CN110483402B - Synthetic method of 3-bromo-5-phenyl-1H-pyrazole - Google Patents
Synthetic method of 3-bromo-5-phenyl-1H-pyrazole Download PDFInfo
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/16—Halogen atoms or nitro radicals
Abstract
The invention provides a synthetic method of 3-bromo-5-phenyl-1H-pyrazole, relates to the field of pharmaceutical chemistry, provides a new scheme for synthesizing 3-bromo-5-phenyl-1H-pyrazole by adopting 3-phenylpyrazole through a three-step method, and provides a new synthetic route for the preparation and synthesis of 3-bromo-5-phenyl-1H-pyrazole; in addition, in the synthetic scheme of the invention, common raw materials are adopted as reactants, the reaction conditions are suitable, the overall yield of the product is high, the preparation process is simple, the cost is low, and the large-scale production can be realized.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a synthetic method of 3-bromo-5-phenyl-1H-pyrazole.
Background
3-bromo-5-phenyl-1H-pyrazoles are important heterocyclic compounds present in a variety of biologically active compounds for synthetic use as starting materials for further functionalization. Wherein the synthesis of a di (hetero) arylcyclohexyl derivative of formula (D) is symptomatic for the inhibition of ATP-sensitive potassium channels in cardiac muscle, for example: the treatment of cardiovascular system diseases, arrhythmia or heart contractility decrease, coronary heart disease, cardiac insufficiency or cardiomyopathy, etc., and is especially suitable for preventing sudden cardiac death.
The prior art synthesis of 3-bromo-5-phenyl-1H-pyrazole has been diversified, including (1) dehydroxyhalogenation, (2) Sandmeyer halodenitrogenation, (3) cycloaddition, (4) N1 alkylation and (5) palladium catalyzed halogenation, which, while successful in many cases, generally require harsh reaction conditions, e.g., the prior art uses genotoxicity-related intermediates (e.g., aminopyrazole derivatives) as reactants, or has a limited substrate concentration range, with low reaction efficiency.
Disclosure of Invention
The invention aims to provide a method for synthesizing 3-bromo-5-phenyl-1H-pyrazole, which adopts a three-step method to synthesize the 3-bromo-5-phenyl-1H-pyrazole under appropriate reaction conditions, and has the advantages of few reaction steps and high yield.
In order to achieve the above purpose, the invention provides the following technical scheme: a synthetic method of 3-bromo-5-phenyl-1H-pyrazole is as follows:
the specific synthesis steps comprise: 1) dissolving 3-phenylpyrazole in a toluene solvent, adding trifluoroacetic acid, heating to 70-100 ℃, adding 3, 4-dihydro-2H-pyran, and reacting at 70-100 ℃ for 16-24H; after the reaction is finished, removing the solvent by spinning, flushing, EA extracting, backwashing by saturated sodium chloride solution, drying, spinning and purifying to obtain a compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole; 2) dissolving a compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole in a tetrahydrofuran solvent, cooling a tetrahydrofuran solution of the compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole to-60 to-80 ℃ under the protection of Ar gas, dropwise adding n-butyllithium into the solution, maintaining the temperature for reaction for a period of time, dropwise adding 1, 2-dibromotetrafluoroethane into the solution, heating the solution to 10 to 30 ℃ after the dropwise addition of the 1, 2-dibromotetrafluoroethane is completed, and reacting for 2 to 5 hours; after the reaction is finished, a compound (2) 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole is obtained through flushing, EA extraction, backwashing of a saturated sodium chloride solution, drying, spin-drying and purification; 3) dissolving a compound (2), namely 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole in a methanol solvent, adding methanesulfonic acid into a methanol solution of the compound (2), namely 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole, and reacting the solution at the temperature of between 10 and 30 ℃ for 1 to 3 hours; after the reaction is finished, the compound (3) 3-bromo-5-phenyl-1H-pyrazole is obtained by flushing ice water, filtering, washing and drying.
Further, in the step 1), the molar ratio of reactants 3-phenylpyrazole, 3, 4-dihydro-2H-pyran and trifluoroacetic acid in a toluene solvent is 1: 1-1.5: 0.05-0.1, preferably 1: 1.05: 0.05.
further, in the step 1), the concentration of the 3-phenylpyrazole in the toluene solvent is 100g/L to 166.67g/L, preferably 151.51 g/L.
Further, in the step 2), the molar ratio of the compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole, n-butyllithium and 1, 2-dibromotetrafluoroethane in a tetrahydrofuran solvent is 1: 1-1.5: 1 to 1.5, preferably 1: 1.1: 1.1.
further, in the step 2), the concentration of the compound (1), 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole in the tetrahydrofuran solvent is 41.33g/L to 62g/L, preferably 50 g/L.
Further, in the step 2), the tetrahydrofuran solution of the compound (1), 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole, is cooled to-60 ℃ to-80 ℃, n-butyllithium is dropwise added into the solution, and the temperature is maintained for reaction for 30 min.
Further, in the step 3), the molar ratio of the compound (2) 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole and methanesulfonic acid in the methanol solvent is 1: 4-7, preferably 1: 5.
further, in the step 3), the concentration of the compound (2), 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole in the methanol solvent is 45.33g/L to 68g/L, preferably 68 g/L.
According to the technical scheme, the synthesis method of the 3-bromo-5-phenyl-1H-pyrazole provided by the technical scheme of the invention has the following beneficial effects:
the invention discloses a synthetic method of 3-bromo-5-phenyl-1H-pyrazole, and provides a new scheme for synthesizing 3-bromo-5-phenyl-1H-pyrazole by adopting 3-phenylpyrazole through a three-step method, so that a new synthetic route is provided for the preparation and synthesis of 3-bromo-5-phenyl-1H-pyrazole; the synthesis scheme of the 3-bromo-5-phenyl-1H-pyrazole has appropriate reaction conditions, the total yield of the product 3-bromo-5-phenyl-1H-pyrazole is about 61.1%, and the reactants adopt common raw materials, so that the preparation process is simple, the cost is low, and the large-scale production can be realized. The 3-bromo-5-phenyl-1H-pyrazole as the drug intermediate is prepared by a high-yield and low-cost synthesis method of 3-bromo-5-phenyl-1H-pyrazole, so that the production cost of preparing a drug for treating the cardiovascular system diseases, particularly preventing sudden cardiac death, is reduced, and the popularization of the drug for treating the cardiovascular system diseases, particularly preventing sudden cardiac death, is further promoted.
It should be understood that all combinations of the foregoing concepts and additional concepts described in greater detail below can be considered as part of the inventive subject matter of this disclosure unless such concepts are mutually inconsistent.
The foregoing and other aspects, embodiments and features of the present teachings can be more fully understood from the following description taken in conjunction with the accompanying drawings. Additional aspects of the present invention, such as features and/or advantages of exemplary embodiments, will be apparent from the description which follows, or may be learned by practice of specific embodiments in accordance with the teachings of the present invention.
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The drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. Embodiments of various aspects of the present invention will now be described, by way of example, with reference to the accompanying drawings, in which:
FIG. 1 is a nuclear magnetic hydrogen spectrum of 3-phenylpyrazole.
Detailed Description
In order to better understand the technical content of the present invention, specific embodiments are described below with reference to the accompanying drawings.
In this disclosure, aspects of the present invention are described with reference to the accompanying drawings, in which a number of illustrative embodiments are shown. Embodiments of the present disclosure are not intended to include all aspects of the present invention. It should be appreciated that the various concepts and embodiments described above, as well as those described in greater detail below, may be implemented in any of numerous ways, as the disclosed concepts and embodiments are not limited to any one implementation. In addition, some aspects of the present disclosure may be used alone, or in any suitable combination with other aspects of the present disclosure.
Based on the scheme that the method for preparing the drug intermediate 3-bromo-5-phenyl-1H-pyrazole for treating the cardiovascular system diseases, particularly suitable for preventing sudden cardiac death, in the prior art is mostly rigorous in reaction condition, low in yield and various in reaction steps, the production cost and the selling price of the drug further produced by the drug intermediate are high; the invention aims to provide a synthesis method of 3-bromo-5-phenyl-1H-pyrazole, which has the advantages of easily available reactant raw materials, few reaction steps and high yield, and can be used for obtaining the 3-bromo-5-phenyl-1H-pyrazole.
The synthesis of 3-bromo-5-phenyl-1H-pyrazole according to the present invention is described in more detail below with reference to the accompanying drawings and examples.
A synthetic method of 3-bromo-5-phenyl-1H-pyrazole is as follows:
the specific synthesis steps comprise: 1) dissolving 3-phenylpyrazole in a toluene solvent, adding trifluoroacetic acid, heating to 70-100 ℃, adding 3, 4-dihydro-2H-pyran, and reacting at 70-100 ℃ for 16-24H; after the reaction is finished, removing the solvent by spinning, flushing, EA extracting, backwashing by saturated sodium chloride solution, drying, spinning and purifying to obtain a compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole; 2) dissolving a compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole in a tetrahydrofuran solvent, cooling a tetrahydrofuran solution of the compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole to-60 to-80 ℃ under the protection of Ar gas, dropwise adding n-butyllithium into the solution, maintaining the temperature for reaction for a period of time, dropwise adding 1, 2-dibromotetrafluoroethane into the solution, heating the solution to 10 to 30 ℃ after the dropwise addition of the 1, 2-dibromotetrafluoroethane is completed, and reacting for 2 to 5 hours; after the reaction is finished, a compound (2) 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole is obtained through flushing, EA extraction, backwashing of a saturated sodium chloride solution, drying, spin-drying and purification; 3) dissolving a compound (2), namely 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole in a methanol solvent, adding methanesulfonic acid into a methanol solution of the compound (2), namely 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole, and reacting the solution at the temperature of between 10 and 30 ℃ for 1 to 3 hours; after the reaction is finished, the compound (3) 3-bromo-5-phenyl-1H-pyrazole is obtained by flushing ice water, filtering, washing and drying.
In the step 1), the molar ratio of reactants 3-phenylpyrazole, 3, 4-dihydro-2H-pyran and trifluoroacetic acid in a toluene solvent is 1: 1-1.5: the concentration of 0.05-0.1, 3-phenylpyrazole in toluene solvent is 100-166.67 g/L. In the step 2), the molar ratio of the compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole, n-butyllithium and 1, 2-dibromotetrafluoroethane in a tetrahydrofuran solvent is 1: 1-1.5: 1 to 1.5; the concentration of the compound (1), namely 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole in a tetrahydrofuran solvent is 41.33 g/L-62 g/L; the tetrahydrofuran solution of the compound (1), 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole is cooled to-60 to-80 ℃, and n-butyllithium is dropwise added into the solution to keep the temperature for reaction for 30 min. In the step 3), the molar ratio of the compound (2) 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole to methanesulfonic acid in a methanol solvent is 1: 4-7; the concentration of the compound (2), 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole in a methanol solvent is 45.33 g/L-68 g/L.
Example 1: preparation of Compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole
Firstly, adding 3-phenylpyrazole (50g, 1eq) into 330ml of toluene solvent for dissolving, then adding trifluoroacetic acid (2.1g, 0.05eq), heating to 80 ℃, then adding 3, 4-dihydro-2H-pyran (30.6g, 1.05eq), and reacting at 80 ℃ overnight; after the reaction is finished, the toluene is removed by spinning, the mixture is flushed by water, EA is extracted, the saturated saline solution is backwashed, sodium sulfate is dried, and 70g of the compound (1), namely the 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole is obtained by spinning, drying and column-passing purification, wherein the yield is about 88.6 percent.
Examples 2 to 5 were prepared in the same manner as in example 1, with the molar ratios of the reactants 3-phenylpyrazole, 3, 4-dihydro-2H-pyran and trifluoroacetic acid in a toluene solvent, the reaction temperatures and the reaction times being changed as shown in Table 1, and the yields of Compound 2 measured are shown in Table 1.
TABLE 1
From the examples shown in the table, it can be seen that when the molar ratio of reactants 3-phenylpyrazole, 3, 4-dihydro-2H-pyran and trifluoroacetic acid in toluene solvent is 1: 1.05: when the concentration of 0.05 and 3-phenylpyrazole in a toluene solvent is 151.51g/L and the reaction time is 24 hours, the yield of the product compound (1), 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole, is highest.
Example 6: preparation of the Compound (2) 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole
Adding a compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole (70g, 1eq) into 700ml of anhydrous Tetrahydrofuran (THF), cooling a tetrahydrofuran solution of the compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole to-78 ℃ under the protection of argon, dropwise adding 2.5M n-butyl lithium (134.9ml, 1.1eq) at-78 ℃, reacting at the temperature of-78 ℃ for 30min, dissolving 1, 2-dibromotetrafluoroethane (88.2g, 1.1eq) into 700ml of an anhydrous THF system, heating to RT after dropping, and reacting for 3H; after the reaction is finished, ice water is poured, EA is used for extraction, saturated sodium chloride is used for backwashing, drying and spin-drying are carried out, 68g of compound (2), namely 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole is obtained through column chromatography, and the yield is about 72.4%.
The synthesis methods of examples 7 to 9 were the same as in example 6, and the molar ratios of the reactant compound (1), 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole, n-butyllithium, and 1, 2-dibromotetrafluoroethane in a tetrahydrofuran solvent were changed, and the reaction time was changed, and the yields of the compound (2), 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole, which were measured at-78 ℃ and shown in table 2, were as shown in table 2.
TABLE 2
From the examples shown in the table, it is understood that when the molar ratio of the reactant compound (1), 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole, n-butyllithium and 1, 2-dibromotetrafluoroethane in a tetrahydrofuran solvent is 1: 1.1: 1.1 when the concentration of the compound (1), 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole in a tetrahydrofuran solvent is 50g/L and the reaction time is 3 hours, the yield of the product compound, 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole, is highest.
Example 10: preparation of Compound (3) 3-bromo-5-phenyl-1H-pyrazole
Adding the compound (2), 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole (68g, 1eq) to 1L of methanol, adding methanesulfonic acid (106g, 5eq) and carrying out RT reaction for 1H; after the reaction, 47g of the compound (3), 3-bromo-5-phenyl-1H-pyrazole was obtained by washing with water, filtration, washing with water, and drying, with a yield of about 95.3%.
Examples 11 to 13 were prepared in the same manner as in example 10 except that the molar ratio of the reactant compound (2), 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole, to methanesulfonic acid in a methanol solvent, the reaction temperature and the reaction time were changed as shown in table 3, and the yields of the compound (3), 3-bromo-5-phenyl-1H-pyrazole, were measured as shown in table 3.
TABLE 3
From the examples shown in the table, when the reactant (2), 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole and methanesulfonic acid, was present in a molar ratio of 1: 5. when the concentration of the compound (2), 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole in a methanol solvent is 68g/L and the reaction time is 1H, the yield of the product, 3-bromo-5-phenyl-1H-pyrazole, is highest.
The nuclear magnetic hydrogen spectrum of the final product compound (3), 3-bromo-5-phenyl-1H-pyrazole is shown in figure 1: 1H NMR (600MHz, CDCl3) δ 7.60-7.54 (m,2H),7.46(dd, J ═ 10.2,4.7Hz,2H), 7.43-7.38 (m,1H),6.57(s, 1H).
Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, the protection scope of the present invention should be determined by the appended claims.
Claims (7)
1. The synthesis method of 3-bromo-5-phenyl-1H-pyrazole is characterized in that the synthesis route is as follows:
the specific synthesis steps comprise:
1) dissolving 3-phenylpyrazole in a toluene solvent, adding trifluoroacetic acid, heating to 70-100 ℃, adding 3, 4-dihydro-2H-pyran, and reacting at 70-100 ℃ for 16-24H; after the reaction is finished, removing the solvent by spinning, flushing, EA extracting, backwashing by saturated sodium chloride solution, drying, spinning and purifying to obtain a compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole; wherein the molar ratio of reactants 3-phenylpyrazole, 3, 4-dihydro-2H-pyran and trifluoroacetic acid in a toluene solvent is 1: 1-1.5: 0.05 to 0.1;
2) dissolving a compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole in a tetrahydrofuran solvent, cooling a tetrahydrofuran solution of the compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole to-60 to-80 ℃ under the protection of argon, dropwise adding n-butyllithium into the solution, maintaining the temperature for reaction for a period of time, dropwise adding 1, 2-dibromotetrafluoroethane into the solution, heating the solution to 10 to 30 ℃ after the dropwise addition of the 1, 2-dibromotetrafluoroethane is completed, and reacting for 2 to 5 hours; after the reaction is finished, a compound (2) 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole is obtained through flushing, EA extraction, backwashing of a saturated sodium chloride solution, drying, spin-drying and purification; wherein, the mol ratio of the compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole, n-butyl lithium and 1, 2-dibromo tetrafluoroethane in a tetrahydrofuran solvent is 1: 1-1.5: 1 to 1.5;
3) dissolving a compound (2), namely 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole in a methanol solvent, adding methanesulfonic acid into a methanol solution of the compound (2), namely 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole, and reacting the solution at the temperature of between 10 and 30 ℃ for 1 to 3 hours; after the reaction is finished, obtaining a compound (3) 3-bromo-5-phenyl-1H-pyrazole through ice water flushing, filtering, water washing and drying; wherein, the mol ratio of the compound (2) 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H pyrazole and methanesulfonic acid in the methanol solvent is 1: 4 to 7.
2. The method for synthesizing 3-bromo-5-phenyl-1H-pyrazole according to claim 1, wherein in the step 1), the molar ratio of reactants of 3-phenylpyrazole, 3, 4-dihydro-2H-pyran and trifluoroacetic acid in a toluene solvent is 1: 1.05: 0.05.
3. the method for synthesizing 3-bromo-5-phenyl-1H-pyrazole according to claim 1, wherein in the step 1), the concentration of 3-phenylpyrazole in the toluene solvent is 100g/L to 166.67 g/L.
4. The method for synthesizing 3-bromo-5-phenyl-1H-pyrazole according to claim 1, wherein in step 2), the molar ratio of the compound (1) 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole, n-butyllithium, and 1, 2-dibromotetrafluoroethane in a tetrahydrofuran solvent is 1: 1.1: 1.1.
5. the method for synthesizing 3-bromo-5-phenyl-1H-pyrazole according to claim 1, wherein in the step 2), the concentration of the compound (1), 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole in the tetrahydrofuran solvent is 41.33g/L to 62 g/L.
6. The method for synthesizing 3-bromo-5-phenyl-1H-pyrazole according to claim 1, wherein in the step 2), the tetrahydrofuran solution of the compound (1), 5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole is cooled to-60 ℃ to-80 ℃, and n-butyllithium is added dropwise to the solution, and then the reaction is maintained at this temperature for 30 min.
7. The method for synthesizing 3-bromo-5-phenyl-1H-pyrazole according to claim 1, wherein in the step 3), the concentration of the compound (2), 3-bromo-5-phenyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole in the methanol solvent is 45.33g/L to 68 g/L.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101679191A (en) * | 2007-06-05 | 2010-03-24 | 塞诺菲-安万特股份有限公司 | Di(hetero)arylcyclohexane derivatives, their preparation, their use and pharmaceutical compositions comprising them |
| WO2018183956A1 (en) * | 2017-03-30 | 2018-10-04 | Genentech, Inc. | Naphthyridines as inhibitors of hpk1 |
| WO2019070093A1 (en) * | 2017-10-02 | 2019-04-11 | 1ST Biotherapeutics, Inc. | Benzothiazol compounds and methods using the same for treating neurodegenerative disorders |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101679191A (en) * | 2007-06-05 | 2010-03-24 | 塞诺菲-安万特股份有限公司 | Di(hetero)arylcyclohexane derivatives, their preparation, their use and pharmaceutical compositions comprising them |
| WO2018183956A1 (en) * | 2017-03-30 | 2018-10-04 | Genentech, Inc. | Naphthyridines as inhibitors of hpk1 |
| WO2019070093A1 (en) * | 2017-10-02 | 2019-04-11 | 1ST Biotherapeutics, Inc. | Benzothiazol compounds and methods using the same for treating neurodegenerative disorders |
Non-Patent Citations (1)
| Title |
|---|
| A Simple, Modular Method for the Synthesis of 3,4,5-Trisubstituted Pyrazoles;Mark McLaughlin，et al.;《J. Org. Chem.》;20081231;第73卷;第4309-4312页 * |
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