CN116102500A - Method for synthesizing 6-chloro-2-methyl-2H-indazole-5-amine - Google Patents
Method for synthesizing 6-chloro-2-methyl-2H-indazole-5-amine Download PDFInfo
- Publication number
- CN116102500A CN116102500A CN202211539750.7A CN202211539750A CN116102500A CN 116102500 A CN116102500 A CN 116102500A CN 202211539750 A CN202211539750 A CN 202211539750A CN 116102500 A CN116102500 A CN 116102500A
- Authority
- CN
- China
- Prior art keywords
- reaction
- formula
- methyl
- chloro
- synthesizing
- 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.)
- Pending
Links
Images
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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a method for synthesizing 6-chloro-2-methyl-2H-indazole-5-amine, which aims at the problems of low safety, low selectivity, low yield, difficulty in obtaining high-purity products and the like in the existing route for synthesizing 6-chloro-2-methyl-2H-indazole-5-amine, and specifically comprises the following reaction steps: 1) Closing a ring of the compound of the formula A03 under the action of sodium nitrite to generate a compound of the formula A04; 2) Compounds of formula A04 in Me 3 OBF 4 Adding a methyl group under the condition to obtain a compound of a formula A05; 3) The compound of the formula A05 is coupled under the action of a catalyst to obtain the compound of the formula B06. 4) Removing PMB from formula B06 under the action of trifluoroacetic acid to obtain the final product. The synthesis method for synthesizing the 6-chloro-2-methyl-2H-indazole-5-amine has the characteristics of novel process route, short route, high chemical purity, easiness in production, environment friendliness, safety, environment friendliness and the like.
Description
Technical Field
The invention belongs to the field of organic chemical synthesis, and particularly relates to a synthesis method of 6-chloro-2-methyl-2H-indazole-5-amine.
Background
6-chloro-2-methyl-2H-indazol-5-amine is a key intermediate for the synthesis of S-217622 of salt wild-type therapeutic novel crown compounds. Ensitrelvir (S-217622) was the first orally active, non-covalent, non-peptide SARS-CoV-2 3CL protease inhibitor. The salt field announced that phase IIb clinical trial analysis of oral novel crown drug S-217622 was completed and production sales approval was applied to the Japanese Ministry of thick students based on phase IIb clinical data.
6-chloro-2-methyl-2H-indazol-5-amine structural formula
The current intermediate for preparing 6-chloro-2-methyl-2H-indazol-5-amine mainly has a synthetic route shown in the following figure. The reaction steps of the route are longer, the second step is a nitration reaction, the productivity is limited during the enlarged production, the selectivity is poor during the synthesis of the 6-chloro-5-nitro-2H-indazole compound in the fourth step, and the potential safety hazard is high during the reduction synthesis of the final product 6-chloro-2-methyl-2H-indazole-5-amine in the sixth step, so that the enlarged production is not suitable.
In view of the above, the development of new crown drugs requires 6-chloro-2-methyl-2H-indazol-5-amine as a pharmaceutical intermediate, however, there is still room for improvement in the current synthetic methods.
Disclosure of Invention
Aiming at the problems of low safety, low selectivity, low yield, difficulty in obtaining high-purity products and the like in the existing route for synthesizing 6-chloro-2-methyl-2H-indazole-5-amine, the invention provides a novel method for synthesizing 6-chloro-2-methyl-2H-indazole-5-amine.
In order to solve the problems of long existing route, low yield, environmental protection, large potential safety hazard and the like, the invention provides a novel method for synthesizing 6-chloro-2-methyl-2H-indazole-5-amine. The method specifically comprises the following reaction steps:
1) Closing a ring of the compound of the formula A03 under the action of sodium nitrite to generate a compound of the formula A04;
the specific operation is as follows:
AcOH (10 vol.), A03 (1.0 eq.) was added to a three-necked flask, stirred to clarify, and a solution of sodium nitrite (1.1 eq.) in water (0.5 vol.) was added dropwise to the reaction mixture, and stirred at room temperature (16 h), and the mixture was sampled and subjected to HPLC control.
Post-treatment: the reaction solution was cooled to 10-15 ℃, and then (20 vol.) ice water was slowly added dropwise (2 h) to the reaction solution, followed by stirring for 0.5h. Filtering, flushing a filter cake with ice water (2 vol.), flushing with n-heptane (2 vol.), and drying the filter cake to obtain yellow solid A04;
2) Compounds of formula A04 in Me 3 OBF 4 Adding a methyl group under the condition to obtain a compound of a formula A05;
the specific operation is as follows:
Post-treatment: filtration gave a yellow solid. The yellow solid was added to the reaction flask, etOAc (20 vol.) and water (10 vol.) were added and stirred, and the yellow solid dissolved. After stirring thoroughly, the insoluble material was filtered through celite, the organic phase was washed with saturated brine (5 vol..3), the organic phase was separated over flash silica gel and concentrated under reduced pressure to no fraction, huang Huise solid a05.
3) The compound of the formula A05 is coupled under the action of a catalyst to obtain the compound of the formula B06.
The specific operation is as follows:
a05 (1.0 eq.) was added to a three-necked flask and para-gram was addedMethoxybenzylamine (1.2 eq.) was added sodium tert-butoxide (3.0 eq.) and catalyst Pd (OAc) was added 2 (0.02 eq.) ligand BINAP (0.02 eq.) was added and dioxane solution (10 vol.) was added. The nitrogen is replaced for protection, the reaction liquid is stirred for reaction at 60-110 ℃, the reaction time can be about 16 hours, and sampling HPLC is used for central control.
Post-treatment: the reaction was cooled to room temperature, the reaction was filtered through celite, the cake was rinsed with EA, the filtrates were combined, and the filtrate was concentrated until no component was eluted. To the concentrated residue were added EtOAc (5 vol.) and water (3 vol.) and the solution was stirred. Separating the organic phase, concentrating and drying the organic phase to obtain purple black solid B06.
4) Removing PMB from formula B06 under the action of trifluoroacetic acid to obtain the final product.
The specific operation is as follows:
b06 (1.0 eq.) was placed in a three-necked flask, DCM (5 vol.) was added, stirring was turned on, organic solvent (6.0 eq.) was added, and after 16h sampling was centered.
Post-treatment: after the raw materials are consumed, the pH of the reaction solution is regulated to 7-8 by using saturated sodium bicarbonate aqueous solution, the reaction solution is stirred for 0.5h and then separated, the organic phase is concentrated and purified by a column to obtain A0.
Alternatively, a method is provided, comprising the steps of:
1) Closing a ring of the compound of the formula A03 under the action of sodium nitrite to generate a compound of the formula A04;
the specific operation is as follows:
AcOH (10 vol.), A03 (1.0 eq.) was added to a three-necked flask, stirred to clarify, and a solution of sodium nitrite (1.1 eq.) in water (0.5 vol.) was added dropwise to the reaction mixture, and stirred at room temperature (16 h), and the mixture was sampled and subjected to HPLC control.
Post-treatment: cooling the reaction solution to 10-15 ℃, then slowly dropwise adding (20 vol.) ice water into the reaction solution for 2h, stirring for 0.5h after dropwise adding, filtering, flushing a filter cake with ice water (2 vol.), flushing with n-heptane (2 vol.), and drying the filter cake to obtain yellow solid A04;
2) Compounds of formula A04 in Me 3 OBF 4 Adding a methyl group under the condition to obtain a compound of a formula A05;
the specific operation is as follows:
will Step 1 crude A04 (1.0 eq.) was added to a three-necked flask, etOAc (12 vol.) was added, and Me was added 3 OBF 4 (1.0 eq.) chloroform (2 vol.) suspension, stirred at room temperature, sampled and submitted to HPLC control.
Post-treatment: filtration gave a yellow solid, which was dissolved with EtOAc (20 vol.) and water (10 vol.) and after thorough stirring the insoluble material was filtered through celite, the organic phase was washed with saturated brine (5 vol..3), the organic phase was separated, the organic phase was over flash silica gel, and the eluent was collected and concentrated under reduced pressure to no fraction to give yellow grey solid a05.
3) A05 (2.46 g,10mmol,1.0 eq.) Cu 2 O (143 mg,1mmol,0.1 eq.), 1, 10-phenanthrine (1, 10-phenanthroline, 180mg,1mmol,0.1 eq.), K 3 PO 4 (4.24 g,20mmol,2.0 eq.) 20% ammonia (15 mL), DMSO (15 mL) was added to the autoclave. And replacing nitrogen for protection. The reaction kettle is placed in an oil bath at 60-150 ℃ for reaction for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature. To the reaction was added water and EtOAc, the solution was separated, and the aqueous phase was extracted with EtOAc. The organic phases were combined, washed 4 times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phases were collected and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography to give the objective compound A0 (1.57 g,87% yield).
The reaction circuit is as follows:
a typical reaction scheme is as follows, wherein X is bromo and R is H:
preferred embodiments of the invention:
1) Preferably, the compounds of the formulae A03, A04 and A05 are of the formula A03, wherein the X position is iodine or bromine, preference being given to using brominated compounds as starting materials;
2) Preferably, the catalyst in step 3) is BocNH 2 Or at least one of p-methoxybenzylamine, wherein R can be H, benzyl, p-methoxybenzyl, boc, cbz or Formoc protecting groups;
3) Preferably, the organic solvent in the step 4) is at least one of ceric ammonium nitrate, triphosgene and trifluoroacetic acid.
The synthesis method for synthesizing the 6-chloro-2-methyl-2H-indazole-5-amine has the advantages of novel process route, short route, high chemical purity, easy production, environment friendliness, safety, environment friendliness and the like, and is particularly as follows:
1) The starting materials are cheap, and the sodium nitrite can be used for closing the ring to obtain the formula A04, so that a nitration reaction route with limited productivity is avoided; the original route is 6 steps, and the route of the invention is a method of 3 steps or 4 steps, and the overall yield can reach more than 63%.
2) The compound of formula A04 has selectivity in the position of methyl group in the process of using methylating agent to obtain compound of formula A05, wherein both nitrogen positions in formula A04 can be methyl groups, we choose Me 3 OBF 4 Is a methylation reagent, and the selectivity is 100%.
Drawings
FIGS. 1-3 are LC-MS spectra in LCMS of A04;
FIG. 4 is a HNMR diagram of A04;
FIGS. 5-7 are LCMS spectra of A05;
FIG. 8 is a HNMR profile of A05;
FIG. 9 is a nuclear magnetic two-dimensional hydrogen spectrum of A05;
FIGS. 10-12 are LC-MS spectra of B06;
FIG. 11 is a positive signal of MS spectrum in LCMS of B06;
FIG. 12 is a MS spectrum in LCMS of B06;
FIG. 13 is a HNMR profile of A0;
FIGS. 14-16 are LC-MS spectra of A0.
Detailed Description
Example 1
AcOH acetate (400 mL), A03 (40.0 g,1.0 eq.) was added to a three-necked flask, stirred to clarify, and a solution of sodium nitrite (13.77 g,1.1 eq.) in water (27 mL) was added dropwise to the reaction mixture, followed by stirring overnight (16 h) at room temperature. HPLC confirmed no starting material for post-treatment, purity 75.67% in a04.
post-treatment: the reaction solution is cooled to 10-15 ℃, and then 800mL of ice water is slowly added dropwise (2 h) into the reaction solution, and stirring is completed for 0.5h. Filtration, washing of the filter cake with ice water (100 mL), washing with n-heptane (100 mL) and drying of the filter cake gave 33.5g of yellow solid A04 in 79.8% yield.
A04 characterization data: 1 H NMR(400MHz,DMSO):δ13.35(s,1H),8.25(s,1H),8.10(s,1H),8.10(s,1H),7.87(s,1H).
FIGS. 1-3 show LC-MS spectra in LCMS of A04, from which it can be seen that the MS positive ion signal of A04 coincides with the structure.
Fig. 4 is a HNMR diagram of a04, from which it can be seen that a04 is structurally correct.
Into a three-necked flask, was added formula A04 (1.0 g,1.0 eq.) and ethyl acetate EtOAc (20 mL) and trimethyloxonium tetrafluoroborate Me were added 3 OBF 4 (1.1 eq.) the chloroform suspension was stirred at room temperature for 0.5h, sampled, centrally controlled, and post-treated after no starting material.
Post-treatment: filtering, separating the filter cake after being cleaned by EA and water, washing an organic phase by saturated saline, separating the liquid, and concentrating and drying the organic phase to obtain yellow solid A05.96 g, wherein the yield is 90.4 percent and the selectivity is 100 percent.
A05 characterization data: 1 H NMR(400MHz,DMSO):δ8.41(s,1H),8.23(s,1H),7.95(s,1H),4.18(s,3H).
FIGS. 5-7 show LCMS spectra of A05, from which it can be seen that the MS positive ion signal of A05 coincides with the structure.
FIG. 8 shows the HNMR of A05, FIG. 9 shows the nuclear magnetic two-dimensional hydrogen spectrum of A05, and from FIGS. 8-9, it can be determined that A05 is structurally correct, and that the methyl group is at the 2-position, without the impurity of the isomer.
A05 (31.0 g,1.0 eq.) was added to a three-necked flask and para-sterilizedMethoxybenzylamine (20.79 g,1.2 eq.), potassium carbonate (0.34 g,3.0 eq.), cuI (0.0155 g,0.1 eq.), DMSO (2 mL), 1,10-phenanthroline (0.0294 g,0.2 eq.). Reflux for 16h at 100℃under nitrogen, sampling and HPLC control. After the post-treatment, the target intermediate B06 with the yield of 85 percent is obtained, B06 is
FIGS. 10-12 are LC-MS spectra of B06, from which it can be seen that the B06 positive ion signal coincides with the structure.
FIG. 11 is a positive signal of MS spectrum in LCMS of B06;
fig. 12 is an MS spectrum in LCMS of B06.
B06 (45.0 g,1.0 eq.) was placed in a three-necked flask, DCM (225 mL,5 vol.) was added, stirring was turned on, trifluoroacetic acid (102.01 g,6.0 eq.) was added, and after 16h sampling was centered. Post-treatment: after the raw materials are consumed, the pH of the reaction solution is regulated to 7-8 by saturated sodium bicarbonate aqueous solution, the reaction solution is stirred for 0.5h and then separated, and the organic phase is concentrated to obtain the product with the formula A0, the yield is 95%, and the purity is 99.35%.
A0 characterization data: 1 H NMR(400MHz,DMSO):δ7.98(s,1H),7.58(s,1H),6.88(s,1H),4.94(s,2H),4.06(s,3H).
FIG. 13 shows the HNMR pattern of A0, and it can be seen from the figure that the nuclear magnetic pattern of A0 is consistent with the structure.
FIGS. 14-16 are LC-MS spectra of A0, from which it can be seen that the positive ion signal of A0 coincides with the structure.
Example 2
In this example, the method for producing a05 may be the method of example 1 or another method.
A05 (2.46 g,10mmol,1.0 eq.) Cu 2 O(143mg,1mmol,0.1eq.),1,10-phenanthroline(180mg,1mmol,0.1eq.),K 3 PO 4 (4.24 g,20mmol,2.0 eq.) 20% ammonia (15 mL), DMSO (15 mL) was added to the autoclave. And replacing nitrogen for protection. The reaction vessel was placed in an oil bath at 140℃for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature. Reaction toTo the solution was added water and EtOAc, the solution was separated, and the aqueous phase was extracted with EtOAc. The organic phases were combined, washed 4 times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phases were collected and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography to give the objective compound A0 (1.57 g,87% yield).
Example 3
Formula a04 (1.0 g,1.0 eq.) was added to a three-necked flask, THF (20 mL) was added, methyl iodide (1.0 eq.) was added, and Cy was added 2 NMe (1.0 eq.) was stirred at room temperature for 0.5h, sampled, centrally controlled, and post-treated after no starting material.
Post-treatment: the mixture was filtered, the filter cake was washed with EtOAc and water, the organic phase was washed with brine, the separated solution and the organic phase was concentrated to dryness to give a yellow solid a05 in 75% yield with 100% methylation selectivity.
Example 4
In this example, the procedure used in step 2 was as follows, with the other steps being the same as in example 1.
Add formula A04 (1.0 g,1.0 eq.) to a three-necked flask, add DCM (20 mL), add CCl 3 CNHOMe (1.0 eq.) and CF was added 3 SO 3 H (1.0 eq.) is stirred for 0.5H at 30 ℃ with heat preservation, sampling, inspection and center control, and after no raw material is adopted, the post treatment is carried out.
Post-treatment: filtering, separating the filter cake after being cleaned by EA and water, washing an organic phase by saturated saline, separating the liquid, and concentrating and drying the organic phase to obtain yellow solid A05, wherein the yield is 90 percent and the methylation selectivity is 100 percent.
Example 5
A05 (2.0 g,1.0 eq.) was added to a three-necked flask and BocNH was added 2 (1.15 g,1.2 eq.). Potassium phosphate (5.19 g,3.0 eq.) was added, and catalyst Pd (OAc) was added 2 (0.0366 g,0.02 eq.) ligand XantPhos (0.1886 g,0.04 eq.) and dioxane solution (40 mL,20 vol.) are added. Reflux is carried out for 16h at 100 ℃ under the protection of nitrogen, sampling HPLC is used for central control, and the purity of the product formula A06 is 88.84%.
Example 6
In this example, the procedure used in step 3 was as follows, with the other steps being the same as in example 1.
A05 (31.0 g,1.0 eq.) is added to a three-necked flask, p-methoxybenzylamine (20.79 g,1.2 eq.) is added, potassium carbonate (0.34 g,3.0 eq.), cuI (0.0155 g,0.1 eq.), DMSO (2 mL), 1,10-phenanthroline (0.0294 g,0.2 eq.). Reflux for 16h at 100℃under nitrogen, sampling and HPLC control. Post-treatment to obtain the target intermediate B0685% yield.
Example 7
In this example, the procedure used in step 3 was as follows, with the other steps being the same as in example 1.
A05 (31.0 g,1.0 eq.) was added to a three-necked flask and PMBNH was added 2 (20.79 g,1.2 eq.) sodium tert-butoxide (36.40 g,3.0 eq.) and catalyst Pd (OAc) were added 2 (0.5670 g,0.02 eq.) ligand BINAP (3.1491 g,0.02 eq.) was added and dioxane solution (310 ml,10 vol.) was added. Reflux for 16h at 100℃under nitrogen, sampling and HPLC control.
Post-treatment: cooling to room temperature, filtering the reaction solution with diatomite, washing a filter cake with EA, combining the filtrates, concentrating the filtrate until no component flows out, dissolving the filtrate with EA (100 mL) and water (50 mL), separating the solution, and concentrating the organic phase to dryness to obtain a purple black solid B06.
Example 8
In this example, the method of preparing B06 may be the method of example 1 or another method.
B06 (1.0 g,1.0 eq.) was placed in a three-necked flask, acetonitrile (1 mL,1 vol.) was added, water (1 mL,1 vol.) was stirred on, ceric ammonium nitrate (0.37 g,2.5 eq.) was added in portions, and after stirring at room temperature for 16h, sampling was performed. Post-treatment: after the raw materials are consumed, the pH of the reaction solution is regulated to 7-8 by using saturated sodium bicarbonate aqueous solution, the reaction solution is stirred for 0.5h and separated, the organic phase is concentrated and purified by a column, and the A0 is obtained with the yield of 70 percent.
Example 9
In this example, the method of preparing B06 may be the method of example 1 or another method.
B06 (1.0 g,1.0 eq.) was placed in a three-necked flask, DCM (2 mL,2 vol.) was added, stirring was turned on, triphosgene (0.20 g,2.5 eq.) was added, stirring was performed at room temperature for 16h, and then sampling was performed for center control. Post-treatment: after the raw materials are consumed, the pH of the reaction solution is regulated to 7-8 by using saturated sodium bicarbonate aqueous solution, the reaction solution is stirred for 0.5h and separated, the organic phase is concentrated and purified by a column, and the A0 is obtained with the yield of 75 percent.
Example 10
In this example, the method of preparing B06 may be the method of example 1 or another method.
B06 (45.0 g,1.0 eq.) was placed in a three-necked flask, DCM (225 mL,5 vol.) was added, stirring was turned on, trifluoroacetic acid (102.01 g,6.0 eq.) was added, and after 16h sampling was centered. Post-treatment: after the raw materials are consumed, the pH of the reaction solution is regulated to 7-8 by using saturated sodium bicarbonate aqueous solution, the reaction solution is stirred for 0.5h and then separated, and the organic phase is concentrated to obtain the product of the formula A0, and the yield is 95%.
1 H NMR(400MHz,DMSO):δ7.98(s,1H),7.58(s,1H),6.88(s,1H),4.94(s,2H),4.06(s,3H)。
Example 11
In this example, the method for producing a05 may be the method of example 1 or another method. In this example, step 5 (i.e., step 5 in the reaction scheme) is used instead of step 3 and step 4 for A05.
A05 (2.46 g,10mmol,1.0 eq.) Cu 2 O(143mg,1mmol,0.1eq.),1,10-phenanthroline(180mg,1mmol,0.1eq.),K 3 PO 4 (4.24 g,20mmol,2.0 eq.) 20% ammonia (15 mL), DMSO (15 mL) was added to the autoclave. And replacing nitrogen for protection. The reaction vessel was placed in an oil bath at 140℃for 24 hours.After the reaction was completed, the reaction solution was cooled to room temperature. To the reaction was added water and EtOAc, the solution was separated, and the aqueous phase was extracted with EtOAc. The organic phases were combined, washed 4 times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phases were collected and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography to give the objective compound A0 (1.57 g,87% yield).
Claims (6)
1. A method of synthesizing 6-chloro-2-methyl-2H-indazol-5-amine, comprising the steps of:
1) Closing a ring of the compound of the formula A03 under the action of sodium nitrite to generate a compound of the formula A04;
2) Compounds of formula A04 in Me 3 OBF 4 Adding a methyl group under the condition to obtain a compound of a formula A05;
3) Will A05, cu 2 O,1,10-phenanthroline,K 3 PO 4 Adding 20% ammonia water and DMSO into a high-pressure reaction kettle, replacing nitrogen for protection, and placing the reaction kettle into an oil bath at 60-150 ℃ for reaction. After the reaction was completed, the reaction solution was cooled to room temperature, water and EtOAc were added to the reaction solution, the solution was separated, and the aqueous phase was extracted with EtOAc; the organic phases are combined, washed, dried, filtered, the organic phases are collected and concentrated under reduced pressure to obtain crude products, and the obtained crude products are purified to obtain the target compound A0.
2. The method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 1, wherein said method comprises the step of replacing said step 3) with the following steps:
3.1 Coupling the compound of the formula A05 under the action of a catalyst to obtain a compound of the formula B06;
3.2 Removing PMB from formula B06 under the action of trifluoroacetic acid to obtain the final product.
3. The method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 1, wherein the specific steps of step 3.1) are:
a05, adding the mixture into a reaction vessel, sequentially adding p-methoxybenzylamine, sodium tert-butoxide, a catalyst and a ligand BINAP, adding dioxane solution, replacing nitrogen protection, and reacting at 60-110 ℃;
the reaction solution was cooled to room temperature, filtered, the filter cake was washed, the filtrates were combined, the filtrate was concentrated until no component flowed out, the solution was separated with EtOAc and water, and the organic phase was concentrated and dried to give a purple black solid B06.
4. The method of synthesizing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 1, wherein the catalyst of step 3.1) is BocNH 2 Or at least one of p-methoxybenzylamine.
The method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 1, wherein the specific steps of step 3.2) are:
placing B06 in a reaction vessel, adding DCM, starting stirring, adding an organic solvent, and reacting;
after the reaction is finished, the pH of the reaction solution is regulated to 7-8, the reaction solution is separated after stirring, the organic phase is concentrated, and the reaction solution is purified by a column to obtain A0.
5. The method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 1, wherein the specific steps of step 1) are:
adding AcOH and A03 into a reaction container, stirring and clarifying, dripping an aqueous solution of sodium nitrite into the reaction liquid, and stirring at room temperature until the reaction is complete;
cooling the reaction liquid to 10-15 ℃, then slowly dripping ice water into the reaction liquid, stirring continuously after dripping, filtering, flushing a filter cake, and drying the filter cake to obtain yellow solid A04.
6. The method for synthesizing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 1, wherein the specific steps of step 2) are:
adding the crude product A04 in the step 1) into a reaction vessel, adding EtOAc and Me 3 OBF 4 Is stirred at room temperature overnight;
the reaction solution was filtered to give a yellow solid, which was dissolved with EtOAc and water, and after thorough stirring, the insoluble material was filtered, the organic phase was washed, separated, the organic phase was silica gel flash and the eluent was concentrated to give a yellow grey solid a05.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211539750.7A CN116102500A (en) | 2022-12-02 | 2022-12-02 | Method for synthesizing 6-chloro-2-methyl-2H-indazole-5-amine |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211539750.7A CN116102500A (en) | 2022-12-02 | 2022-12-02 | Method for synthesizing 6-chloro-2-methyl-2H-indazole-5-amine |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116102500A true CN116102500A (en) | 2023-05-12 |
Family
ID=86264666
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211539750.7A Pending CN116102500A (en) | 2022-12-02 | 2022-12-02 | Method for synthesizing 6-chloro-2-methyl-2H-indazole-5-amine |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116102500A (en) |
-
2022
- 2022-12-02 CN CN202211539750.7A patent/CN116102500A/en active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2928242C (en) | Process for the preparation of a pde4 inhibitor | |
AU1461401A (en) | Process and intermediates for the preparation of imidazolidinone alpha v integrin antagonists | |
CN114605328A (en) | Preparation method of 6-chloro-2-methyl-2H-indazole-5-amine | |
CN108727334A (en) | A kind of production technology of dabigatran etexilate methanesulfonate | |
US6924291B2 (en) | Process for making spiro isobenzofuranone compounds | |
JP6692408B2 (en) | Dimer impurities of apixaban and method for removing the same | |
CN116102500A (en) | Method for synthesizing 6-chloro-2-methyl-2H-indazole-5-amine | |
CN111233866B (en) | Process for the preparation of tofacitinib or a salt thereof | |
CN111320548A (en) | Synthesis method of anticancer drug intermediate 2-fluoro-3-methyl aminobenzoate | |
CN114591273B (en) | Synthesis method and application of N-methyl-N' -tetrahydrofuranyl propylenediamine oxalate | |
CN115960059A (en) | Method for synthesizing furosemide impurity D with high yield and high purity | |
JP7237385B2 (en) | Synthesis of 3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl)-2-hydroxybenzonitrile | |
US6407241B1 (en) | Process and intermediates for the preparation of imidazolidinone αv integrin antagonists | |
US6111109A (en) | Process for the preparation of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide | |
CN114341155A (en) | Preparation method of peptide amide compound and intermediate thereof | |
JP2022535112A (en) | 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1 ,5-a]pyrazin-2-yl]-carboxylic acids | |
WO2016071382A1 (en) | Synthesis of pi3k inhibitor and salts thereof | |
CN111995569B (en) | Preparation method of cyclin-dependent kinase inhibitor intermediate | |
EP4375282A1 (en) | Preparation method for hepatitis b virus nucleocapsid inhibitor | |
US4011231A (en) | 2-Phenyl-6-(1-hydroxy-2-t-butylaminoethyl)-4H-pyrido[3,2-d]-1,3-dioxin maleate and its use as an intermediate | |
CN111100112B (en) | Benzothiophene derivative and process for producing the same | |
NL8003822A (en) | PROCESS FOR THE PREPARATION OF EBURAN DERIVATIVES. | |
CN118047687A (en) | Compound for modifying 20 (S) camptothecin structure and synthesis method thereof | |
CN114213261A (en) | Preparation method of 4-methoxy-2-nitroaniline | |
JP2023532317A (en) | Intermediate for synthesizing camptothecin derivative, method for producing the same, and use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |