CN111138419B - 4-tetrazolyl substituted-benzoxazine derivative and synthesis method thereof - Google Patents
4-tetrazolyl substituted-benzoxazine derivative and synthesis method thereof Download PDFInfo
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- CN111138419B CN111138419B CN202010077775.4A CN202010077775A CN111138419B CN 111138419 B CN111138419 B CN 111138419B CN 202010077775 A CN202010077775 A CN 202010077775A CN 111138419 B CN111138419 B CN 111138419B
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- -1 4-tetrazolyl substituted-benzoxazine Chemical class 0.000 title claims abstract description 24
- 238000001308 synthesis method Methods 0.000 title description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 150000002527 isonitriles Chemical class 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000376 reactant Substances 0.000 claims abstract description 10
- NHTBGGLIHGSCFA-UHFFFAOYSA-N 2-azidobenzaldehyde Chemical compound [N-]=[N+]=NC1=CC=CC=C1C=O NHTBGGLIHGSCFA-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000004440 column chromatography Methods 0.000 claims abstract description 7
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 claims abstract description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims abstract description 4
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- 239000012043 crude product Substances 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 3
- 238000009509 drug development Methods 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 13
- RETFIEPIZUQCDL-UHFFFAOYSA-N oxazin-2-amine Chemical compound NN1OC=CC=C1 RETFIEPIZUQCDL-UHFFFAOYSA-N 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 150000005130 benzoxazines Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical compound NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 description 1
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical compound C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 description 1
- 102000052510 DNA-Binding Proteins Human genes 0.000 description 1
- 101710096438 DNA-binding protein Proteins 0.000 description 1
- 229940123486 Hormone receptor agonist Drugs 0.000 description 1
- 229940123263 Phosphodiesterase 3 inhibitor Drugs 0.000 description 1
- 229940122055 Serine protease inhibitor Drugs 0.000 description 1
- 101710102218 Serine protease inhibitor Proteins 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000000698 hormone receptor stimulating agent Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000006452 multicomponent reaction Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002570 phosphodiesterase III inhibitor Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000001072 progestational effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000003001 serine protease inhibitor Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000010490 three component reaction Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The invention discloses a 4-tetrazolyl substituted-benzoxazine derivative, the structure of which is shown as formula I:
wherein R is 1 Selected from H, 4-CH 3 And 5-Cl; r 2 Selected from Ph, t-Bu, phCH 2 One of (a) and (b); r is 3 Selected from t-Bu, phCH 2 、c‑C 6 H 11 、1‑adamantyl、Ph、4‑CH 3 OC 6 H 4 、4‑BrC 6 H 4 To (3) is provided. The preparation method comprises the following steps: (1) Dissolving o-azidobenzaldehyde, trimethyl azido silane and isonitrile I in dichloromethane, stirring for reaction completely, and removing the solvent to obtain a reactant A; (2) Dissolving the reactant A in tetrahydrofuran, and adding Pd (PPh) 3 ) 4 And isocyanide II, heating to react completely, removing the solvent to obtain a product B; (3) And separating the product B by column chromatography to obtain the 4-tetrazolyl substituted-benzoxazine derivative. The synthesis route provided by the invention has the advantages of easily available raw materials, simple process, mild conditions, simple and efficient process, and capability of obtaining a target product by two steps in one pot. The target product has high yield and novel structure, and has potential application value in drug development.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a 4-tetrazolyl substituted-benzoxazine derivative and a synthesis method thereof.
Background
The benzoxazine compound shows wide biological activity, and many natural products and synthetic drugs contain the heterocyclic skeleton, for example, some benzoxazine derivatives show good bactericidal activity, anticonvulsant activity, herbicidal activity and the like. In addition, the benzoxazine molecule can also be used as a potent non-steroidal progestational hormone receptor agonist, a C1r serine protease inhibitor, a DNA binding protein anti-tumor drug and the like.
There are many methods for synthesizing benzoxazine derivatives, and representative methods include: (1) Synthesizing 4H-3,1 benzoxazine compound (Adv. Synth. Catal.2010,352, 341-346) by using simple raw materials of o-aminobenzyl alcohol and aldehyde under the condition of strong oxidant NaClO; (2) 2-aminobenzonitrile is used as a starting material, DMF is used as a solvent, and ketone is added in ZnCl 2 The benzoxazine compound (Tetrahedron, 2006,62,7999-8005) is obtained by high-temperature reflux cyclization under the catalysis of (1). The above synthesis method requires a strong oxidant and a high temperature environment, which limits its application. Therefore, a method for synthesizing the compound with mild reaction conditions, simple steps and good yield is urgently needed to develop。
The tetrazole skeleton has excellent physiological and medicinal activity, and can be used for preparing anticancer drugs, PDE3 inhibitors, anti-inflammatory agents, antihypertensive agents, etc. However, a structure in which a tetrazole group is linked to the 4-position of benzoxazine has been reported recently. In addition, a method for synthesizing the 4-tetrazolyl substituted-benzoxazine derivative with simple reaction, mild reaction conditions and high yield is lacked.
Disclosure of Invention
In order to solve the technical problems, the invention provides a synthesis method of a 4-tetrazolyl substituted-benzoxazine derivative. The method utilizes simple and easily obtained raw materials to participate in the Passerini multicomponent reaction to design and synthesize the 4-tetrazolyl substituted-benzoxazine compound with a novel structure.
The invention uses o-azidobenzaldehyde (formula II), trimethyl azido silane and isonitrile I (R) 2 NC) as raw material, carrying out Passerini three-component reaction at normal temperature by taking dichloromethane as solvent to obtain azide intermediate (formula III), using tetrahydrofuran as solvent instead of separation, and adding catalytic amount of Pd (PPh) into the system 3 ) 4 And isonitrile I (R) 3 NC), heating to react until the reaction is finished, removing the solvent under reduced pressure, and separating and purifying the residue by column chromatography to obtain the 4-tetrazolyl substituted-benzoxazine derivative (shown in formula I).
The technical scheme provided by the invention is as follows:
a4-tetrazolyl substituted-benzoxazine derivative has a structure shown in formula I:
wherein,
R 1 selected from H, 4-CH 3 And 5-Cl;
R 2 selected from Ph, t-Bu, phCH 2 One of (1);
R 3 selected from t-Bu, phCH 2 、c-C 6 H 11 、1-adamantyl、Ph、4-CH 3 OC 6 H 4 、4-BrC 6 H 4 One kind of (1).
A method for synthesizing 4-tetrazolyl substituted-benzoxazine derivatives, comprising the steps of:
(1) Dissolving o-azidobenzaldehyde, trimethyl azido silane and isonitrile I in dichloromethane, stirring for reaction completely, and removing the solvent to obtain a reactant A;
(2) Dissolving the reactant A in tetrahydrofuran, and adding Pd (PPh) 3 ) 4 And reacting the mixture with isonitrile II at a high temperature, and removing the solvent to obtain a crude product B;
(3) And separating the crude product B by column chromatography to obtain the 4-tetrazolyl substituted-benzoxazine derivative.
Preferably, the molar ratio of o-azidobenzaldehyde, trimethylazidosilane and isonitrile I in step (1) is 1.
Preferably, the reactant A, pd (PPh) in step (2) 3 ) 4 And the molar ratio of isonitrile II is 1.1.
Further, the structure of the o-azidobenzaldehyde is shown as formula II:
wherein R is 1 Selected from H, 4-CH 3 And 5-Cl.
Further, the structure of the isonitrile I is R 2 NC, wherein R 2 Selected from Ph, t-Bu, phCH 2 To (3) is provided.
Further, the reaction temperature in the step (1) was room temperature, and the completion of the reaction was monitored by TLC.
Further, the structure of the reactant A is shown as the formula III:
wherein R is 1 Selected from H, 4-CH 3 5-Cl;
R 2 selected from Ph, t-Bu, phCH 2 One ofAnd (4) seed preparation.
Further, the structure of the isonitrile II is R 3 NC, wherein R 3 Selected from t-Bu, phCH 2 、c-C 6 H 11 、1-adamantyl、Ph、4-CH 3 OC 6 H 4 、4-BrC 6 H 4 One kind of (1).
Further, the reaction temperature of the step (2) is 60 ℃, and the reaction time is 6-12 hours.
Further, the solvent for column chromatography separation in the step (3) is a mixed solution of ethyl acetate and petroleum ether, wherein the volume ratio of ethyl acetate to petroleum ether is 1.
Further, the structure of the 4-tetrazolyl substituted-benzoxazine derivative in the step (3) is shown in formula I:
wherein,
R 1 selected from H, 4-CH 3 And 5-Cl;
R 2 selected from Ph, t-Bu, phCH 2 One of (1);
R 3 selected from t-Bu, phCH 2 、c-C 6 H 11 、1-adamantyl、Ph、4-CH 3 OC 6 H 4 、4-BrC 6 H 4 One kind of (1).
The synthetic route is as follows:
the invention has the beneficial effects that:
the synthetic route provided by the invention has the advantages of easily available raw materials, simple process and mild conditions, the target product can be obtained by two steps in one pot, and the simple and efficient synthetic method of the 4-tetrazolyl substituted-benzoxazine compound is provided. The target product has high yield and novel structure, and has potential application value in drug development.
Detailed Description
The invention will be further illustrated with reference to specific examples, to which the present invention is not at all restricted.
Examples
The general synthesis method comprises the following steps:
(1) A50 mL round bottom flask was charged with ortho-azidobenzaldehyde (formula II,2 mmol), trimethylazidosilane (2 mmol) and isonitrile I (R) 2 NC,2 mmol), dissolving in dichloromethane, stirring at normal temperature for 2-3 days, monitoring by TLC until the reaction is complete, and removing the solvent by reduced pressure distillation to obtain a reactant A (formula III);
(2) A round-bottomed flask was charged with 5ml of tetrahydrofuran solution, followed by addition of Pd (PPh) 3 ) 4 (0.2 mmol), isonitrile II (R) 3 NC,3 mmol), the temperature was raised to 60 ℃ and reacted for 12 hours to give crude product B;
(3) And (3) separating the crude product B by column chromatography (ethyl acetate: petroleum ether =1: 10v/v) to obtain the target product 4-tetrazolyl substituted-benzoxazine derivative I.
The synthetic route is as follows:
preparation of 4-tetrazolyl-substituted-benzoxazines I
Nuclear magnetic attribution:
N-(tert-butyl)-4-(1-(tert-butyl)-1H-tetrazol-5-yl)-4H-benzo[d][1,3]oxazin-2-amine(Ⅰa):yellow solid(84％),mp 145-146℃； 1 H NMR(CDCl 3 ,600MHz)δ(ppm)7.26(t,J＝8.4Hz,1H),7.07(d,J＝7.8Hz,1H),6.89(t,J＝7.2Hz,2H),6.46(d,J＝7.8Hz,1H),4.40(s,1H),1.68(s,9H),1.40(s,9H)； 13 C NMR(CDCl 3 ,150MHz)δ(ppm)151.9,150.3,141.8,130.0,123.6,123.0,122.7,119.8,70.0,62.6,51.5,30.4,29.2.LCMS(ESI)m/z[M+H] + :329.Anal.Calcd for C 17 H 24 N 6 O:C,62.17；H,7.37；N,25.59；Found:C,62.49；H,7.81；N,25.72.
N-(tert-butyl)-4-(1-(tert-butyl)-1H-tetrazol-5-yl)-6-methyl-4H-benzo[d][1,3]oxazin-2-amine(Ⅰb):yellow solid(81％),mp 136-137℃； 1 H NMR(CDCl 3 ,400MHz)δ(ppm)7.08-7.05(m,2H),6.87(s,1H),6.27(s,1H),4.37(br,1H),2.19(s,3H),1.73(s,9H),1.38(s,9H)； 13 C NMR(CDCl 3 ,100MHz)δ(ppm)152.0,150.0,139.1,132.4,130.7,124.1,122.7,119.5,70.1,62.6,51.5,30.4,29.3,20.8.LCMS(ESI)m/z[M+H] + :343.Anal.Calcd for C 18 H 26 N 6 O:C,63.13；H,7.65；N,24.54；Found:C,62.74；H,7.95；N,24.90.
4-(1-(tert-butyl)-1H-tetrazol-5-yl)-7-chloro-N-cyclohexyl-4H-benzo[d][1,3]oxazin-2-amine(Ⅰc):yellow solid(80％),mp 182-183℃； 1 H NMR(CDCl 3 ,400MHz)δ(ppm)7.09-6.86(m,3H),6.45(d,J＝8.4Hz,1H),4.42(br,1H),3.69(br,1H),2.00-1.98(m,2H),1.74-1.12(m,17H)； 13 C NMR(CDCl 3 ,100MHz)δ(ppm)151.6,143.6,135.6,124.8,122.7,122.3,117.9,69.7,62.7,50.3,33.2,33.1,30.3,25.4,24.7,24.6.LCMS(ESI)m/z[M+H] + :389.Anal.Calcd for C 19 H 25 ClN 6 O:C,58.68；H,6.48；N,21.61；Found:C,58.94；H,6.91；N,22.02.
4-(1-(tert-butyl)-1H-tetrazol-5-yl)-N-phenyl-4H-benzo[d][1,3]oxazin-2-amine(Ⅰd):yellow solid(70％),mp 190-191℃； 1 H NMR(CDCl 3 ,400MHz)δ(ppm)7.46(d,J＝7.6Hz,2H),7.33-6.98(m,8H),6.61(d,J＝7.2Hz,1H),1.71(s,9H)； 13 C NMR(CDCl 3 ,100MHz)δ(ppm)151.6,148.3,140.2,138.2,128.9,124.0,123.8,123.7,120.4,119.5,118.7,70.5,62.8,30.3.LCMS(ESI)m/z[M+H] + :349.Anal.Calcd for C 19 H 20 N 6 O:C,65.50；H,5.79；N,24.12；Found:C,65.27；H,5.35；N,24.01.
4-(1-(tert-butyl)-1H-tetrazol-5-yl)-N-(4-methoxyphenyl)-4H-benzo[d][1,3]oxazin-2-amine(Ⅰe):yellow solid(78％),mp 176-177℃； 1 H NMR(DMSO-d 6 ,600MHz)δ(ppm)9.14(br,1H),7.54(br,2H),7.31-7.28(m,2H),7.04(d,J＝7.8Hz,1H),6.97(t,J＝7.2Hz,1H),6.87(t,J＝9.0Hz,3H),3.71(s,3H),1.81(s,9H)； 13 C NMR(DMSO-d 6 ,150MHz)δ(ppm)154.8,152.6,148.5,141.4,132.5,129.6,125.1,122.6,121.1,120.4,120.0,113.9,67.7,62.7,55.2,39.9,39.7,29.7.LCMS(ESI)m/z[M+H] + :379.Anal.Calcd for C 20 H 22 N 6 O 2 :C,63.48；H,5.86；N,22.21；Found:C,62.77；H,6.17；N,21.67.
4-(1-(tert-butyl)-1H-tetrazol-5-yl)-7-chloro-N-phenyl-4H-benzo[d][1,3]oxazin-2-amine(Ⅰf):yellow solid(69％),mp 192-193℃； 1 H NMR(CDCl 3 ,400MHz)δ(ppm)7.46(d,J＝8.0Hz,2H),7.31-6.94(m,5H),6.53(d,J＝8.0Hz,1H),1.72(s,9H)； 13 C NMR(CDCl 3 ,100MHz)δ(ppm)151.4,148.9,142.1,137.5,135.9,129.0,125.0,124.0,123.6,123.4,120.4,117.9,69.9,62.9,30.3.LCMS(ESI)m/z[M+H] + :383.Anal.Calcd for C 19 H 19 ClN 6 O:C,59.61；H,5.00；N,21.95；Found:C,59.44；H,5.17；N,22.27.
N-(4-bromophenyl)-4-(1-(tert-butyl)-1H-tetrazol-5-yl)-4H-benzo[d][1,3]oxazin-2-amine(Ⅰg):yellow solid(62％),mp 195-196℃； 1 H NMR(DMSO-d 6 ,600MHz)δ(ppm)9.46(br,1H),7.68(br,2H),7.47-7.32(m,4H),7.10(d,J＝7.2Hz,1H),7.03-6.91(m,2H),1.82(s,9H)； 13 C NMR(DMSO-d 6 ,150MHz)δ(ppm)152.5,148.2,138.8,136.1,131.4,129.7,125.2,123.3,121.2,118.2,113.9,67.8,62.7,29.7.LCMS(ESI)m/z[M+H] + :427.Anal.Calcd for C 19 H 19 BrN 6 O:C,53.41；H,4.48；N,19.67；Found:C,53.67；H,4.82；N,19.90.
4-(1-(tert-butyl)-1H-tetrazol-5-yl)-N-cyclohexyl-6-methyl-4H-benzo[d][1,3]oxazin-2-amine(Ⅰh):yellow solid(82％),mp 168-170℃； 1 H NMR(CDCl 3 ,400MHz)δ(ppm)7.08-7.05(m,1H),6.97(d,J＝8.0Hz,1H),6.89(s,1H),6.30(s,1H),4.35(br,0.7H),4.11(br,0.3H),4.35(br,0.7H),3.47(br,0.3H),2.01-1.98(m,2H),1.73-1.11(m,15H)； 13 C NMR(CDCl 3 ,100MHz)δ(ppm)151.9,150.7,139.2,132.1,130.6,124.1,122.4,119.2,70.2,62.6,50.8,48.9(minor),33.8(minor),33.3,33.2,30.3,25.5(minor),25.4,24.9(minor),24.7,24.6,20.7.LCMS(ESI)m/z[M+H] + :369.Anal.Calcd for C 20 H 28 N 6 O:C,65.19；H,7.66；N,22.81；Found:C,65.70；H,7.91；N,22.52.
N-benzyl-4-(1-(tert-butyl)-1H-tetrazol-5-yl)-4H-benzo[d][1,3]oxazin-2-amine(Ⅰi):yellow solid(78％),mp 143-145℃； 1 H NMR(CDCl 3 ,600MHz)δ(ppm)7.32-7.25(m,7H),7.08(d,J＝7.2Hz,1H),6.93-6.90(m,2H),6.54(d,J＝7.2Hz,1H),4.55-4.49(m,2H),1.68(s,9H)； 13 C NMR(CDCl 3 ,150MHz)δ(ppm)151.8,141.5,138.1,130.2,128.7,128.5,127.5,127.4,123.8,123.0,122.8,119.5,70.2,62.6,45.5,30.3.LCMS(ESI)m/z[M+H] + :363.Anal.Calcd for C 20 H 22 N 6 O:C,66.28；H,6.12；N,23.19；Found:C,66.59；H,6.44；N,23.55.
N-(tert-butyl)-4-(1-(tert-butyl)-1H-tetrazol-5-yl)-7-chloro-4H-benzo[d][1,3]oxazin-2-amine(Ⅰj):yellow solid(77％),mp 131-132℃； 1 H NMR(CDCl 3 ,400MHz)δ(ppm)7.10-6.86(m,2H),6.83(s,1H),6.43(d,J＝8.4Hz,1H),4.44(br,1H),1.74(s,3H),1.40(s,9H)； 13 C NMR(CDCl 3 ,100MHz)δ(ppm)151.6,150.6,143.4,135.5,124.7,123.0,122.4,118.1,69.5,62.6,51.7,30.4,29.1.LCMS(ESI)m/z[M+H] + :363.Anal.Calcd for C 17 H 23 ClN 6 O:C,56.27；H,6.39；N,23.16；Found:C,56.54；H,6.55；N,23.41.
4-(1-benzyl-1H-tetrazol-5-yl)-N-(tert-butyl)-4H-benzo[d][1,3]oxazin-2-amine(Ⅰk):yellow solid(78％),mp 140-142℃； 1 H NMR(CDCl 3 ,600MHz)δ(ppm)7.26(t,J＝8.4Hz,1H),7.07(d,J＝7.8Hz,1H),6.89(t,J＝7.2Hz,2H),6.46(d,J＝7.8Hz,1H),4.40(s,1H),1.68(s,9H),1.40(s,9H)； 13 C NMR(CDCl 3 ,150MHz)δ(ppm)151.9,150.3,141.8,130.0,123.6,123.0,122.7,119.8,70.0,62.6,51.5,30.4,29.2.LCMS(ESI)m/z[M+H] + :329.Anal.Calcd for C 17 H 24 N 6 O:C,62.17；H,7.37；N,25.59；Found:C,62.49；H,7.81；N,25.72.
N-((1R,3S,5r,7r)-adamantan-2-yl)-4-(1-(tert-butyl)-1H-tetrazol-5-yl)-7-chloro-4H-benzo[d]-[1,3]oxazin-2-amine(Ⅰl):yellow solid(75％),mp 189-190℃； 1 H NMR(CDCl 3 ,600MHz)δ(ppm)7.08(s,1H),6.87-6.83(m,2H),6.41(d,J＝8.4Hz,1H),4.35(br,1H),2.09(s,3H),2.04-1.99(m,6H),1.74(s,9H),1.68(s,6H)； 13 C NMR(CDCl 3 ,150MHz)δ(ppm)151.6,150.5,143.5,135.6,124.7,122.9,122.4,118.2,69.6,62.7,52.2,41.9,36.2,30.4,29.5.LCMS(ESI)m/z[M+H] + :441.Anal.Calcd for C 23 H 29 ClN 6 O:C,62.65；H,6.63；N,19.06；Found:C,62.89；H,6.91；N,19.50.
N-(tert-butyl)-4-(1-phenyl-1H-tetrazol-5-yl)-4H-benzo[d][1,3]oxazin-2-amine(Ⅰm):yellow solid(59％),mp 128-129℃； 1 H NMR(CDCl 3 ,600MHz)δ(ppm)7.50(t,J＝7.2Hz,1H),7.44(t,J＝7.8Hz,2H),7.27-7.18(m,3H),6.91(d,J＝7.8Hz,1H),6.85(d,J＝7.2Hz,1H),6.78(s,1H),6.58(d,J＝7.8Hz,1H),4.24(s,1H),1.31(s,9H)； 13 C NMR(CDCl 3 ,150MHz)δ(ppm)153.1,149.9,141.3,133.7,130.5,130.1,129.5,125.4,123.8,123.1,122.6,117.8,69.4,51.3,29.1.LCMS(ESI)m/z[M+H] + :349.Anal.Calcd for C 19 H 20 N 6 O:C,65.50；H,5.79；N,24.12；Found:C,65.20；H,5.44；N,24.67.
while the invention has been described with reference to specific embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (4)
1. A method for synthesizing a 4-tetrazolyl substituted-benzoxazine derivative, comprising the steps of:
(1) Dissolving o-azidobenzaldehyde, trimethyl azido silane and isonitrile I in dichloromethane, stirring for reaction completely, and removing the solvent to obtain a reactant A;
the structure of the o-azidobenzaldehyde is shown as a formula II:
(II)
wherein R is 1 Selected from H, 4-CH 3 And 5-Cl;
the structure of the isonitrile I is R 2 NC, wherein R 2 Selected from Ph,t-Bu、PhCH 2 One of (1);
(2) Dissolving the reactant A in tetrahydrofuran, and adding Pd (PPh) 3 ) 4 And isocyanide II, heating to react completely, removing the solvent to obtain a crude product B;
the structure of the reactant A is shown as the formula III:
(III)
wherein R is 1 Selected from H, 4-CH 3 5-Cl;
R 2 selected from Ph,t-Bu、PhCH 2 One of (1);
the structure of the isonitrile II is R 3 NC, wherein R 3 Is selected fromt-Bu、PhCH 2 、c-C 6 H 11 、1-adamantyl、Ph、4-CH 3 OC 6 H 4 、4-BrC 6 H 4 One of (1);
(3) The crude product B is separated by column chromatography to obtain a 4-tetrazolyl substituted-benzoxazine derivative;
the structure of the 4-tetrazolyl substituted-benzoxazine derivative is shown as a formula I:
(I)
wherein,
R 1 selected from H, 4-CH 3 5-Cl;
R 2 selected from Ph,t-Bu、PhCH 2 One of (1);
R 3 is selected fromt-Bu、PhCH 2 、c-C 6 H 11 、1-adamantyl、Ph、4-CH 3 OC 6 H 4 、4-BrC 6 H 4 One kind of (1).
2. The method of synthesizing 4-tetrazolyl-substituted-benzoxazine derivatives according to claim 1, wherein: the reaction temperature in step (1) was room temperature and completion of the reaction was monitored by TLC.
3. The method of synthesizing 4-tetrazolyl-substituted-benzoxazine derivatives according to claim 1, wherein: the reaction temperature of the step (2) is 60 ℃, and the reaction time is 6-12 hours.
4. The method of synthesizing 4-tetrazolyl-substituted-benzoxazine derivatives according to claim 1 wherein: the solvent for column chromatography separation in the step (3) is a mixed solution of ethyl acetate and petroleum ether, wherein the volume ratio of ethyl acetate to petroleum ether is 1 to 20-1.
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