CN110734393B - Preparation method of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride - Google Patents
Preparation method of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride Download PDFInfo
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- CN110734393B CN110734393B CN201911092000.8A CN201911092000A CN110734393B CN 110734393 B CN110734393 B CN 110734393B CN 201911092000 A CN201911092000 A CN 201911092000A CN 110734393 B CN110734393 B CN 110734393B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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Abstract
The invention provides a preparation method of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride, which comprises the following steps: (1) preparation of intermediate 2: dissolving N-benzyl glycine ethyl ester in an organic solvent, adding 4-halogenated ethyl butyrate and alkali, and reacting to obtain N-benzyl glycine ethyl ester; (2) dissolving the intermediate 2 in an organic solvent, reacting with alkali, adjusting the pH to 7-8 after the reaction is finished, adding water for washing, adjusting the pH to 1-2 in an organic layer, and separating out crystals to obtain a crude product; (3) and dissolving the crude product in water, adding alkali to adjust the pH to 7-8, adding an organic solvent to extract and wash, adjusting the pH to 1-2 in an organic layer, and crystallizing to obtain the product. The method has the advantages of simple process operation, high product yield, high purity and easy industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride.
Background
The N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride is an important intermediate of a new generation fluoroquinolone antibacterial drug balofloxacin, and the current synthetic method (CN105622444B) is as follows: a process for preparing N-benzyl glycine ethyl ester includes such steps as dissolving benzylamine in organic solvent, adding 2-haloethyl acetate, alkali and quaternary ammonium salt, and reacting. Also discloses a preparation method of the 1-benzyl-3-piperidone hydrochloride, which comprises the following specific steps of (1) preparing an intermediate 1 (N-benzyl glycine ethyl ester); (2) dissolving the intermediate 1 in an organic solvent, adding 4-halogenated ethyl butyrate and alkali, and reacting to obtain an intermediate 2; (3) reacting the intermediate 2 with alkali, adjusting pH to 6-8, concentrating under reduced pressure, extracting with ethyl acetate, washing, drying, and concentrating under reduced pressure to obtain intermediate 3; (4) and (3) reacting the intermediate 3 with acid, performing rotary evaporation and concentration, and adding a crystallization solvent for crystallization to obtain a product. CN105622444B intermediate 3 in the present invention is the free base form of the product of the present invention. The disadvantages of this synthetic method are: the intermediate 3 is obtained by adopting a reduced pressure concentration mode, and the product purity is low and is about 90-93 percent.
Disclosure of Invention
The purpose of the invention is as follows: the invention provides a preparation method of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride.
The technical scheme is as follows:
a preparation method of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride comprises the following reaction equation:
the method comprises the following specific steps:
(1) preparation of intermediate 2: dissolving N-benzyl glycine ethyl ester in an organic solvent, adding 4-halogenated ethyl butyrate and alkali, and reacting to obtain 4- [ benzyl (ethoxycarbonylmethyl) amino ] ethyl butyrate;
(2) dissolving the intermediate 2 in an organic solvent, reacting with alkali, adjusting the pH to 7-8 after the reaction is finished, adding water for washing, adjusting the pH to 1-2 in an organic layer, and separating out crystals to obtain a crude product;
(3) and dissolving the crude product in water, adding alkali to adjust the pH to 7-8, adding an organic solvent to extract and wash, adjusting the pH to 1-2 in an organic layer, and crystallizing to obtain the product.
The preparation method of the N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride comprises the step (1), wherein the molar ratio of the N-benzyl glycine ethyl ester to the 4-halogenated ethyl butyrate to the alkali is 1: 1-1.5.
The preparation method of the N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride comprises the step (2), wherein the molar ratio of the intermediate 2 to the alkali is 1: 1-1.5.
The preparation method of the N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride comprises the following steps of (1) selecting the organic solvent from one of methanol, ethanol, toluene or benzene; the 4-halogenated ethyl butyrate is one of 4-chloroethyl butyrate or 4-bromoethyl butyrate; the alkali is selected from one of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
In the preparation method of the ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride, the organic solvent in the step (2) is selected from one of ethyl acetate, tetrahydrofuran, toluene or benzene; the alkali is selected from one of sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide.
In the preparation method of the N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride, the alkali in the step (3) is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate; the organic solvent is selected from: toluene, benzene, ethyl acetate or dichloromethane.
The invention has the beneficial effects that: the method for preparing the N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride by condensing the N-benzyl glycine ethyl ester serving as the starting raw material with the 4-halogenated ethyl acetate and then cyclizing the condensation product has the advantages of short synthetic route step, simple process operation, low cost of the used raw materials, high product yield and high purity, and is easy for industrial production.
Detailed Description
The foregoing aspects of the present invention are described in further detail below by way of examples, but it should not be construed that the scope of the subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above aspects of the present invention are within the scope of the present invention.
Example 1: preparation of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride
The method comprises the following steps:
(1) preparation of intermediate 2
6kg (31mol) of ethyl N-benzylglycinate is added into a 20L four-mouth reaction bottle, 6.65kg (34.1mol) of ethyl 4-bromobutyrate is added, 6L of methanol and 3.6kg (34.1mol) of sodium carbonate are added, the mixture is heated to reflux, the reflux reaction is carried out under the condition of heat preservation for 10 hours, the reaction is stopped after the TLC detection is carried out to complete the basic reaction, the reaction liquid is cooled to the room temperature, the filtration is carried out, the filtrate is concentrated under the reduced pressure, and 29.41 kg of an intermediate is obtained, and the yield is 98.6%.
(2) Preparation of crude product
Adding the intermediate 2 prepared in the previous step into a 20L four-mouth reaction bottle, adding 10L of ethyl acetate, adding 1.84kg (34.1mol) of sodium methoxide, heating to reflux, carrying out heat preservation and reflux reaction for 4hr, stopping the reaction after the TLC detection shows that the basic reaction is complete, cooling the reaction liquid to room temperature, adding water for extraction and washing, adjusting the pH of an organic layer to be 1-2 by hydrochloric acid, precipitating a solid, filtering and drying to obtain 8.81kg of a crude product, wherein the yield is 96.6%.
(3) Preparation of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride
Adding the crude product prepared in the previous step into a 20L four-mouth reaction bottle, adding 5L of water, stirring to dissolve, adjusting the pH value to 7-8 with 30% sodium hydroxide aqueous solution, adding 5L of ethyl acetate to extract, and washing the water layer with 1L multiplied by 2 of ethyl acetate for 2 times. The organic layers are combined, the pH value is adjusted to 1-2 by hydrochloric acid, solid is separated out, and the solid is filtered and dried to obtain 8.6kg of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride, the yield is 97.6%, the purity is 99.5% by HPLC detection, and the total yield is 93.0%.
Example 2: preparation of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride
The method comprises the following steps:
(1) preparation of intermediate 2
6kg (31mol) of ethyl N-benzylglycinate is added into a 20L four-mouth reaction bottle, 7kg (46.5mol) of ethyl 4-chlorobutyrate is added, 6L of toluene and 6.43kg (46.5mol) of potassium carbonate are added, the mixture is heated to reflux, the reflux reaction is carried out under the condition of heat preservation for 8 hours, the reaction is stopped after the TLC detection is carried out to complete the basic reaction, the reaction liquid is cooled to the room temperature, the filtration is carried out, the filtrate is concentrated under the reduced pressure, 29.46 kg of an intermediate is obtained, and the yield is 99.1%.
(2) Preparation of crude product
Adding the intermediate 2 prepared in the previous step into a 20L four-mouth reaction bottle, adding 10L of toluene, adding 5.22kg (46.5mol) of potassium tert-butoxide, heating to reflux, carrying out heat preservation and reflux reaction for 3hr, stopping the reaction after the TLC detection shows that the reaction is almost complete, cooling the reaction liquid to room temperature, adding water for extraction and washing, adjusting the pH value of an organic layer to 1-2 by hydrochloric acid, precipitating a solid, filtering and drying to obtain 8.82kg of a crude product, wherein the yield is 96.4%.
(3) Preparation of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride
Adding the crude product prepared in the previous step into a 20L four-mouth reaction bottle, adding 5L of water, stirring to dissolve, adjusting the pH to 7-8 with 30% potassium hydroxide aqueous solution, adding 5L of toluene to extract, and washing an aqueous layer with 1L of toluene multiplied by 2 for 2 times. The organic layers are combined, the pH value is adjusted to 1-2 by hydrochloric acid, solid is separated out, and the solid is filtered and dried to obtain 8.55kg of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride, the yield is 96.9%, the purity is 99.6% by HPLC detection, and the total yield is 92.6%.
Example 3: preparation of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride
The method comprises the following steps:
(1) preparation of intermediate 2
Adding 6kg (31mol) of ethyl N-benzylglycinate into a 20L four-mouth reaction bottle, adding 7.86kg (40.3mol) of ethyl 4-bromobutyrate, adding 6L of ethanol and 1.61kg (40.3mol) of sodium hydroxide, heating to reflux, keeping the temperature for reflux reaction for 12hr, stopping the reaction after TLC detection is completed, cooling the reaction solution to room temperature, filtering, and concentrating the filtrate under reduced pressure to obtain 29.4 kg of an intermediate with the yield of 98.5%
(2) Preparation of crude product
Adding the intermediate 2 prepared in the previous step into a 20L four-mouth reaction bottle, adding 10L tetrahydrofuran, adding 2.74kg (40.3mol) of sodium ethoxide, heating to reflux, carrying out heat preservation and reflux reaction for 4hr, stopping the reaction after TLC detection shows that the reaction is almost complete, cooling the reaction liquid to room temperature, adding water for extraction and washing, adjusting the pH value of an organic layer to be 1-2 by using hydrochloric acid, separating out a solid, filtering and drying to obtain 8.88kg of a crude product, wherein the yield is 97.5%.
(3) Preparation of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride
Adding the crude product prepared in the previous step into a 20L four-mouth reaction bottle, adding 5L of water, stirring to dissolve, adjusting the pH value to 7-8 with 20% sodium carbonate aqueous solution, adding 5L of dichloromethane for extraction, and washing an aqueous layer with 1L multiplied by 2 dichloromethane for 2 times. The organic layers are combined, the pH value is adjusted to 1-2 by hydrochloric acid, solid is precipitated, and the solid is filtered and dried to obtain 8.62kg of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride, the yield is 97.1%, the purity is 99.5% by HPLC detection, and the total yield is 93.3%.
Comparative example 1: according to the synthesis method in CN 105622444B: a preparation method of 1-benzyl-3-piperidone hydrochloride comprises the following specific steps: (1) preparing an intermediate 1 (N-benzyl glycine ethyl ester); (2) dissolving the intermediate 1 in tetrahydrofuran, adding 4-bromo-ethyl butyrate and sodium carbonate, and reacting to obtain an intermediate 2(4- [ benzyl (ethoxycarbonylmethyl) amino ] ethyl butyrate); (3) reacting the intermediate 2 with sodium tert-butoxide, adding acetic acid to adjust the pH value to 7 after the reaction is finished, concentrating under reduced pressure, extracting with ethyl acetate, washing, drying, and concentrating under reduced pressure to obtain the intermediate 3-N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester, namely the free base form, wherein the total yield in 3 steps is 86.6%, and the purity is 92.6% by HPLC detection.
Comparative example 2: according to the synthesis method in CN 105622444B: a preparation method of 1-benzyl-3-piperidone hydrochloride comprises the following specific steps: (1) preparing an intermediate 1 (N-benzyl glycine ethyl ester); (2) dissolving the intermediate 1 in chloroform, adding 4-chlorobutyric acid ethyl ester and potassium carbonate, and reacting to obtain an intermediate 2(4- [ benzyl (ethoxycarbonylmethyl) amino ] butyric acid ethyl ester); (3) reacting the intermediate 2 with potassium tert-butoxide, adding acetic acid to adjust the pH value to 7 after the reaction is finished, concentrating under reduced pressure, extracting with ethyl acetate, washing, drying, and concentrating under reduced pressure to obtain the intermediate 3-N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester, namely the free base form, wherein the total yield in 3 steps is 86.6%, and the purity is 93.2% by HPLC detection.
Comparative example 3: according to the synthesis method in CN 105622444B: a preparation method of 1-benzyl-3-piperidone hydrochloride comprises the following specific steps: (1) preparing an intermediate 1 (N-benzyl glycine ethyl ester); (2) dissolving the intermediate 1 in toluene, adding 4-bromo-ethyl butyrate and sodium carbonate, and reacting to obtain an intermediate 2(4- [ benzyl (ethoxycarbonylmethyl) amino ] ethyl butyrate); (3) reacting the intermediate 2 with sodium tert-butoxide, adjusting the pH value to 6-8, concentrating under reduced pressure, extracting with ethyl acetate, washing, drying, and concentrating under reduced pressure to obtain the intermediate 3-N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester, i.e. the free base form of the invention, wherein the total yield in 3 steps is 88.0%, and the purity is 90.9% by HPLC detection.
Example 4: purity determination of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride
Taking the ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride prepared in examples 1 to 4 of the present invention and comparative example 1, respectively, and testing the hydrochloride by high performance liquid chromatography (the general rule 0512 of the Chinese pharmacopoeia 2015), using octadecyl silica gel as a filler (Waters Symmetry C18 is applicable, 250 mm. times.4.6 mm, 5 μm); the mobile phase A is 0.1 percent trifluoroacetic acid, the mobile phase B is acetonitrile, and gradient elution is carried out according to the following table; the column temperature is 30 ℃; the flow rate was 1.0ml/min and the detection wavelength was 250 nm.
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 95 | 5 |
| 10 | 65 | 35 |
| 25 | 65 | 35 |
| 26 | 20 | 80 |
| 29 | 20 | 80 |
| 30 | 95 | 5 |
| 40 | 95 | 5 |
Taking a proper amount of the product, precisely weighing, adding water to dissolve and dilute to prepare a solution containing 0.5mg per 1ml, and shaking up to obtain a test solution. Precisely measuring 20 μ l of the above solution, injecting into a liquid chromatograph, and recording chromatogram. According to a peak area normalization method, if an impurity peak exists in a chromatogram of a test solution, the maximum single impurity cannot exceed 0.2%, the total amount of impurities cannot exceed 2.0%, and experimental results are shown in the following table.
From the above results, it is known that in the experimental scheme of examples 1-3, the purity of the product obtained by adjusting N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride with acid and base is higher than that of comparative examples 1-3, which indicates that most of the impurities in the invention are removed by organic solvent extraction after base adjustment and crystallization filtration of hydrochloride, and the yield is high, thus being suitable for industrial production.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And such obvious changes and modifications which fall within the spirit of the invention are deemed to be covered by the present invention.
Claims (6)
1. A preparation method of N-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride is characterized in that the reaction equation is as follows:
x: br or Cl, and (b) in the presence of a catalyst,
the method comprises the following specific steps:
(1) preparation of intermediate 2: dissolving N-benzyl glycine ethyl ester in an organic solvent, adding 4-halogenated ethyl butyrate and alkali, and reacting to obtain 4- [ benzyl (ethoxycarbonylmethyl) amino ] ethyl butyrate;
(2) dissolving the intermediate 2 in an organic solvent, reacting with alkali, adjusting the pH to 7-8 after the reaction is finished, adding water for washing, adjusting the pH to 1-2 in an organic layer, and separating out crystals to obtain a crude product;
(3) and dissolving the crude product in water, adding alkali to adjust the pH to 7-8, adding an organic solvent to extract and wash, adjusting the pH to 1-2 in an organic layer, and crystallizing to obtain the product.
2. The method for preparing ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride according to claim 1, wherein in step (1), the molar ratio of ethyl N-benzylglycine to ethyl 4-halobutyrate to base is 1:1 to 1.5.
3. The method for preparing ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride according to claim 1, wherein in step (2), the molar ratio of intermediate 2 to base is 1:1 to 1.5.
4. The process for preparing ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride according to claim 1, wherein the organic solvent in step (1) is one selected from methanol, ethanol, toluene and benzene; the 4-halogenated ethyl butyrate is one of 4-chloroethyl butyrate or 4-bromoethyl butyrate; the alkali is selected from one of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
5. The process for preparing ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride according to claim 1, wherein the organic solvent in step (2) is one selected from ethyl acetate, tetrahydrofuran, toluene and benzene; the alkali is selected from one of sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide.
6. The process for preparing ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride according to claim 1, wherein in step (3) the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; the organic solvent is selected from: toluene, benzene, ethyl acetate or dichloromethane.
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| CN1315319A (en) * | 2000-03-22 | 2001-10-03 | 弗·哈夫曼-拉罗切有限公司 | Process for preparing ethyl-sulfonylpiperidine derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1315319A (en) * | 2000-03-22 | 2001-10-03 | 弗·哈夫曼-拉罗切有限公司 | Process for preparing ethyl-sulfonylpiperidine derivatives |
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| Title |
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| Efficient Enantioselective Synthesis of the NMDA 2B Receptor Antagonist Ro67-8867;Michelangelo Scalone等;《Organic Process Research & Development》;20030404;第 418-425页 * |
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