CN112608303B - Piperazine intermediate, preparation method and application thereof - Google Patents
Piperazine intermediate, preparation method and application thereof Download PDFInfo
- Publication number
- CN112608303B CN112608303B CN202011560939.5A CN202011560939A CN112608303B CN 112608303 B CN112608303 B CN 112608303B CN 202011560939 A CN202011560939 A CN 202011560939A CN 112608303 B CN112608303 B CN 112608303B
- Authority
- CN
- China
- Prior art keywords
- piperazine
- chloro
- tetrazol
- indole
- phenylpropionamido
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application belongs to the technical field of chemical drugs and relates to a piperazine intermediate and a preparation method and application thereof, wherein the preparation method comprises the following steps: the anhydrous dimethyl sulfoxide solvent of the 5-chloro-2- (1H-tetrazole-1-yl) phenyl tetrafluoroborate diazonium salt and the piperazine-2, 3-diketone are added into the alkaline solution and react under the action of the catalyst to generate the 1- (5-chloro-2- (1H-tetrazole-1-yl) phenyl) piperazine-2, 3-diketone, so that the adoption of a virulent compound can be avoided, the safe production is realized, the production process is simple, the product yield is high, the purity is good, and the industrial application is facilitated.
Description
Technical Field
The application relates to the technical field of chemical drugs, in particular to a piperazine intermediate and a preparation method and application thereof.
Background
Antithrombotic drugs are mainly classified into antiplatelet drugs (such as clopidogrel, aspirin, ticagrelor and the like), anticoagulant drugs (such as heparin, low molecular heparin, hirudin, warfarin and the like) and thrombolytic drugs (such as urokinase, streptokinase, plasmin and the like). In clinical application, antiplatelet drugs and anticoagulant drugs are mainly used for preventing arterial and venous thrombosis, and thrombolytic drugs are used for dissolving thrombus.
The human coagulation process comprises two processes: the intrinsic pathway and the extrinsic pathway and a common pathway. The extrinsic pathway is the binding of tissue factor to activated factor vii (fviia) to form a complex under injury and various external stimuli, which then reactivates factor x (fx) to form activated fx (fxa). FXa converts prothrombin into thrombin, and thrombin catalyzes fibrinogen to form fibrin, thereby playing a role in blood coagulation. The intrinsic pathway belongs to the intrinsic pathway of the body, and all factors involved in blood coagulation come from blood. Factor xii (fxii), activated fxii (fxiia), activated factor xi (fxi), activated fxi (fxia), activated factor ix (fix), activated fix (fixa) and thus FX, are activated by a cascade reaction. Thrombin is then produced via a common pathway, which in turn activates FXI.
The risk of bleeding is a major problem with antithrombotic drugs. Therefore, coagulation factors that target the intrinsic pathway without affecting the extrinsic and common pathways are ideal anti-thrombotic drug targets. In view of the unique role of FXI/FXIa in coagulation pathways and coagulation processes, as well as the important feature that FXI gene defects can prevent thrombosis and do not significantly increase the risk of bleeding, FXI/FXIa has become an important target for the development of novel anticoagulant drugs.
At present, there are patent reports of macrocyclic derivatives as FXIa inhibitors from several companies, such as BMS patents WO2011100401, WO2011100402, WO2013022814, WO2013022818, WO2014022766, WO2014022767, WO2015116882, WO2015116885, WO2015116886 and WO 2016053455; patents WO2017074832 and WO2017074833 from Merck corporation; patent WO2018133793 from toyokuang pharmaceutical co.
However, the current synthetic route of the macrocyclic derivatives is complicated, and toxic compounds are used in the synthetic process, which is not favorable for safe production.
Disclosure of Invention
In view of the problems and requirements in the prior art, the application provides the piperazine intermediate and the preparation method and application thereof, so that toxic compounds can be avoided, safe production can be realized, the process is simple, and the industrial application is facilitated.
In a first aspect, the application provides a preparation method of a piperazine intermediate, which specifically comprises the following steps:
adding an anhydrous dimethyl sulfoxide solvent of 5-chloro-2- (1H-tetrazol-1-yl) phenyl tetrafluoroborate diazonium salt and piperazine-2, 3-dione into an alkaline solution, and reacting under the action of a catalyst to generate 1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) piperazine-2, 3-dione;
preferably, the preparation method further comprises the following steps:
a: reacting 5-chloro-2-fluoronitrobenzene with tetrazole under an alkaline condition to generate 1- (4-chloro-2-nitrophenyl) -1H-tetrazole;
b, adding 1- (4-chloro-2-nitrophenyl) -1H-tetrazole into an ester solvent, and reacting with stannous chloride dihydrate under an acidic condition to generate 5-chloro-2- (1H-tetrazole-1-yl) aniline;
c, reacting 5-chloro-2- (1H-tetrazol-1-yl) aniline with sodium nitrite aqueous solution and tetrafluoroboric acid to generate 5-chloro-2- (1H-tetrazol-1-yl) phenyl tetrafluoroboric acid diazonium salt;
preferably, the catalyst comprises ketone iodide and tetrabutylammonium iodide, and the alkaline solution comprises one of N, N-dimethylethylenediamine and N, N-dimethylformamide, preferably N, N-dimethylethylenediamine.
Preferably, the diazonium salt of 5-chloro-2- (1H-tetrazol-1-yl) benzenetetrafluoroborate is reacted with piperazine-2, 3-dione in N2And under protection, keeping the temperature at 110 ℃ for reaction for 8-16h, preferably 12 h.
In a second aspect, the present application also provides a process for producing a piperazine compound, which comprises producing the piperazine compound further using the intermediate (I) produced by the process for producing a piperazine intermediate (I) according to any one of the above.
Preferably, the method further comprises:
(1) reacting said intermediate (I)1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) piperazine-2, 3-dione with intermediate (II) (R) -5- (2- (((4-nitrophenyl) sulfonyl) oxy) -3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester in basic solution to give (S) -5- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2, 3-dioxopiperazin-1-yl) -3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester;
(2) reacting (S) -tert-butyl 5- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2, 3-dioxopiperazin-1-yl) -3-phenylpropionamido) -1H-indole-2-carboxylate with trifluoroacetic acid to give the piperazine compound (S) -5- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2, 3-dioxopiperazin-1-yl) -3-phenylpropionamido) -1H-indole-2-carboxylic acid;
preferably, the preparation method of the intermediate (II) comprises the following steps:
reacting (R) -2-hydroxy-3-phenylpropionic acid with tert-butyl 5-amino-1H-indole-2-carboxylate to produce tert-butyl (R) -5- (2-hydroxy-3-phenylpropionamido) -1H-indole-2-carboxylate;
reacting (R) -5- (2-hydroxy-3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester with 4-nitrobenzenesulfonyl chloride to generate (R) -5- (2- (((4-nitrophenyl) sulfonyl) oxy) -3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester;
preferably, in the first step of reaction, firstly, dissolving (R) -2-hydroxy-3-phenylpropionic acid in dry tetrahydrofuran, stirring in ice water bath for 15 minutes under the protection of nitrogen, slowly dropwise adding thionyl chloride, heating to 50 ℃ after dropwise adding, and reacting for 3 hours to obtain a reaction solution; and dissolving 5-amino-1H-indole-2-carboxylic acid tert-butyl ester and N, N-diisopropylethylamine in dry tetrahydrofuran, stirring in an ice bath for 15 minutes under the protection of nitrogen, and slowly dropwise adding the reaction solution.
Preferably, in the second step reaction, under the condition of ice-water bath, dichloromethane containing triethylamine is added to (R) -5- (2-hydroxy-3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester, then 4-nitrobenzenesulfonyl chloride is slowly added, and stirring is carried out at room temperature for 2 hours.
In a third aspect, the present application also provides an intermediate compound selected from compounds of formula (I) and formula (II):
compared with the prior art, the piperazine intermediate, the preparation method and the application thereof have the following advantages and beneficial effects:
1. the method avoids the adoption of virulent sodium azide for synthesizing the piperazine compound containing tetrazole, and can realize safe production.
2. The method shortens the process flow required for synthesizing the dioxopiperazine compound, is simple in process and convenient for industrial application, saves raw materials required for production, improves the product yield and reduces the production cost.
Detailed Description
The present application will be described in further detail with reference to examples, but the embodiments of the present application are not limited thereto.
Example 1: preparation of piperazine intermediate (I).
Step 1: synthesis of 1- (4-chloro-2-nitrophenyl) -1H-tetrazole.
1.0 g (5.7 mmol) of 5-chloro-2-fluoronitrobenzene, 476.0 mg (6.8 mmol) of tetrazole, and 945.4 mg (6.8 mmol) of potassium carbonate were added to N, N-dimethylformamide (10.0 mL) at room temperature, and N was added2The reaction was carried out at 80 ℃ for 1.5 hours under protection.
After the reaction is finished, the anhydrous sodium sulfate is filled in the reaction kettle for suction filtration, the filter cake is washed by ethyl acetate, the filtrate is extracted by ethyl acetate, the organic phases are combined, the organic phases are washed by saturated saline solution firstly, then dried by the anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: pure hexane). 1.15 g of 1- (4-chloro-2-nitrophenyl) -1H-tetrazole are obtained as a milky white solid in a yield of 89.3%. LCMS RT 1.89min, [ M + H]+＝226.06。
Step 2: synthesis of 5-chloro-2- (1H-tetrazol-1-yl) aniline.
1.15 g (5.1 mmol) of 1- (4-chloro-2-nitrophenyl) -1H-tetrazole was added to ethyl acetate (10 ml) at room temperature, and the mixture was partitioned in an ice-water bathStannous chloride dihydrate 11.51 g (51.0 mmol), N, was added in portions2The reaction was carried out at room temperature for 2 hours under protection.
After the reaction is finished, quenching the mixture by using a saturated sodium bicarbonate aqueous solution, adding excessive sodium bicarbonate solid, adjusting the pH value to be alkalescent, filtering the mixture by using kieselguhr, washing a filter cake by using ethyl acetate, extracting filtrate by using ethyl acetate, combining organic phases, washing the organic phases by using saturated saline solution, drying the organic phases by using anhydrous sodium sulfate, and finally concentrating the organic phases under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: pure hexane). 897.9 mg of 5-chloro-2- (1H-tetrazol-1-yl) aniline are obtained as a cream solid in 90% yield. LCMS RT 1.75min, [ M + H]+＝196.09。
And step 3: synthesizing 5-chloro-2- (1H-tetrazole-1-yl) phenyl tetrafluoroborate diazonium salt.
To concentrated hydrochloric acid (5 ml) containing 937.8 mg (4.8 mmol) of 5-chloro-2- (1H-tetrazol-1-yl) aniline at zero degrees Centigrade, 363.9 mg (5.3 mmol) of an aqueous sodium nitrite solution and 1.0 ml of water were slowly added dropwise, and after completion of the addition, N was added2After the reaction was carried out for 1 hour while maintaining the temperature under the protection, 4.6 ml of tetrafluoroboric acid was slowly added dropwise, and the reaction was continued for 2 hours while maintaining the temperature.
After the reaction, suction filtration is carried out, the filter cake is washed by ice water, and the filter cake is dried in vacuum to obtain 1.13 g of white solid 5-chloro-2- (1H-tetrazole-1-yl) phenyl tetrafluoroborate diazonium salt, with the yield: 80.0%, LCMS RT 1.24 min.
And 4, step 4: synthesis of intermediate (I)1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) piperazine-2, 3-dione.
To anhydrous dimethyl sulfoxide (6 ml) containing 1.13 g (3.9 mmol) of diazonium salt of 5-chloro-2- (1H-tetrazol-1-yl) benzenetetrafluoroborate at room temperature were added 296.4 mg (2.6 mmol) of piperazine-2, 3-dione and iodineCuprous oxide 74.3 mg (0.39 mmol), N-dimethylethylenediamine 34.4 mg (0.39 mmol), tetrabutylammonium iodide 1.34 g (3.64 mmol) and potassium carbonate 1.08 g (7.8 mmol), N2And reacting at 110 ℃ for 12h under protection, wherein the room temperature is 20-25 ℃.
After the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through celite, the filtrate was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane: 1/4) to give 343.2 mg of 1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) piperazine-2, 3-dione as a white solid in 30% yield and 85% purity. LCMS RT 1.72min, [ M + H]+＝293.18。
The results of the comparative experiments for example 1 and comparative examples 1, 2,3, 4 are shown in the following table:
from the above experimental data, it can be seen that example 1 of the present application, which synthesizes 1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) piperazine-2, 3-dione by reacting with a catalyst of iminoctadine at 110 ℃ for 12 hours, and extracts with ethyl acetate, has a higher yield and a better purity than 1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) piperazine-2, 3-dione synthesized according to comparative examples 1, 2,3 and 4.
Example 2: and (3) preparation of piperazine compounds.
Step 1: synthesizing (R) -5- (2-hydroxy-3-phenyl propionamido) -1H-indole-2-carboxylic acid tert-butyl ester.
At room temperature, 4.0 g (24.1 mmol) of (R) -2-hydroxy-3-phenylpropionic acid is dissolved in dry tetrahydrofuran (60.0 ml), the mixture is placed in a dry three-neck flask, after nitrogen protection and stirring in an ice-water bath for 15 minutes, 2.86 g (48.2 mmol) of thionyl chloride is slowly dripped into the reaction solution, after 30 minutes of dripping, the reaction solution is cooled to room temperature after heating to 50 ℃ and stirring at constant temperature for 3 hours, spin-dried, and vacuumized by an oil pump for 15 minutes, and the obtained residue is directly used in the next step.
4.67 g (20.1 mmol) of tert-butyl 5-amino-1H-indole-2-carboxylate, N, N-diisopropylethylamine (9.34 g (72.3 mmol) was dissolved in dry tetrahydrofuran (40.0 ml), the mixture was placed in a dry three-neck flask, after stirring in an ice bath for 15 minutes under nitrogen protection, a tetrahydrofuran solution (20.0 ml) of the above residue was slowly added dropwise to the mixture, and the mixture was reacted at zero degrees centigrade for 1 hour.
The reaction solution was quenched by adding water, the mixture was extracted with ethyl acetate, the organic phases were combined, dried first with saturated brine, then with anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether ═ 1/4) to give 6.92 g of (R) -5- (2-hydroxy-3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester as a yellow solid in a yield of 75.5%. LCMS: RT 1.79min, [ M-H ]]-＝379.18。
Step 2: synthesis of intermediate (II) (R) -5- (2- (((4-nitrophenyl) sulfonyl) oxy) -3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester.
To dichloromethane (60.0 ml) containing 6.92 g (18.2 mmol) of (R) -5- (2-hydroxy-3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester and 5.5 ml (54.3 mmol) of triethylamine was slowly added 5.5 g (24.9 mmol) of 4-nitrobenzenesulfonyl chloride under an ice-water bath, and the mixture was stirred at room temperature for 2 hours, wherein the room temperature was 20 to 25 ℃.
The reaction was quenched by adding saturated sodium bicarbonate solution to the reaction solution. The mixture was extracted with ethyl acetate. The organic phases were combined. The organic phase was dried with saturated brine, then with anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane, and dropwise added to n-hexane to precipitate a white solid, which was filtered, and the filter cake was washed with n-hexane and dried to obtain 8.2 g of (R) -5- (2- (((4-nitrophenyl) sulfonyl) oxy) -3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester as a white solid, with a yield of 79.6% and a purity of 92%. LCMS RT 1.98 min.
And step 3: synthesis of (S) -5- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2, 3-dioxopiperazin-1-yl) -3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester.
To N, N-dimethylformamide (5.0 ml), 514.8 mg (1.76 mmol) of 1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) piperazine-2, 3-dione, (R) -5- (2- (((4-nitrophenyl) sulfonyl) oxy) -3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester 995.5 mg (1.76 mmol) and 485.7 mg (3.52 mmol) were added at room temperature, and reacted at room temperature for 12 hours.
After the reaction, water was added for quenching, the mixture was extracted with ethyl acetate, and the organic phases were combined, dried with saturated brine, then with anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane 1/2). 634.1 mg of (S) -5- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2, 3-dioxopiperazin-1-yl) -3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester are obtained as a pale yellow solid in 55% yield and 90% purity. LCMS RT 1.97min, [ M + H]+＝656.21。
And 4, step 4: synthesis of (S) -5- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2, 3-dioxapiperazin-1-yl) -3-phenylpropionamido) -1H-indole-2-carboxylic acid.
951.2 mg (1.45 mmol) of tert-butyl (S) -5- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2, 3-dioxopiperazin-1-yl) -3-phenylpropionamido) -1H-indole-2-carboxylate was added to dichloromethane (4.0 ml) at room temperature, and trifluoroacetic acid (1.0 ml) was added dropwise to react at room temperature for 2 hours, wherein the room temperature was 20 to 25 ℃.
At the end of the reaction, the dichloromethane was evaporated and trifluoroacetic acid was pumped off using an oil pump, the residue obtained was taken up in dichloromethane and added dropwise to n-hexane, a white solid precipitated which was filtered off with suction, the filter cake was washed with n-hexane and dried to yield 620.3 mg of (S) -5- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2, 3-dioxapiperazin-1-yl) -3-phenylpropionamido) -1H-indole-2-carboxylic acid as a white solid in 71.4% yield and 93% purity. LCMS RT 1.68min, [ M-H]-＝597.32。
The results of the comparative experiments of example 2 and comparative examples 5 and 6 are shown in the following table:
as can be seen from the above table results, example 2 of the present application synthesized (R) -5- (2-hydroxy-3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester by using organic solvent tetrahydrofuran and treating the residue with eluent (ethyl acetate/petroleum ether 1/4), the final yield and purity were higher than those of the products obtained by treating the residue with organic solvent and eluent in comparative example 5 and comparative example 6; synthesis of tert-butyl (S) -5- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2, 3-dioxoindol) -1H-indole-2-carboxylate by reacting 1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) piperazine-2, 3-dione with tert-butyl (R) -5- (2- (((4-nitrophenyl) sulfonyl) oxy) -3-phenylpropionamido) -1H-indole-2-carboxylate in N, N-dimethylformamide, the final yield and purity were higher than those obtained with the solvents in comparative examples 5 and 6.
The dioxopiperazine compound is prepared by synthesizing a new synthetic route, so that on one hand, a highly toxic sodium azide medicine is avoided in the synthetic process, and safe production is realized; on the other hand, the method not only shortens the process flow for synthesizing the dioxopiperazine compound and is beneficial to industrialized production, but also can save materials required by production, improve the product yield and reduce the production cost.
The above embodiments are preferred embodiments of the present application, but the present application is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present application should be construed as equivalents and are included in the scope of the present application.
Claims (11)
1. A preparation method of a piperazine intermediate (I), which is characterized by comprising the following steps:
adding an anhydrous dimethyl sulfoxide solution of 5-chloro-2- (1H-tetrazol-1-yl) benzenetetrafluoroborate diazonium salt and piperazine-2, 3-dione into an alkaline solution, and reacting under the action of a catalyst selected from the group consisting of a cuprous iodide and tetrabutylammonium iodide to produce 1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) piperazine-2, 3-dione;
2. the process for producing a piperazine based intermediate (I) according to claim 1, further comprising the steps of:
a: reacting 5-chloro-2-fluoronitrobenzene with tetrazole under an alkaline condition to generate 1- (4-chloro-2-nitrophenyl) -1H-tetrazole;
b: adding 1- (4-chloro-2-nitrophenyl) -1H-tetrazole into an ester solvent, and reacting with stannous chloride dihydrate under an acidic condition to generate 5-chloro-2- (1H-tetrazol-1-yl) aniline;
c, reacting 5-chloro-2- (1H-tetrazol-1-yl) aniline with sodium nitrite aqueous solution and tetrafluoroboric acid to generate 5-chloro-2- (1H-tetrazol-1-yl) phenyl tetrafluoroboric acid diazonium salt;
3. a process for producing a piperazine-based intermediate (I) according to claim 1 or 2, wherein the basic solution is one selected from N, N-dimethylethylenediamine and N, N-dimethylformamide.
4. A process for producing a piperazine intermediate (I) according to claim 1 or 2, wherein the diazonium salt of 5-chloro-2- (1H-tetrazol-1-yl) benzenetetrafluoroborate is reacted with piperazine-2, 3-dione in the presence of N2And under protection, keeping the temperature at 110 ℃ and reacting for 8-16 h.
5. A process for the preparation of piperazine based intermediate (I) according to claim 4, wherein the reaction is carried out for 12h while maintaining the temperature at 110 ℃.
6. A process for producing a piperazine compound, which comprises producing a piperazine compound represented by the following formula, using the intermediate (I) produced by the process for producing a piperazine intermediate (I) according to any one of claims 1 to 5:
7. the method for preparing piperazine compounds according to claim 6, further comprising:
(1) reacting said intermediate (I)1- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) piperazine-2, 3-dione with intermediate (II) (R) -5- (2- (((4-nitrophenyl) sulfonyl) oxy) -3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester in basic solution to give (S) -5- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2, 3-dioxopiperazin-1-yl) -3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester;
(2) reacting (S) -tert-butyl 5- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2, 3-dioxopiperazin-1-yl) -3-phenylpropionamido) -1H-indole-2-carboxylate with trifluoroacetic acid to give the piperazine compound (S) -5- (2- (4- (5-chloro-2- (1H-tetrazol-1-yl) phenyl) -2, 3-dioxopiperazin-1-yl) -3-phenylpropionamido) -1H-indole-2-carboxylic acid;
8. the process for producing a piperazine compound according to claim 7, wherein the intermediate (II) is produced by a process comprising:
the first step of reaction: reacting (R) -2-hydroxy-3-phenylpropionic acid with tert-butyl 5-amino-1H-indole-2-carboxylate to produce tert-butyl (R) -5- (2-hydroxy-3-phenylpropionamido) -1H-indole-2-carboxylate;
the second step of reaction: reacting (R) -5- (2-hydroxy-3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester with 4-nitrobenzenesulfonyl chloride to generate an intermediate (II) (R) -5- (2- (((4-nitrophenyl) sulfonyl) oxy) -3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester;
9. the preparation method of piperazine compounds according to claim 8, wherein in the first step of reaction, (R) -2-hydroxy-3-phenylpropionic acid is dissolved in dry tetrahydrofuran, after stirring in an ice-water bath for 15 minutes under the protection of nitrogen, thionyl chloride is slowly added dropwise, and after the addition, the reaction solution is heated to 50 ℃ and reacted for 3 hours to obtain a reaction solution; and dissolving 5-amino-1H-indole-2-carboxylic acid tert-butyl ester and N, N-diisopropylethylamine in dry tetrahydrofuran, stirring in an ice bath for 15 minutes under the protection of nitrogen, and slowly dropwise adding the reaction solution.
10. A process for preparing piperazine compounds according to claim 8, wherein in the second reaction step, under the ice-water bath condition, triethylamine-containing dichloromethane is added to (R) -5- (2-hydroxy-3-phenylpropionamido) -1H-indole-2-carboxylic acid tert-butyl ester, followed by slow addition of 4-nitrobenzenesulfonyl chloride, followed by stirring at room temperature for 2 hours.
11. A compound selected from the group consisting of compounds of formula (I) and formula (II):
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011560939.5A CN112608303B (en) | 2020-12-25 | 2020-12-25 | Piperazine intermediate, preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011560939.5A CN112608303B (en) | 2020-12-25 | 2020-12-25 | Piperazine intermediate, preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112608303A CN112608303A (en) | 2021-04-06 |
| CN112608303B true CN112608303B (en) | 2021-10-26 |
Family
ID=75245108
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011560939.5A Active CN112608303B (en) | 2020-12-25 | 2020-12-25 | Piperazine intermediate, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112608303B (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2124511C1 (en) * | 1993-05-14 | 1999-01-10 | Фармасьютикал Ко., Лтд | Piperazine derivatives |
| WO2007008142A1 (en) * | 2005-07-08 | 2007-01-18 | Astrazeneca Ab | Heterocyclic sulfonamide derivatives as inhibitors of factor xa |
| US8324199B2 (en) * | 2008-03-13 | 2012-12-04 | Bristol-Myers Squibb Company | Pyridazine derivatives as factor xia inhibitors |
| US9359367B2 (en) * | 2012-07-09 | 2016-06-07 | Lupin Limited | Tetrahydroquinazolinone derivatives as PARP inhibitors |
-
2020
- 2020-12-25 CN CN202011560939.5A patent/CN112608303B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN112608303A (en) | 2021-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1332939C (en) | Novel compounds inhibiting factor Xa activity | |
| JPS6157587A (en) | Condensed heterocyclic derivative and antiulcerative | |
| JP2019517460A (en) | N-[(6-Cyano-2-fluoro-3-methoxyphenyl) methyl] -3- (methoxymethyl) -1-({4-[(2-oxopyridin-1-yl) methyl] as a kallikrein inhibitor Polymorphs of (phenyl) methyl) pyrazole-4-carboxamide | |
| KR100898361B1 (en) | Fxa inhibitors with cyclic amidoxime or cyclic amidrazone as p4 subunit, processes for their preparations, and pharmaceutical compositions and derivatives thereof | |
| CN116082303A (en) | Novel oxopyridines, intermediates and uses thereof | |
| JP2009511516A (en) | Imidazole derivatives as inhibitors of TAFIa | |
| CN112608303B (en) | Piperazine intermediate, preparation method and application thereof | |
| CN102131802A (en) | New heterocyclic carboxamides for use as thrombin inhibitors | |
| EP1513806B1 (en) | Sulphonic acid salts of mandelic acid derivatives | |
| FR2873372A1 (en) | PROCESS FOR THE PREPARATION OF N-PIPERIDINO-1,5-DIPHENYLPYRAZOLE-3-CARBOXAMIDE DERIVATIVES | |
| AU2007242884A1 (en) | Dicarboxamide derivatives | |
| JPH01132579A (en) | Indole derivative | |
| KR20050044381A (en) | Deuterated pyrazolopyrimidinones and drugs containing said compounds | |
| CN1322001C (en) | Novel compounds that inhibit factor Xa activity | |
| CA2166032A1 (en) | 1-oxo-2-(phenylsulfonylamino)pentylpiperidine; process for preparing them and their use as therapeutic agents | |
| CN104277040A (en) | Acyl piperazinone substituent-containing pyrazolopiperidone compound and composition and use thereof | |
| CN104447730B (en) | Oxazolidinone compounds and its application in medicine | |
| CN110452231B (en) | Tryptophan compound and preparation method and application thereof | |
| EP4201933A1 (en) | Crystallisation process for rivaroxaban | |
| CN113698386B (en) | 4 (1H) -pyridone compound, and pharmaceutical composition and application thereof | |
| CN107365299B (en) | Preparation method of dabigatran etexilate and intermediate thereof | |
| MXPA05002331A (en) | Inhibitors of post-amadori advanced glycation end products. | |
| CN116621728A (en) | Novel preparation method of oxo-pyridine compound and key intermediate | |
| CN104311541B (en) | Containing substituted pyrazole compound of ketone and combinations thereof and purposes | |
| KR100503267B1 (en) | Method for the preparation of 2-acetyloxy-4-trifluoromethyl benzoic acid |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |