5. the preparation method of the described 2-amino of claim 1-3-perfluor acetyl indole compounds is characterized in that: reacted by 2-amino-Benzazole compounds and trifluoroacetic anhydride.
6. the preparation method of 2-amino according to claim 5-3-perfluor acetyl indole compounds; It is characterized in that: with 2-amino-Benzazole compounds and trifluoroacetic anhydride in the organic solvent after no water treatment, under the anhydrous and oxygen-free condition; Under 0～40 ℃, react, wherein: the mol ratio of 2-amino-Benzazole compounds and trifluoroacetic anhydride is 1: 2～1: 5.
7. the preparation method of 2-amino according to claim 6-3-perfluor acetyl indole compounds, it is characterized in that: described organic solvent is an ether, 1,4-dioxane, THF, methyltetrahydrofuran or N, dinethylformamide.
8. the preparation method of 2-amino according to claim 7-3-perfluor acetyl indole compounds, it is characterized in that: described organic solvent is ether or THF.
9. the preparation method of the verivate of the described 2-amino of claim 3-3-perfluor acetyl indole compounds is characterized in that: reacted by 2-amino-3-perfluor acetyl indole compounds and Grignard reagent or acetone.
10. the preparation method of the verivate of 2-amino according to claim 9-3-perfluor acetyl indole compounds; It is characterized in that: in the organic solvent after no water treatment, under the anhydrous and oxygen-free condition; 2-amino-3-perfluor acetyl indole compounds and Grignard reagent are reacted under-20～40 ℃, and wherein: the mol ratio of 2-amino-3-perfluor acetyl indole compounds and Grignard reagent is 1: 2～1: 5; Described Grignard reagent is R
1MgBr or R
1MgCl, R
1Be C
1-C
4Alkyl or C
1-C
4Unsaturated alkyl.
11. the preparation method of the verivate of 2-amino according to claim 10-3-perfluor acetyl indole compounds is characterized in that: the temperature of reaction of 2-amino-3-perfluor acetyl indole compounds and Grignard reagent is 0～40 ℃.
12. the preparation method of the verivate of 2-amino according to claim 10-3-perfluor acetyl indole compounds is characterized in that: the mol ratio of 2-amino-3-perfluor acetyl indole compounds and Grignard reagent is 1: 2～1: 3.
13. the preparation method of the verivate of 2-amino according to claim 10-3-perfluor acetyl indole compounds is characterized in that: described organic solvent is THF, methyltetrahydrofuran, t-butyl methyl ether, ether or 1, the 4-dioxane.
14. the preparation method of the verivate of 2-amino according to claim 13-3-perfluor acetyl indole compounds, it is characterized in that: described organic solvent is THF, methyltetrahydrofuran or ether.
15. the preparation method of the verivate of 2-amino according to claim 9-3-perfluor acetyl indole compounds; It is characterized in that: in organic solvent, 2-amino-3-perfluor acetyl indole compounds and acetone, proline and Potassium ethanoate; Under 0～100 ℃, react, wherein: the feed ratio of 2-amino-3-perfluor acetyl indole compounds and acetone is 1mmol: 1mL～1mmol: 10mL; The mol ratio of 2-amino-3-perfluor acetyl indole compounds and proline is 1: 0.1～1: 0.5; The mol ratio of proline and Potassium ethanoate is 1: 0.5～1: 2.
16. the preparation method of the verivate of 2-amino according to claim 15-3-perfluor acetyl indole compounds is characterized in that: the temperature of reaction of 2-amino-3-perfluor acetyl indole compounds and acetone, proline and Potassium ethanoate is 0～60 ℃.
17. the preparation method of the verivate of 2-amino according to claim 15-3-perfluor acetyl indole compounds is characterized in that: the feed ratio of 2-amino-3-perfluor acetyl indole compounds and acetone is 1mmol: 1mL～1mmol: 5mL.
18. the preparation method of the verivate of 2-amino according to claim 15-3-perfluor acetyl indole compounds, it is characterized in that: the mol ratio of proline and Potassium ethanoate is 1: 1.
19. the preparation method of the verivate of 2-amino according to claim 15-3-perfluor acetyl indole compounds; It is characterized in that: described organic solvent is an ether, 1; 4-dioxane, THF, methyltetrahydrofuran, N, dinethylformamide or DMSO 99.8MIN. (DMSO).
20. the preparation method of the verivate of 2-amino according to claim 19-3-perfluor acetyl indole compounds, it is characterized in that: described organic solvent is ether, THF, N, dinethylformamide or DMSO.
21. the application of the described 2-amino of claim 1-3-perfluor acetyl indole compounds is characterized in that: be used to prepare hiv reverse transcriptase inhibitor.
22. the application of 2-amino according to claim 21-3-perfluor acetyl indole compounds is characterized in that: the compound that is used to prepare hiv reverse transcriptase inhibitor is selected from following chemical structural formula:
23. the application of the verivate of the described 2-amino of claim 3-3-perfluor acetyl indole compounds is characterized in that: be used to prepare hiv reverse transcriptase inhibitor.
24. the application of the verivate of 2-amino according to claim 23-3-perfluor acetyl indole compounds is characterized in that: the verivate that is used to prepare hiv reverse transcriptase inhibitor is selected from following chemical structural formula:
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| WO2005030756A1 (en) * | 2003-09-25 | 2005-04-07 | Wyeth | Substituted pyrrole-indoles as inhibitors of pai-1 |
| CN1827605A (en) * | 2006-04-07 | 2006-09-06 | 中国科学院上海有机化学研究所 | 4,4-disubstituted-3,4-dihydro-2(1H)- quinolones and synthesis process and use thereof |
| CN101245046A (en) * | 2008-03-05 | 2008-08-20 | 中国科学院上海有机化学研究所 | Process for synthesizing 3-indole-1-propylene compounds and uses thereof |
| WO2009025477A1 (en) * | 2007-08-17 | 2009-02-26 | Lg Life Sciences Ltd. | Indole compounds as an inhibitor of cellular necrosis |
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| WO2005030756A1 (en) * | 2003-09-25 | 2005-04-07 | Wyeth | Substituted pyrrole-indoles as inhibitors of pai-1 |
| CN1827605A (en) * | 2006-04-07 | 2006-09-06 | 中国科学院上海有机化学研究所 | 4,4-disubstituted-3,4-dihydro-2(1H)- quinolones and synthesis process and use thereof |
| WO2009025477A1 (en) * | 2007-08-17 | 2009-02-26 | Lg Life Sciences Ltd. | Indole compounds as an inhibitor of cellular necrosis |
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