CN106316958A - Preparation method of indazole and application of indazole in medicine synthesis - Google Patents
Preparation method of indazole and application of indazole in medicine synthesis Download PDFInfo
- Publication number
- CN106316958A CN106316958A CN201510345123.3A CN201510345123A CN106316958A CN 106316958 A CN106316958 A CN 106316958A CN 201510345123 A CN201510345123 A CN 201510345123A CN 106316958 A CN106316958 A CN 106316958A
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- indazole
- amoh
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CCC#CCN=N* Chemical compound CCC#CCN=N* 0.000 description 13
- MJZKTBSNJBTIQN-UHFFFAOYSA-N C(c1ccccc1)[n]1nc(C2=CC=C[U]2)c2ccccc12 Chemical compound C(c1ccccc1)[n]1nc(C2=CC=C[U]2)c2ccccc12 MJZKTBSNJBTIQN-UHFFFAOYSA-N 0.000 description 1
- KQAIGJAVKRTCKN-ALOFPCHZSA-N C/C(/CO)=C\C=C(\C(c(cccc1)c1NCc1ccccc1)=N)/O Chemical compound C/C(/CO)=C\C=C(\C(c(cccc1)c1NCc1ccccc1)=N)/O KQAIGJAVKRTCKN-ALOFPCHZSA-N 0.000 description 1
- WPPWXGRZZHPTAJ-IOCXFXADSA-N C[C@@H]1C=NC(/C=C/c2n[nH]c3cc(I)ccc23)=CC=C1 Chemical compound C[C@@H]1C=NC(/C=C/c2n[nH]c3cc(I)ccc23)=CC=C1 WPPWXGRZZHPTAJ-IOCXFXADSA-N 0.000 description 1
- WBBQLNHGQFDVLW-UHFFFAOYSA-N O=C(c1ccc[o]1)c1ccccc1Br Chemical compound O=C(c1ccc[o]1)c1ccccc1Br WBBQLNHGQFDVLW-UHFFFAOYSA-N 0.000 description 1
- GGTLRAQCZKLGIQ-UHFFFAOYSA-N O=Cc1ccc(-c2n[n](Cc3ccccc3)c3ccccc23)[o]1 Chemical compound O=Cc1ccc(-c2n[n](Cc3ccccc3)c3ccccc23)[o]1 GGTLRAQCZKLGIQ-UHFFFAOYSA-N 0.000 description 1
- NDOPHXWIAZIXPR-UHFFFAOYSA-N O=Cc1ccccc1Br Chemical compound O=Cc1ccccc1Br NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to the field of chemicals, and relates to a preparation method of indazole and an application of the indazole in medicine synthesis. The invention discloses a preparation method of indazole and an application of the indazole in synthesizing 1H-indazole-3-carboxylic acid, lonidamine, a compound 8, a compound 9, a compound 10, axitinib, YD-3, YC-1 and similar substances thereof.
Description
Technical field
The invention belongs to chemical field, relate to the preparation method of a kind of indazole and the application in pharmaceutical synthesis thereof.
Background technology
Due to the biological activity that it is good, the attention of indazole compounds causes drug research day by day person.Much there is bioactive indazole derivative
In succession it is synthesized, and is applied to clinic, such as: KP1019 has passed through a clinical trial phase of colorectal cancer；Lonidamine is a kind of narrow
Spectrum antineoplastic agent, is clinically used for the treatment of various tumor, especially pulmonary carcinoma, carcinoma of prostate and cerebroma；AF-2785 is a kind of to be in experimental stage
Male contraceptive pill；According to the literature, YC-1 has good active anticancer to root, and YD-3 shows good anti-angiogenesis activity；
Nausea and vomiting that granisetron causes for cytotoxic chemotherapy and radiotherapy clinically and the postoperative pernicious vomiting of prophylactic treatment；
FDA approval axitinib listing on January 27th, 2012, for the advanced renal cell cancer that other systematic treating is invalid.Bindarit is in June, 2010
Enter the clinical research of III phase, be the medicine of a kind of Selective depression chronic inflammatory reaction developed by Angelini drugmaker of Italy, as newly
Type monocyte chemoattractant protein MCP-1 inhibitor, can regulate the expression of MCP-1 gene, suppresses and reduces the synthesis of MCP-1 thus alleviate kidney
The reaction of dirty local chronic inflammatory.
Synthetic method about indazole has lot of documents to report in recent years.As shown in formula one, 2004 and 2007, Inamoto and Sakamoto
Et al. first reported the adjacent bromine aroma type Tosylhydrazone of Pd catalysis under the common effect of alkali and part, prepared by intramolecular cyclization reaction
The method (Tetrahedron 2007,63,2695.Chem.Lett.2004,33,1026) of indazole.They point out that the benzene sulfonyl hydrazone of Z-formula structure exists simultaneously
Reaction obtains good result, and the benzene sulfonyl hydrazone of E-formula structure has not the most obtained corresponding product (route A).For
Improving the utilization rate of raw material, Tois in 2010 et al. reports a kind of benzene sulphur being prepared Z-formula structure by bromophenyl ethyl ketone and derivatives selectively thereof
The method of acylhydrazone, and at CuI, DMEDA and Na2CO3Under conditions of achieve its cyclization (Tetrahedron Lett.2010,51,3613).
2013, Bolm et al. utilized identical raw material, achieves its cyclization and prepare indazole under the conditions of the alkalescence not using metallic catalyst
(Angew.Chem.Int.Ed.2013,52,7509) (route B).
In sum, it will be seen that at present it has been reported that to be prepared indazole by adjacent bromine aroma type benzene sulfonyl hydrazone by intramolecular cyclization reaction main
There is following defect.1) reaction must be carried out in the basic conditions.But Tosylhydrazone is easily by Bamford Stevens under the conditions of alkalescence
Reaction generates diazonium compound, and the use of alkali simultaneously is necessarily unfavorable for the tolerance of substrate functional group.2) under current reaction condition, Z-formula structure
Benzene sulfonyl hydrazone obtained good result in the reaction, and the benzene sulfonyl hydrazone of E-formula structure does not the most obtain corresponding product.
With this paradoxically, under normal circumstances when preparing hydrazone with aroma type aldehyde or ketone and tolysulfonyl hydrazine reaction, the benzene sulfonyl hydrazone of E-formula structure is
Primary product.Although Tois et al. reports a kind of method of benzene sulfonyl hydrazone being prepared Z-formula structure by bromophenyl ethyl ketone and derivatives selectively thereof,
But its substrate scope of application is limited only to bromophenyl ethyl ketone and derivant thereof.2013, Bolm et al. once attempted the method by illumination and made E-formula
The benzene sulfonyl hydrazone of structure is changed into the benzene sulfonyl hydrazone of Z-formula structure by isomerization, but the effect (route C) not obtained.3) in reaction
The scope of application of substrate is narrower, and the intramolecular cyclization that the benzene sulfonyl hydrazone prepared by aldehyde at present participates in is prepared the reaction of indazole and do not appeared in the newspapers.
The present invention, under conditions of not using alkali, achieves E-formula benzene sulfonyl hydrazone and the isomerization of Z-formula benzene sulfonyl hydrazone, at Cu first by heating2O
Effect under achieve its cyclization and prepare indazole, reaction yield height, wide application range of substrates, easily operated (formula two).Utilize this anti-simultaneously
Should be committed step and complete the synthesis of several indazole medicine and some important medicine intermediates.
Summary of the invention
It is an object of the invention to disclose the preparation method of a kind of indazole, its reaction expression is as shown in formula three.
Hydrazone used by the present invention is prepared through condensation reaction in methanol solvate by corresponding aldehydes or ketones and unifor or methylsulfonyl hydrazine.Wherein
R1Can be: hydrogen atom, C1-6Alkyl, phenyl, substituted-phenyl, benzyl, methylol, furyl, replacement or unsubstituted double bond；R2Can be:
Hydrogen atom, fluorine atom, bromine atoms, atomic iodine, methoxyl group, hydroxyl, nitro, piperonyl；R3Can be: mesyl, p-toluenesulfonyl；
X can be: Cl, Br, I, preferably Br.
First step reaction mantoquita used can be: CuO, Cu2O、Cu(OH)2、Cu2(OH)2CO3, preferably Cu2O.Solvent for use can be: i-AmOH,
T-AmOH, EtOH, MeOH, toluene, dioxane, preferably i-AmOH.Temperature used is backflow.
Second step reaction condition used is TBAF and THF or Mg and methanol.
Another object of the present invention is to open 1H-indazole-3-carboxylic acid, lonidamine, compound 8, compound 9, compound 10, axitinib,
The synthetic method of YD-3, YC-1 and the like.
1H-indazole-3-carboxylic acid is important medical synthetic intermediate, can be used to prepare the medicines such as granisetron, lonidamine.The present invention is with chemical combination
Thing 4 for initiation material through become hydrazone, cyclisation generate indazole 5, after generate 1H-indazole-3-carboxylic acid through de-p-toluenesulfonyl and oxidation, reaction equation
As shown in formula four.
Compound 6 and 2, the reaction of 4-dichlorobenzyl chloride can obtain compound 7, and compound 7 is through CrO3Oxidation can complete the synthesis of lonidamine.Compound
7 can complete the synthesis of compound 8 through PCC oxidation, and reaction equation is as shown in formula five.Root compound 8 according to the literature can be used to prepare AF-2785
The analog (US20070043057A1) of (Synthetic Commun.2013,43,2236-2241) and various lonidamine.
Compound 6 and bromobenzyl reaction can obtain compound 9, and compound 9 can complete the synthesis of compound 10, reaction equation such as formula six institute through PCC oxidation
Show.According to the literature, compound 9 can be used to prepare Bindarit (WO2011015501A1) root.Compound 10 can be used to prepare various 1-benzyl
The derivant (WO2009109654A2) of base-3-methylol indazole.
The present invention with o-bromobenzaldehye as initiation material, through nucleophilic addition, oxidation be prepared for compound 12, compound 12 through ammonium ceric nitrate oxidation and
Ethyl esterified reaction can obtain compound 13, compound 13 through becoming hydrazone, cyclisation to generate indazole 14, after complete through de-p-toluenesulfonyl and Benzylation reaction
Having become the synthesis of YD-3, reaction equation is as shown in formula seven.
The present invention is with 1, and 3-dibromobenzene and chloroacetic chloride are that initiation material prepares compound 16a, compound 16a and pyridine-2-through Friedel-Crafts reaction
Formaldehyde generation aldol reaction generates compound 17a, compound 17a through becoming hydrazone, cyclisation to generate indazole 18a, indazole 18a and slough toluene sulphur
Acyl group obtains compound 19a, compound 19a and 20 can complete the synthesis of axitinib by coupling reaction, and reaction equation is as shown in formula eight.
The present invention is with 1, and 3-diiodo-benzene and chloroacetic chloride are that initiation material prepares compound 16b, compound 16b and pyridine-2-through Friedel-Crafts reaction
Formaldehyde generation aldol reaction generates compound 17b, compound 17b through becoming hydrazone, cyclisation to generate indazole 18b, indazole 18b and slough toluene sulphur
Acyl group obtains compound 19b, compound 19b and 20 can complete the synthesis of axitinib by coupling reaction, and reaction equation is as shown in formula nine.
The present invention, with o-bromobenzaldehye as initiation material, is prepared for compound 22 through nucleophilic addition, oxidation, and compound 22 generates through becoming hydrazone, cyclisation
Indazole 23, indazole 23 sloughs p-toluenesulfonyl, Benzylation reacts to obtain compound 25, and compound 25 is through Vilsmeier-Haack formylation reaction
With the synthesis that reduction completes YC-1, reaction equation is as shown in formula ten.
1H-indazole 24 can obtain compound 27 through Benzylation reaction, and compound 27 completes chemical combination through Vilsmeier-Haack formylation reaction and reduction
The synthesis of thing 29, reaction equation is as shown in formula 11.
Benzylating reagent X used in reaction can be Cl or Br, R can be monosubstituted, two replacements or trisubstituted F, Cl, Br, I.
Detailed description of the invention
It is below embodiments of the invention, but present disclosure is not limited thereto.
Embodiment one, the preparation of indazole compound 2:
Under argon shield, Tosylhydrazone 1 (0.2mmol) is dissolved in i-AmOH (2mL), adds Cu2O (0.1mmol), temperature rising reflux is anti-
Should be wholly absent (1-10 hour) to Tosylhydrazone 1, product-ethyl acetate (200mL) extracts, and organic facies Sal is washed, anhydrous MgSO4
Being dried, remove solvent under reduced pressure, column chromatography for separation obtains indazole compound 2.
Spectral data is as follows:
1H NMR(400MHz,CDCl3) δ=2.35 (s, 3H), 7.23 (d, J=8.4Hz, 2H), 7.30-7.34 (m, 1H), 7.53-7.58 (m, 1H),
7.68 (d, J=8.0Hz, 1H), 7.87 (d, J=8.4Hz, 2H), 8.18-8.23 (m, 2H) ppm；13C NMR(100MHz,CDCl3) δ=21.6,
113.1,121.3,124.1,125.8,127.5,129.2,129.8,134.6,140.3,141.2,145.3ppm；HRMS(ESI):Calcd for
C14H13N2O2S[M+H]+:273.0692,found:273.0695.
1H NMR(400 MHz,CDCl3) δ=2.34 (s, 3H), 3.83 (s, 3H), 7.02 (d, J=2.4 Hz, 1H), 7.17-7.23 (m, 3H), 7.83
(d, J=8.0 Hz, 2H), 8.07-8.09 (m, 2H) ppm；13C NMR(100 MHz,CDCl3) δ=21.6,55.7,101.3,114.1,120.2,
126.8,127.4,129.8,134.5,135.7,141.1,145.2,156.9 ppm；HRMS(ESI):Calcd for C15H15N2O3S[M+H]+:
303.0798,found:303.0795.
1H NMR(400 MHz,CDCl3) δ=2.36 (s, 3H), 6.07 (s, 2H), 6.91 (s, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.62 (s,
1H), 7.83 (d, J=8.4 Hz, 2H), 7.97 (d, J=0.8 Hz, 1H) ppm；13C NMR(100 MHz,CDCl3) δ=21.6,93.7,98.1,
102.2,120.4,127.5,129.8,134.5,137.1,140.9,145.3,146.3,150.7 ppm；HRMS(ESI):Calcd for C15H13N2O4S
[M+H]+:317.0591,found:317.0594.
1H NMR(400 MHz,CDCl3) δ=2.35 (s, 3H), 4.06 (s, 3H), 5.81 (s, 1H), 7.08 (s, 1H), 7.23 (d, J=8.0 Hz,
2H), 7.65 (s, 1H), 7.82 (d, J=8.0 Hz, 2H), 8.0 (s, 1H) ppm；13C NMR(100 MHz,CDCl3) δ=21.6,56.5,94.6,
103.5,119.5,127.4,129.7,134.5,135.7,141.3,144.2,145.2,149.5 ppm；HRMS(ESI):Calcd for C15H15N2O4S
[M+H]+:319.0747,found:319.0751.
1H NMR(400 MHz,CDCl3) δ=2.37 (s, 3H), 7.07-7.12 (m, 1H), 7.26-7.28 (m, 2H), 7.62-7.66 (m, 1H),
7.87-7.92 (m, 3H), 8.14 (d, J=0.8 Hz, 1H) ppm；13C NMR(100 MHz,CDCl3) δ=21.6,99.9,100.2,113.6,113.8,
122.3,122.6,122.7,127.6,129.9,134.4,140.8,140.88,140.93,145.7,162.2,164.7 ppm；HRMS(ESI):Calcd for
C14H12FN2O2S[M+H]+:291.0598,found:291.0602.
1H NMR(400 MHz,CDCl3) δ=2.37 (s, 3H), 7.24-7.26 (m, 2H), 7.29-7.34 (m, 2H), 7.86 (d, J=8.4 Hz,
2H),8.15(s,1H),8.16-8.20(m,1H)ppm；13C NMR(100 MHz,CDCl3) δ=21.6,105.9,106.1,114.5,114.6,
118.1,118.4,126.4,126.5,127.6,128.7,129.7,129.9,134.4,137.0,140.7,140.8,145.6,158.4,160.8 ppm；
HRMS(ESI):Calcd for C14H12FN2O2S[M+H]+:291.0598,found:291.0596.
HRMS(ESI):Calcd for C14H12N3O4S[M+H]+:318.0543,found:318.0541.
1H NMR(400 MHz,CDCl3) δ=2.34 (s, 3H), 2.52 (s, 3H), 7.21 (d, J=8.4 Hz, 2H), 7.26-7.33 (m, 1H),
7.51-7.59 (m, 2H), 7.83 (d, J=8.0 Hz, 2H), 8.16 (d, J=8.4 Hz, 1H) ppm；13C NMR(100 MHz,CDCl3) δ=12.2,
21.5,113.3,120.5,123.8,126.1,127.4,129.1,129.7,134.7,141.1,145.0,150.7 ppm.
1H NMR(400 MHz,CDCl3) δ=2.33 (s, 3H), 7.21-7.25 (m, 2H), 7.35-7.37 (m, 1H), 7.38-7.52 (m, 3H),
7.55-7.60 (m, 1H), 7.89-7.93 (m, 5H), 8.27 (d, J=8.8 Hz, 1H) ppm；13C NMR(100 MHz,CDCl3) δ=21.6,113.6,
121.6,124.3,124.4,127.6,128.3,128.8,129.0,,129.5,129.8,131.4,134.7,141.9,145.2,151.7 ppm.
1H NMR(400 MHz,CDCl3) δ=2.31 (s, 3H), 2.41 (s, 3H), 7.19 (d, J=8.0 Hz, 2H), 7.28-7.36 (m, 3H),
7.53-7.58 (m, 1H), 7.80 (d, J=8.0 Hz, 2H), 7.88-7.91 (m, 3H), 8.25 (d, J=8.4 Hz, 1H) ppm；13C NMR(100
MHz,CDCl3) δ=21.4,21.5,113.5,121.7,124.3,124.4,127.5,128.1,128.5,128. 9,129.5,129.7,134.6,139.6,
141.8,145.1,151.7 ppm；HRMS(ESI):Calcd for C21H19N2O2S[M+H]+:363.1162,found:363.1167.
1H NMR(400 MHz,CDCl3) δ=2.35 (s, 3H), 4.27 (s, 2H), 7.12-7.22 (m, 8H), 7.36 (d, J=8.4 Hz,
1H), 7.45-7.49 (m, 1H), 7.82 (d, J=8.4 Hz, 2H), 8.15 (d, J=8.4 Hz, 1H) ppm；13C NMR(100 MHz,CDCl3) δ=
21.6,33.7,113.5,121.0,124.0,125.5,126.7,127.4,128.5,128.6,129.0,129.6,134.5,137.0,141.7,145.0,153.1
ppm；HRMS(ESI):Calcd for C21H19N2O2S[M+H]+:363.1162,found:363.1159.
1H NMR(400 MHz,CDCl3) δ=2.31 (s, 3H), 4.97 (s, 2H), 7.38 (d, 2H), 7.47 (dd, 1H), 7.68 (dd, 1H), 7.81
(d,2H),7.92(d,1H),8.12(d,1H)ppm.
1H NMR(400MHz,CDCl3) δ=3.25 (s, 3H), 7.37-7.41 (m, 1H), 7.55-7.59 (m, 1H), 7.79 (d, J=8.0Hz, 1H),
8.09 (dd, J=8.4,0.8Hz, 1H), 8.30 (d, J=0.8Hz, 1H) ppm；13C NMR(100MHz,CDCl3) δ=40.9,113.0,121.4,
124.3,125.5,129.4,140.2,141.2ppm.
1H NMR(400MHz,CDCl3) δ=2.62 (s, 3H), 3.19 (s, 3H), 7.38 (t, J=7.6Hz, 1H), 7.55 (t, J=8.0Hz, 1H),
7.69 (d, J=8.0Hz, 1H), 8.03 (d, J=8.4Hz, 1H) ppm；13C NMR(100MHz,CDCl3) δ=12.3,40.5,113.2,120.6,
124.0,125.8,129.3,141.0,150.7ppm.
Embodiment two, the preparation of 1H-indazole 3:
Route one: under argon shield, is dissolved in compound 2 (0.2mmol) in 2mL methanol, adds magnesium powder, room temperature reaction 3 hours, decompression
Methanol is evaporated off, and ethyl acetate extracts, organic facies saturated ammonium chloride solution and Sal washing, anhydrous MgSO4It is dried, removes solvent, post under reduced pressure
Chromatography obtains compound 3.
1H NMR(400MHz,CDCl3) δ=7.16-7.20 (m, 1H), 7.36-7.42 (m, 1H), 7.52 (dd, J=8.4,0.8Hz, 1H), 7.78
(d, J=8.4Hz, 1H), 8.13 (s, 1H), 10.0 (brs, 1H) ppm；13C NMR(100MHz,CDCl3) δ=109.8,120.9,121.0,123.1,
126.9,134.7,140.0ppm.
1H NMR(400MHz,CDCl3) δ=3.86 (s, 3H), 7.09-7.11 (m, 2H), 7.40 (d, J=9.6Hz, 1H), 8.03 (brs, 1H)
ppm.
1H NMR(400MHz,CDCl3) δ=6.93-6.98 (m, 1H), 7.16 (d, J=9.2Hz, 1H), 7.71 (dd, J=8.8,5.2Hz, 1H),
8.10(s,1H),10.35(brs,1H)ppm；13C NMR(100MHz,CDCl3) δ=95.4,95.7,111.0,111.3,122.2,122.4,134.8,
161.3,163.7ppm.
1H NMR(400MHz,CDCl3) δ=7.15-7.20 (m, 1H), 7.38 (dd, J=8.4,2.0Hz, 1H), 7.46 (dd, J=9.2,4.0Hz,
1H),8.10(s,1H),10.12(brs,1H)ppm；13C NMR(100MHz,CDCl3) δ=104.7,104.9,110.9,111.0,116.5,116.7,
134.5,137.1,156.8,159.1ppm.
1H NMR(400MHz,CDCl3) δ=2.63 (s, 3H), 7.14 (dd, J=7.2,7.2Hz, 1H), 7.35-7.39 (m, 1H), 7.44 (d, J=
8.4Hz, 1H), 7.69 (d, J=8.0Hz, 1H) ppm；13C NMR(100MHz,CDCl3) δ=12.0,109.7,120.1,120.2,122.7,
126.7,141.1,143.2ppm.
1H NMR(400MHz,CDCl3) δ=7.14-7.23 (m, 2H), 7.29-7.33 (m, 1H), 7.43-7.46 (m, 1H), 7.51-7.55 (m, 2H),
8.00-8.04(m,3H)ppm；13C NMR(100MHz,CDCl3) δ=110.3,120.9,121.0,121.3,126.7,127.8,128.2,129.0,
133.6,141.7,145.6ppm.
1H NMR(400MHz,CDCl3) δ=2.44 (s, 3H), 7.18-7.22 (m, 1H), 7.30-7.38 (m, 4H), 7.90 (d, J=8.0Hz, 2H),
8.02 (d, J=8.4Hz, 1H) ppm；13C NMR(100MHz,CDCl3) δ=21.3,110.2,120.9,121.16,121.18,126.7,127.5,
129.6,130.7,138.0,141.6,145.7ppm.
Route two: be dissolved in 4ml THF by compound 2 (189mg, 0.45mmol) under room temperature, adds TBAF (258mg, 0.83mmol),
System is warming up to 50 DEG C of reaction 12h.Dichloromethane extracts, and organic facies Sal is washed, anhydrous MgSO4It is dried, removes solvent, post layer under reduced pressure
Analysis separates to obtain compound 3.
Spectral data is as follows:
1H NMR(400MHz,d6-DMSO)δ=7.71 (d, J=9.2Hz, 1H), 8.17 (dd, J=9.2,2.0Hz, 1H), 8.39 (s, 1H),
8.81 (d, J=2.0Hz, 1H), 13.7 (brs, 1H) ppm；13C NMR(100MHz,d6-DMSO) δ=110.9,118.8,120.8,122.1,
136.8,141.5,141.7ppm.
Embodiment three, the synthesis of 1H-indazole-3-carboxylic acid:
Under argon shield, bromophenyl ethyl ketone (148mg, 0.74mmol) is dissolved in methanol (5mL), be sequentially added into KOH (230mg,
4.09mmol), iodobenzene diacetate (287mg, 0.89mmol), room temperature reaction 5 hours, remove methanol under reduced pressure, ethyl acetate extracts, organic
Mutually with water and Sal washing, anhydrous MgSO4It is dried, removes solvent under reduced pressure.Crude product is dissolved in methanol (5mL), adds 2M hydrochloric acid (2mL),
Room temperature reaction 12 hours, removes methanol under reduced pressure, and ethyl acetate extracts, the saturated Na of organic facies2CO3Solution and Sal washing, anhydrous MgSO4
Being dried, remove solvent under reduced pressure, column chromatography for separation obtains compound 4 (121mg, 76% productivity).
Under room temperature, compound 4 (67mg, 0.31mmol) and unifor (64mg, 0.34mmol) are dissolved in 2ml methanol, room temperature
Reaction 36h.Ethyl acetate extracts, and organic facies Sal is washed, anhydrous MgSO4It is dried, removes solvent under reduced pressure.Under argon shield, by gained
Crude product is dissolved in 2mL i-AmOH, adds Cu2O (21mg, 0.15mmol), temperature rising reflux reacts 5 hours, removes solvent, post layer under reduced pressure
Analysis separates to obtain compound 5 (57mg, 60% productivity).
Under argon shield, compound 5 (299mg, 0.99mmol) is dissolved in 10mL methanol, adds magnesium powder (238mg, 9.90mmol),
Room temperature reaction 1 hour, removes methanol under reduced pressure, and ethyl acetate extracts, organic facies saturated ammonium chloride solution and Sal washing, anhydrous MgSO4Dry
Dry, remove solvent under reduced pressure, column chromatography for separation obtains compound 6 (137mg, 93% productivity).
Under room temperature, by CrO3(57mg, 0.57mmol) is dissolved in 1.5M H2SO4(0.5mL), in, compound 6 (20mg, 0.14mmol) is instilled
Acetone (1.5mL) solution, room temperature reaction 24 hours, dichloromethane extract, organic phases washed with water, anhydrous MgSO4It is dried, removes under reduced pressure molten
Agent, column chromatography for separation obtains 1H-indazole-3-carboxylic acid (14mg, 64% productivity).
Spectral data is as follows:
1H NMR(400MHz,CDCl3) δ=3.41 (brs, 1H), 4.79 (s, 2H), 7.36-7.45 (m, 2H), 7.53-7.56 (m, 1H),
7.67-7.69(m,1H)ppm；13C NMR(100MHz,CDCl3) δ=67.9,119.8,127.5,129.3,33.0,134.3,136.7,201.5
ppm.
1H NMR(400MHz,CDCl3) δ=2.33 (s, 3H), 2.71 (brs, 1H), 5.00 (s, 2H), 7.19 (d, J=8.0Hz, 2H),
7.30-7.34 (m, 1H), 7.54-7.58 (m, 1H), 7.76-7.83 (m, 3H), 8.17 (d, J=8.8Hz, 1H) ppm；13C NMR(100MHz,
CDCl3) δ=21.6,58.3,113.3,121.1,124.1,124.2,127.4,129.5,129.8,134. 4,141.3,145.4,152.6ppm；HRMS
(ESI):Calcd for C15H15N2O3S[M+H]+:303.0798,found:303.0794.
1H NMR(400MHz,d6-DMSO) δ=4.74 (d, J=5.6Hz, 2H), 5.16 (t, J=5.6Hz, 1H), 7.02-7.05 (m, 1H),
7.25-7.29 (m, 1H), 7.42 (d, J=8.4Hz, 1H), 7.79 (d, J=8.0Hz, 1H), 12.72 (s, 1H) ppm；13C NMR(100MHz,
d6-DMSO) δ=56.8,110.0,119.6,120.6,121.4,125.9,141.0,145.6ppm.
1H NMR(400MHz,d6-DMSO) δ=7.26-7.30 (m, 1H), 7.40-7.44 (m, 1H), 7.64 (d, J=8.4Hz, 1H), 8.09 (d,
J=8.0Hz, 1H), 13.02 (brs, 1H), 13.79 (brs, 1H) ppm；13C NMR(100MHz,d6-DMSO) δ=111.0,121.2,122.4,
122.6,126.5,135.9,141.1,163.8ppm.
Embodiment four, the synthesis of lonidamine:
Under argon shield, compound 6 (71mg, 0.48mmol) is dissolved in 2mL DMF, is sequentially added into potassium carbonate (133mg, 0.96mmol),
2,4-dichlorobenzyl chlorides (80uL, 0.58mmol), room temperature reaction 12 hours, ethyl acetate extracts, and organic facies saturated common salt is washed, anhydrous MgSO4
Being dried, remove solvent under reduced pressure, column chromatography for separation obtains compound 7 (110mg, 79% productivity).
Under room temperature, by CrO3(27mg, 0.27mmol) is dissolved in 1.5M H2SO4(0.5mL), in, compound 7 (18mg, 0.06mmol) is instilled
Acetone (1.5mL) solution, room temperature reaction 24 hours, dichloromethane extract, organic phases washed with water, anhydrous MgSO4It is dried, removes under reduced pressure molten
Agent, column chromatography for separation obtains lonidamine (15mg, 80% productivity).
Spectral data is as follows:
1H NMR(400MHz,CDCl3) δ=2.69 (s, 1H), 5.05 (s, 2H), 5.55 (s, 2H), 6.60 (d, J=8.4Hz, 1H), 6.97-7.00
(m, 1H), 7.17-7.21 (m, 1H), 7.28 (dd, J=8.8,8.8Hz, 1H), 7.36-7.40 (m, 2H), 7.84 (d, J=8.4Hz, 1H) ppm；13C
NMR(100MHz,CDCl3) δ=49.3,58.1,109.2,120.7,121.0,122.2,127.2,127.4,129.3,129. 4,133.0,134.1,
140.8,145.3ppm.
1H NMR(400MHz,d6-DMSO) δ=5.83 (s, 2H), 6.96 (d, J=8.4Hz, 1H), 7.32-7.39 (m, 2H), 7.47-7.51 (m,
1H), 7.67 (d, J=2.0Hz, 1H), 7.80 (d, J=8.4Hz, 1H), 8.13 (d, J=8.0Hz, 1H), 13.16 (s, 1H)；13C NMR(100
MHz,d6-DMSO) δ=49.7,110.6,121.6,123.0,123.1,127.0,127.8,129.0,131.0,133 .18,133.24,133.4,135.8,
140.9,163.3ppm
Embodiment five, the synthesis of compound 8:
Under room temperature, compound 7 (30mg, 0.10mmol) is dissolved in 2mL dichloromethane, adds PCC (42mg, 0.19mmol), room temperature
Reacting 0.5 hour, dichloromethane extracts, organic phases washed with water, anhydrous MgSO4Being dried, remove solvent under reduced pressure, column chromatography for separation obtains compound 8
(17mg, 57% productivity).
1H NMR(400MHz,CDCl3) δ=5.76 (s, 2H), 6.82 (d, J=8.4Hz, 1H), 7.15 (dd, J=8.4,2.4Hz, 1H),
7.36-7.49 (m, 4H), 8.34 (d, J=8.0Hz, 1H), 10.26 (s, 1H)；13C NMR(100MHz,CDCl3) δ=50.5,109.6,122.2,
122.4,124.3,127.7,127.9,129.6,129.8,131.7,133.4,134.9,141.1,143.7,186.8ppm
Embodiment six, the synthesis of compound 10:
Under argon shield, compound 6 (30mg, 0.20mmol) is dissolved in 1mL DMF, is sequentially added into potassium carbonate (56mg, 0.40mmol),
Bromobenzyl (35uL, 0.30mmol), room temperature reaction 12 hours, ethyl acetate extracts, and organic facies saturated common salt is washed, anhydrous MgSO4It is dried,
Removing solvent under reduced pressure, column chromatography for separation obtains compound 7 (34mg, 71% productivity).
Under room temperature, compound 7 (24mg, 0.10mmol) is dissolved in 2mL dichloromethane, adds PCC (44mg, 0.20mmol), room temperature
Reacting 0.5 hour, dichloromethane extracts, organic phases washed with water, anhydrous MgSO4Being dried, remove solvent under reduced pressure, column chromatography for separation obtains compound 8
(14mg, 60% productivity).
1H NMR(400MHz,d6-DMSO) δ=4.79 (d, J=5.2Hz, 2H), 5.29 (t, J=5.2Hz, 1H), 5.60 (s, 2H), 7.10-7.14
(m, 1H), 7.21-7.32 (m, 5H), 7.34-7.36 (m, 1H), 7.65 (d, J=8.4Hz, 1H), 7.86 (d, J=8.0Hz, 1H) ppm；13C NMR
(100MHz,d6-DMSO) δ=51.5,56.6,109.7,120.0,120.9,122.2,126.2,127.35,127.41,12 8.5,137.7,140.3,
145.2ppm.
1H NMR(400MHz,CDCl3) δ=5.69 (s, 2H), 7.24-7.30 (m, 2H), 7.32-7.40 (m, 4H), 7.41-7.43 (m, 2H), 8.32
(d, J=8.4Hz, 1H), 10.27 (s, 1H).
Embodiment seven, the synthesis of YD-3:
Under argon shield, parabromotoluene (1.6mL, 13mmol) is dissolved in 30mL THF, adds magnesium powder (311mg, 13mmol),
Temperature rising reflux reacts 3 hours, and system drops to 0 DEG C, is slowly dropped into by THF (5mL) solution of o-bromobenzaldehye (1mL, 8.63mmol), low
Temperature reaction 1 hour, ethyl acetate extracts, organic facies saturated ammonium chloride solution and Sal washing, anhydrous MgSO4It is dried, removes solvent under reduced pressure,
Column chromatography for separation obtains compound 11 (2.37g, 99% productivity).
Compound 11 (146mg, 0.53mmol) is dissolved in 4mL dichloromethane, adds DMP (269mg, 0.63mmol), room temperature reaction
1 hour, ethyl acetate extracted, organic facies Na2CO3Solution and Sal washing, anhydrous MgSO4Being dried, remove solvent under reduced pressure, column chromatography divides
From obtaining compound 12 (145mg, 99% productivity).
Compound 12 (0.50g, 1.8mmol) is dissolved in the nitric acid of 20mL 8mol/L, adds CAN (9.00g, 16mmol), backflow
Reacting 36 hours, ethyl acetate extracts, organic phases washed with water, Na2CO3Solution and Sal washing, anhydrous MgSO4 is dried, and removes under reduced pressure molten
Agent.Crude product is dissolved in 5mL DMF, is sequentially added into iodoethane (290uL, 3.6mmol) and potassium carbonate (620mg, 4.5mmol) room temperature reaction 10
Hour, ethyl acetate extracts, and organic facies Sal is washed, anhydrous MgSO4Being dried, remove solvent under reduced pressure, column chromatography for separation obtains compound 13 (259
Mg, 43% productivity).
Under room temperature, compound 13 (60mg, 0.18mmol) and unifor (37mg, 0.20mmol) are dissolved in 2ml ethanol, add 40
Ul concentrated hydrochloric acid, system is warming up to 50 DEG C and reacts 12 hours.Ethyl acetate extracts, organic facies Na2CO3Solution and Sal washing, anhydrous MgSO4
It is dried, removes solvent under reduced pressure.Under argon shield, gained crude product is dissolved in 2ml i-AmOH, adds Cu2O (13mg, 0.09mmol),
Temperature rising reflux reacts 10 hours, removes solvent under reduced pressure, and column chromatography for separation obtains compound 14 (60mg, 79% productivity).
Under room temperature, compound 14 (38mg, 0.09mmol) is dissolved in 4mL THF, adds TBAF (60mg, 0.19mmol), system liter
Temperature reacts 12h to 50 DEG C.Ethyl acetate extracts, and organic facies Sal is washed, anhydrous MgSO4It is dried, removes solvent, column chromatography for separation under reduced pressure
Obtain compound 15 (24mg, 99% productivity).
Under argon shield, compound 15 (37mg, 0.14mmol) is dissolved in 2mL DMF, is sequentially added into potassium carbonate (25mg, 0.18mmol),
Bromobenzyl (30uL, 0.25mmol), room temperature reaction 2 hours, ethyl acetate extracts, and organic facies saturated common salt is washed, anhydrous MgSO4It is dried,
Removing solvent under reduced pressure, column chromatography for separation obtains YD-3 (39mg, 79% productivity).
Spectral data is as follows:
1H NMR(400MHz,CDCl3) δ=2.30 (s, 3H), 2.54 (brs, 1H), 6.08 (s, 1H), 7.08-7.12 (m, 3H), 7.21-7.25 (m,
2H), 7.29-7.32 (m, 1H), 7.49 (d, J=8.0Hz, 1H), 7.57 (dd, J=7.6,1.2Hz, 1H) ppm；13C NMR(100MHz,CDCl3)
δ=21.1,74.5,122.6,127.0,127.6,128.2,128.9,129.1,132.7,137. 4,139.2,142.5ppm.
1H NMR(400MHz,CDCl3) δ=2.42 (s, 3H), 7.24-7.26 (m, 2H), 7.31-7.35 (m, 2H), 7.38-7.42 (m, 1H), 7.63
(d, J=8.4Hz, 1H), 7.71 (d, J=8.4Hz, 2H) ppm；13C NMR(100MHz,CDCl3) δ=21.7,119.4,127.1,128.8,
129.3,130.3,130.9,133.1,133.6,140.9,144.8,195.4ppm.
1H NMR(400MHz,CDCl3) δ=1.41 (t, J=7.2Hz, 3H), 4.41 (q, J=7.2Hz, 2H), 7.36-7.47 (m, 3H),
7.65-7.67 (m, 1H), 7.86 (dd, J=6.8Hz, 1.6Hz, 2H), 8.13 (dd, J=6.8Hz, 1.6Hz, 2H) ppm；13C NMR(100MHz,
CDCl3) δ=14.2,61.5,119.5,127.4,129.2,129.7,129.9,131.6,133.3,134. 6,139.3,140.1,165.6,195.3ppm；
HRMS(ESI):Calcd for C16H14Br1O3[M+H]+:333.0121,found:333.0125.
1H NMR(400MHz,CDCl3) δ=1.42 (t, J=7.2Hz, 3H), 2.34 (s, 3H), 4.42 (q, J=7.2Hz, 2H), 7.24 (d, J=
8.0Hz, 2H), 7.40 (dd, J=7.2,7.2Hz, 1H), 7.58-7.62 (m, 1H), 7.91-7.93 (m, 3H), 8.00 (d, J=8.4,2H), 8.17 (d, J
=8.4,2H), 8.29 (d, J=8.8,2H) ppm；13C NMR(100MHz,CDCl3) δ=14.3,21.6,61.2,113.6,121.4,124.0,
124.6,127.6,128.0,129.2,129.8,130.0,131.2,134.5,135.6,141.8,145.4,150.4,166.1ppm；HRMS(ESI):
Calcd for C23H21N2O4S1[M+H]+:421.1217,found:421.1223.
1H NMR(400MHz,CDCl3) δ=1.43 (t, J=7.2Hz, 3H), 4.43 (q, J=7.2Hz, 2H), 7.23-7.27 (m, 1H), 7.40
(d, J=3.6Hz, 2H), 8.03 (d, J=8.0Hz, 1H), 8.08 (d, J=8.0Hz, 2H), 8.20 (d, J=8.4,2H) ppm；13C NMR(100
MHz,CDCl3) δ=14.3,61.1,110.3,120.9,121.9,127.1,127.3,129.8,130.1,137. 8,141.7,144.4,166.5ppm.
1H NMR(400MHz,d6-DMSO) δ=1.34 (t, J=7.2Hz, 3H), 4.34 (q, J=7.2Hz, 2H), 5.77 (s, 2H), 7.23-7.33
(m, 6H), 7.44-7.48 (m, 1H), 7.81 (d, J=8.4Hz, 1H), 8.10 (d, J=8.4Hz, 2H), 8.16 (dd, J=8.0,6.0Hz, 3H) ppm；13C NMR(100MHz,d6-DMSO) δ=14.2,52.1,60.8,110.6,120.9,121.0,121.9,126.66,126.73,127 .4,127.6,
128.6,128.8,129.8,137.2,137.7,141.0,141.5,165.5ppm.
Embodiment eight, the synthesis of axitinib:
Under argon shield, by 1,3-dibromobenzene (4.1g, 17.5mmol) and AlCl3(5.6g, 42mmol) is placed in bis-mouthfuls of bottles of 50ml, room
Under temperature, chloroacetic chloride (2.0ml, 28mmol) is slowly dropped into, drips complete system and be to slowly warm up to 100 DEG C, have a large amount of HCl gas to release,
Pyroreaction 1.5 hours.System drops to room temperature, is poured slowly in trash ice and concentrated hydrochloric acid.Ethyl acetate extracts, organic phases washed with water, Na2CO3Molten
Liquid and Sal washing, anhydrous MgSO4Being dried, remove solvent under reduced pressure, column chromatography for separation obtains compound 16a (4.5g, 93% productivity).
1.4g KOH is dissolved in 15ml water, is cooled to room temperature.Under room temperature, pyridine-2-formaldehyde (1.0ml, 10.5mmol) is dissolved in 5ml methanol
In, above-mentioned KOH solution is added thereto, under room temperature, methanol (30ml) solution of compound 16a (2.9g, 10.4mmol) is slowly dropped into
Reaction system.Room temperature reaction 1.5 hours, system has faint yellow solid to separate out, sucking filtration, washes to obtain compound 17a (3.8g, 99% productivity).
Under room temperature, compound 17a (167mg, 0.45mmol) and unifor (93mg, 0.50mmol) are dissolved in 2ml methanol, add
40ul concentrated hydrochloric acid, system is warming up to 50 DEG C of reaction 12h.Ethyl acetate extracts, organic facies Na2CO3Solution and Sal washing, anhydrous MgSO4
It is dried, removes solvent under reduced pressure.Under argon shield, gained crude product is dissolved in 2mL i-AmOH, adds Cu2O (33mg, 0.23mmol),
Temperature rising reflux reacts 10 hours, removes solvent under reduced pressure, and column chromatography for separation obtains compound 18a (189mg, 91% productivity).
Under room temperature, compound 18a (189mg, 0.45mmol) is dissolved in 4mL THF, adds TBAF (258mg, 0.83mmol), body
System is warming up to 50 DEG C of reaction 12h.Dichloromethane extracts, organic phases washed with water, anhydrous MgSO4It is dried, removes solvent, column chromatography for separation under reduced pressure
Obtain compound 19a (124mg, 99% productivity).
Under argon shield, compound 19a (30mg, 0.10mmol) and compound 20 (20mg, 0.12mmol) are dissolved in 2mL dioxy
In six rings, add i-Pr2NEt (35uL, 0.20mmol), Xantphos (6mg, 0.01mmol) and Pd (OAc)2(2mg, 0.01mmol),
Temperature rising reflux reacts 48 hours, removes solvent under reduced pressure, and column chromatography for separation obtains Axitinib (21mg, 54% productivity).
Spectral data is as follows:
1H NMR(400MHz,CDCl3) δ=2.62-2.63 (m, 3H), 7.37 (dd, J=8.0,1.2Hz, 1H), 7.50-7.53 (m, 1H),
7.80 (dd, J=2.8,1.6Hz, 1H) ppm；13C NMR(100MHz,CDCl3) δ=30.2,119.9,125.4,130.2,130.7,136.3,
139.9,200.1ppm.
1H NMR(400MHz,CDCl3) δ=7.28-7.36 (m, 2H), 7.43-7.56 (m, 4H), 7.72-7.82 (m, 2H), 8.67 (d, J=3.6
Hz,1H)ppm；13C NMR(100MHz,CDCl3) δ=120.4,124.7,124.8,124.9,128.8,130.3,130.6,135.9,136.8,
139.5,145.1,150.3,152.6,193.5ppm；HRMS(ESI):Calcd for C14H10Br2NO[M+H]+:367.9103,found:
367.9105.
1H NMR(400MHz,CDCl3) δ=2.36 (s, 3H), 7.21-7.28 (m, 3H), 7.45-7.50 (m, 2H), 7.62-7.83 (m, 4H),
7.90 (d, J=8.4Hz, 2H), 8.42 (d, J=1.6Hz, 1H), 8.63 (d, J=4.4Hz, 1H) ppm；13C NMR(100MHz,CDCl3) δ=
21.6,116.4,121.0,122.0,122.8,123.2,123.4,123.8,127.6,128.0,129.9,134.2,134.5,136.8,142.1,145.7,148.8,
149.8,154.2ppm；HRMS(ESI):Calcd for C21H17BrN3O2S[M+H]+:454.0219,found:454.0221.
1H NMR(400MHz,d6-DMSO) δ=7.26-7.29 (m, 1H), 7.35 (dd, J=8.4,1.2Hz, 1H), 7.54 (d, J=16.4Hz,
1H), 7.66 (d, J=7.6Hz, 1H), 7.78-7.82 (m, 2H), 7.90 (d, J=16.4Hz, 1H), 8.13 (d, J=8.4Hz, 1H), 8.58 (d, J=
4.0Hz,1H)ppm；13C NMR(100MHz,d6-DMSO) δ=113.5,120.0,120.2,122.7,122.9,123.6,124.6,129.8,
137.3,142.4,149.8,154.9ppm；HRMS(ESI):Calcd for C14H11Br1N3[M+H]+:300.0131,found:300.0138.
1H NMR(400MHz,d6-DMSO) δ=2.78 (d, J=4.4Hz, 3H), 7.05 (d, J=7.6Hz, 1H), 7.19 (d, J=8.8Hz,
1H), 7.25-7.34 (m, 3H), 7.50 (dd, J=7.2,1.6Hz, 1H), 7.58 (d, J=16.4Hz, 1H), 7.61 (s, 1H), 7.66 (d, J=8.0Hz,
1H), 7.78-7.83 (m, 1H), 7.96 (d, J=16.4Hz, 1H), 8.21 (d, J=8.8Hz, 1H), 8.39 (q, J=4.8Hz, 1H), 8.60 (d, J=
4.0Hz,1H),13.36(s,1H)ppm；13C NMR(100MHz,d6-DMSO) δ=26.5,115.0,120.7,122.1,122.8,123.0,
124.0,125.9,126.5,128.2,129.6,130.4,130.7,132.9,136.0,137.2,137.4,142.2,142.4,149.9,155.3,168.2ppm.
Embodiment nine, the synthesis of axitinib:
Under argon shield, by 1,3-diiodo-benzene (4.94g, 15.0mmol) and AlCl3(4.85g, 36.5mmol) is placed in bis-mouthfuls of bottles of 50ml,
Under room temperature, chloroacetic chloride (1.6ml, 22.5mmol) is slowly dropped into, drips complete system and be to slowly warm up to 100 DEG C, have a large amount of HCl gas to put
Go out, pyroreaction 1.5 hours.System drops to room temperature, is poured slowly in trash ice and concentrated hydrochloric acid.Ethyl acetate extracts, organic phases washed with water, Na2CO3
Solution and Sal washing, anhydrous MgSO4Being dried, remove solvent under reduced pressure, column chromatography for separation obtains compound 16b (3.2g, 58% productivity).
218mg KOH is dissolved in 5ml water, is cooled to room temperature.Under room temperature, pyridine-2-formaldehyde (0.2ml, 2.1mmol) is dissolved in 5ml methanol
In, above-mentioned KOH solution is added thereto, under room temperature, methanol (10ml) solution of compound 16b (615mg, 1.6mmol) is slowly dripped
Enter reaction system.Room temperature reaction 1.5 hours, system has faint yellow solid to separate out, sucking filtration, washes to obtain compound 17b (640mg, 84% productivity).
Under room temperature, compound 17b (200mg, 0.4mmol) and unifor (93mg, 0.5mmol) are dissolved in 5ml methanol, add 40
Ul concentrated hydrochloric acid, system is warming up to 50 DEG C of reaction 12h.Ethyl acetate extracts, organic facies Na2CO3Solution and Sal washing, anhydrous MgSO4
It is dried, removes solvent under reduced pressure.Under argon shield, gained crude product is dissolved in 2mL i-AmOH, adds Cu2O (33mg, 0.23mmol),
Temperature rising reflux reacts 10 hours, removes solvent under reduced pressure, and column chromatography for separation obtains compound 18b (133mg, 61% productivity).
Under room temperature, compound 18b (90mg, 0.2mmol) is dissolved in 2mL THF, adds TBAF (114mg, 0.4mmol), system
It is warming up to 50 DEG C of reaction 12h.Dichloromethane extracts, organic phases washed with water, anhydrous MgSO4Being dried, remove solvent under reduced pressure, column chromatography for separation obtains
Compound 19b (62mg, 99% productivity).
Under argon shield, compound 19b (35mg, 0.10mmol) and compound 20 (20mg, 0.12mmol) are dissolved in 2mL dioxy
In six rings, add i-Pr2NEt (35uL, 0.20mmol), Xantphos (6mg, 0.01mmol) and Pd (OAc)2(2mg, 0.01mmol),
Temperature rising reflux reacts 36 hours, removes solvent under reduced pressure, and column chromatography for separation obtains Axitinib (25mg, 64% productivity).
1H NMR(400MHz,CDCl3) δ=2.59 (s, 3H), 7.20 (d, J=8.0Hz, 1H), 7.75 (dd, J=8.0,1.6Hz, 1H), 8.32
(d, J=1.6Hz, 1H) ppm；13C NMR(100MHz,CDCl3) δ=29.3,92.0,97.8,129.4,137.2,143.0,148.5,200.7
ppm.
1H NMR(400MHz,CDCl3) δ=7.17 (d, J=8.0Hz, 1H), 7.30-7.32 (m, 1H), 7.41-7.55 (m, 3H), 7.73-7.79
(m, 2H), 8.31 (d, J=1.6Hz, 1H), 8.68 (d, J=4.4Hz, 1H) ppm；13C NMR(100MHz,CDCl3) δ=93.1,97.1,
124.7,124.9,128.4,129.7,136.9,137.1,143.5,145.4,147.7,150.3,152.7,194.9ppm.
1H NMR(400MHz,CDCl3) δ=2.36 (s, 3H), 7.22-7.28 (m, 3H), 7.73-7.47 (m, 1H), 7.62-7.80 (m, 5H), 7.89
(d, J=8.4Hz, 2H), 8.64 (s, 2H) ppm；13C NMR(100MHz,CDCl3) δ=21.6,95.4,121.0,122.1,122.4,123.9,
127.6,127.7,129.9,133.5,134.3,134.5,136.7,142.3,145.7,148.8ppm.
1H NMR(400MHz,d6-DMSO) δ=7.25-7.29 (m, 2H), 7.49-7.58 (m, 2H), 7.67 (d, J=8.0Hz, 1H),
7.78-7.82(m,1H),7.89-8.03(m,2H),8.59-8.60(m,1H),13.34(s,1H)ppm；13C NMR(100MHz,d6-DMSO)δ
=92.5,119.2,122.5,122.6,123.4,129.4,129.5,130.4,132.6,136 .8,142.1,142.6,149.5,154.8ppm.
1H NMR(400MHz,d6-DMSO) δ=2.78 (d, J=4.4Hz, 3H), 7.05 (d, J=7.6Hz, 1H), 7.19 (d, J=8.8Hz,
1H), 7.25-7.34 (m, 3H), 7.50 (dd, J=7.2,1.6Hz, 1H), 7.58 (d, J=16.4Hz, 1H), 7.61 (s, 1H), 7.66 (d, J=8.0Hz,
1H), 7.78-7.83 (m, 1H), 7.96 (d, J=16.4Hz, 1H), 8.21 (d, J=8.8Hz, 1H), 8.39 (q, J=4.8Hz, 1H), 8.60 (d, J=
4.0Hz,1H),13.36(s,1H)ppm；13C NMR(100MHz,d6-DMSO) δ=26.5,115.0,120.7,122.1,122.8,123.0,
124.0,125.9,126.5,128.2,129.6,130.4,130.7,132.9,136.0,137.2,137.4,142.2,142.4,149.9,155.3,168.2ppm.
Embodiment ten, the synthesis of YC-1:
Under argon shield, n-BuLi (1.7mL, 4.25mmol) is slowly dropped into the THF (10mL) of furan (0.4ml, 5.50mmol)
In solution, reacting 2 hours under room temperature, system drops to-80 DEG C, by THF (10mL) solution of o-bromobenzaldehye (0.4ml, 3.45mmol)
It is slowly dropped into, drips reaction 30min under complete low temperature.Ethyl acetate extracts, organic facies saturated ammonium chloride solution and Sal washing, anhydrous MgSO4
Being dried, remove solvent under reduced pressure, column chromatography for separation obtains compound 21 (813mg, 93% productivity).
Under argon shield, compound 21 (3.06g, 12.0mmol) is dissolved in dichloromethane (10mL), adds activity MnO2(10.0g,
114.9mmol), room temperature reaction 10 hours, it is filtered to remove MnO2, remove solvent under reduced pressure, column chromatography for separation obtain compound 22 (2.79g, 92%
Productivity).
Under room temperature, compound 22 (125mg, 0.50mmol) and unifor (103mg, 0.55mmol) are dissolved in 2ml methanol, add
40ul concentrated hydrochloric acid, system is warming up to 50 DEG C and reacts 12 hours.Ethyl acetate extracts, organic facies Na2CO3Solution and Sal washing, anhydrous
MgSO4It is dried, removes solvent under reduced pressure.Under argon shield, gained crude product is dissolved in 2ml i-AmOH, adds Cu2O(36mg,0.25
Mmol), temperature rising reflux reacts 10 hours, removes solvent under reduced pressure, and column chromatography for separation obtains compound 23 (156mg, 92% productivity).
Under argon shield, compound 23 (169mg, 0.50mmol) is dissolved in 5mL methanol, adds magnesium powder (120mg, 5.0mmol), room
Temperature reaction 3 hours, removes methanol under reduced pressure, and ethyl acetate extracts, organic facies saturated ammonium chloride solution and Sal washing, anhydrous MgSO4It is dried,
Removing solvent under reduced pressure, column chromatography for separation obtains compound 24 (87mg, 96% productivity).
Under argon shield, compound 24 (50mg, 0.27mmol) is dissolved in 2mL DMF, is sequentially added into potassium carbonate (75mg, 0.54mmol),
Bromobenzyl (40uL, 0.34mmol), room temperature reaction 12 hours, ethyl acetate extracts, and organic facies saturated common salt is washed, anhydrous MgSO4It is dried,
Removing solvent under reduced pressure, column chromatography for separation obtains compound 25 (63mg, 85% productivity).
Under argon shield, compound 25 (56mg, 0.20mmol) is dissolved in 1.5mL DMF, adds phosphorus oxychloride (190uL, 2mmol),
Room temperature reaction 1 hour, is slowly added to water (50mL) and terminates reaction, and ethyl acetate extracts, the saturated Na of organic facies2CO3Wash with Sal, nothing
Water MgSO4Being dried, remove solvent under reduced pressure, column chromatography for separation obtains compound 26 (51mg, 83% productivity).
Under ice-water bath, compound 26 (28mg, 0.10mmol) is dissolved in 1.5mL methanol, is sequentially added into CeCl3.7H2O(7mg,
0.02mmol), NaBH4(4mg, 0.11mmol), room temperature reaction 1 hour, ethyl acetate extracts, and organic facies Sal is washed, anhydrous MgSO4
Being dried, remove solvent under reduced pressure, column chromatography for separation obtains YC-1 (25mg, 89% productivity).
Spectral data is as follows:
1H NMR(400 MHz,CDCl3) δ=2.62 (s, 1H), 6.07 (d, J=3.2 Hz, 1H), 6.17 (s, 1H), 6.30 (dd, J=3.2,2.0 Hz,
1H), 7.16-7.20 (m, 1H), 7.35-7.40 (m, 2H), 7.53-7.66 (m, 1H), 7.68 (d, J=1.6 Hz, 1H) ppm；13C NMR(100 MHz,
CDCl3) δ=69.0,108.1,110.3,122.5,127.7,128.3,129.4,132.7,139.8,142 .7,154.4 ppm；HRMS(ESI):Calcd
for C11H9BrO2Na[M+Na]+:274.9678,found:274.9683.
1H NMR(400 MHz,CDCl3) δ=6.58 (dd, J=3.6,1.6 Hz, 1H), 7.04 (d, J=3.6 Hz, 1H), 7.34-7.45 (m, 3H),
7.64-7.66(m,1H),7.70(m,1H)ppm；13C NMR(100 MHz,CDCl3) δ=112.6,119.8,121.7,127.0,129.1,131.5,
133.3,139.4,148.0,151.7,182.6 ppm.
1H NMR(400 MHz,CDCl3) δ=2.32 (s, 3H), 6.57 (dd, J=3.2,2.0 Hz, 1H), 7.13 (d, J=3.2 Hz, 1H), 7.21
(d, J=8.0 Hz, 2H), 7.36-7.40 (m, 1H), 7.55-7.61 (m, 2H), 7.88 (d, J=8.4 Hz, 2H), 8.12 (d, J=8.0 Hz, 1H), 8.22
(d, J=8.8 Hz, 1H) ppm；13C NMR(100 MHz,CDCl3) δ=21.6,110.4,111.7,113.4,122.3,123.4,124.6,127.6,
129.3,129.8,134.5,141.4,143.3,143.7,145.3,147.2 ppm；HRMS(ESI):Calcd for C18H15N2O3S[M+H]+:
339.0978,found:339.0802.
1H NMR(400 MHz,CDCl3) δ=6.58 (dd, J=3.6,2.0 Hz, 1H), 6.97 (d, J=3.6 Hz, 1H), 7.21-7.25 (m, 1H),
7.37-7.39 (m, 1H), 7.40-7.47 (m, 1H), 7.60 (d, J=1.2 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H) ppm；13C NMR(100
MHz,CDCl3) δ=107.3,110.3,111.5,120.1,121.3,121.5,127.2,137.6,141.2,14 2.3,148.8 ppm.
1H NMR(400 MHz,CDCl3) δ=5.62 (s, 2H), 6.55 (dd, J=3.2,1.6 Hz, 1H), 6.92 (dd, J=3.2,0.4 Hz, 1H),
7.17-7.35 (m, 8H), 7.57 (dd, J=1.6,0.4 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H) ppm；13C NMR(100 MHz,CDCl3) δ=
53.1,106.9,109.5,111.4,121.3,121.6,126.7,127.0,127.7,128.7,136.3,136.6,140.4,142.1,148.8 ppm.
1H NMR(400MHz,CDCl3) δ=5.66 (s, 2H), 7.11 (d, J=4.0Hz, 1H), 7.22-7.41 (m, 9H), 8.26 (d, J=8.0
Hz,1H),9.74(s,1H)ppm；13C NMR(100MHz,CDCl3) δ=53.5,108.9,109.8,121.8,121.9,122.5,127.1,127.2,
128.0,128.8,134.9,136.1,140.5,152.0,154.9,177.2ppm.
1H NMR(400MHz,CDCl3) δ=4.74 (s, 2H), 5.65 (s, 2H), 6.47 (d, J=3.2Hz, 1H), 6.87 (d, J=3.2Hz,
1H), 7.20-7.37 (m, 8H), 8.05 (d, J=8.0Hz, 1H) ppm；13C NMR(100MHz,CDCl3) δ=53.2,57.6,107.9,109.6,
109.7,121.3,121.4,121.5,126.9,127.0,127.8,128.7,136.2,136.6,140.5,148.6,153.9ppm.
Embodiment 11, the synthesis of YC-1 analog 29a:
Under argon shield, compound 24 (37mg, 0.20mmol) is dissolved in 2mLDMF, is sequentially added into potassium carbonate (56mg, 0.40mmol),
Adjacent bromine bromobenzyl (61mg, 0.24mmol), room temperature reaction 12 hours, ethyl acetate extracts, and organic facies saturated common salt is washed, anhydrous MgSO4
Being dried, remove solvent under reduced pressure, column chromatography for separation obtains compound 27a (58mg, 81% productivity).
Under argon shield, compound 27a (39mg, 0.11mmol) is dissolved in 1.5mL DMF, adds phosphorus oxychloride (100uL, 1.1mmol),
Room temperature reaction 1 hour, is slowly added to water (50mL) and terminates reaction, and ethyl acetate extracts, the saturated Na of organic facies2CO3Wash with Sal, nothing
Water MgSO4Being dried, remove solvent under reduced pressure, column chromatography for separation obtains compound 28a (41mg, 98% productivity).
Under ice-water bath, compound 28a (32mg, 0.08mmol) is dissolved in 1.5mL methanol, is sequentially added into CeCl3.7H2O(7mg,
0.02mmol), NaBH4(4mg, 0.11mmol), room temperature reaction 1 hour, ethyl acetate extracts, and organic facies Sal is washed, anhydrous MgSO4
Being dried, remove solvent under reduced pressure, column chromatography for separation obtains compound 29a (25mg, 78% productivity).
Spectral data is as follows:
1H NMR(400MHz,CDCl3) δ=5.72 (s, 2H), 6.57 (dd, J=3.6,2.0Hz, 1H), 6.63-6.66 (m, 1H), 6.94-6.95
(m, 1H), 7.07-7.11 (m, 2H), 7.22-7.26 (m, 1H), 7.30-7.55 (m, 2H), 7.56-8.11 (m, 2H), 8.13 (d, J=0.8Hz, 1H)
ppm；13C NMR(100MHz,CDCl3) δ=52.7,107.1,109.4,111.4,121.2,121.5,121.7,122.0,127.0,127 .8,128.2,
129.1,132.6,136.0,136.9,140.8,142.3,148.7ppm；HRMS(ESI):Calcd for C18H14BrN2O[M+H]+:353.0284,
found:353.0287.
1H NMR(400MHz,CDCl3) δ=5.75 (s, 2H), 6.67 (dd, J=5.2,3.6Hz, 1H), 7.11-7.16 (m, 3H), 7.31-7.45
(m, 4H), 7.58-7.61 (m, 1H), 8.30 (d, J=8.0Hz, 1H), 9.75 (s, 1H) ppm；13C NMR(100MHz,CDCl3) δ=53.1,
109.0,109.7,121.6,121.9,122.2,122.7,127.5,127.8,128.2,129.4,132.8,135.40,135.43,140.9,152.1,154.7,
177.2ppm；HRMS(ESI):Calcd for C19H14BrN2O2[M+H]+:381.0233,found:381.0240.
1H NMR(400MHz,CDCl3) δ=4.74 (s, 2H), 5.73 (s, 2H), 6.47 (d, J=3.2Hz, 1H), 6.61 (dd, J=3.2Hz,
1H), 6.89 (d, J=3.2Hz, 1H), 7.08-7.12 (m, 2H), 7.22-7.24 (m, 1H), 7.32 (d, J=8.8Hz, 1H), 7.36-7.40 (m, 1H),
7.56-7.60 (m, 1H), 8.09 (d, J=8.0Hz, 1H) ppm；13C NMR(100MHz,CDCl3) δ=52.8,57.6,108.1,109.5,
109.6,121.1,121.59,121.63,122.0,127.1,127.8,128.1,129.1,132.7,135.9,136.7,140.8,148.5,154.0ppm；
HRMS(ESI):Calcd for C19H16BrN2O2[M+H]+:383.0390,found:383.0395.
Embodiment 12, the synthesis of YC-1 analog 29b:
Under argon shield, compound 24 (37mg, 0.20mmol) is dissolved in 2mL DMF, is sequentially added into potassium carbonate (56mg, 0.40mmol),
2,4-dichlorobenzyl chlorides (40uL, 0.29mmol), room temperature reaction 12 hours, ethyl acetate extracts, and organic facies saturated common salt is washed, anhydrous MgSO4
Being dried, remove solvent under reduced pressure, column chromatography for separation obtains compound 27b (62mg, 90% productivity).
Under argon shield, compound 27b (35mg, 0.10mmol) is dissolved in 1.5mL DMF, adds phosphorus oxychloride (100uL, 1.1mmol),
Room temperature reaction 1 hour, is slowly added to water (50mL) and terminates reaction, and ethyl acetate extracts, the saturated Na of organic facies2CO3Wash with Sal, nothing
Water MgSO4Being dried, remove solvent under reduced pressure, column chromatography for separation obtains compound 28b (28mg, 74% productivity).
Under ice-water bath, compound 28b (19mg, 0.05mmol) is dissolved in 1.5mL methanol, is sequentially added into CeCl3.7H2O(5mg,
0.01mmol), NaBH4(3mg, 0.08mmol), room temperature reaction 1 hour, ethyl acetate extracts, and organic facies Sal is washed, anhydrous MgSO4
Being dried, remove solvent under reduced pressure, column chromatography for separation obtains compound 29b (16mg, 84% productivity).
Spectral data is as follows:
1H NMR(400MHz,CDCl3) δ=5.69 (s, 2H), 6.57 (dd, J=3.6,2.0Hz, 1H), 6.67 (d, J=8.4Hz, 1H), 6.94
(d, J=3.6Hz, 1H), 7.05 (dd, J=8.4,2.0Hz, 1H), 7.22-7.31 (m, 2H), 7.37-7.41 (m, 2H), 7.59 (d, J=1.6Hz, 1H),
8.11 (d, J=8.4Hz, 1H) ppm；13C NMR(100MHz,CDCl3) δ=49.6,107.2,109.2,111.4,121.2,121.6,121.7,
127.2,127.5,129.21,129.23,132.9,133.0,134.0,137.1,140.7,142.3,148.6ppm；HRMS(ESI):Calcd for
C18H13Cl2N2O[M+H]+:343.0399,found:343.0403.
1H NMR(400MHz,CDCl3) δ=5.73 (s, 2H), 6.72 (d, J=8.4Hz, 1H), 7.08-7.12 (m, 2H), 7.32-7.47 (m, 5H),
8.29 (d, J=8.4Hz, 1H), 9.75 (s, 1H) ppm；13C NMR(100MHz,CDCl3) δ=50.0,109.1,109.5,121.7,122.0,
122.8,127.59,127.64,129.36,129.40,132.5,133.1,134.4,135.6,140.8,152.2,154.6,177.2ppm；HRMS(ESI):
Calcd for C19H13Cl2N2O2[M+H]+:371.0349,found:371.0354.
1H NMR(400MHz,CDCl3) δ=4.75 (s, 2H), 5.71 (s, 2H), 6.48 (d, J=3.6Hz, 1H), 6.64 (d, J=8.4Hz, 1H),
6.89 (d, J=3.2Hz, 1H), 7.06 (dd, J=8.4,2.0Hz, 1H), 7.24-7.32 (m, 2H), 7.38-7.42 (m, 2H), 8.09 (d, J=8.4Hz,
1H)ppm；13C NMR(100MHz,CDCl3) δ=49.7,57.6,108.2,109.3,109.7,121.2,121.67,121.75,127.3,12 7.5,
129.2,129.3,132.9,133.0,134.1,136.9,140.7,148.4,154.1ppm；HRMS(ESI):Calcd for C19H15Cl2N2O2
[M+H]+:373.0505,found:373.0510.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, although the present invention having been carried out in detail with reference to previous embodiment
Explanation, for a person skilled in the art, the technical scheme described in foregoing embodiments still can be modified by it, or to it
Middle part technical characteristic carries out equivalent.All within the spirit and principles in the present invention, any modification, equivalent substitution and improvement etc. made, all
Within protection scope of the present invention should being included in.
Claims (11)
1. a preparation method for indazole, its reaction expression is as shown in formula three.
Hydrazone used by the present invention is prepared through condensation reaction in methanol solvate by corresponding aldehydes or ketones and unifor or methylsulfonyl hydrazine.Wherein R1Can
For: hydrogen atom, C1-6Alkyl, phenyl, substituted-phenyl, benzyl, methylol, furyl, replacement or unsubstituted double bond；R2Can be: hydrogen is former
Son, fluorine atom, bromine atoms, atomic iodine, methoxyl group, hydroxyl, nitro, piperonyl；R3Can be: mesyl, p-toluenesulfonyl；X can
For: Cl, Br, I, preferably Br.
Second step reaction mantoquita used can be: CuO, Cu2O、Cu(OH)2、Cu2(OH)2CO3, preferably Cu2O.Solvent for use can be: i-AmOH,
T-AmOH, EtOH, MeOH, toluene, dioxane, preferably i-AmOH.Reaction temperature used is backflow.
Condition used by three-step reaction is TBAF and THF or Mg and methanol.
2. a preparation method for 1H-indazole-3-carboxylic acid, reaction equation is as shown in formula four, it is characterised in that the method comprises the following steps:
(1) compound 4 reacts into hydrazone with unifor in methanol.Hydrazone is cyclized generation indazole 5 under the effect of mantoquita, and reaction mantoquita used can be:
CuO、Cu2O、Cu(OH)2、Cu2(OH)2CO3, preferably Cu2O, solvent for use can be: i-AmOH, t-AmOH, EtOH, MeOH,
Toluene, dioxane, preferably i-AmOH, reaction temperature used is backflow.
(2) indazole 5 is sloughed p-toluenesulfonyl and is obtained compound 6, and reaction condition used is Mg and methanol.
(3) the oxidized reaction of compound 6 generates 1H-indazole-3-carboxylic acid, and reaction condition used is CrO3And H2SO4。
3. a synthetic method of lonidamine, reaction equation is as shown in formula five, it is characterised in that the method comprises the following steps:
(1) compound 6 is through the Benzylation compound 7 that reacts to obtain, and reaction benzylating reagent used is 2, and 4-dichlorobenzyl chloride, reaction is at K2CO3With in DMF
Carry out.
(2) the oxidized reaction of compound 7 generates lonidamine, and reaction condition used is CrO3And H2SO4。
4. a synthetic method for compound 8, reaction equation is as shown in formula five, it is characterised in that the method comprises the following steps:
(1) compound 6 is through the Benzylation compound 7 that reacts to obtain, and reaction benzylating reagent used is 2, and 4-dichlorobenzyl chloride, reaction is at K2CO3With in DMF
Carry out.
(2) the oxidized reacting generating compound of compound 78, reaction condition used is PCC and CH2Cl2。
5. compound 9 and a synthetic method for compound 10, reaction equation is as shown in formula six, it is characterised in that the method comprises the following steps:
(1) compound 6 is through the Benzylation compound 9 that reacts to obtain, and reaction benzylating reagent used is bromobenzyl, and reaction is at K2CO3Carry out with in DMF.
(2) the oxidized reacting generating compound of compound 9 10, reaction condition used is PCC and CH2Cl2。
6. a synthetic method of YD-3, reaction equation is as shown in formula seven, it is characterised in that the method comprises the following steps:
(1) o-bromobenzaldehye and Grignard reagent generate compound 11 through nucleophilic addition, and this reaction, at-80 DEG C, is carried out in THF solution.
(2) compound 11 is prepared for compound 12 through DMP oxidation, and this reaction at room temperature, is carried out in dichloromethane solution.
(3) compound 12 aoxidizes in nitric acid through ammonium ceric nitrate and can obtain compound 13 with ethyl esterified reaction, and ethyl esterified reagent used is iodoethane.
(4) compound 13 reacts into hydrazone in ethanol with unifor.Hydrazone is cyclized generation indazole 14 under the effect of mantoquita, and reaction mantoquita used can
For: CuO, Cu2O、Cu(OH)2、Cu2(OH)2CO3, preferably Cu2O, solvent for use can be: i-AmOH, t-AmOH, EtOH,
MeOH, toluene, dioxane, preferably i-AmOH, reaction temperature used is backflow.
(5) indazole 14 is sloughed p-toluenesulfonyl and is obtained compound 15, and reaction condition used is TBAF and THF.
(6) compound 15 completes the synthesis of YD-3 through Benzylation reaction, and reaction benzylating reagent used is benzyl chloride or bromobenzyl, and reaction is at K2CO3With
DMF is carried out.
7. a synthetic method of axitinib, reaction equation is as shown in formula eight, it is characterised in that the method comprises the following steps:
(1) 1,3-dibromobenzene and chloroacetic chloride prepare compound 16a by Friedel-Crafts reaction, and the condition used by this reaction is AlCl3。
(2) occur aldol reaction to generate compound 17a under the conditions of compound 16a and pyridine-2-formaldehyde alkalescence, the alkali used by this reaction be KOH or
NaOH, with water and methanol as solvent.
(3) compound 17a reacts into hydrazone with unifor in methanol.Hydrazone is cyclized generation indazole 18a under the effect of mantoquita, reaction mantoquita used
Can be: CuO, Cu2O、Cu(OH)2、Cu2(OH)2CO3, preferably Cu2O, solvent for use can be: i-AmOH, t-AmOH, EtOH,
MeOH, toluene, dioxane, preferably i-AmOH, reaction temperature used is backflow.
(4) indazole 18a sloughs p-toluenesulfonyl and obtains compound 19a, and reaction condition used is TBAF and THF.
(5) compound 19a and 20 completes the synthesis of axitinib by coupling reaction.Catalyst used by this reaction can be: Pd2(dba)3、Pd(OAc)2,
Part is Xantphos, and solvent for use can be: dioxane, DMF, DMSO, and alkali used can be: Li2CO3, Na2CO3, K2CO3、Cs2CO3、
i-Pr2NEt、i-Pr2NH、NEt3、NHEt2, preferably Cs2CO3Or i-Pr2NEt。
8. a synthetic method of axitinib, reaction equation is as shown in formula nine, it is characterised in that the method comprises the following steps:
(1) 1,3-diiodo-benzene and chloroacetic chloride prepare compound 16b by Friedel-Crafts reaction, and the condition used by this reaction is AlCl3。
(2) occur aldol reaction to generate compound 17b under the conditions of compound 16b and pyridine-2-formaldehyde alkalescence, the alkali used by this reaction be KOH or
NaOH, with water and methanol as solvent.
(3) compound 17b reacts into hydrazone with unifor in methanol.Hydrazone is cyclized generation indazole 18b under the effect of mantoquita, reaction mantoquita used
Can be: CuO, Cu2O、Cu(OH)2、Cu2(OH)2CO3, preferably Cu2O, solvent for use can be: i-AmOH, t-AmOH, EtOH,
MeOH, toluene, dioxane, preferably i-AmOH, reaction temperature used is backflow.
(4) indazole 18b sloughs p-toluenesulfonyl and obtains compound 19b, and reaction condition used is TBAF and THF.
(5) compound 19b and 20 completes the synthesis of axitinib by coupling reaction.Catalyst used by this reaction can be: Pd2(dba)3、Pd(OAc)2,
Part is Xantphos, and solvent for use can be: dioxane, DMF, DMSO, and alkali used can be: Li2CO3、Na2CO3、K2CO3、Cs2CO3、
i-Pr2NEt、i-Pr2NH、NEt3、NHEt2, preferably Cs2CO3Or i-Pr2NEt。
9. a synthetic method of YC-1, reaction equation is as shown in formula ten, it is characterised in that the method comprises the following steps:
(1) o-bromobenzaldehye and 2-furyl lithium generate compound 21 through nucleophilic addition, and this reaction, at-80 DEG C, is carried out in THF solution.
(2) compound 21 is through activity MnO2Oxidation is prepared for compound 22, and this reaction at room temperature, is carried out in dichloromethane solution.
(3) compound 22 reacts into hydrazone with unifor in methanol.Hydrazone is cyclized generation indazole 23 under the effect of mantoquita, and reaction mantoquita used can
For: CuO, Cu2O、Cu(OH)2、Cu2(OH)2CO3, preferably Cu2O, solvent for use can be: i-AmOH, t-AmOH, EtOH,
MeOH, toluene, dioxane, preferably i-AmOH, reaction temperature used is backflow.
(4) indazole 23 is sloughed p-toluenesulfonyl and is obtained compound 24, and reaction condition used is Mg and methanol.
(5) compound 24 is through the Benzylation compound 25 that reacts to obtain, and reaction benzylating reagent used is benzyl chloride or bromobenzyl, and reaction condition used is K2CO3
And DMF.
(6) compound 25 obtains compound 26 through Vilsmeier-Haack formylation reaction, and reaction condition used is POCl3And DMF.
(7) compound 26 is through NaBH4Reduction completes the synthesis of YC-1, and this reaction is carried out in methanol.
10. a synthetic method for YC-1 analog, reaction equation is as shown in formula 11, it is characterised in that the method comprises the following steps:
(1) compound 24 is through the Benzylation compound 27 that reacts to obtain, and reaction benzylating reagent used is substituted benzyl chloride or bromobenzyl, and reaction condition used is
K2CO3And DMF.
(2) compound 27 obtains compound 28 through Vilsmeier-Haack formylation reaction, and reaction condition used is POCl3And DMF.
(3) compound 28 is through NaBH4Reduction completes the synthesis of YC-1 analog, and this reaction is carried out in methanol.
11. methods according to claim 10, it is characterised in that benzylating reagent X used in the method step " (1) " can be Cl or Br,
R can be monosubstituted, two replacements or trisubstituted F, Cl, Br, I.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510345123.3A CN106316958B (en) | 2015-06-19 | 2015-06-19 | A kind of preparation method of indazole and its application in pharmaceutical synthesis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510345123.3A CN106316958B (en) | 2015-06-19 | 2015-06-19 | A kind of preparation method of indazole and its application in pharmaceutical synthesis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106316958A true CN106316958A (en) | 2017-01-11 |
| CN106316958B CN106316958B (en) | 2018-08-14 |
Family
ID=57728736
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510345123.3A Expired - Fee Related CN106316958B (en) | 2015-06-19 | 2015-06-19 | A kind of preparation method of indazole and its application in pharmaceutical synthesis |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106316958B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112574267A (en) * | 2019-09-28 | 2021-03-30 | 鲁南制药集团股份有限公司 | Epirubicin hydrochloride intermediate compound III |
| CN112574150A (en) * | 2019-09-28 | 2021-03-30 | 鲁南制药集团股份有限公司 | Epirubicin hydrochloride intermediate compound II |
-
2015
- 2015-06-19 CN CN201510345123.3A patent/CN106316958B/en not_active Expired - Fee Related
Non-Patent Citations (12)
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112574267A (en) * | 2019-09-28 | 2021-03-30 | 鲁南制药集团股份有限公司 | Epirubicin hydrochloride intermediate compound III |
| CN112574150A (en) * | 2019-09-28 | 2021-03-30 | 鲁南制药集团股份有限公司 | Epirubicin hydrochloride intermediate compound II |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106316958B (en) | 2018-08-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2003302220B2 (en) | Tricyclic steroid hormone nuclear receptor modulators | |
| JPH11322751A (en) | 7-hetero-bicyclo(2.2.1)-heptanes | |
| WO1995035298A1 (en) | PYRAZOLO[1,5-a]PYRIMIDINE DERIVATIVE | |
| JPH054983A (en) | Isoquinolinone derivative, its production and 5-ht3 receptor antagonist containing the derivative as active component | |
| JP2000507949A (en) | Piperazine and piperidine compounds | |
| CA2068766A1 (en) | Benzofuran derivatives | |
| WO1987000838A1 (en) | Novel benzothiazine derivatives | |
| CN106316958B (en) | A kind of preparation method of indazole and its application in pharmaceutical synthesis | |
| Besong et al. | A synthesis of (aR, 7S)-(−)-N-acetylcolchinol and its conjugate with a cyclic RGD peptide | |
| CN112939988B (en) | Synthesis method and anticancer activity research of indenopyrazolo pyrazolone compounds | |
| JPH08509972A (en) | Pyrimidine derivative | |
| JPH0317833B2 (en) | ||
| CA2729048A1 (en) | Substituted 7-sulfanylmethyl, 7-sulfinylmethyl and 7-sulfonylmethyl indoles and use thereof | |
| EP0109866A1 (en) | Sulfonyl urea derivatives, process for their preparation and pharmaceutical compositions containing them | |
| JP4181219B2 (en) | Ring-condensed dihydropyrans, process for their production and use thereof | |
| JPH06502658A (en) | dihydroxyindanone compound | |
| JP2726999B2 (en) | Imidazo [2,1-b] benzothiazole derivatives and anti-ulcer agents containing the compounds as active ingredients | |
| CN112174901B (en) | Synthesis method and anticancer activity of 1, 3-benzodiazepine compound | |
| WO2005121099A1 (en) | 2h or 3h-benzo[e]indazol-1-yle carbamate derivatives, the preparation and therapeutic use thereof | |
| CA2618110C (en) | Derivatives of 5-pyridazinyl-1-azabicyclo[3.2.1]octane, preparation method thereof and use of same in therapeutics | |
| WO1999002527A1 (en) | Naphthyridine derivatives | |
| KR20070044799A (en) | Pyrazoline derivatives useful for the treatment of cancer | |
| JP4566749B2 (en) | 3- (Cyclopenten-1-yl) -benzyl- or 3- (cyclopenten-1-yl) -heteroarylmethylamine derivatives and their use as medicaments for treating schizophrenia | |
| US3381005A (en) | 2, 5-dihydro-4-hydroxy-2-oxothiophen-3-carboxylates | |
| US4038413A (en) | Treating iron deficiency anaemia |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180814 Termination date: 20210619 |