CN1837216A - Process for preparing 2,4-disubstituted heterocyclo [4,5-e][1,2,4] thiadiazine derivatives - Google Patents

Process for preparing 2,4-disubstituted heterocyclo [4,5-e][1,2,4] thiadiazine derivatives Download PDF

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CN1837216A
CN1837216A CN 200610043834 CN200610043834A CN1837216A CN 1837216 A CN1837216 A CN 1837216A CN 200610043834 CN200610043834 CN 200610043834 CN 200610043834 A CN200610043834 A CN 200610043834A CN 1837216 A CN1837216 A CN 1837216A
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CN100393726C (en
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刘新泳
徐文方
闫任章
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SHANDONG DAYIN MARINE BIOTECHNOLOGICAL PHARM HOLDINGS CO Ltd
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Shandong University
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Abstract

The invention discloses a 2, 4-disubstituted heterocycle parallel [4,5-e][1,2,4] thiadiazines derivant preparing method in the chemical technique domain, which comprises the following steps: dissolving heterocycle parallel [1,2,4] thiadiazines parent in dimethyl formamide; adding in sodium hydride; stiring under 10 deg.c to white sediment; filling in halocarbon R2X; stirring and reacting; adding halocarbon R1X in liquor; reacting at 25-60deg.c for 10-24 hours; reducing pressure and steaming dissolvant; rinshing leavings; recrystallizating by organic solvent. R1, R2 represents bromine benzyl, double-bromine-bromine-benzyl, meta- bromine-bromine-benzyl and so on. The invention simplifies the operation, which has high yield.

Description

2,4-two substituted heterocycles are [4,5-e] [1,2,4] thiadiazine derivatives preparation method also
(1) technical field
The present invention relates to 2,4-two substituted heterocycles are [4,5-e] [1,2,4] thiadiazine derivatives preparation method also, is specifically related to 1,1, and 3-three oxygen-2,4-dihydro heterocycle are [4,5-e] [1,2,4] thiadiazine N also 2, N 4" one kettle way " preparation method of-disubstituted derivatives belongs to technical field of chemistry.
(2) background technology
N 2, N 4-dibasic thieno-diazthines derivative (TTDs) is a category of HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTIs).The synthetic of TTDs is to encircle 1,1 with mother, and 3-three oxygen-2,4-dihydro-thiophene also [4,5-e] [1,2,4] thiadiazine are raw material, the N that at first encircles mother in the presence of sodium hydride 2The position is introduced substituting group and is obtained N 2-mono-substituted thieno-[4,5-e] [1,2,4] thiadiazine derivatives intermediate; Monosubstituted derivative continues at N through behind the column chromatographic isolation and purification again 4Second substituting group introduced in the position, obtains N thus 2, N 4-dibasic thieno-[4,5-e] [1,2,4] thiadiazine derivatives.Referring to Easter. A Ruizi, Hu An. A Daizi etc. can suppress the new non-nucleoside reverse transcriptase inhibitor 1 that HIV-1 duplicates, 1,3-three oxygen-2,4-dihydro-thiophene also [3,4-e] [1,2,4] thiadiazine derivatives. pharmaceutical chemistry magazine .1998,41,4109-4117. (Esther Arranz, JuanA.D 1' az, et al.Novel 1,1,3-Trioxo-2H, 4H-thieno[3,4-e] [1,2,4] thiadiazine Derivatives asNon-Nucleoside Reverse Transcriptase Inhibitors That Inhibit Human Immunodeficiency VirusType 1 Replication.J.Med.Chem.1998,41,4109-4117)
Reaction scheme is as follows:
a：NaH/R 1X，DMF b：NaH/R 2X，DMF
This method is at the N of the first step 2Position R 1In the hydrocarbyl reaction, because some R 1Hydrocarbyl substituent is bigger, is subjected to sterically hindered the influence, and its by product is more (mainly to comprise N 4The hydrocarbonylation product of position and the hydrocarbonylation product of 3 ketonic oxygens), thereby yield is low; In addition, because reaction product needs column chromatography for separation, so complex operation step.
N 2The preparation of position mono-substituted thieno-[4,5-e] [1,2,4] thiadiazine derivatives can be adopted directional synthesis method, promptly makes through hydrazinolysis, diazotization, Curtius rearrangement reaction cyclization generation respectively by 3-(sulphonamide that N-replaces) 4-thiophene ethyl formate.The latter is again at N 4The position is introduced second substituting group and is obtained N 2, N 4-dibasic thieno-[4,5-e] [1,2,4] thiadiazine derivatives.Reaction scheme is as follows:
Figure A20061004383400032
a：N 2H 4·H 2O/EtOH b：2N HCl，NaNO 2，H 2O c：△/toluene d：NaH/R 2X，DMF
Though this synthetic method can obtain the N that target is single, purity is higher 2Position mono-substituted thieno-[4,5-e] [1,2,4] thiadiazine derivatives intermediate, but because reactions steps is longer, be subjected to the restriction of reaction raw materials (replacement) benzylamine kind makes N 2The single substituent convertible number in position is restricted, thereby can not satisfy the multifarious requirement of structure activity study desired structure.
In order further to optimize the structure of TTDs bisubstituted compound, verify five annulus part and N in female ring 2, N 4-disubstituted part is to active influence, illustrate the structure activity relationship of this compounds, finishing screen is selected has more highly active lead compound, need synthesize a series of is the heterocycle also [4 of lead compound with TTDs, 5-e] [1,2,4] derivative of thiadiazine (for example pyrazolo thiadiazine derivatives).Synthetic similar substantially to the female ring of synthetic and thieno-[4,5-e] [1,2,4] thiadiazine of these new female cyclic cpdss, key need find N simple to operate, that productive rate is high, selectivity is good 2, N 4The new synthetic method of-two alkylation reactions is to obtain the derivative of structure diversity.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of simple to operate, productive rate is high, selectivity the is good synthetic disubstituted heterocycle and the novel method of thiadiazine derivatives are provided.
The N that the present invention relates to 2, N 4-two replace-1,1, and 3-three oxygen-2,4-dihydro heterocycle are [4,5-e] [1,2,4] thiadiazine derivatives also, has following general formula:
Figure A20061004383400041
W＝S，C，N，NCH 3，O；Y＝S，C，N，NCH 3，O；Z＝S，C，N，NCH 3，O
R 1=benzyl, single substituted benzyl, two substituted benzyl; R 2=hydrogen, benzyl, single substituted benzyl, two substituted benzyl or cyanogen methyl
Above-mentioned single substituted benzyl is selected to bromobenzyl, a bromobenzyl, adjacent bromobenzyl, to cyano group benzyl, o-cyanobenzyl, a cyano group benzyl, p-chlorobenzyl, m-chloro benzyl, o-chlorobenzyl, to methyl-benzyl, adjacent methyl-benzyl, to Ethylbenzyl, to tertiary butyl benzyl, to luorobenzyl or adjacent luorobenzyl.
Above-mentioned two substituted benzyls are selected from 2,4-dichloro benzyl, 2,6-dichloro benzyl or 3,4-dichloro benzyl.
Preferably, the present invention relates to derivative is the N with following general formula 2, N 4-two replacement-7-methyl isophthalic acids, 1,3-three oxygen-2,4-dihydro-pyrazolo [4,5-e] [1,2,4] thiadiazine derivatives:
Figure A20061004383400042
Preferably, the present invention relates to derivative is the N with following general formula 2, N 4-two replace-1,1, and 3-three oxygen-2,4-dihydro-thiophene are [4,5-e] [1,2,4] thiadiazine derivatives also:
Figure A20061004383400043
N of the present invention 2, N 4-two replace-1,1, and 3-three oxygen-2,4-dihydro heterocycle are the preparation method of [4,5-e] [1,2,4] thiadiazine derivatives also, and the synthetic route general formula is as follows:
Figure A20061004383400051
a：2NaH/R 2X，DMF b：R 1X，DMF(X＝Cl，Br，I)
W＝S，C，N，NCH 3，O；Y＝S，C，N，NCH 3，O；Z＝S，C，N，NCH 3，O
N of the present invention 2, N 4-two replace-1,1, and 3-three oxygen-2,4-dihydro heterocycle are the preparation method of [4,5-e] [1,2,4] thiadiazine derivatives also, it is characterized in that adopting the synthetic method of ' one kettle way ', and the concrete operations step is as follows:
(1) synthetic:
With the 7-methyl isophthalic acid, 1,3-three oxygen-2,4-dihydro heterocycle are 1 one equivalents of [4,5-e] [1,2,4] thiadiazine also, are dissolved in the exsiccant dimethyl formamide (DMF), at N 2Protection down adds 2 normal sodium hydrides that contain 60% mineral oil, and holding temperature is lower than 10 ℃, finishes, and stirs the sufficiently long time until white precipitate occurring, slowly adds a normal halocarbon (R again 2X).Reaction mixture continues to stir 10-24h in 25-60 ℃.Any processing of reaction Bi Bujing directly adds a normal halocarbon (R again in reaction soln 1X), be reflected at 40-80 ℃ of reaction 10-24h, TLC detects, and reaction is finished, cooling, pressure reducing and steaming solvent.Recrystallization with an organic solvent after the residue washing.
(2) residue uses ethyl alcohol recrystallization.
Above-mentioned halocarbon R 1X, R 2It is one of following that X is selected from respectively: bromobenzyl, to bromine bromobenzyl, a bromine bromobenzyl, adjacent bromine bromobenzyl, to cyano group benzyl chloride, adjacent cyano group benzyl chloride, a cyano group benzyl chloride, 2,4-dichlorobenzyl chloride, 2,6-dichlorobenzyl chloride, 3,4-dichlorobenzyl chloride, 4-chlorobenzyl chloride, a chlorobenzyl chloride, adjacent chlorobenzyl chloride, to methyl benzyl chloride, adjacent methyl benzyl chloride, to ethyl benzyl chloride, 4 tert butylbenzyl chloride, chloromethyl cyanide, to fluorobenzyl chloride, adjacent fluorobenzyl chloride.
Above-mentioned halocarbon R 1X and R 2X can be identical, also can be different.
Below in conjunction with preferred N 2, N 4-two replace-1,1,3-three oxygen-2,4-dihydro-pyrazolo [4,5-e] [1,2,4] thiadiazine derivatives and N 2, N 4-two replacement-7-methyl isophthalic acids, 1,3-three oxygen-2,4-dihydro-thiophene are [4,5-e] [1,2,4] thiadiazine derivatives also, and preparation method of the present invention is elaborated.
1.N 2, N 4-two replace-1,1,3-three oxygen-2,4-dihydro-pyrazolo [4,5-e] [1,2,4] thiadiazine derivatives and N 2, N 4-two replacement-7-methyl isophthalic acids, 1,3-three oxygen-2,4-dihydro-thiophene are the reaction expression of [4,5-e] [1,2,4] thiadiazine derivatives also.
With the 7-methyl isophthalic acid, 1,3-three oxygen-2,4-dihydro-pyrazolo [4,5-e] [1,2,4] thiadiazines (1) are the synthetic N of raw material 2, N 4-two replace-1,1,3-three oxygen-2, and 4-dihydro-pyrazolo [4,5-e] [1,2,4] thiadiazine, synthetic route is as follows:
Figure A20061004383400052
a：2NaH/R 2X，DMF b：R 1X，DMF
With the 7-methyl isophthalic acid, 1,3-three oxygen-2,4-dihydro-thiophene also [4,5-e] [1,2,4] thiadiazines (1) are the synthetic N of raw material 2, N 4-two replace-1,1, and 3-three oxygen-2,4-dihydro-thiophene are [4,5-e] [1,2,4] thiadiazine also, and synthetic route is as follows:
Figure A20061004383400061
a：2NaH/R 2X，DMF b：R 1X，DMF
2.N 2, N 4-two replacement-7-methyl isophthalic acids, 1,3-three oxygen-2, the preparation method of 4-dihydro-pyrazolo [4,5-e] [1,2,4] thiadiazine derivatives:
(1) synthetic:
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 1 equivalent of 4-pyrazoline [4,5-e] [1,2,4] thiadiazine is dissolved in the exsiccant dimethyl formamide (DMF), at N 2Protection down adds 2 normal sodium hydrides that contain 60% mineral oil, and holding temperature is lower than 10 ℃, finishes, and stirs the sufficiently long time until white precipitate occurring, slowly adds 1 normal halocarbon (R again 2X).Reaction mixture continues to stir 10-24h in 25-60 ℃.Any processing of reaction Bi Bujing directly adds 1 normal halocarbon (R again in reaction soln 1X), be reflected at 40-80 ℃ of reaction 10-24h, TLC detects, and reaction is finished, cooling, pressure reducing and steaming solvent.Recrystallization with an organic solvent after the residue washing.
(2) residue uses ethyl alcohol recrystallization.
Above-mentioned halocarbon R 1X, R 2It is one of following that X is selected from respectively: bromobenzyl, to bromine bromobenzyl, a bromine bromobenzyl, adjacent bromine bromobenzyl, to cyano group benzyl chloride, adjacent cyano group benzyl chloride, a cyano group benzyl chloride, 2,4-dichlorobenzyl chloride, 2,6-dichlorobenzyl chloride, 3,4-dichlorobenzyl chloride, 4-chlorobenzyl chloride, a chlorobenzyl chloride, adjacent chlorobenzyl chloride, to methyl benzyl chloride, adjacent methyl benzyl chloride, to ethyl benzyl chloride, 4 tert butylbenzyl chloride, chloromethyl cyanide, to fluorobenzyl chloride, adjacent fluorobenzyl chloride.
Above-mentioned halocarbon R 1X and R 2X can be identical, also can be different.
The structure of table 1 the inventive method synthetic target compound (numbering 3.01-3.21)
Figure A20061004383400062
Compound number R 1 R 2
3.01 To nitrobenzyl Benzyl
3.02 Adjacent bromobenzyl Benzyl
3.03 To bromobenzyl Adjacent bromobenzyl
3.04 P-chlorobenzyl Adjacent bromobenzyl
3.05 Adjacent bromobenzyl Adjacent bromobenzyl
3.06 To bromobenzyl To bromobenzyl
3.07 To tertiary butyl benzyl To tertiary butyl benzyl
3.08 Adjacent bromobenzyl The m-chloro benzyl
3.09 P-chlorobenzyl P-chlorobenzyl
3.10 2, the 4-dichloro benzyl 2, the 4-dichloro benzyl
3.11 P-chlorobenzyl 2, the 4-dichloro benzyl
3.12 2, the 4-dichloro benzyl O-chlorobenzyl
3.13 To nitrobenzyl O-chlorobenzyl
3.14 To bromobenzyl O-chlorobenzyl
3.15 O-chlorobenzyl O-chlorobenzyl
3.16 P-chlorobenzyl O-chlorobenzyl
3.17 O-cyanobenzyl O-chlorobenzyl
3.18 Between the cyano group benzyl O-chlorobenzyl
3.19 To the cyano group benzyl O-chlorobenzyl
3.20 To Ethylbenzyl O-chlorobenzyl
3.21 To tertiary butyl benzyl O-chlorobenzyl
3.N 2, N 4-two replace-1,1, and 3-three oxygen-2,4-dihydro-thiophene are the preparation method of [4,5-e] [1,2,4] thiadiazine derivatives also:
(1) synthetic:
With the 7-methyl isophthalic acid, 1,3-three oxygen-2,4-dihydro-thiophene also (1) 1 equivalent of [4,5-e] [1,2,4] thiadiazine are dissolved in the exsiccant dimethyl formamide (DMF), at N 2Protection down adds 2 normal sodium hydrides that contain 60% mineral oil, and holding temperature is lower than 10 ℃, finishes, and stirs the sufficiently long time until white precipitate occurring, slowly adds 1 normal halocarbon (R again 2X).Reaction mixture continues to stir 10-24h in 25-60 ℃.Any processing of reaction Bi Bujing directly adds 1 normal halocarbon (R again in reaction soln 1X), be reflected at 40-80 ℃ of reaction 10-24h, TLC detects, and reaction is finished, cooling, pressure reducing and steaming solvent.Recrystallization with an organic solvent after the residue washing.
(2) residue uses ethyl alcohol recrystallization.
Above-mentioned halocarbon R 1X, R 2It is one of following that X is selected from respectively: bromobenzyl, to bromine bromobenzyl, a 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, a chlorobenzyl chloride, adjacent chlorobenzyl chloride, to methyl benzyl chloride, adjacent methyl benzyl chloride, to ethyl benzyl chloride, 4 tert butylbenzyl chloride, chloromethyl cyanide, to fluorobenzyl chloride, adjacent fluorobenzyl chloride.
Above-mentioned halocarbon R 1X and R 2X can be identical, also can be different.
The structure of table 2 the inventive method synthetic target compound (numbering 4.01-4.06)
Figure A20061004383400071
Compound number R 1 R 2
4.01 Benzyl Benzyl
4.02 The m-chloro benzyl Adjacent luorobenzyl
4.03 The m-chloro benzyl Adjacent bromobenzyl
4.04 The m-chloro benzyl 2, the 4-dichloro benzyl
4.05 The m-chloro benzyl 2, the 6-dichloro benzyl
4.06 Between bromobenzyl Adjacent luorobenzyl
The present invention adopts one-pot synthesis, and is simple to operate, productive rate is high, selectivity good, is the novel method of synthetic disubstituted heterocycle and thiadiazine derivatives.
(4) embodiment
The present invention will be further described below in conjunction with embodiment, and the numbering of all compounds is identical with table 1.
Embodiment 1.2-is to nitrobenzyl-4-benzyl-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.01)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2,1 equivalent of 4-dihydro-pyrazolo [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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal bromobenzyl.Reaction mixture continues to stir 12h in 35 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal to the nitro bromobenzyl, elevated temperature to 50 ℃ continues reaction 12h, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 85%, white solid, mp202-204 ℃.
The production spectra diagram data is as follows: IR (KBr, cm -1): 1692 (C=O); 1327,1190 (SO 2); 1514,1214 (NO 2). 1HNMR (DMSO-d 6, 600MHz) δ: 7.84 (s, 1H, PyH), 8.21 (d, 2H, J=8.72Hz, PhH), 7.63 (d, 2H, J=8.70Hz, PhH), 7.26-7.34 (m, 5H, PhH), 5.19 (s, 2H, NCH 2), 5.10 (s, 2H, NCH 2), 4.06 (s, 3H, CH 3). 13CNMR (CDCl 3, 600MHz) 149.0 (C=O), 135.8 (C-1 '), 144.0 (C-1 "), 128.8,128.7,127.1,123.7,147.1,127.8,126.3 (C-4a), 125.6 (C-5), 122.0 (C-7a), 48.8 (N 4-CH 2), 43.4 (N 2-CH 2), 39.0 (CH 3) MS:m/z 428.4 (M+1)
The adjacent bromobenzyl of embodiment 2.2--4-benzyl-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.02)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 1 equivalent of 4-dihydro-pyrazolo [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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal bromobenzyl.Reaction mixture continues to stir 12h in 35 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal adjacent bromine bromobenzyl, elevated temperature to 50 ℃ continues reaction 12h, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 80%, white solid, mp122-124 ℃.
The production spectra diagram data is as follows:
IR(KBr，cm -1)：1701(C＝O)；1337，1192(SO 2). 1HNMR(DMSO-d 6，600MHz)δ：7.88(s，1H，PyH)，7.66(dd，1H，J＝7.93Hz，J＝1.08Hz，PhH)，7.19(dd，1H，J＝7.72Hz，J＝1.10Hz，PhH)，7.25-7.37(m，7H，PhH)，5.12(s，2H，NCH 2)，5.08(s，2H，NCH 2)，4.06(s，3H，CH 3). 13C NMR(DMSO-d 6，600MHz)148.9(C＝O)，134.7(C-1’)，135.9(C-1”)，132.7，129.6，128.9，128.2，127.9，127.6，127.2，126.4，125.7(C-4a)，122.0(C-5)，121.7(C-7a)，48.5(N 4-CH 2)，44.4(N 2-CH 2)，38.9(CH 3).MS：m/z463.3(M+2)，461.4(M+)
Embodiment 3.2-is to the adjacent bromobenzyl of bromobenzyl-4--7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.03)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 1 equivalent of 4-dihydro-pyrazolo [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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal adjacent bromine bromobenzyl.Reaction mixture continues to stir 12h in 40 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal to the bromine bromobenzyl, elevated temperature to 50 ℃ continues reaction 12h, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 85%, white solid, mp146-148 ℃.
The production spectra diagram data is as follows: IR (KBr, cm -1): 1696 (C=O); 1330,1192 (SO 2). 1H NMR (DMSO-d 6, 600MHz) δ: 7.74 (s, 1H, PyH), 7.67 (d, 1H, J=7.81Hz, PhH), 7.53 (d, 2H, J=8.42Hz, PhH), 6.93 (d, 1H, J=7.58Hz, PhH), 7.24-7.32 (m, 4H, PhH), 5.10 (s, 2H, NCH 2), 5.01 (s, 2H, NCH 2), 4.08 (s, 3H, CH 3) .MS:m/z 541.2 (M+1).
The adjacent bromobenzyl of embodiment 4.2-p-chlorobenzyl-4--7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.04)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 1 equivalent of 4-dihydro-pyrazolo [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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal adjacent bromine bromobenzyl.Reaction mixture continues to stir 12h in 40 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal 4-chlorobenzyl chloride, elevated temperature to 50 ℃ continues reaction 12h, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 80%, white solid, mp128-130 ℃.
The production spectra diagram data is as follows: IR (KBr, cm -1): 1695 (C=O); 1331,1192 (SO 2). 1H NMR (CDCl 3, 600MHz) δ: 7.12 (s, 1H, PyH), 7.60 (dd, 1H, J=7.83Hz, J=1.15Hz, PhH), 6.88-7.47 (m, 7H, PhH), 5.15 (s, 2H, NCH 2), 5.08 (s, 2H, NCH 2), 4.14 (s, 3H, CH 3) .MS:m/z 497.3 (M+2), 495.2 (M+)
Embodiment 5.2,4-two adjacent bromobenzyl-7-methyl isophthalic acids, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.05)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 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 add 2 normal sodium hydrides that contain 60% mineral oil; holding temperature is lower than 10 ℃, finishes, and stirs the sufficiently long time until white precipitate occurring; slowly add 2 normal adjacent bromine bromobenzyls; reaction mixture is in 50 ℃ of stirring 20h, and TLC detects, and reaction is finished; cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 80%, white solid, mp120-122 ℃.
The production spectra diagram data is as follows:
IR(KBr，cm -1)：1697(C＝O)；1322，1193(SO 2). 1H NMR(DMSO-d 6，600MHz)δ：7.79(s，1H，PyH)，7.67(dd，1H，J＝7.95Hz，J＝1.10Hz，PhH)，7.40(d，1H，J＝7.52Hz，PhH)，7.03(dd，1H，J＝7.70Hz，J＝1.23Hz，PhH)，7.23-7.38(m，5H，PhH)，5.12(s，2H，NCH 2)，5.06(s，2H，NCH 2)，4.09(s，3H，CH 3). 13CNMR(DMSO-d 6，600MHz)148.7(C＝O)，134.4(C-1’)，134.6(C-1”)，133.2，132.7，129.7，129.6，128.3，128.1，127.7，127.2，126.4，125.9，122.1(C-4a)，122.0(C-5)，121.6(C-7a)，49.7(N 4-CH 2)，44.2(N 2-CH 2)，39.2(CH 3)MS：m/z 541.3(M+1)
Embodiment 6.2, two pairs of bromobenzyls of 4--7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.06)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 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 add 2 normal sodium hydrides that contain 60% mineral oil; holding temperature is lower than 10 ℃, finishes, and stirs the sufficiently long time until white precipitate occurring; slowly add 2 normal to the bromine bromobenzyl; reaction mixture is in 50 ℃ of stirring 20h, and TLC detects, and reaction is finished; cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 83%, white solid, mp182-184 ℃.
The production spectra diagram data is as follows: IR (KBr, cm -1): 1693 (C=O); 1329,1189 (SO 2). 1H NMR (DMSO-d 6, 600MHz) δ: 7.83 (s, 1H, PyH), 7.31 (d, 2H, J=8.41Hz, PhH), 7.21 (d, 2H, J=8.38Hz, PhH), 7.53-7.55 (m, 4H, PhH), 5.07 (s, 2H, NCH 2), 5.01 (s, 2H, NCH 2), 4.05 (s, 3H, CH 3). 13C NMR (DMSO-d 6, 600MHz) 150.0 (C=O), 135.4 (C-1 '), 135.6 (C-1 "), 131.7 131.4 130.0,129.4,126.2,125.5,122.1 (C-4a), 121.0 (C-5), 120.9 (C-7a), 48.2 (N 4-CH 2), 43.5 (N 2-CH 2), 39.0 (CH 3) .MS:m/z541.2 (M+1)
Embodiment 7.2, two pairs of tertiary butyl benzyl-7-methyl isophthalic acids of 4-, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.07)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 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 add 2 normal sodium hydrides that contain 60% mineral oil; holding temperature is lower than 10 ℃, finishes, and stirs the sufficiently long time until white precipitate occurring; slowly add 2 normal 4 tert butylbenzyl chlorides; reaction mixture is in 70-80 ℃ of stirring 24h, and TLC detects, and reaction is finished; cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 65%, white solid, mp130-132 ℃.
The production spectra diagram data is as follows:
IR(KBr，cm -1)：1695(C＝O)；1334，1186(SO 2). 1H NMR(CDCl 3，600MHz)δ：7.19(s，1H，PyH)，7.44(d，2H，J＝8.33Hz，PhH)，7.37(d，2H，J＝8.39Hz，PhH)，7.32(d，2H，J＝8.33Hz，PhH)，7.14(d，2H，J＝8.30Hz，PhH)，5.09(s，2H，NCH 2)，5.03(s，2H，NCH 2)，4.12(s，3H，CH 3)，1.32(s，9H，CH 3)，1.30(s，9H，CH 3). 13C NMR(CDCl 3，600MHz)150.7(C＝O)，131.5(C-1’)，132.3(C-1”)，150.6，149.2，128.3，126.5，125.6，125.5，125.2，125.0(C-4a)，122.5(C-5)，122.0(C-7a)，48.8(N 4-CH 2)，44.0(N 2-CH 2)，38.8(CH 3)，34.3，34.2(2C)，31.0，30.9(6C，CH 3).MS：m/z 495.5(M+1).
The adjacent bromobenzyl of embodiment 8.2--4-m-chloro benzyl-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.08)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 1 equivalent of 4-dihydro-pyrazolo [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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal chlorobenzyl chloride.Reaction mixture continues to stir 20h in 50 ℃.Thin layer (TLC) detects, and after question response is complete, adds 1 normal adjacent bromine bromobenzyl in reaction solution, and 50 ℃ are continued reaction 12h, and TLC detects, and reacts and finishes, and cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 75%, white solid, mp108-110 ℃.
The production spectra diagram data is as follows:
IR(KBr，cm -1)：1680(C＝O)；1327，1192(SO 2). 1H NMR(DMSO-d 6，600MHz)δ：7.91(s，1H，PyH)，7.66(dd，1H，J＝7.40Hz，J＝0.92Hz，PhH)，7.20(d，1H，J＝7.70Hz，PhH)，7.23-7.38(m，6H，PhH)，5.16(s，2H，NCH 2)，5.07(s，2H，NCH 2)，4.07(s，3H，CH 3).MS：m/z 497.2(M+2)，495.2(M+).
Embodiment 9.2,4-two p-chlorobenzyls-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.09)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 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 add 2 normal sodium hydrides that contain 60% mineral oil; holding temperature is lower than 10 ℃, finishes, and stirs the sufficiently long time until white precipitate occurring; slowly add 2 normal 4-chlorobenzyl chlorides; reaction mixture is in 60-70 ℃ of stirring 24h, and TLC detects, and reaction is finished; cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 75%, white solid, mp146-148 ℃.
The production spectra diagram data is as follows:
IR(KBr，cm -1)：1696(C＝O)；1332，1190(SO 2).1H NMR(DMSO-d 6，600MHz)δ：7.84(s，1H，PyH)，7.28(d，2H，J＝8.50Hz，PhH)，7.37-7.42(m，6H，PhH)，5.09(s，2H，NCH 2)，5.03(s，2H，NCH 2)，4.05(s，3H，CH 3). 13C NMR(DMSO-d 6，600MHz)149.0(C＝O)，135.0(C-1’)，135.3(C-1”)，132.5，132.6，129.8，129.2，128.9，128.6，126.3(C-4a)，125.5(C-5)，122.2(C-7a)，48.2(N 4-CH 2)，43.4(N 2-CH 2)，39.1(CH 3).MS：m/z 451.4(M+).
Embodiment 10.2,4-two (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 (3.10)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 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 add 2 normal sodium hydrides that contain 60% mineral oil, holding temperature is lower than 10 ℃, finishes; stir the sufficiently long time until white precipitate occurring; slowly add 2 normal 2, the 4-dichlorobenzyl chloride, reaction mixture stirs 24h in 60-70 ℃; TLC detects; reaction is finished, and cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 76%, white solid, mp176-178 ℃.
The production spectra diagram data is as follows:
IR(KBr，cm -1)：1698(C＝O)；1326，1186(SO 2). 1H NMR(DMSO-d 6，600MHz)δ：7.82(s，1H，PyH)，7.69(d，1H，J＝2.12Hz，PhH)，7.66(d，1H，J＝2.14Hz，PhH)，7.31(d，1H，J＝8.47Hz，PhH)，7.12(d，1H，J＝8.41Hz，PhH)，7.38-7.43(m，2H，PhH)，5.13(s，2H，NCH 2)，5.08(s，2H，NCH 2)，4.08(s，3H，CH 3). 13C NMR(DMSO-d 6，600MHz)148.6(C＝O)，133.0(C-1’)，133.2(C-1”)，133.1，132.7，132.6，132.2，129.5，129.4，129.1，128.9，127.8，127.7，126.4(C-4a)，125.8(C-5)，122.0(C-7a)，47.1(N 4-CH 2)，41.4(N 2-CH 2)，39.1(CH 3).MS：m/z 519.2(M+).
Embodiment 11.2-p-chlorobenzyl-4-(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 (3.11)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 1 equivalent of 4-dihydro-pyrazolo [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 the sufficiently long time until white precipitate occurring, slowly add 1 normal 2, the 4-dichlorobenzyl chloride.Reaction mixture continues to stir 20h in 50 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal 4-chlorobenzyl chloride, elevated temperature to 60 ℃ continues reaction 20h, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 74%, white solid, mp150-152 ℃.
The production spectra diagram data is as follows:
IR(KBr，cm -1)：1694(C＝O)；1333，1192(SO 2). 1H NMR(DMSO-d 6，600MHz)δ：7.78(s，1H，PyH)，7.68(d，1H，J＝2.15Hz，PhH)，7.05(d，1H，J＝8.39Hz，PhH)，7.36-7.41(m，5H，PhH)，5.12(s，2H，NCH 2)，5.01(s，2H，NCH 2)，4.08(s，3H，CH 3). 13C NMR(DMSO-d 6，600MHz)148.8(C＝O)，133.2(C-1’)，135.2(C-1”)，133.1，132.4，132.3，129.8，129.4，129.2，129.0，128.9，128.5，127.8，126.3(C-4a)，125.7(C-5)，122.2(C-7a)，47.0(N 4-CH 2)，43.5(N 2-CH 2)，39.1(CH 3)MS：m/z 487.3(M+2)，485.3(M+).
Embodiment 12.2-(2, the 4-dichloro benzyl)-4-o-chlorobenzyl-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.12)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 1 equivalent of 4-dihydro-pyrazolo [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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal adjacent chlorobenzyl chloride.Reaction mixture continues to stir 20h in 50-60 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal 2,4-dichlorobenzyl chloride, elevated temperature continue reaction 12h to 60-70 ℃, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 72%, white solid, mp138-140 ℃.
The production spectra diagram data is as follows:
IR(KBr，cm -1)：1698(C＝O)；1330，1196(SO 2). 1H NMR(CDCl 3，600MHz)δ：7.25(s，1H，PyH)，7.02(d，1H，J＝7.26Hz，PhH)，7.20-7.43(m，6H，PhH)，5.24(s，2H，NCH 2)，5.22(s，2H，NCH 2)，4.15(s，3H，CH 3). 13C NMR(CDCl 3，600MHz)149.1(C＝O)，133.3(C-1’)，133.7(C-1”)，132.5，131.7，131.6，129.7，129.2，129.1，128.6，128.5，127.2，126.0，125.2(C-4a)，125.1(C-5)，122.6(C-7a)，46.7(N 4-CH 2)，41.4(N 2-CH 2)，38.9(CH 3).MS：m/z 487.3(M+2).
Embodiment 13.2-is to nitrobenzyl-4-o-chlorobenzyl-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.13)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 1 equivalent of 4-dihydro-pyrazolo [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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal adjacent chlorobenzyl chloride.Reaction mixture continues to stir 20h in 50-60 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal to the nitro bromobenzyl, 50 ℃ are continued reaction 12h, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 80%, white solid, mp210-212 ℃.
The production spectra diagram data is as follows:
IR(KBr，cm -1)：1689(C＝O)；1331，1193(SO 2)；1520，1278(NO 2). 1H NMR(DMSO-d 6，600MHz)δ：7.78(s，1H，PyH)，7.49(dd，1H，J＝7.34Hz，J＝1.28Hz，PhH)，7.05(dd，1H，J＝7.68Hz，J＝2.10Hz，PhH)，7.29-8.21(m，6H，PhH)，5.18(s，2H，NCH 2)，5.15(s，2H，NCH 2)，4.09(s，3H，CH 3).MS：m/z462.4(M+1)
Embodiment 14.2-is to bromobenzyl-4-o-chlorobenzyl-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.14)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 1 equivalent of 4-dihydro-pyrazolo [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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal adjacent chlorobenzyl chloride.Reaction mixture continues to stir 20h in 50-60 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal to the bromine bromobenzyl, 50 ℃ are continued reaction 12h, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 78%, white solid, mp148-150 ℃.
The production spectra diagram data is as follows: IR (KBr, cm -1): 1696 (C=O); 1330,1192 (SO 2). 1H NMR (DMSO-d 6, 600MHz) δ: 7.75 (s, 1H, PyH), 7.53 (d, 2H, J=8.39Hz, PhH), 7.50 (d, 1H, J=7.76Hz, PhH), 7.00 (d, 1H, J=7.34Hz, PhH), 7.28-7.32 (m, 4H, PhH), 5.15 (s, 2H, NCH 2), 5.00 (s, 2H, NCH 2), 4.08 (s, 3H, CH 3) .MS:m/z 497.2 (M+2), 495.2 (M+)
Embodiment 15.2,4-two o-chlorobenzyls-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.15)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 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 add 2 normal sodium hydrides that contain 60% mineral oil; holding temperature is lower than 10 ℃, finishes, and stirs the sufficiently long time until white precipitate occurring; slowly add 2 normal adjacent chlorobenzyl chlorides; reaction mixture is in 60-70 ℃ of stirring 24h, and TLC detects, and reaction is finished; cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 75%, white solid, mp116-118 ℃.
The production spectra diagram data is as follows:
IR(KBr，cm -1)：1699(C＝O)；1331，1195(SO 2). 1H NMR(DMSO-d 6，600MHz)δ：7.80(s，1H，PyH)，7.09(dd，1H，J＝7.58Hz，J＝1.52Hz，PhH)，7.26-7.51(m，7H，PhH)，5.17(s，2H，NCH 2)，5.11(s，2H，NCH 2)，4.08(s，3H，CH 3). 13C NMR(DMSO-d 6，600MHz)148.7(C＝O)，132.9(C-1’)，133.2(C-1”)，132.1，131.6，129.9，129.5，129.4，129.3，127.8，127.7，127.6，127.5，126.4(C-4a)，125.9(C-5)，122.2(C-7a)，47.3(N 4-CH 2)，41.7(N 2-CH 2)，39.1(CH 3)MS：m/z 453.4(M+2)，451.4(M+)
Embodiment 16.2-p-chlorobenzyl-4-o-chlorobenzyl-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.16)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 1 equivalent of 4-dihydro-pyrazolo [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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal adjacent chlorobenzyl chloride.Reaction mixture continues to stir 20h in 50-60 ℃.Thin layer (TLC) detects, and after question response is complete, adds 1 normal 4-chlorobenzyl chloride in reaction solution, and elevated temperature continues reaction 20h to 60-70 ℃, and TLC detects, and reacts and finishes, and cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 70%, white solid, mp128-130 ℃.
The production spectra diagram data is as follows:
IR(KBr，cm -1)：1693(C＝O)；1331，1193(SO 2). 1HNMR(DMSO-d 6，600MHz)δ：7.75(s，1H，PyH)，7.50(dd，1H，J＝7.86Hz，J＝1.23Hz，PhH)，7.01(dd，1H，J＝7.63Hz，J＝1.25Hz，PhH)，7.26-7.41(m，6H，PhH)，5.15(s，2H，NCH 2)，5.02(s，2H，NCH 2)，4.08(s，3H，CH 3). 13C NMR(DMSO-d 6，600MHz)148.8(C＝O)，133.0(C-1’)，135.2(C-1”)，132.1，132.4，129.9，129.8，129.5，128.5，127.7，127.4，126.3(C-4a)，125.8(C-5)，122.2(C-7a)，47.2(N 4-CH 2)，43.5(N 2-CH 2)，39.1(CH 3).MS：m/z453.4(M+2)，451.4(M+)
Embodiment 17.2-o-cyanobenzyl-4-o-chlorobenzyl-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.17)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 1 equivalent of 4-dihydro-pyrazolo [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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal adjacent chlorobenzyl chloride.Reaction mixture continues to stir 20h in 50-60 ℃.Thin layer (TLC) detects, and after question response is complete, adds 1 normal adjacent cyano group benzyl chloride in reaction solution, and elevated temperature continues reaction 24h to 70-80 ℃, and TLC detects, and reacts and finishes, and cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 65%, white solid, mp130-134 ℃.
The production spectra diagram data is as follows: IR (KBr, cm -1): 2226 (CN); 1695 (C=O); 1317,1192 (SO 2). 1HNMR (DMSO-d 6, 600MHz) δ: 7.77 (s, 1H, PyH), 7.84 (dd, 1H, J=7.73Hz, J=1.31Hz, PhH), 7.04 (dd, 1H, J=7.57Hz, J=1.27Hz, PhH), 7.25-7.71 (m, 6H, PhH), 5.22 (s, 2H, NCH 2), 5.15 (s, 2H, NCH 2), 4.09 (s, 3H, CH 3). 13C NMR (DMSO-d 6, 600MHz) 148.8 (C=O), 133.7 (C-1 '), 139.6 (C-1 "), 133.1,132.8,132.0; 129.9,129.5,128.6,127.8,127.7,127.5; 110.9,126.3 (C-4a), 125.8 (C-5), 112.1 (C-7a), 117.2 (CN), 47.3 (N 4-CH 2), 42.4 (N 2-CH 2), 39.1 (CH 3) .MS:m/z 442.4 (M+1)
Cyano group benzyl between embodiment 18.2--4-o-chlorobenzyl-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.18)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 1 equivalent of 4-dihydro-pyrazolo [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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal adjacent chlorobenzyl chloride.Reaction mixture continues to stir 20h in 50-60 ℃.Thin layer (TLC) detects, and after question response is complete, adds 1 normal cyano group benzyl chloride in reaction solution, and elevated temperature continues reaction 24h to 70-80 ℃, and TLC detects, and reacts and finishes, and cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 66%, white solid, mp116-118 ℃.
The production spectra diagram data is as follows:
IR(KBr，cm -1)：2233(CN)；1693(C＝O)；1329，1192(SO 2). 1H NMR(DMSO-d 6，600MHz)δ：7.70(s，1H，PyH)，7.79(s，1H，PhH)，7.50(dd，1H，J＝7.86Hz，J＝1.23Hz，PhH)，7.06(dd，1H，J＝7.63Hz，J＝1.28Hz，PhH)，7.27-7.76(m，5H，PhH)，5.15(s，2H，NCH 2)，5.10(s，2H，NCH 2)，4.08(s，3H，CH 3). 13CNMR(DMSO-d 6，600MHz)148.8(C＝O)，133.0(C-1’)，138.0(C-1”)，132.6，132.1，131.6，131.2，129.9，129.8，129.5，127.6，127.5，111.5，126.3(C-4a)，125.9(C-5)，112.0(C-7a)，118.8(CN)，47.3(N 4-CH 2)，43.2(N 2-CH 2)，39.1(CH 3).MS：m/z 442.4(M+1).
Embodiment 19.2-is to cyano group benzyl-4-o-chlorobenzyl-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.19)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 1 equivalent of 4-dihydro-pyrazolo [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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal adjacent chlorobenzyl chloride.Reaction mixture continues to stir 20h in 50-60 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal to the cyano group benzyl chloride, elevated temperature continues reaction 24 to 70-80 ℃, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 66%, white solid, mp164-166 ℃.
The production spectra diagram data is as follows: IR (KBr, cm -1): 2227 (CN); 1690 (C=O); 1334,1193 (SO 2). 1HNMR (DMSO-d 6, 600MHz) δ: 7.78 (s, 1H, PyH), 7.79 (s, 1H, PhH), 7.04 (d, 1H, J=7.61Hz, PhH), 7.27-7.85 (m, 7H, PhH), 5.15 (s, 2H, NCH 2), 5.12 (s, 2H, NCH 2), 4.08 (s, 3H, CH 3). 13CNMR (DMSO-d 6, 600MHz) 148.9 (C=O), 132.9 (C-1 '), 141.9 (C-1 "), 132.8,132.1,129.9; 129.5,128.4,127.9,127.7,127.5,126.3; 110.5 (C-4 '), 126.2 (C-4a), 125.9 (C-5), 112.0 (C-7a), 118.8 (CN), 47.3 (N 4-CH 2), 43.7 (N 2-CH 2), 39.1 (CH 3) MS:m/z 442.5 (M+1)
Embodiment 20.2-is to Ethylbenzyl-4-o-chlorobenzyl-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.20)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 1 equivalent of 4-dihydro-pyrazolo [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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal adjacent chlorobenzyl chloride.Reaction mixture continues to stir 20h in 50-60 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal to the ethyl benzyl chloride, elevated temperature continues reaction 24h to 70-80 ℃, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 64%, white solid, mp112-114 ℃.
The production spectra diagram data is as follows:
IR(KBr，cm -1)：1699(C＝O)；1338，1192(SO 2). 1H NMR(DMSO-d 6，600MHz)δ：7.74(s，1H，PyH)，7.50(dd，1H，J＝7.75Hz，J＝0.75Hz，PhH)，6.99(d，1H，J＝7.25Hz，PhH)，6.16-7.32(m，6H，PhH)，5.16(s，2H，NCH 2)，4.99(s，2H，NCH 2)，4.08(s，3H，CH 3)，2.54-2.58(q，2H，J＝7.59Hz，CH 2)，1.13-1.16(t，3H，J＝7.59Hz，CH 3). 13C NMR(DMSO-d 6，600MHz)148.9(C＝O)，133.0(C-1’)，133.4(C-1”)，143.4，132.1，129.9，129.5，128.0，127.9，127.7，127.4，126.2(C-4a)，125.8(C-5)，122.4(C-7a)，47.1(N 4-CH 2)，44.0(N 2-CH 2)，39.1(Py-CH 3)，28.0(1C，CH 2)，15.8(1C，CH 3).MS：m/z 445.5(M+1).
Embodiment 21.2-is to tertiary butyl benzyl-4-o-chlorobenzyl-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-pyrazoline [4,5-e] [1,2,4] thiadiazines (3.21)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2, (1) 1 equivalent of 4-dihydro-pyrazolo [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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal adjacent chlorobenzyl chloride.Reaction mixture continues to stir 20h in 50-60 ℃.Thin layer (TLC) detects, and after question response is complete, adds 1 normal 4 tert butylbenzyl chloride in reaction solution, and elevated temperature continues reaction 24h to 70-80 ℃, and TLC detects, and reacts and finishes, and cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 63%, white solid, mp140-142 ℃.
The production spectra diagram data is as follows: IR (KBr, cm -1): 1700 (C=O); 1344,1189 (SO 2). 1H NMR (DMSO-d 6, 600MHz) δ: 7.75 (s, 1H, PyH), 7.50 (dd, 1H, J=7.90Hz, J=1.08Hz, PhH), 7.00 (dd, 1H, J=7.52Hz, J=1.02Hz, PhH), 7.26-7.35 (m, 6H, PhH), 5.16 (s, 2H, NCH 2), 4.99 (s, 2H, NCH 2), 4.08 (s, 3H, CH 3), 1.25 (s, 9H, CH 3). 13C NMR (DMSO-d 6, 600MHz) 150.2 (C=O), 133.0 (C-1 '), 133.1 (C-1 "), 148.9,132.1,129.9,129.5,127.7,127.6,127.4,126.3,125.8 (C-4a), 125.3 (C-5), 122.4 (C-7a), 47.1 (N 4-CH 2), 43.9 (N 2-CH 2), 39.1 (CH 3), 34.4 (C), 31.2 (3C, CH 3) .MS:m/z 473.3 (M+1)
Embodiment 22.2-benzyl-4-benzyl-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-dihydro-thiophene [4,5-e] [1,2,4] thiadiazines (4.01)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2,4-dihydro-thiophene are 1 equivalent of [4,5-e] [1,2,4] thiadiazine also, 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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal bromobenzyl.Reaction mixture continues to stir 12h in 35 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal bromobenzyl, elevated temperature to 40 ℃ continues reaction 12h, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 90%, white solid, mp128-130 ℃.
The production spectra diagram data is as follows: IR (KBr, cm -1): 1695 (C=O); 1315,1165 (SO 2). 1H NMR (DMSO-d 6, 600MHz) δ: 7.91 (d, 1H, J=3.3Hz, thiophene), 7.45-7.08 (m, 10H, PhH), 6.44 (d, 1H, J=3.3Hz, thiophene), 5.07 (s, 2H, NCH 2), 5.03 (s, 2H, NCH 2). 13C NMR (CDCl 3, 600MHz) 150.3 (C=O), 136.1 (C-1 '), 135.0 (C-1 "), 135.0,129.8,129.7,129.5,127.9,127.8 (C-4a), 126.5,124.7 (C-7a), 50.0 (N-CH 2), 45.1 (N-CH 2) MS:m/z 385.1 (M+1)
The adjacent luorobenzyl of embodiment 23.2-m-chloro benzyl-4--7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-dihydro-thiophene [4,5-e] [1,2,4] thiadiazines (4.02)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2,4-dihydro-thiophene are 1 equivalent of [4,5-e] [1,2,4] thiadiazine also, 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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal adjacent fluorobenzyl chloride.Reaction mixture continues to stir 12h in 50 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal chlorobenzyl chloride, elevated temperature to 60 ℃ continues reaction 12h, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 80%, white solid, mp104-107 ℃.
The production spectra diagram data is as follows: IR (KBr, cm -1): 1690 (C=O); 1330,1175 (SO 2). 1H NMR (DMSO-d 6, 600MHz) δ: 8.73 (d, 1H, J=3.2Hz, thiophene), 7.39-7.11 (m, 8H, PhH), 7.42 (d, 1H, J=3.2Hz, thiophene), 5.25 (s, 2H, NCH 2), 5.01 (s, 2H, NCH 2). 13C NMR (CDCl 3, 600MHz) 149.5 (C=O), 138.7 (C-1 '), 133.5 (C-1 "), 160.1,132.9,125.9,122.5,130.3,129.6,128.1,127.6,127.5,127.2,126.3,124.5,115.6,109.2,43.9 (N-CH 2), 43.7 (N-CH 2) MS:m/z 437.4 (M+1)
The adjacent bromobenzyl of embodiment 24.2-m-chloro benzyl-4--7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-dihydro-thiophene [4,5-e] [1,2,4] thiadiazines (4.03)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2,4-dihydro-thiophene are 1 equivalent of [4,5-e] [1,2,4] thiadiazine also, 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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal adjacent bromine bromobenzyl.Reaction mixture continues to stir 12h in 40 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal chlorobenzyl chloride, elevated temperature to 60 ℃ continues reaction 12h, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 50%, white solid, mp161-162 ℃.
The production spectra diagram data is as follows: IR (KBr, cm -1): 1672 (C=O); 1315,1170 (SO 2). 1H NMR (DMSO-d 6, 600MHz) δ: 8.76 (d, 1H, J=3.1Hz, thiophene), 7.69 (dd, 2H, J=1.4Hz, J=7.3Hz, PhH), 6.96 (dd, 2H, J=2.1Hz, J=7.4Hz, PhH), 7.40-7.20 (m, 4H, PhH), 7.30 (d, 1H, J=3.1Hz, thiophene), 5.25 (s, 2H, NCH 2), 5.01 (s, 2H, NCH 2). 13C NMR (CDCl 3, 600MHz) 149.6 (C=O), 138.9 (C-1 '), 134.1 (C-1 "), 133.6,133.1,130.5,129.5,128.0,127.7,127.6,127.5,126.8,126.4,125.9,122.1,109.5,49.9 (N-CH 2), 44.1 (N-CH 2) MS:m/z 498.4 (M+1)
Embodiment 25.2-m-chloro benzyl-4-(2, the 4-dichloro benzyl)-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-dihydro-thiophene [4,5-e] [1,2,4] thiadiazines (4.04)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2,4-dihydro-thiophene are 1 equivalent of [4,5-e] [1,2,4] thiadiazine also, 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 the sufficiently long time until white precipitate occurring, slowly add 1 normal 2, the 4-dichlorobenzyl chloride.Reaction mixture continues to stir 12h in 50 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal chlorobenzyl chloride, elevated temperature to 60 ℃ continues reaction 12h, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 75%, white solid, mp149-151 ℃.
The production spectra diagram data is as follows: IR (KBr, cm -1): 1675 (C=O); 1320,1150 (SO 2). 1H NMR (DMSO-d 6, 600MHz) δ: 8.76 (d, 1H, J=3.1Hz, thiophene), 7.05 (d, 1H, J=1.9Hz, PhH), 7.08 (d, 1H, J=8.4Hz, PhH), 7.40-7.32 (m, 5H, PhH and thiophene), 5.20 (s, 2H, NCH 2), 5.00 (s, 2H, NCH 2). 13CNMR (CDCl 3, 600MHz) 149.5 (C=O), 138.8 (C-1 '), 133.5,133.0,132.9,132.8,131.9,125.9,130.3,129.2,128.6,127.6,127.5,127.4,126.3,109.4,47.1 (N-CH 2), 44.1 (N-CH 2) MS:m/z 488.6 (M+1)
Embodiment 26.2-m-chloro benzyl-4-(2, the 6-dichloro benzyl)-7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-dihydro-thiophene [4,5-e] [1,2,4] thiadiazines (4.05)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2,4-dihydro-thiophene are 1 equivalent of [4,5-e] [1,2,4] thiadiazine also, 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 the sufficiently long time until white precipitate occurring, slowly add 1 normal 2, the 6-dichlorobenzyl chloride.Reaction mixture continues to stir 12h in 50 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal chlorobenzyl chloride, elevated temperature to 60 ℃ continues reaction 12h, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 74%, white solid, mp174-177 ℃.
The production spectra diagram data is as follows: IR (KBr, cm -1): 1665 (C=O); 1330,1150 (SO 2). 1H NMR (DMSO-d 6, 600MHz) δ: 8.67 (d, 1H, J=3.2Hz, thiophene), 7.40-7.32 (m, 8H, PhH andthiophene), 5.39 (s, 2H, NCH 2), 4.96 (s, 2H, NCH 2). 13CNMR (CDCl 3, 600MHz) 149.3 (C=O), 138.9 (C-1 '), 135.1 (C-1 "), 133.8,132.9,130.4,130.3,130.2,129.0,127.4,127.3,127.1,126.1,108.5,45.7 (N-CH 2), 43.7 (N-CH 2) MS:m/z 488.6 (M+1)
The adjacent luorobenzyl of bromobenzyl between embodiment 27.2--4--7-methyl isophthalic acid, 1,3-three oxygen-2, the preparation of 4-dihydro-thiophene [4,5-e] [1,2,4] thiadiazines (4.06)
With the 7-methyl isophthalic acid, 1,3-three oxygen-2,4-dihydro-thiophene are 1 equivalent of [4,5-e] [1,2,4] thiadiazine also, 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 the sufficiently long time until white precipitate occurring, slowly adds 1 normal adjacent fluorobenzyl chloride.Reaction mixture continues to stir 12h in 50 ℃.Thin layer (TLC) detects, question response fully after, in reaction solution, add 1 normal bromine bromobenzyl, elevated temperature to 60 ℃ continues reaction 12h, TLC detects, reaction is finished, cooling removes solvent under reduced pressure.Purify with ethyl alcohol recrystallization in residue washing back.Productive rate 80%, white solid, mp123-126 ℃.
The production spectra diagram data is as follows: IR (KBr, cm -1): 1695 (C=O); 1330,1160 (SO 2). 1H NMR (DMSO-d 6, 600MHz) δ: 8.74 (d, 1H, J=3.2Hz, thiophene), 7.53-7.10 (m, 8H, PhH), 7.41 (d, 1H, J=3.2Hz, thiophene), 5.25 (s, 2H, NCH 2), 5.00 (s, 2H, NCH 2). 13CNMR (CDCl 3, 600MHz) 149.5 (C=O), 139.2 (C-1 '), 160.2,133.5,126.0,122.6,121.6,130.5,130.3,130.2,129.4,127.9,127.1,126.5,124.3,115.4,109.1,43.9 (N-CH 2), 43.7 (N-CH 2) MS:m/z 482.1 (M+1).

Claims (3)

1.N 2, N 4-two replacement-7-methyl isophthalic acids, 1,3-three oxygen-2, the preparation method of 4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives is characterized in that, adopts one-pot synthesis, synthetic route is as follows:
a：2NaH/R 2X，DMF b：R 1X，DMF(X＝Cl，Br，I)
W＝S，C，N，NCH 3，O；Y＝S，C，N，NCH 3，O；Z＝S，C，N，NCH 3，O。
2. N as claimed in claim 1 2, N 4-two replace-1,1, and 3-three oxygen-2,4-dihydro heterocycle are the preparation method of [4,5-e] [1,2,4] thiadiazine derivatives also, it is characterized in that described one-pot synthesis, and the concrete operations step is as follows:
With 1 equivalent 1,1,3-three oxygen-2,4-dihydro heterocycle are [4,5-e] [1,2,4] thiadiazine also, is dissolved in the exsiccant dimethyl formamide, at N 2Protection down adds 2 equivalents of sodium hydride that contain 60% mineral oil, and holding temperature is lower than 10 ℃, finishes, and stirs until white precipitate occurring, adds 1 normal halocarbon R 2X, reaction mixture continues to stir 10-24h in 25-60 ℃, and then adds 1 normal halocarbon R in solution 1X, at 25-60 ℃ of reaction 10-24h, reaction is finished, cooling, pressure reducing and steaming solvent then, recrystallization with an organic solvent after the residue washing.
3. N as claimed in claim 1 or 2 2, N 4-two replacement-7-methyl isophthalic acids, 1,3-three oxygen-2, the preparation method of 4-pyrazoline [4,5-e] [1,2,4] thiadiazine derivatives is characterized in that described halocarbon R 1X and R 2It is one of following that X is selected from respectively: bromobenzyl, to bromine bromobenzyl, a bromine bromobenzyl, adjacent bromine bromobenzyl, to cyano group benzyl chloride, adjacent cyano group benzyl chloride, a cyano group benzyl chloride, 2,4-dichlorobenzyl chloride, 2,6-dichlorobenzyl chloride, 3,4-dichlorobenzyl chloride, 4-chlorobenzyl chloride, a chlorobenzyl chloride, adjacent chlorobenzyl chloride, to methyl benzyl chloride, adjacent methyl benzyl chloride, to ethyl benzyl chloride, 4 tert butylbenzyl chloride, chloromethyl cyanide, to fluorobenzyl chloride, adjacent fluorobenzyl chloride.
CNB2006100438346A 2006-04-20 2006-04-20 Process for preparing 2,4-disubstituted heterocyclo [4,5-e][1,2,4] thiadiazine derivatives Expired - Fee Related CN100393726C (en)

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CN104016977B (en) * 2014-06-13 2016-06-22 山东大学 A kind of replacement thiadiazine diketone derivative and preparation method thereof and application

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