CN112028754A - Preparation method of safinamide mesylate intermediate - Google Patents
Preparation method of safinamide mesylate intermediate Download PDFInfo
- Publication number
- CN112028754A CN112028754A CN202010554694.9A CN202010554694A CN112028754A CN 112028754 A CN112028754 A CN 112028754A CN 202010554694 A CN202010554694 A CN 202010554694A CN 112028754 A CN112028754 A CN 112028754A
- Authority
- CN
- China
- Prior art keywords
- cooling
- stirring
- mesylate intermediate
- speed
- safinamide mesylate
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
Abstract
The invention relates to a preparation method of a safinamide mesylate intermediate, which comprises the steps of adding a concentrated organic phase into an organic solvent under the protection of nitrogen, heating to 40-45 ℃, then cooling to 28-35 ℃ in a uniform speed cooling manner, and adding a mixture of seed crystals and the organic solvent; and (3) cooling the solution system to 3-8 ℃ in a gradient cooling mode, filtering and drying to obtain a target product, namely a safinamide mesylate intermediate, namely the compound 4- (3-fluorobenzyloxy) -benzaldehyde of the formula 4. According to the invention, the organic phase obtained after the reflux reaction is subjected to purification and crystallization treatment in a gradient cooling mode, and the product is directly obtained through one-step purification, so that the method has the advantages of simple operation steps, greatly improved efficiency and purity, reduced solvent usage amount, mild reaction conditions, environmental friendliness, increased preparation safety and reliability, contribution to embodying of safe and controllable medication principles, and higher industrial development prospect.
Description
Technical Field
The invention relates to the technical field of preparation of pharmaceutical intermediates, and in particular relates to a preparation method of a safinamide mesylate intermediate 4- (3-fluorobenzyloxy) -benzaldehyde.
Background
Safinamide mesylate (compound of formula 1 below), the chinese name (2S) - [4- (3-fluorobenzyloxy) benzylamino ] propanamide-mesylate, marketed in 2017 in the united states as a selective monoamine oxidase B inhibitor, was approved for the adjuvant treatment of parkinson' S disease patients with "off-phase events". Safinamide was first disclosed in european patent EP0400495B filed on 25.5.1990, co-developed by the panbang group of italy and the newanlang biopharmaceutical under the trade name Xadago.
Chinese patent No. cn200880120328.x (granted publication no: CN101896456B), applied by nieron pharmaceutical company on 1/12/2008, discloses a method for preparing safinamide mesylate, and mentions that impurities of the compound of the following formula 2 are easily generated during the preparation of safinamide, and the chemical name of the impurities is: (S) -2- [3- (3-fluorobenzyl) -4- (3-fluorobenzyloxy) -benzylamino ] propanamide. The impurities have extremely high toxicity to enzymes of a cytochrome P450 system, and once entering a human body, extremely serious side reactions are caused, so that the preparation process of raw material medicines or intermediates thereof and the obtained products need to be strictly controlled, and the content of the impurities is required to be lower than 0.03 percent.
According to the study, the initial source of impurities in the drug substance (compound of formula 2) is the compound of formula 3 (chemical name: 3- (3-fluorobenzyl) -4- (3-fluorobenzyloxy) benzaldehyde), and the synthetic process is shown in FIG. 1. The compound of formula 3 is subjected to a subsequent reaction together with the main product of the reaction of this step, a compound of formula 4 (chemical name: 4- (3-fluorobenzyloxy) -benzaldehyde), to give a compound of formula 2. The synthesis of the compound of formula 2 is shown in figure 2. Since such di-alkylated impurities have chemical-physical properties similar to those of alkylated derivatives and are difficult to purify by conventional methods, the impurities are controlled by purifying the product obtained in the first synthesis step of fig. 1, i.e., the intermediate in the process of preparing safinamide mesylate, which is an extremely effective method for controlling the subsequent impurities.
The above patent cn200880120328.x also discloses a purification process of the compound of formula 4, which is obtained by stirring crude 4- (2-fluorobenzyloxy) benzaldehyde prepared by phase transfer catalysis at 30-35 ℃ for 30min, then adding n-hexane (11kg) to the mixture at 30-35 ℃ over 30min with keeping stirring, cooling to 0-5 ℃ and stirring at that temperature for 1 hour more, then collecting the solid by filtration and drying under reduced pressure: 8.0kg (89% yield) of 4- (2-fluorobenzyloxy) benzaldehyde; 1Kg of the product prepared above is dissolved in 2Kg of diisopropyl ether under reflux and stirring, the solution is cooled to 50-55 ℃ in 10-15min and seeded with 5g of highly pure 4- (2-fluorobenzyloxy) benzaldehyde (GC purity 99.9 area% and (VIb) content below 0.005%), the suspension is cooled to 10-15 ℃ in 45-60min and stirred for a further 1 h, the precipitate is finally collected by filtration, washed with cold diisopropyl ether (0.2Kg) and dried under reduced pressure to give 0.93Kg of 4- (2-fluorobenzyloxy) benzaldehyde having a 3- (2-fluorobenzyl) -4- (2-fluorobenzyloxy) benzaldehyde content of 0.005% by weight.
When the method is used for preparing the 4- (2-fluorobenzyloxy) benzaldehyde, two-step purification is needed, the impurity content can be controlled to be 50ppm, the method and the steps are complicated, the operation is complex, and the solvent consumption is large; the impurity content of one-step purification is 100ppm, the impurity content is high, and adverse effects are easily caused on the safety, effectiveness and quality controllability of subsequent compounds (bulk drug safinamide or mesylate thereof) and preparations containing the bulk drug.
Therefore, how to efficiently produce high-purity 4- (3-fluorobenzyloxy) -benzaldehyde is in need of improvement.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of a safinamide mesylate intermediate for improving the purity of a product by gradient cooling aiming at the current situation of the prior art, wherein the purification process of the product in the preparation method is completed in one step, the operation is simple, and the solvent consumption is small.
The technical scheme adopted by the invention for solving the technical problems is as follows: a preparation method of a safinamide mesylate intermediate comprises the following steps:
under the condition of stirring, carrying out reflux reaction on 2-fluorobenzyl chloride, 4-hydroxy-benzaldehyde, potassium carbonate and a phase transfer catalyst in an organic solvent in a nitrogen atmosphere, and carrying out pretreatment after the reaction is finished to obtain a concentrated organic phase; the method is characterized by further comprising the following steps:
adding the concentrated organic phase into an organic solvent under the protection of nitrogen, heating to 40-45 ℃, then cooling to 28-35 ℃ in a uniform speed cooling manner, and adding a mixture of seed crystals and the organic solvent;
cooling the solution system to 3-8 ℃ in a gradient cooling mode, filtering and drying to obtain a target product of a safinamide mesylate intermediate, namely a compound 4- (3-fluorobenzyloxy) -benzaldehyde of the following formula 4,
preferably, the gradient cooling mode at least comprises three gradient temperatures, each gradient temperature is obtained by uniform cooling under the stirring condition, and the temperature is kept and stirred for 1-4 hours at each gradient temperature.
Preferably, the stirring speed is 250-300rpm, and the temperature reduction speed is 5-15 ℃/h, preferably 5-10 ℃/h.
Preferably, the gradient cooling mode is that the temperature is reduced to 25 ℃ at the speed of 5-10 ℃/h, and the temperature is kept and the stirring is carried out for 3 hours; then continuously cooling to 20 ℃ at the speed of 5-10 ℃/h, preserving heat and stirring for 3 hours; then continuously cooling to 15 ℃ at the speed of 5-10 ℃/h, and stirring for 2 hours under heat preservation; then the temperature is reduced to 5 ℃ at the speed of 5-10 ℃/h, and the mixture is stirred for 3 hours under the condition of heat preservation. By adopting the method, the product with high yield and high purity can be obtained through one-step purification.
In the scheme, after the mixture of the seed crystal and the organic solvent is added, the stirring speed is controlled to be 250-300rpm, the stirring is carried out for 20-30 minutes, and then the gradient temperature reduction is carried out.
Preferably, the concentrated organic phase is added to a mixed solvent of toluene and cyclohexane, wherein the volume ratio of toluene to cyclohexane is 1/(6-10). Further preferably 1/8.
In the invention, the pretreatment process comprises the steps of cooling a solution system after reflux reaction to 20-40 ℃, filtering, washing an obtained organic phase with water, replacing with nitrogen, and concentrating the organic phase.
Preferably, the phase transfer catalyst is tetradecyltrimethylammonium bromide or tetrabutylammonium bromide.
In each of the above embodiments, the mixture of the seed crystal and the organic solvent is a mixture of 4- (3-fluorobenzyloxy) -benzaldehyde and cyclohexane after crystallization, and the ratio of the two is 1: 4.
Compared with the prior art, the invention has the advantages that: according to the invention, the organic phase obtained after the reflux reaction is subjected to purification and crystallization treatment in a gradient cooling mode, and the product is directly obtained through one-step purification, so that the method has the advantages of simple operation steps, greatly improved efficiency and purity, reduced solvent usage amount, mild reaction conditions, environmental friendliness, increased preparation safety and reliability, contribution to embodying of safe and controllable medication principles, and higher industrial development prospect.
Drawings
FIG. 1 is a diagram illustrating the steps in the synthesis of a compound of formula 3 in the background of the invention;
FIG. 2 is a diagram showing the steps of synthesizing a compound of formula 2 according to the background of the present invention;
FIG. 3 is a LC-MS detection of impurities in the product of example 1 of the present invention;
FIG. 4 is a LC-MS detection of impurities in the product of comparative example 1 of the present invention;
FIG. 5 is an LC-MS detection spectrum of a 4- (2-fluorobenzyloxy) benzaldehyde standard substance in the prior art.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
Example 1:
the preparation method of safinamide mesylate intermediate (4- (3-fluorobenzyloxy) -benzaldehyde) in this example is as follows:
a mixture of 2-fluorobenzyl chloride (6.0kg, 41.50moL), 4-hydroxy-benzaldehyde (4.7kg, 38.33moL), potassium carbonate (5.2kg, 37.33moL) and tetradecyltrimethylammonium bromide (0.49kg, 1.46moL) in toluene (11.4kg) was slowly brought to reflux under stirring in a nitrogen atmosphere for 6 h;
after the reaction is finished, cooling to 20-40 ℃, filtering, washing an organic phase with purified water, replacing the organic phase with nitrogen, concentrating the organic phase, adding toluene/cyclohexane (1/8, 9V), protecting with nitrogen, and heating to 40-45 ℃;
heating to clarify the solution, stirring for 10-20 min, and cooling at 5 deg.C/h with stirring speed of 100-; adding the mixed solution of the seed crystal and cyclohexane when the temperature is reduced to 30 ℃, controlling the stirring speed to be 250-year stirring at 300rpm for 20-30 minutes, then continuously reducing the temperature to 25 ℃ at the speed of 5 ℃/h, and keeping the temperature and stirring for 3 hours; then continuously cooling to 20 ℃ at the speed of 5 ℃/h, preserving heat and stirring for 3 hours; then continuously cooling to 15 ℃ at the speed of 5 ℃/h, and stirring for 2 hours under heat preservation; then cooling to 5 ℃ at the speed of 5 ℃/h, and stirring for 3 hours under heat preservation;
filtering, leaching a filter cake with cyclohexane, and drying to obtain a target product. The yield is 93 percent, the obtained product is detected by LC-MS, and the content of impurities in the product is calculated by an external standard method.
Example 2:
the preparation method of safinamide mesylate intermediate (4- (3-fluorobenzyloxy) -benzaldehyde) in this example is as follows:
a mixture of 2-fluorobenzyl chloride (6.0kg, 41.50moL), 4-hydroxy-benzaldehyde (4.7kg, 38.33moL), potassium carbonate (5.2kg, 37.33moL) and tetrabutylammonium bromide (0.49kg, 1.46moL) in toluene (11.4kg) was slowly brought to reflux under stirring in a nitrogen atmosphere for 6 h;
after the reaction is finished, cooling to 20-40 ℃, filtering, washing an organic phase with purified water, replacing the organic phase with nitrogen, concentrating the organic phase, adding toluene/cyclohexane (1/8, 9V), protecting with nitrogen, and heating to 40-45 ℃;
heating to clarify the solution, stirring for 10-20 min, cooling at 10 deg.C/h with stirring speed of 100 plus 120rpm, adding the mixed liquid of seed crystal and cyclohexane when the temperature is reduced to 30 deg.C, stirring at 250 plus 300rpm for 20-30 min, cooling to 25 deg.C at 10 deg.C/h, and stirring for 2 hr; then continuously cooling to 20 ℃ at the speed of 10 ℃/h, and stirring for 2 hours under heat preservation; then continuously cooling to 15 ℃ at the speed of 10 ℃/h, and stirring for 3 hours under heat preservation; then cooling to 5 ℃ at the speed of 10 ℃/h, and stirring for 3 hours under heat preservation;
filtering, leaching filter cake with cyclohexane, and drying. The yield thereof was found to be 90%.
Comparative example 1:
4- (3-fluorobenzyloxy) -benzaldehyde was prepared according to the procedure in patent CN200880120328.X as follows:
a first step of slowly refluxing a mixture of 2-fluorobenzyl chloride (6.0kg, 41.50moL), 4-hydroxy-benzaldehyde (4.7kg, 38.33moL), potassium carbonate (5.2kg, 37.33moL) and tetradecyltrimethylammonium bromide (0.49kg, 1.46moL) in toluene (11.4kg) under stirring for 6h in a nitrogen atmosphere;
a second step of concentrating the solution at atmospheric pressure, adding 3.6kg of toluene and distilling off and repeating the operation again;
in a third step, the heterogeneous mixture was cooled to room temperature and the solid was removed by filtration, followed by removal of the residual solvent under reduced pressure and addition of 1.4kg of toluene to the oily residue; the mixture was heated to 30-35 ℃ and seeded with 3% pure 4- (2-fluorobenzyloxy) benzaldehyde;
fourthly, stirring the heterogeneous mixture at 30-35 ℃ for 30min, and then adding n-hexane (11kg) to the mixture at 30-35 ℃ for 30min while keeping stirring;
fifth step, after cooling to 0-5 ℃ and stirring at this temperature for another 1 hour, the solid was collected by filtration and dried under reduced pressure to give: 8.0kg, yield 89%. And performing LC-MS detection on the obtained product, and calculating the content of impurities in the product by an external standard method.
Table 1 shows the method for determining the content of 3- (3-fluorobenzyl) -4- (3-fluorobenzyloxy) benzaldehyde, an intermediate impurity, in example 1 and comparative example 1. The content of impurities in the sample is calculated by an external standard method, and a standard product 3- (3-fluorobenzyl) -4- (3-fluorobenzyloxy) benzaldehyde is prepared into a solution of 250ng/mL and is injected. Meanwhile, the sample is accurately weighed into a 250ng/mL solution and injected. And calculating the content of the impurities in the sample according to the peak area ratio.
TABLE 13- (3-Fluorobenzyl) -4- (3-fluorobenzyloxy) benzaldehyde LC-MS detection method
Table 2 shows the detection data and the corresponding impurity content results of the samples of example 1 and comparative example 1, and the impurity peak-off time is about 10.972 min; FIGS. 3 and 4 are LC-MS detection charts of impurities in the samples of example 1 and comparative example 1, respectively, and FIG. 5 is an LC-MS detection chart of a 4- (2-fluorobenzyloxy) benzaldehyde standard product in the prior art. It can be seen that the impurity level of example 1 is much lower than that of comparative example 1.
TABLE 2 test results
| Sample (I) | Peak area | Content of impurities | Intermediate particle size |
| Comparative example 1 | 2352 | 158.1ppm | 1410μm |
| Example 1 | 205 | 12.0ppm | 49.5μm |
Claims (9)
1. A preparation method of a safinamide mesylate intermediate comprises the following steps:
under the condition of stirring, carrying out reflux reaction on 2-fluorobenzyl chloride, 4-hydroxy-benzaldehyde, potassium carbonate and a phase transfer catalyst in an organic solvent in a nitrogen atmosphere, and carrying out pretreatment after the reaction is finished to obtain a concentrated organic phase; the method is characterized by further comprising the following steps:
adding the concentrated organic phase into an organic solvent under the protection of nitrogen, heating to 40-45 ℃, then cooling to 28-35 ℃ in a uniform speed cooling manner, and adding a mixture of seed crystals and the organic solvent;
cooling the solution system to 3-8 ℃ in a gradient cooling mode, filtering and drying to obtain a target product of a safinamide mesylate intermediate, namely a compound 4- (3-fluorobenzyloxy) -benzaldehyde of the following formula 4,
2. the process for producing a safinamide mesylate intermediate according to claim 1, wherein: the gradient cooling mode at least comprises three gradient temperatures, each gradient temperature is obtained by uniform cooling under the stirring condition, and the temperature is kept and stirred for 1-4h at each gradient temperature.
3. The process for producing a safinamide mesylate intermediate according to claim 2, wherein: the stirring speed is 250-300rpm, and the cooling speed is 5-15 ℃/h.
4. A process for the preparation of a safinamide mesylate intermediate according to claim 3, wherein: the gradient cooling mode is that the temperature is reduced to 25 ℃ at the speed of 5-10 ℃/h, and the temperature is kept and the stirring is carried out for 3 hours; then continuously cooling to 20 ℃ at the speed of 5-10 ℃/h, preserving heat and stirring for 3 hours; then continuously cooling to 15 ℃ at the speed of 5-10 ℃/h, and stirring for 2 hours under heat preservation; then the temperature is reduced to 5 ℃ at the speed of 5-10 ℃/h, and the mixture is stirred for 3 hours under the condition of heat preservation.
5. The process for producing a safinamide mesylate intermediate according to claim 1, wherein: after the mixture of the seed crystal and the organic solvent is added, the stirring speed is controlled to be 250-300rpm, the stirring is carried out for 20-30 minutes, and then the gradient temperature reduction is carried out.
6. The method for producing a safinamide mesylate intermediate according to any one of claims 1 to 5, wherein: and adding the concentrated organic phase into a mixed solvent of toluene and cyclohexane, wherein the volume ratio of the toluene to the cyclohexane is 1/(6-10).
7. The method for producing a safinamide mesylate intermediate according to any one of claims 1 to 5, wherein: the pretreatment process comprises the steps of cooling a solution system after the reflux reaction to 20-40 ℃, filtering, washing an obtained organic phase with water, replacing with nitrogen, and concentrating the organic phase.
8. The method for producing a safinamide mesylate intermediate according to any one of claims 1 to 5, wherein: the phase transfer catalyst is tetradecyl trimethyl ammonium bromide or tetrabutyl ammonium bromide.
9. The method for producing a safinamide mesylate intermediate according to any one of claims 1 to 5, wherein: the mixture of the seed crystal and the organic solvent is a mixed solution of crystallized 4- (3-fluorobenzyloxy) -benzaldehyde and cyclohexane, and the ratio of the two is 1: 4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010554694.9A CN112028754A (en) | 2020-06-17 | 2020-06-17 | Preparation method of safinamide mesylate intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010554694.9A CN112028754A (en) | 2020-06-17 | 2020-06-17 | Preparation method of safinamide mesylate intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112028754A true CN112028754A (en) | 2020-12-04 |
Family
ID=73578903
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010554694.9A Pending CN112028754A (en) | 2020-06-17 | 2020-06-17 | Preparation method of safinamide mesylate intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112028754A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113444010A (en) * | 2020-03-28 | 2021-09-28 | 南京正大天晴制药有限公司 | Preparation method of safinamide related substances |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090156678A1 (en) * | 2006-06-19 | 2009-06-18 | Newron Pharmaceuticals S.P.A. | Process for the production of 2-[4-(3- and 2-fluorobenzyloxy) benzylamino] propanamides |
| CN104523668A (en) * | 2007-12-11 | 2015-04-22 | 纽朗制药有限公司 | High purity 2-[4-(3- or 2-fluorobenzyloxy)benzylamino]propanamides and methods of use thereof |
| CN104803976A (en) * | 2015-05-18 | 2015-07-29 | 苏州亚宝药物研发有限公司 | Industrial production method of Alogliptin benzoate raw material medicine |
-
2020
- 2020-06-17 CN CN202010554694.9A patent/CN112028754A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090156678A1 (en) * | 2006-06-19 | 2009-06-18 | Newron Pharmaceuticals S.P.A. | Process for the production of 2-[4-(3- and 2-fluorobenzyloxy) benzylamino] propanamides |
| CN104523668A (en) * | 2007-12-11 | 2015-04-22 | 纽朗制药有限公司 | High purity 2-[4-(3- or 2-fluorobenzyloxy)benzylamino]propanamides and methods of use thereof |
| CN104803976A (en) * | 2015-05-18 | 2015-07-29 | 苏州亚宝药物研发有限公司 | Industrial production method of Alogliptin benzoate raw material medicine |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113444010A (en) * | 2020-03-28 | 2021-09-28 | 南京正大天晴制药有限公司 | Preparation method of safinamide related substances |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2373834C (en) | A process for the production of thiazolidine | |
| AU2005257478B2 (en) | Method for producing (Z)-1-phenyl-1-diethylaminocarbonyl-2-aminomethyl cyclopropane hydrochloride | |
| JP4752989B2 (en) | Method for producing (2R) -2-propyloctanoic acid | |
| CN112028754A (en) | Preparation method of safinamide mesylate intermediate | |
| JP4933253B2 (en) | Method for producing iohexol | |
| WO2008077035A2 (en) | Processes for the preparation of levetiracetam | |
| KR100517588B1 (en) | Process for Iohexol Manufacture | |
| CN100410248C (en) | Modifications of the trometamol salt of R-thioctic acid as well as a process for their production | |
| CN114773176B (en) | Chlorpheniramine maleate impurity and preparation method and application thereof | |
| CN110845403A (en) | Preparation method of nicorandil | |
| JP2005120024A (en) | Method for producing 4'-cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3'-trifluoromethylpropionanilide | |
| CN114591203A (en) | Preparation method of high-purity creatine | |
| KR100390079B1 (en) | Preparation of benzophennone imines | |
| US6153765A (en) | Process for producing and method of crystallizing 2-azabicyclo(2.2.1)hept-5-en-3-one | |
| CN103772256B (en) | A kind of preparation method of high-purity Sulpiride or its optical isomer | |
| IL192153A (en) | Process for manufacturing entacapone | |
| JP3042122B2 (en) | Method for producing N-cyanoacetamidine derivative | |
| WO2004020396A1 (en) | Crystalline form of nateglinide and process for preparation thereof | |
| CN114315627B (en) | Method for synthesizing doxycycline dehydrate by catalyzing with normal-temperature ionic liquid and zeolite | |
| CN106967000B (en) | Preparation method of medical intermediate for preventing and treating tumor chemotherapy | |
| JP4505911B2 (en) | Method for producing diarylamine | |
| EP1489066B1 (en) | Process for production of optically active carboxylic acid | |
| CN114763334A (en) | Levetiracetam 3-site isomer impurity and preparation method thereof | |
| WO2006108910A1 (en) | Detomidine hydrochloride crystallization method | |
| JP4873207B2 (en) | Method for purifying optically active carboxylic acid chloride |
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 |