CN113372260A - Synthesis method of carvedilol impurity - Google Patents
Synthesis method of carvedilol impurity Download PDFInfo
- Publication number
- CN113372260A CN113372260A CN202110757266.0A CN202110757266A CN113372260A CN 113372260 A CN113372260 A CN 113372260A CN 202110757266 A CN202110757266 A CN 202110757266A CN 113372260 A CN113372260 A CN 113372260A
- Authority
- CN
- China
- Prior art keywords
- impurity
- carvedilol
- synthesizing
- impurities
- methyl
- 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
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles 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 carbon atoms of the ring system
Abstract
The invention discloses a method for synthesizing carvedilol impurities, and belongs to the technical field of medicine synthesis. Carvedilol is taken as a raw material and reacts with a methylating reagent in the presence of an acid-binding agent and reacts with methyl halide in the presence of deprotonated strong base to respectively generate a secondary amine nitrogen methylated impurity a and a carbazole nitrogen methylated impurity b; a is taken as a raw material and is reacted with methyl halide to generate a double methylated impurity c in the presence of strong base with deprotonation; the obtained compound is subjected to ESI-MS,1HNMR、13The corresponding structure is confirmed by spectrum analysis of CNMR, HSQC and the like. The method synthesizes potential impurities with similar structures of carvedilol, and the synthesis of the impurities has certain significance for the declaration and quality research of the imitation drugs.
Description
Technical Field
The invention relates to a method for synthesizing carvedilol impurities, and belongs to the technical field of drug synthesis.
Background
Carvedilol, CAS: 72956-09-3, english name: carvedilol, a non-selective beta blocker Carvedilol, is a uniquely effective drug for treating cardiac arrhythmias in patients with heart failure. The high concentration of carvedilol has a blocking effect on calcium ion channels, which causes the expansion of two capillaries through alpha 1 receptor blocking effect and non-selective beta receptor blocking effect, reduces peripheral resistance and lowers blood pressure, and the vasodilatation effect of carvedilol is mainly generated through the alpha 1 receptor blocking effect.
In the process of research, development and synthesis of the medicine, adverse reactions generated in clinical use of the medicine are not only related to the pharmacological activity of the medicine, but also have great relationship with impurities existing in the medicine sometimes, and scientific data of the impurities related to the product prove that the impurities existing in the medicine can be controlled in a safe and reasonable range. The synthesis of impurities and characterization by analysis is one of the very important steps.
The research on impurities is an important content of drug development, sometimes drug impurities can cause adverse drug reactions, with the progress of times and the improvement of technological level, people have more sufficient understanding on the importance of scientific evaluation of quality, safety and efficacy before the drugs come into the market, the drug impurities are closely related to the quality, safety and efficacy of the drugs, the importance of the drug impurities in the drug development is more and more emphasized, and the systematic research on the impurities and the control of the impurities within the safe and reasonable limit range can directly relate to the quality and safety of the drugs.
The literature [ Journal of medicinal Chemistry,2013, vol.56, #21, p.8626-8655] has the following synthetic route for impurities a-c:
impurity a:
impurity b:
impurity c:
impurity a, CAS: 72956-35-5; impurity b, CAS: 933442-47-8; impurity c, CAS: 1479052-24-8.
During the research process of the impurities, the applicant finds that: when the reaction is carried out according to the synthesis method of the impurity a in the literature, the carbazole nitrogen methylation product is actually obtained as the impurity b (90%) and a small amount of the impurity c (5%). Analysis speculates that compared with the intramolecular linear chain N-H, the N-H on carbazole is conjugate acid to form SP2Hybridization, N-H forms conjugation with ortho-biphenyl rings. NaH is a strong base that is deprotonated, first by N-H on the carbazole, and subsequently by methyl iodide, in the case of an equivalent amount of NaH. For the verification of the reasoning, the reaction route of the impurity a is changed, carvedilol is used as a raw material, and the raw material is subjected to weak base potassium carbonate and large baseThe polar solvent DMF reacts with methyl iodide, and the yield is 87 percent after column chromatography separation. The reaction equation is as follows:
and (4) analyzing the hydrocarbon relation and ESI-MS analysis through a two-dimensional nuclear magnetic resonance spectrogram (HSQC), and judging the result to be the impurity a. Meanwhile, the impurity c is obtained by reacting the impurity a. Based on the above actual reaction results, it is necessary for the drug synthesis to re-optimize the reaction conditions and accurately confirm the reaction products.
Disclosure of Invention
In order to overcome the technical defects, the invention discloses a method for synthesizing carvedilol impurities. Carvedilol is taken as a raw material and reacts with a methylating reagent in the presence of an acid-binding agent and reacts with methyl halide in the presence of deprotonated strong base to respectively generate a secondary amine nitrogen methylated impurity a and a carbazole nitrogen methylated impurity b; a is taken as a raw material and is reacted with methyl halide to generate a double methylated impurity c in the presence of strong base with deprotonation; ESI-MS of the obtained compound,1HNMR、13The corresponding structure is confirmed by CNMR and HSQC analysis; is summarized as the following reaction equation:
the invention relates to a method for synthesizing carvedilol impurity, which comprises the following steps:
impurity a: mixing carvedilol, an acid-binding agent and an organic solvent, and then adding a methylating agent to react to obtain a secondary amine nitrogen methylated impurity a;
impurity b: mixing carvedilol, deprotonated strong base and an organic solvent, adding methyl halide at low temperature, and reacting to obtain carbazole nitrogen methylated impurities b.
Impurity c: adding the impurity a into deprotonated strong base and an organic solvent, adding methyl halide at low temperature, and reacting to obtain a double methylated impurity c;
further, in the above technical solution, in the process of synthesizing the impurity a, the organic solvent is selected from acetonitrile, dioxane, acetone, DMSO or DMF; DMF is preferred.
Further, in the technical scheme, in the process of synthesizing the impurity a, the acid-binding agent is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, diisopropylethylamine or triethylamine.
Further, in the above technical scheme, during the synthesis of the impurity a, the methylating agent is selected from methyl p-toluenesulfonate, methyl methanesulfonate or methyl iodide.
Further, in the above technical scheme, in the process of synthesizing the impurity a, the mole ratio of carvedilol, the acid-binding agent and the methylating agent is 1: 1.0-1.1: 0.98-1.0.
Further, in the above technical solution, in the process of synthesizing the impurity b, the organic solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran.
Further, in the technical scheme, in the process of synthesizing the impurity b, the deprotonating strong base is selected from sodium hydride, n-butyl lithium, potassium tert-butoxide or sodium tert-butoxide, and the methyl halide is selected from methyl iodide or methyl bromide.
Further, in the above technical scheme, in the process of synthesizing the impurity b, the mole ratio of carvedilol, deprotonated strong base and methyl halide is 0.95-0.98: 1: 0.98-1.0.
Further, in the above technical solution, in the process of synthesizing the impurity c, the synthesis method is the same as that of the impurity b.
Advantageous effects of the invention
The impurity a is synthesized by adopting an acid-binding agent and a methylation reagent, and preferentially reacts with N-H with nucleophilicity. The impurity c is synthesized by reacting the impurity a with methyl halide under strong base with deprotonation. The impurity b is synthesized by deprotonating strong base (such as NaH, n-butyl lithium, potassium tert-butoxide and sodium tert-butoxide) at about 0 deg.C (preferentially reacting with carbazole nitrogen hydrogen with strong acidity), and then methylating to avoid reacting with hydroxyl at high temperature to form ether.
Carvedilol is combined with alkali through different methylating agents to synthesize methyl products on different N-H with high selectivity, and the methyl position is analyzed and judged through two-dimensional nuclear magnetism, so that impurities can be effectively detected and controlled in products, qualified impurities are provided for clinical tests, and reasonable impurity limit is determined through clinical research, so that the quality and the safety of the medicine are ensured.
Drawings
FIG. 1 shows that impurity a is obtained in example 11HNMR spectrogram;
FIG. 2 shows the impurity a obtained in example 113CNMR spectrogram;
FIG. 3 is a DEPT 135 spectrum of impurity a obtained in example 1;
FIG. 4 is the HSQC spectrum of impurity a obtained in example 1;
FIG. 5 is the HMBC spectrum of impurity a obtained in example 1;
FIG. 6 shows the impurity b obtained in example 21HNMR spectrogram;
FIG. 7 shows the impurity c obtained in example 21HNMR spectrogram.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Synthesis of impurity a
Example 1
Adding carvedilol (5.0g, 12.3mmol, 1.0eq), potassium carbonate (1.70g, 12.3mmol, 1.0eq) and DMF (30mL) into a 100mL reaction flask under the protection of nitrogen, cooling to an internal temperature of 0 ℃, and dropwise adding methyl iodide(1.75g, 12.3mmol, 1.0eq), after the addition was complete, the temperature was naturally raised to room temperature, the mixture was stirred for 3h, the reaction was monitored by TLC (PE/EA 1/1, containing 1% triethylamine), a small amount of starting material remained, and a point of reduced polarity newly occurred. And (3) pouring the reaction liquid into water for quenching, extracting by using ethyl acetate 60mL by 3, combining organic phases, concentrating the organic phases under reduced pressure to obtain an oily substance, and performing column chromatography on the oily substance to obtain a solid product 4.52g with the yield of 87%. [ M + H ]]+421.2160。
And (3) carrying out structural analysis by combining a hydrogen spectrum, a carbon spectrum and a two-dimensional correlation spectrum in the attached drawing, and judging that the compound is an impurity a, wherein the analysis result is as follows:
example 2
Under the protection of nitrogen, adding anhydrous THF (20mL) and 60% sodium hydride (1.0g, 25.0mmol and 1.0eq) into a 100mL reaction bottle, cooling and keeping the temperature at-2 ℃, dropwise adding a carvedilol (9.96g, 24.5mmol and 0.98eq)/THF (35mL) solution, and stirring for 20min after dropwise adding. Methyl iodide (3.55g, 25.0mmol, 1.0eq) was added dropwise while maintaining the original temperature, and after the addition was complete, the temperature was naturally raised to room temperature, and the mixture was stirred for 3 hours. The reaction was monitored by TLC (PE/EA-1/1 with 1% triethylamine) and a small amount of starting material remained, giving rise to two new points of reduced polarity. Pouring the reaction solution into water (100mL) for quenching, extracting dichloromethane 100mL by 3, combining organic phases, concentrating the organic phases under reduced pressure to obtain oily substance, adding ethyl acetate, precipitating a large amount of solid, filtering, drying to obtain solid 8.94g with yield of 85%,1HNMR characterization, presuming this solid as impurity b. Concentrating the mother liquor, performing column chromatography on the obtained oily substance to obtain 543mg of a solid product with the yield of 5 percent,1the HNMR is used for characterization,this solid was presumed to be impurity c.
Specifically, the following description is provided: the document [ J.Med.chem.,2013,56(21), 8626-one 8655] uses this process to obtain a product, defined as impurity a.
Example 3
Carvedilol (5.0g, 12.3mmol, 1.0eq), potassium carbonate (1.70g, 12.3mmol, 1.0eq) and acetone (30mL) were added to a 100mL reaction flask under nitrogen protection, methyl methanesulfonate (1.35g, 12.3mmol, 1.0eq) was added dropwise at room temperature, the temperature was raised to 40-42 ℃ after completion of addition, stirring was continued for 1 hour, and the reaction was monitored by TLC (PE/EA ═ 1/1, containing 1% triethylamine), leaving a small amount of starting material. Cooling to room temperature, pouring the reaction liquid into water for quenching, extracting by ethyl acetate 60mL x 3, combining organic phases, concentrating the organic phases under reduced pressure, adding n-heptane to precipitate solids, and filtering to obtain an impurity a 4.82g with the yield of 93.1%.
Example 4
Carvedilol (5.0g, 12.3mmol, 1.0eq), sodium carbonate (1.30g, 12.3mmol, 1.0eq) and acetonitrile (50mL) were added to a 100mL reaction flask under nitrogen protection, methyl p-toluenesulfonate (2.29g, 12.3mmol, 1.0eq) was added dropwise at room temperature, the temperature was raised to 80-82 ℃ after completion of addition, stirring was carried out for 3 hours, and the reaction was monitored by TLC (PE/EA ═ 1/1, containing 1% triethylamine), leaving a small amount of starting material. Cooling to room temperature, pouring the reaction liquid into water for quenching, extracting by ethyl acetate 60mL x 3, combining organic phases, concentrating the organic phases under reduced pressure, adding n-heptane to precipitate solids, and filtering to obtain an impurity a 4.70g with the yield of 90.9%.
Example 5
Under the protection of nitrogen, carvedilol (5.0g, 12.3mmol, 1.0eq), methyl iodide (1.75g, 12.3mmol, 1.0eq) and dichloromethane (30mL) are added into a 100mL reaction bottle, the temperature is reduced to 0 ℃ in the inner temperature, triethylamine is added dropwise, the temperature is naturally raised to room temperature after the triethylamine is added dropwise, the mixture is stirred for 8 hours, TLC (PE/EA is 1/1 and contains 1% of triethylamine) is used for monitoring reaction, a small amount of raw materials are remained, diluted hydrochloric acid is added for quenching, layering is carried out, an organic phase is washed by sodium bicarbonate solution, is concentrated, ethyl acetate is replaced, n-heptane is added for precipitating solids, and the impurities are filtered to obtain 4.79g and the yield is 92.6%.
Example 6
Adding carvedilol (9.96g, 24.50mmol, 0.98eq) and anhydrous THF (30mL) into a 100mL reaction bottle under the protection of nitrogen, cooling to-5 ℃, adding methyl iodide (3.55g, 25.0mmol, 1.0eq), dropwise adding 20% potassium tert-butoxide/tetrahydrofuran solution (14.0g, 25.00mmol, 1.0eq) at 5-5 ℃, naturally raising the temperature to room temperature after dropwise adding, and stirring for 3 hours. The reaction was monitored by TLC (PE/EA 1/1, 1% triethylamine), quenched with water, extracted with dichloromethane 100mL by 3, the organic phases combined, the organic phase concentrated under reduced pressure to give an oil which was added to ethyl acetate to precipitate a large amount of solid which was filtered and dried to give a solid 9.40g with a yield of 91.2%.
Example 7
Under the protection of nitrogen, carvedilol (9.96g, 24.50mmol, 0.98eq) and anhydrous 2-MeTHF (45mL) are added into a 100mL reaction bottle, the temperature is reduced to-5 ℃, methyl iodide (3.55g, 25.0mmol, 1.0eq) is added, 2.5M n-butyllithium (10mL, 25.0mmol, 1.0eq) is added dropwise at the temperature of-5 ℃, then the mixture is naturally raised to the room temperature, and the mixture is stirred for 4 hours. The reaction was monitored by TLC (PE/EA ═ 1/1, containing 1% triethylamine), quenched with water, extracted with 20mL of 2-methyltetrahydrofuran, the organic phases were combined and concentrated under reduced pressure to give an oil which was added with ethyl acetate to precipitate a large amount of solid which was filtered and dried to give 9.32g of solid in 90.5% yield.
Example 8
Under the protection of nitrogen, adding anhydrous THF (20mL) and 60% sodium hydride (1.00g, 25.0mmol and 1.0eq) into a 100mL reaction bottle, cooling and keeping the temperature at-2 ℃, dropwise adding an impurity a (10.3g, 24.5mmol and 0.98eq)/THF (35mL), and stirring for 20min after dropwise adding. Continuously dropwise adding methyl iodide (3.55g, 25.0mmol, 1.0eq) while keeping the original temperature, naturally heating to room temperature after dropwise adding, and stirring for 3 h. The reaction was monitored by TLC (PE/EA 1/1, 1% triethylamine) and quenched by pouring the reaction into water (100mL), extracted with dichloromethane 100mL 3, the organic phases combined and concentrated under reduced pressure to give an oil which was added to ethyl acetate to precipitate a large amount of solid which was filtered and dried to give a solid 9.37g with 88% yield.
Example 9
Under the protection of nitrogen, adding an impurity a (10.3g, 24.5mmol, 0.98eq) and anhydrous THF (30mL) into a 100mL reaction bottle, cooling to-5 ℃, adding methyl iodide (3.55g, 25.0mmol, 1.0eq), dropwise adding a 20% potassium tert-butoxide/tetrahydrofuran solution (14.0g, 25.0mmol, 1.0eq) at 5-5 ℃, naturally heating to room temperature after dropwise adding, and stirring for 3 hours. The reaction was monitored by TLC (PE/EA 1/1, 1% triethylamine), quenched with water, extracted with dichloromethane 100mL by 3, the organic phases combined, the organic phase concentrated under reduced pressure to give an oil which was added to ethyl acetate to precipitate a large amount of solid which was filtered and dried to give a solid 9.53g with 89.5% yield.
Example 10
Under the protection of nitrogen, adding the impurity a (10.3g, 24.50mmol, 0.98eq) and anhydrous 2-MeTHF (50mL) into a 100mL reaction bottle, cooling to-5 ℃, adding methyl iodide (3.55g, 25.0mmol, 1.0eq), adding sodium tert-butoxide (2.4g, 25.00mmol, 1.0eq) in batches at 5-5 ℃, naturally raising the temperature to room temperature, and stirring for 4 hours. The reaction was monitored by TLC (PE/EA ═ 1/1, containing 1% triethylamine), quenched with water, extracted with 20mL of 2-methyltetrahydrofuran, the organic phases were combined and concentrated under reduced pressure to give an oily oil, ethyl acetate was added to precipitate a large amount of solid, which was filtered and dried to give 9.48g of solid in 89.1% yield.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (9)
1. A method for synthesizing carvedilol impurities is characterized by comprising the following steps:
impurities a and c: mixing carvedilol, an acid-binding agent and an organic solvent, and then adding a methylating agent to react to obtain a secondary amine nitrogen methylated impurity a; adding deprotonated strong base and an organic solvent, adding methyl halide at low temperature, and reacting to obtain a double methylated impurity c;
impurity b: mixing carvedilol, deprotonated strong base and an organic solvent, adding methyl halide at low temperature, and reacting to obtain carbazole nitrogen methylated impurities b.
2. The method of claim 1, wherein the carvedilol impurity is synthesized by: during the synthesis of the impurity a, the organic solvent is selected from acetonitrile, dioxane, acetone, DMSO or DMF.
3. The method of claim 1, wherein the carvedilol impurity is synthesized by: in the process of synthesizing the impurity a, the acid-binding agent is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, diisopropylethylamine or triethylamine.
4. The method of claim 1, wherein the carvedilol impurity is synthesized by: in the process of synthesizing the impurity a, the methylating agent is selected from methyl p-toluenesulfonate, methyl methanesulfonate or methyl iodide.
5. The method of claim 1, wherein the carvedilol impurity is synthesized by: in the process of synthesizing the impurity a, the mole ratio of carvedilol, weak base and methylating agent is 1: 1.0-1.1: 0.98-1.0.
6. The method for synthesizing carvedilol impurity of claim 1, characterized by comprising the following steps: in the process of synthesizing the impurity b, the organic solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran.
7. The method for synthesizing carvedilol impurity of claim 1, characterized by comprising the following steps: in the process of synthesizing the impurity b, the strong base is selected from sodium hydride, n-butyl lithium, potassium tert-butoxide or sodium tert-butoxide, and the methyl halide is selected from methyl iodide or methyl bromide.
8. The method for synthesizing carvedilol impurity of claim 1, characterized by comprising the following steps: in the process of synthesizing the impurity b, the mole ratio of carvedilol, deprotonated strong base and halogenated methane is 0.95-0.98: 1: 0.98-1.0.
9. The method for synthesizing carvedilol impurity of claim 1, characterized by comprising the following steps: during the synthesis of impurity c, the deprotonated strong base and the organic solvent are the same as those in impurity b.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110757266.0A CN113372260A (en) | 2021-07-05 | 2021-07-05 | Synthesis method of carvedilol impurity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110757266.0A CN113372260A (en) | 2021-07-05 | 2021-07-05 | Synthesis method of carvedilol impurity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113372260A true CN113372260A (en) | 2021-09-10 |
Family
ID=77580899
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110757266.0A Pending CN113372260A (en) | 2021-07-05 | 2021-07-05 | Synthesis method of carvedilol impurity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113372260A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4503067A (en) * | 1978-04-13 | 1985-03-05 | Boehringer Mannheim Gmbh | Carbazolyl-(4)-oxypropanolamine compounds and therapeutic compositions |
| WO2007144785A2 (en) * | 2006-03-26 | 2007-12-21 | Uti Limited Partnership | Ryanodine receptor inhibitors and methods relating thereto |
| WO2015031914A1 (en) * | 2013-08-30 | 2015-03-05 | Uti Limited Partnership | Store overload-induced calcium release inhibitors and methods for producing and using the same |
-
2021
- 2021-07-05 CN CN202110757266.0A patent/CN113372260A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4503067A (en) * | 1978-04-13 | 1985-03-05 | Boehringer Mannheim Gmbh | Carbazolyl-(4)-oxypropanolamine compounds and therapeutic compositions |
| WO2007144785A2 (en) * | 2006-03-26 | 2007-12-21 | Uti Limited Partnership | Ryanodine receptor inhibitors and methods relating thereto |
| WO2015031914A1 (en) * | 2013-08-30 | 2015-03-05 | Uti Limited Partnership | Store overload-induced calcium release inhibitors and methods for producing and using the same |
Non-Patent Citations (2)
| Title |
|---|
| CHRIS D. SMITH，ET AL.: "Novel Carvedilol Analogues That Suppress Store-Overload-Induced Ca2+ Release", 《J. MED. CHEM.》 * |
| 田铁牛 主编: "《有机合成单元过程》", 30 September 2006, 化学工业出版社 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104447739B (en) | A kind of deuterated Palbociclib derivative, preparation method and application | |
| JPH052678B2 (en) | ||
| EP2575899A1 (en) | Pet radiopharmaceuticals for differential diagnosis between bilateral and unilateral conditions of primary hyperaldosteronism | |
| CN106967064B (en) | Deuterated Palbociclib derivative, preparation method and applications | |
| CN113372260A (en) | Synthesis method of carvedilol impurity | |
| CN109369766A (en) | Uliprista acetate relevant chiral impurity and its synthesis preparation method | |
| CN113372305A (en) | Preparation method of eribulin intermediate | |
| CN114539304B (en) | Synthesis method and application of 1,3-azasilane compound | |
| CN103467449B (en) | Piperidine derivative, and preparation method and application thereof in preparation of halofuginone | |
| Day et al. | Carbon-nitrogen cleavage and carbon-carbon coupling processes in the reactions of triruthenium dodecacarbonyl with tertiary amines | |
| KR101407970B1 (en) | Sulfonate compound having 1,2,3-triazolium salt, preparation method thereof and intramolecular nucleophilic fluorination using the same | |
| CN109485661B (en) | Method for synthesizing benzoxazole-oxazole compound by [3+2] cycloaddition | |
| EP4177243A1 (en) | Preparation method for aromatic ether compound | |
| CA2997543C (en) | Therapeutic compounds for pain and synthesis thereof | |
| CN108912018A (en) | The preparation method and its usage of impurity compound in a kind of key intermediate for synthesizing Sulpiride | |
| CN115073547B (en) | Steroid carboline derivative, preparation method and application thereof, and anti-tumor pharmaceutical composition | |
| CN105820096B (en) | A kind of method for preparing substitution ethyl aryl sulfone | |
| Szechner et al. | Synthesis and absolute configuration of four diastereoisomeric 1-(2-furyl)-2-aminobutane-1, 3-diols | |
| CN110105371B (en) | Impurities in doladazole bulk drug and preparation method thereof | |
| CN113135893B (en) | Benzocycloheptapyridine compounds, process for their preparation and their use | |
| CN106220637A (en) | The control hydroxylating of a kind of symmetrical prestox hexa-atomic melon ring and the method for derivatization | |
| CN102558083B (en) | Synthesizing method for N, N-double substitution-3-amino isoxazole-5-methanol compound | |
| De Felice et al. | C–C coupling of aryl groups and allyl derivatives on Pt (II)-phenanthroline fragments: crystal and molecular structure of the tbp [(η1, η2-2-allyl, 5-methyl-phenyl) iodo (1, 10-phenanthroline) platinum (II)] complex containing the N–N ligand in axial-equatorial coordination mode | |
| JP2007031647A (en) | Method for producing compound containing nuclide with ultrashort half-life by utilizing solid-phase synthesis, and compound usable therefor | |
| EA044038B1 (en) | METHOD FOR PRODUCING P300 AND/OR CBP MODULATORS |
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 |