CN1740179A - N4-substituent pyrazolyl [4,5-e][1,2,4] thiadiazine derivative and its prepn process and medicine composition - Google Patents
N4-substituent pyrazolyl [4,5-e][1,2,4] thiadiazine derivative and its prepn process and medicine composition Download PDFInfo
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Abstract
The present invention is N4-substituent-7-methyl-1, 1, 3-trioxy-2, 4-dihydropyrazolyl[4, 5-e][1, 2, 4] thiadiazine derivative as HIV-1 non-nucleoside reverse transcriptase inhibitor and its preparation process and medicine composition, and belongs to the field of derivative medicine technology. The preparation process of N4-substituent-7-methyl-1, 1, 3-trioxy-2, 4-dihydropyrazolyl[4, 5-e][1, 2, 4] thiadiazine derivative includes the following steps: synthesizing intermediate, dissolving the intermediate in dimethyl formamide, adding sodium hydride, stirring at temperature lower than 10 deg.c, adding alkyl halide, stirring the mixture at 25-60 deg.c, cooling, separating and purifying and re-crystallizing in organic solvent. The derivative is one heterocyclic system in novel structure, has HIV-1 reverse transcriptase inhibiting activity and may be used as precursor compound for preparing medicine to resist AIDS.
Description
(1) technical field
The present invention relates to a kind of HIV-1 non-nucleoside reverse transcriptase inhibitor N
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives and preparation method thereof, and, belong to the derivative drugs technical field with this derivative and auxiliary material composition pharmaceutical composition.
(2) background technology
Acquired immune deficiency syndrome (AIDS) is commonly called as acquired immune deficiency syndrome (AIDS) (Acquried immunodeficiency syndromeAIDS), is the serious communicable disease that is caused by human immunodeficiency virus (Human immunodeficiency virus HIV).HIV is a kind of retrovirus, is divided into two types of HIV-1 and HIV-2.HIV-1 reversed transcriptive enzyme (reverse transcriptase RT) plays an important role in viral life cycle.Virus is double-stranded DNA by reversed transcriptive enzyme with the single stranded RNA reverse transcription, and viral DNA is incorporated in the host RNA rapidly subsequently, thus finish transcribe, whole life such as translation.The unique function of reversed transcriptive enzyme in viral life cycle makes it become the important target spot of antiviral therapy.Reverse transcriptase inhibitors is divided into two classes: ucleosides and non-nucleoside reverse transcriptase inhibitor.Efabirenz (NRTIs) by with the similarity of substrate, combine with reversed transcriptive enzyme competitively, thus the extension of blocking virus RNA chain, as end stopper of chain and the activity of inhibitory enzyme; Non-nucleoside reverse transcriptase inhibitor (NNRTIs) then is by combining with the near zone noncompetitive of the effect substrate deoxy-ribonucleoside triphosphate action site of reversed transcriptive enzyme, thereby changes the activity of the conformation inhibitory enzyme of action site.In recent years, because NRTIs class drug side effect causes the restriction of clinical application and the advantage of NNRTIs class medicine high-efficiency low-toxicity, people begin to pay close attention to more the development of NNRTIs, referring to Zhou Ting, Xie Lan, HIV non-nucleoside reverse transcriptase inhibitor progress, Acta Pharmaceutica Sinica, 2004,39:666-672.
NNRTIs is that a class formation is widely different, but the similar compound of mechanism of action.Found at present that tens class specificitys suppress the NNRTIs of HIV-1 RT, comprise the HEPT analog derivative, the TIBO analog derivative, the BIRG analog derivative, BHAP analog derivative, TSAO analog derivative, the benzoxazoles analog derivative, indole derivatives, TTDs class, quinazolinone] class etc., and nevirapine (Nevirapine), oneself has passed through the FDA authentication efavirenz (Efavirenz) and three kinds of NNRTIs of U-90152 (Delavirdine), be used for the treatment of HIV-1 and infect, referring to Xu Yuwen, Zhao Guisen, the anti-AIDS drug progress, China's pharmaceutical chemistry magazine, 2002,12:119-124.
The thiophene [3 that replaces, 4-e] [1,2,4] diazthines derivative (TTDs) compound is the novel HIV-1RT inhibitor of a class, meet the requirement of RT-NNRTIs " butterfly " model three-dimensional structure suitability, restrain referring to de cler, the prospect that non-nucleoside reverse transcriptase inhibitor treatment HIV-1 infects, pharmaceutical journal, 1999,54:26-45 (Erik De Clercq, Perspectives ofnon-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection, I1Farmaco, 1999,54:26-45), its structural formula is as follows:
QM96521
TTDs lead compound QM96521 (R=H) and RT bonded conformation model are similar to Nevirapine very much, and not only the position of their fused rings overlaps, and N in the QM96521 molecule
4The cyanogen methyl of position has also been simulated the locus of cyclopropane base in the Nevirapine molecule.QM96521 shows higher activity (QM96521, EC to HIV-1
50And CC
50Be respectively 0.18 and 126 μ M, SI=700).Discover that this compounds not only has restraining effect to the anti-AIDS medicine of ucleosides AZT (3-zidovudine) multidrug resistant disease strain (ADP141), and to the variation and the multidrug resistant disease strain (L100I of some other non-nucleoside reverse transcriptase inhibitor, K103N V106A) also has certain restraining effect.
Based on former structure activity relationship analysis and molecular simulation experiment, learn 1,1,3-three oxygen-2,2 of 4-dihydro-thiophene [3,4-e] [1,2,4] thiadiazine ring and 4 are two, and to replace for the maintenance antiviral activity be essential, and N
2The single replacement in position then loses activity fully, simultaneously at N
4It also is essential replacing with the group that contains πDian Zi on the side chain of position.Though set up overall structure activity relationship, N
4Whether position replacement separately has activity, and is N
2Position or N
4The position has partly formed " butterfly " configuration with the thieno-thiadiazine still needs further research.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, specifically at N
4Whether position replacement separately has activity, is N
2Position or N
4The position has partly formed these two problems of " butterfly " configuration with the thieno-thiadiazine, and HIV-1 non-nucleoside reverse transcriptase inhibitor N is provided
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives and preparation method thereof and screening active ingredients result, and provide and had active N4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2,4-pyrazoline [4,5-e] medicinal application of [1,2,4] thiadiazine derivatives.
Technical scheme of the present invention is as follows:
1.N
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives
The present invention replaces thiophene [3,4-e] [1,2 with methyl substituted pyrazoles ring, 4] thiphene ring in diazthines derivative (TTDs) molecular structure, and keep the thiadiazine ring constant, and 4 bit substituents then are benzyl, single substituted benzyl, two substituted benzyl or ethoxy carbonyl methyl, N has been synthesized in design thus
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2,4-dihydro-pyrazolo diazthines derivative, general structure is as follows:
R=benzyl, single substituted benzyl, two substituted benzyl or ethoxy carbonyl methyl.
N4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2, the synthetic route of 4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives is as follows:
Reagent is in the formula: a:N
2H
4H
2O/EtOH, b:2N HCl, NaNO
2, H
2O, c: △/toluene, d:NaH/RX, DMF.
2. intermediate 7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation method of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (4)
With 1-methyl-5-sulfoamido-4-pyrazole carboxylic acid ethyl ester (1) is starting raw material; get 1-methyl-5-sulfoamido-4-pyrazoles-formyl hydrazine (2) through hydrazinolysis; in nitrous acid solution, carry out again obtaining acyl azide white solid (3) behind the azido reaction; owing to have explosivity; so do not purify; identify 2148cm through infrared spectra
-1Be N
3Charateristic avsorption band.(3) reflux in dry toluene becomes ring to generate female ring 7-methyl isophthalic acid, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazines (4) through the Curtius rearrangement reaction.
3.N
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation method (1) of 4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives 5a-5k is synthetic:
With intermediate 7-methyl isophthalic acid, 1,3-three oxygen-2, (4) 1 equivalents of 4-pyrazoline [4,5-e] [1,2,4] thiadiazine are dissolved in the exsiccant dimethyl formamide (DMF), at N
2Protection down slowly adds 2 normal sodium hydrides that contain 60% mineral oil, and holding temperature is lower than 10 ℃, finishes, and stirs 15-20min, slowly adds 1 normal halocarbon again.Reaction mixture continues to stir 10-24h in 25-60 ℃.Cooling back pressure reducing and steaming solvent.Residue separates with rapid column chromatography purifies.
(2) rapid column chromatography separates purification, eluting solvent system: methylene chloride.The organic solvent recrystallization obtains crystal.Above-mentioned halocarbon is: bromobenzyl, to bromine bromobenzyl, adjacent bromine bromobenzyl; To cyano group benzyl chloride, adjacent cyano group benzyl chloride, a cyano group benzyl chloride; 2,4-dichlorobenzyl chloride, 4-chlorobenzyl chloride, 4 tert butylbenzyl chloride, a chlorobenzyl chloride or ethyl bromoacetate.
The organic solvent of above-mentioned recrystallization is: the mixed solvent of ethanol and ethyl acetate/hexanaphthene.
The structure of table 1 the inventive method synthetic target compound 5a-5k
4. the external anti-HIV-1 RT activity experiment of target compound
(1) principle
The template of HIV-1RT effect is coated on the enzyme plate, in the suitableeest enzyme reaction condition and reaction system, HIV-1RT can be added on the reaction template containing the Biotin-dUTP substrate, reflects the activity of enzyme with Biotin-dUTP incorporation in the horseradish peroxidase measurement of enzymatic reaction products of streptavidin mark.In reaction system, add the inhibitor that sample can be used for screening this enzyme.
(2) method
Sample HIV-1RT faces with before being dissolved in DMSO and is made into proper concn, and does 5 times of dilutions with hydrogen peroxide, each 5 extent of dilution.Add behind the diluted sample and contain among the reaction Buffer of Biotin-dUTP and genetically engineered target enzyme, under optimum reaction condition, hatch,, measure OD with the horseradish peroxidase system colour developing of the plain mark of affinity
450Value.With QM96521 and the positive contrast of Nevirapine.
Table 2 compound is to the inhibition activity (unit: μ M/ml) of HIV-1RT
| NO. | IC 50 | NO. | IC 50 | NO. | IC 50 |
| 5a | ＞230 | 5f | ＞260 | 5k | ＞400 |
| 5b | ＞280 | 5g | 80 | Nevirapine | 4.5 |
| 5c | 50 | 5h | ＞290 | QM96521 | 16.4 |
| 5d | 90 | 5i | ＞300 | ||
| 5e | ＞320 | 5j | ＞210 |
As can be seen from Table 2, institute synthetic target compound (5a-k) has certain inhibition activity, and 5c wherein, 5d and 5g show higher enzymic activity, the IC of pressing down
50Be respectively 50 μ M/ml, 90 μ M/ml and the 80 μ M/ml (IC of contrast QM96521 and Nevirapine
50Be respectively 16.4,4.5 μ M/ml).
Activity research shows, N
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives has the similar activity of TTDs, is the HIV-1RT inhibitor of novel structure, the lead compound of the anti-AIDS drug that can be used as.
A kind of pharmaceutical composition contains above-mentioned N
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives, N
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] diazthines derivative and auxiliary material be mixed routinely, makes the medicine of different dosage form.
Described N
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2, the application of 4-pyrazoline [4,5-e] [1,2,4] diazthines derivative is used to prepare the medicine for the treatment of acquired immune deficiency syndrome (AIDS) as the HIV-1 reverse transcriptase inhibitors.
(4) embodiment
Embodiment 1. intermediate 7-methyl isophthalic acids, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (4)
In the 100ml flask, add 1-methyl-5-sulfoamido-4-pyrazole carboxylic acid ethyl ester (1) 5.1g (22mmol), 85% hydrazine hydrate 3.8g (66mmol) and 25ml ethanol, heated and stirred backflow 10h, remove solvent and unreacted hydrazine hydrate under reduced pressure, residual oily matter dehydrated alcohol recrystallization gets white solid (2).2.19g (10mmol) (2) is dissolved among the 50ml 2N HCl, slowly drips the NaNO of 2ml
2(holding temperature is lower than 10 ℃ for 0.85g, the 12mmol) aqueous solution, and mixture continues stir about 2h under this temperature, separate out white solid (3), filters washing.Product does not have further to purify owing to unstable, but its purity is enough to carry out next step reaction.8.8g (40mmol) (3) is added in the toluene of 100ml, heated and stirred backflow 7h, reaction is finished, and filters the white solid of separating out, and ethyl alcohol recrystallization gets 6.78g, productive rate 84%, 216 ℃ of mp.
Embodiment 2.2-benzyl-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (5a)
With the intermediate 7-methyl isophthalic acid of embodiment 1 preparation, 1,3-three oxygen-2,1 equivalent of 4-pyrazoline [4,5-e] [1,2,4] thiadiazine is dissolved in the exsiccant dimethyl formamide (DMF), at N
2Protection down slowly adds 2 normal sodium hydrides that contain 60% mineral oil, and holding temperature is lower than 10 ℃, finishes, and stirs 15-20min, slowly adds 1 normal and bromobenzyl again.Reaction mixture continues to stir 10h in 28 ℃.Cooling back pressure reducing and steaming solvent.Residue separates with rapid column chromatography purifies.Eluent: methylene dichloride: methyl alcohol (4: 1), the organic solvent recrystallization obtains crystal.Productive rate 65%, white solid, mp187 ℃ of (dec) (ethanol).The production spectra diagram data is as follows:
IR(KBr，cm
-1)：3430(NH)，3032(Py-CH)，1594(C＝O)，1342，1141(SO
2).
1H-NMR(DMSO-d
6)δ：7.29-7.18(m，5H，Ar-H)；7.09(s，1H，Py-H)；4.90(s，2H，CH
2)；3.83(s，3H，CH
3).
13C-NMR(DMSO-d
6)δ：152(C
3＝O)，138(C-1′)，128.4(C-7a)，128.2(2C，C-2′，6′)，127(2C，C-3′，5′)，126(C-4′)，125(C-4a)，123(C-5)，46(CH
2)，37(CH
3).MS(EI)m/z 292(M+1)。
Embodiment 3.2-(to the cyano group benzyl)-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (5b), preparation method such as embodiment 2, different is:
With the 7-methyl isophthalic acid of embodiment 1 preparation, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazine and to 30-40 ℃ of cyano group benzyl chloride reaction 12h, eluent: methylene dichloride: methyl alcohol (4: 1), productive rate 55%, white solid, 244 ℃ of (dec) (ethanol) of mp.The production spectra diagram data is as follows:
IR(KBr，cm
-1)：3461(NH)，2236(CN)，1598(C＝O)；1338，1143(SO
2).
1H-NMR(DMSO-d
6)δ：7.74(d，2H，J＝8.0Hz，Ar-H)；7.41(d，2H，J＝8.0Hz，Ar-H)；7.12(s，1H，Py-H)；4.97(s，2H，CH
2)；3.84(s，3H，CH
3).
13C-NMR(DMSO-d
6)δ：152(C
3＝O)，144(C-1′)，132(2C，C-3′，5′)，128(C-7a)，127(2C，C-2′，6′)，125(C-4a)，123(C-5)，118(C-4′)，109(CN)，46(CH
2)，37(CH
3).MS(EI)m/z 318(M+1)。
Embodiment 4.4-(to bromobenzyl)-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (5c), preparation method such as embodiment 2, different is:
With the 7-methyl isophthalic acid of embodiment 1 preparation, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazine and to 26 ℃ of reactions of bromine bromobenzyl 10h, eluent: methylene dichloride: methyl alcohol (3: 1), productive rate 60%, white solid, 240 ℃ of (dec) (ethanol) of mp.The production spectra diagram data is as follows:
IR(KBr，cm
-1)：3201(NH)，1593(C＝O)；1323，1136(SO
2).
1H-NMR(DMSO-d
6)δ：7.47(d，2H，J＝8.32Hz，Ar-H)；7.20(d，2H，J＝8.28Hz，Ar-H)；7.14(s，1H，Py-H)；4.85(s，2H，CH
2)；3.82(s，3H，CH
3).
13C-NMR(DMSO-d
6)δ：152(C
3＝O)，138(C-1′)，131(2C，C-3′，5′)，129(2C，C-2′，6′)，128(C-7a)，125(C-4a)，123(C-5)，119(C-4′)，47(CH
2)，37(CH
3).MS(EI)m/z 371(M+1)。
Embodiment 5.4-(adjacent bromobenzyl)-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,3-e] [1,2,4] thiadiazines (5d), preparation method such as embodiment 2, different is:
With the 7-methyl isophthalic acid of embodiment 1 preparation, 1,3-three oxygen-2,25 ℃ of reactions of 4-pyrazoline [4,5-e] [1,2,4] thiadiazine and adjacent bromine bromobenzyl 10h, eluent: methylene dichloride: methyl alcohol (3: 1), productive rate 56%, white solid, 135 ℃ of (dec) (ethanol) of mp.The production spectra diagram data is as follows:
IR(KBr，cm
-1)：3189(NH)，3059(Py-CH)，1594(C＝O)；1324，1136(SO
2).
1H-NMR(DMSO-d
6)δ：7.62(d，1H，J＝7.96Hz，Ar-H)；7.27(t，1H，J＝7.36Hz，Ar-H)；7.17(t，1H，J＝7.42Hz，Ar-H)；6.99(s，1H，Py-H)；6.81(d，1H，J＝7.57Hz，Ar-H)；4.88(s，2H，CH
2)；3.86(s，3H，CH
3).
13C-NMR(DMSO-d
6)δ：152(C
3＝O)，136(C-1′)，132，128.7，128.4(C-7a)，127.8，127，125(C-4a)，123(C-5)，122(C-2′)，47(CH
2)，37(CH
3).MS(EI)m/z 371(M+1)。
Embodiment 6.2-(2, the 4-dichloro benzyl)-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (5f), preparation method such as embodiment 2, different is:
With the 7-methyl isophthalic acid of embodiment 1 preparation, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazine and 2,50-60 ℃ of reaction of 4-dichlorobenzyl chloride 24h, eluent: methylene dichloride: methyl alcohol (4: 1), productive rate 54%, white solid, 250 ℃ of (dec) (ethanol) of mp.The production spectra diagram data is as follows:
IR(KBr，cm
-1)：3206(NH)，1594(C＝O)；1327，1137(SO
2).
1H-NMR(DMSO-d
6)δ：7.61(d，1H，J＝1.79Hz，Ar-H)；7.35(dd，1H，J＝1.71，8.4Hz，Ar-H)；7.04(s，1H，Py-H)；6.84(d，1H，J＝8.4Hz，Ar-H)；4.90(s，2H，CH
2)；3.86(s，3H，CH
3).
13C-NMR(DMSO-d
6)δ：151(C
3＝O)，135(C-1′)，132.7，132.0，128.8，128.4，128.3(C-7a)，127，125(C-4a)，123(C-5)，44(CH
2)，37(CH
3).MS(EI)m/z361(M+1)。
Embodiment 7.4-(p-chlorobenzyl)-7-methyl isophthalic acid, 1,3-three oxygen-2, the system of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (5g) is equipped with, preparation method such as embodiment 2, different is:
With the 7-methyl isophthalic acid of embodiment 1 preparation, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazine and 4-chlorobenzyl chloride 50-60 ℃ of reaction 24h, eluent: methylene dichloride: methyl alcohol (4: 1), productive rate 51%, white solid, 218 ℃ of (dec) (ethanol) of mp.The production spectra diagram data is as follows:
IR(KBr，cm
-1)：3200(NH)，1592(C＝O)；1327，1135(SO
2).
1H-NMR(DMSO-d
6)δ：7.34(d，2H，J＝8.4Hz，Ar-H)；7.33(d，2H，J＝8.4Hz，Ar-H)；7.14(s，1H，Py-H)；4.86(s，2H，CH
2)；3.82(s，3H，CH
3).
13C-NMR(DMSO-d
6)δ：152(C
3＝O)，137(C-1′)，131(C-4’)，128.9(2C，C-2’，6’)，128.3(C-7a)，128.1(2C，C-3′，5′)，125(C-4a)，123(C-5)，46(CH
2)，37(CH
3).MS(EI)m/z 327(M+1)。
Embodiment 8.2-(4-tertiary butyl benzyl)-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (5i), preparation method such as embodiment 2, different is:
With the 7-methyl isophthalic acid of embodiment 1 preparation, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazine and 4 tert butylbenzyl chloride 50-60 ℃ of reaction 24h, eluent: methylene dichloride: methyl alcohol (4: 1), productive rate 51%, white solid, 205 ℃ of (dec) (ethyl acetate-hexanaphthenes) of mp.The production spectra diagram data is as follows:
IR(KBr，cm
-1)：3225(NH)，1591(C＝O)；1329，1135(SO
2).
1H-NMR(DMSO-d
6)δ：7.29(d，2H，J＝8.23Hz，Ar-H)；7.17(d，2H，J＝8.18Hz，Ar-H)；7.13(s，1H，Py-H)；4.83(s，2H，CH
2)；3.82(s，3H，Py-CH
3)，1.23(s，9H，-C(CH
3)
3).
13C-NMR(DMSO-d
6)δ：152(C
3＝O)，149(C-4′)，135(C-1′)，128(C-7a)，126(2C，C-2′，6′)，125(C-4a)，124(2C，C-3′，5′)，123(C-5)，46(CH
2)，37(Py-CH
3)，34(-C(CH
3)
3)，31(-C(CH
3)
3).MS(EI)m/z 349(M+1)。
Embodiment 9.2-(ethoxy carbonyl methyl)-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,3-e] [1,2,4] thiadiazines (5k), preparation method such as embodiment 2, different is:
With the 7-methyl isophthalic acid of embodiment 1 preparation, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazine and ethyl bromoacetate room temperature reaction 10h, eluent: methylene dichloride: methyl alcohol (4: 1), productive rate 50%, white solid, 300 ℃ of (dec) (ethyl acetate-hexanaphthenes) of mp.The production spectra diagram data is as follows:
IR(KBr，cm
-1)：3441(NH)，3111(Py-CH)，1732(-CH
2C＝O)，1602(C
3＝O)；1360，1144(SO
2).
1H-NMR(DMSO-d
6)δ：7.22(s，1H，Py-H)；4.38(s，2H，-CH
2C＝O)；4.08(q，2H，J＝7Hz，-OCH
2CH
3)，3.84(s，3H，Py-CH
3)，1.18(t，3H，J＝7Hz，-OCH
2CH
3).
13C-NMR(DMSO-d
6)δ：169(-CH
2C＝O)，151(C
3＝O)，128(C-7a)，125(C-4a)，123(C-5)，60(-OCH
2CH
3)，45(-CH
2C＝O)，37(Py-CH
3)，14(-OCH
2CH
3).MS(EI)m/z 289(M+1)。
Claims (8)
1.N
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives is characterized in that general structure is as follows:
R=benzyl, single substituted benzyl, two substituted benzyl or ethoxy carbonyl methyl.
2.N
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation method of 4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives is characterized in that synthetic route is as follows:
In the formula, a:N
2H
4H
2O/EtOH, b:2N HCl, NaNO
2, H
2O, C: Δ/toluene, d:NaH/RX, DMF, intermediate 4 is the 7-methyl isophthalic acid, 1,3-three oxygen-2 ,-pyrazoline [4,5-e] [1,2,4] thiadiazine.
3. N as claimed in claim 2
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation method of 4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives is characterized in that, intermediate 7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation method of 4-pyrazoline [4,5-e] [1,2,4] thiadiazine 4 is as follows:
With 1-methyl-5-sulfoamido-4-pyrazole carboxylic acid ethyl ester 1 is starting raw material; get 1-methyl-5-sulfoamido-4-pyrazoles-formyl hydrazine 2 through hydrazinolysis; in nitrous acid solution, carry out again obtaining acyl azide white solid 3 behind the azido reaction, identify that through infrared spectra 2148cm-1 is N
3Charateristic avsorption band, acyl azide 3 reflux in dry toluene becomes ring to generate female ring 7-methyl isophthalic acid, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazine 4 through the Curtius rearrangement reaction.
4. N as claimed in claim 2
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation method of 4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives is characterized in that the concrete operations step is as follows:
(1) synthetic: with 1 normal intermediate 7-methyl isophthalic acid, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazine 4 is dissolved in the exsiccant dimethyl formamide, at N
2Protection down, slowly add 2 equivalents of sodium hydride contain 60% mineral oil, holding temperature is lower than 10 ℃, finish, stir 15-20min, slowly add 1 normal halocarbon again, reaction mixture continues to stir 10-24h in 25-60 ℃, cooling back pressure reducing and steaming solvent, residue separate with rapid column chromatography purifies;
(2) rapid column chromatography separates purification, and the eluting solvent system is a methylene chloride, and the organic solvent recrystallization obtains crystalline product.
5. N as claimed in claim 4
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation method of 4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives is characterized in that, the halocarbon in the described step (1) is selected from bromobenzyl, to bromine bromobenzyl, adjacent bromine bromobenzyl; To cyano group benzyl chloride, adjacent cyano group benzyl chloride, a cyano group benzyl chloride; 2,4-dichlorobenzyl chloride, 4-chlorobenzyl chloride, 4 tert butylbenzyl chloride, a chlorobenzyl chloride or ethyl bromoacetate.
6. N as claimed in claim 4
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation method of 4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives is characterized in that the organic solvent of the recrystallization in the described step (2) is: the mixed solvent of ethanol and ethyl acetate/hexanaphthene.
7. pharmaceutical composition contains the N of claim 1
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2,4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives, this derivative mixes with auxiliary material, makes the medicine of different dosage form.
8. the described N of claim 1
4-replacement-7-methyl isophthalic acid, 1,3-three oxygen-2, the application of 4-pyrazoline [4,5-e] [1,2,4] diazthines derivative is used to prepare the medicine for the treatment of acquired immune deficiency syndrome (AIDS) as the HIV-1 reverse transcriptase inhibitors.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100393726C (en) * | 2006-04-20 | 2008-06-11 | 山东大学 | Process for preparing 2,4-disubstituted heterocyclo [4,5-e][1,2,4] thiadiazine derivatives |
| CN100519565C (en) * | 2007-06-22 | 2009-07-29 | 山东大学 | N1, N3-disubstituted-7-methylpyrazole [4,5-e] [2,1,3] thiadiazin-2, 2, 4-triketone derivatives, their preparation method and application |
| CN102321102A (en) * | 2011-07-19 | 2012-01-18 | 山东大学 | N2,N4-disubstituted-2H,4H-pyrrole[1,2-b][1,2,4,6] thiatriazine-1,1,3-triketone derivatives as well as preparation and application thereof |
| CN105130856A (en) * | 2015-08-20 | 2015-12-09 | 成都化润药业有限公司 | Preparation method for diphenyl ether serial sulfonyl azide compounds |
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2005
- 2005-08-25 CN CNB2005100442972A patent/CN100484944C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100393726C (en) * | 2006-04-20 | 2008-06-11 | 山东大学 | Process for preparing 2,4-disubstituted heterocyclo [4,5-e][1,2,4] thiadiazine derivatives |
| CN100519565C (en) * | 2007-06-22 | 2009-07-29 | 山东大学 | N1, N3-disubstituted-7-methylpyrazole [4,5-e] [2,1,3] thiadiazin-2, 2, 4-triketone derivatives, their preparation method and application |
| CN102321102A (en) * | 2011-07-19 | 2012-01-18 | 山东大学 | N2,N4-disubstituted-2H,4H-pyrrole[1,2-b][1,2,4,6] thiatriazine-1,1,3-triketone derivatives as well as preparation and application thereof |
| CN102321102B (en) * | 2011-07-19 | 2013-11-27 | 山东大学 | N2, N4-disubstituted-2H, 4H-pyrrole [1,2-b] [1,2,4,6] thiatriazine-1, 1, 3-trione derivatives and their preparation and application |
| CN105130856A (en) * | 2015-08-20 | 2015-12-09 | 成都化润药业有限公司 | Preparation method for diphenyl ether serial sulfonyl azide compounds |
| CN105130856B (en) * | 2015-08-20 | 2019-03-19 | 成都化润药业有限公司 | The preparation method of diphenyl ether sulfonyl azide compound |
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