CN112358439A - Omeprazole process impurity and preparation method thereof - Google Patents

Omeprazole process impurity and preparation method thereof Download PDF

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CN112358439A
CN112358439A CN202011348990.XA CN202011348990A CN112358439A CN 112358439 A CN112358439 A CN 112358439A CN 202011348990 A CN202011348990 A CN 202011348990A CN 112358439 A CN112358439 A CN 112358439A
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omeprazole
dimethyl
reaction
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methoxypyridine
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王启卫
钟菁
庞嘉东
缪小荣
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Chengdu Baiquan Biomedical Technology Co ltd
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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Abstract

The invention relates to an omeprazole process impurity and a preparation method thereof, wherein the omeprazole process impurity has a structure shown in a formula (1): wherein R is H or methyl. The separation, confirmation and preparation of the omeprazole process impurities are beneficial to the impurity analysis of the omeprazole intermediate and the omeprazole raw material medicine, and the improvement of the synthesis process of the omeprazole intermediate and the omeprazole raw material medicine, so that the quality standard and control of the omeprazole raw material medicine are further perfected, the quality level of the raw material medicine is improved, and the guarantee is provided for the medication safety of people.
Figure DDA0002800719110000011

Description

Omeprazole process impurity and preparation method thereof
Technical Field
The invention relates to the technical field of medicines, in particular to an omeprazole process impurity and a preparation method thereof.
Background
Omeprazole (Omepazole), chemical name 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] sulfinyl ] -1H-benzimidazole, is a benzimidazole proton pump inhibitor and is used for treating peptic ulcer, esophageal reflux disease, gastrinoma syndrome and helicobacter pylori. 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride is a key intermediate for preparing omeprazole.
The US patent US4544750A describes a process for the preparation of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride, a key intermediate of omeprazole, by first obtaining N-methoxy-4-methoxy-3, 5-dimethylpyridine sulfonic acid monomethyl ester salt; the method is characterized in that the N-methoxy-4-methoxy-3, 5-dimethylpyridine sulfonic acid monomethyl ester salt is subjected to rearrangement reaction in a methanol solution containing ammonium persulfate to obtain (2-hydroxymethyl-3, 5-dimethyl-4-methoxypyridine; and the 2-hydroxymethyl-3, 5-dimethyl-4-methoxypyridine is further reacted with a chlorine-dehydroxylation reagent to obtain 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride.
Impurities are of great importance to the safety and effectiveness of drugs, and are also paid more and more attention by drug administration departments. An impurity in a drug substance refers to any component that is present in the drug substance but whose chemical structure is not the same as the drug substance. Because the impurities in the medicine have no treatment effect, and may affect the stability and curative effect of the medicine, even harm the health of people, the impurities in the medicine must be checked and controlled to ensure the safety and effectiveness of the medicine quality and clinical medication, and meanwhile, a basis is provided for the medicine quality management in the production and circulation processes.
Although the quality and safety of drugs are highly regarded by the relevant national departments, each drug may contain various impurities and the content of the impurities is often very low, so that the separation, structure confirmation and synthesis preparation of the drug are difficult, the impurity reference substances of many drugs are difficult to source, and the quality research and the clinical medication safety monitoring work are difficult to develop. Therefore, the research work of impurities is still a weak link of many drug research and development institutions and manufacturers. Therefore, careful and sufficient research on medicine impurities can quickly and efficiently obtain impurity reference substances, which becomes a necessary requirement for the current medicine production and research, and especially, the research on new process impurities generated in the medicine synthesis process is particularly important for the perfection and improvement of the quality standard of raw material medicines.
Disclosure of Invention
Based on the technical scheme, the invention provides a new omeprazole process impurity, which is beneficial to the impurity analysis of an omeprazole intermediate and an omeprazole raw material drug and the improvement of the synthesis process of the omeprazole intermediate and the omeprazole raw material drug, thereby being beneficial to further perfecting the quality standard and control of the omeprazole raw material drug, improving the quality level of the raw material drug and providing guarantee for the medication safety of people.
The specific technical scheme is as follows:
an omeprazole process impurity having the structure of formula (1):
Figure BDA0002800719090000021
wherein R is H or methyl.
The invention also provides a preparation method of the omeprazole process impurity.
The specific technical scheme is as follows:
a preparation method of omeprazole process impurities comprises the following steps: 3, 5-dimethyl-4-methoxypyridine nitroxide shown in formula II in ZrCl4In the presence of (A), carrying out reduction reaction with a reducing agent to obtain 3, 5-dimethyl-4-methoxypyridine shown in a formula III;
the reaction formula is as follows:
Figure BDA0002800719090000031
in some of these embodiments, the reducing agent is NaBH4。
In some of these embodiments, the solvent for the reduction reaction is tetrahydrofuran.
In some of these embodiments, the 3, 5-dimethyl-4-methoxypyridine nitroxide and ZrCl4The molar ratio of (A) to (B) is 1: 0.9-1.2.
In some of these embodiments, the molar ratio of the 3, 5-dimethyl-4-methoxypyridine nitroxide to the reducing agent is 1: 2-6.
In some embodiments, the ratio of the 3, 5-dimethyl-4-methoxypyridine nitrogen oxide to the solvent for the reduction reaction is 1g: 50-150 mL.
In some of these embodiments, the temperature of the reduction reaction is 0-40 ℃.
In some embodiments, the method for preparing omeprazole process impurities comprises the following steps: reacting the ZrCl4Dissolving in dry tetrahydrofuran, adding NaBH in portions under nitrogen atmosphere4Stirring for 5-15 min to obtain reaction liquid A; dissolving the 3, 5-dimethyl-4-methoxypyridine oxynitride in dry tetrahydrofuran to obtain a reaction solution B; and adding the reaction liquid B into the reaction liquid A at the temperature of 0-5 ℃, heating to 15-30 ℃, and stirring for reaction to obtain the catalyst.
In some embodiments, the preparation method of omeprazole process impurities further comprises the following steps: demethylating the 3, 5-dimethyl-4-methoxypyridine under an acidic condition to obtain 3, 5-dimethyl-4-hydroxypyridine shown in a formula IV;
the reaction formula is as follows:
Figure BDA0002800719090000032
in some of these embodiments, the acid used in the demethylation reaction is hydrochloric acid.
In some of these embodiments, the hydrochloric acid is concentrated hydrochloric acid having a concentration of 8 to 12 mol/L.
In some of these embodiments, the solvent used in the demethylation reaction is toluene.
In some embodiments, the ratio of the 3, 5-dimethyl-4-methoxypyridine to the toluene is 1g:8-20 mL.
In some embodiments, the ratio of the 3, 5-dimethyl-4-methoxypyridine to the hydrochloric acid is 1g:0.5-1.0 mL.
In some of these embodiments, the demethylation is performed at a temperature of 90 to 120 ℃ for a time of 8 to 16 hours.
In some embodiments, the preparation method of omeprazole process impurities further comprises the following steps: dissolving the 3, 5-dimethyl-4-methoxypyridine in toluene, adding hydrochloric acid, heating and refluxing, and reacting for 10-14 hours to obtain the compound.
The novel omeprazole process impurity and the preparation method thereof provided by the invention have the following beneficial effects:
the invention discovers and separates two new process impurities of 3, 5-dimethyl-4-methoxypyridine and 3, 5-dimethyl-4-hydroxypyridine for the first time in the process of researching the preparation process of omeprazole. In the process of drug development and quality control, the discovery and preparation of new impurities often have important functions for the quality research of the drug varieties. Aiming at the quality control of omeprazole, the inventor of the invention discovers and confirms the existence of two new process impurities of 3, 5-dimethyl-4-methoxypyridine and 3, 5-dimethyl-4-hydroxypyridine through deep research on a synthesis process. The simple preparation method for obtaining the two process impurities through further research can stably prepare and provide the two new impurities, can provide impurity reference substances for quality research of omeprazole intermediate and an omeprazole bulk drug, and ensures that the impurity reference substances are very conveniently applied to qualitative and quantitative analysis of impurities in an omeprazole intermediate and omeprazole production, so that the quality standard of omeprazole can be further improved, the quality level of the bulk drug can be improved, and important guiding significance is provided for process improvement, quality control and safe medication of omeprazole.
The preparation method of the 3, 5-dimethyl-4-methoxypyridine and the 3, 5-dimethyl-4-hydroxypyridine provided by the invention has the advantages of mild reaction conditions, simple process, simplicity and convenience in operation, few byproducts, high yield, capability of obtaining high-purity products and the like, and is beneficial to process amplification, so that the 3, 5-dimethyl-4-methoxypyridine and the 3, 5-dimethyl-4-hydroxypyridine can be prepared in high yield and in large batch, and the preparation method is beneficial to providing impurity reference substances for quality research of omeprazole intermediate and omeprazole bulk drugs.
Drawings
FIG. 1 is a nuclear magnetic spectrum of Compound A.
FIG. 2 is a nuclear magnetic spectrum of Compound B.
Figure 3 is a nuclear magnetic spectrum of compound C.
FIG. 4 is an HPLC chromatogram of 2-hydroxymethyl-3, 5-dimethyl-4-methoxypyridine prepared in example 1.
FIG. 5 is an HPLC chromatogram of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride prepared in example 1.
FIG. 6 is a nuclear magnetic spectrum of impurity I.
FIG. 7 is a nuclear magnetic spectrum of impurity III.
FIG. 8 is a nuclear magnetic spectrum of impurity IV.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusions. For example, a process, method, apparatus, article, or device that comprises a list of steps is not limited to only those steps or modules listed, but may alternatively include other steps not listed or inherent to such process, method, article, or device.
The "plurality" referred to in the present invention means two or more. "and/or" describes the association relationship of the associated objects, meaning that there may be three relationships, e.g., a and/or B, which may mean: a exists alone, A and B exist simultaneously, and B exists alone. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.
The temperature range of the room temperature is 15-30 ℃.
EXAMPLE 1 Generation, isolation and characterization of impurities
This example refers to the procedure in patent US4544750A for the preparation of omeprazole intermediate 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride.
Step A: synthesis of Compound A:
Figure BDA0002800719090000061
taking 3, 5-dimethyl-4-methoxypyridine nitroxide (35.9g, 0.235mol) and adding 145mL of chloroform into a single-mouth bottle, stirring and dissolving, heating to 60 ℃, dropwise adding dimethyl sulfate (24.4mL, 0.258mol), closing heating after 5 hours, and stopping the reaction. Cooling, adding water for extraction, and evaporating to dryness to obtain compound A solid 65.0g (23.29mmol) with yield of 99.1%. The nmr spectrum is shown in fig. 1.
And B: synthesis of Compound B
Figure BDA0002800719090000062
20mL of methanol was added to compound A (4.9g, 17.56mmol), dissolved by stirring, and the mixture was heated to reflux. Dropwise adding an ammonium persulfate solution (4.01g, 17.57mmol, ammonium persulfate dissolved in 7.5mL of water) into the reaction system, dropwise adding for 1.75 hours, continuing to react for 1.5 hours, stopping the reaction, adding 20mL of methanol, filtering, concentrating the filtrate under reduced pressure to remove the methanol, adjusting the pH of the residue to 10 by using a 10mol/L NaOH solution under an ice water bath, extracting an aqueous phase by using dichloromethane, combining organic phases, drying by using anhydrous sodium sulfate, and concentrating to obtain a compound B (2-hydroxymethyl-3, 5-dimethyl-4-methoxypyridine), 1.67g of a brownish black oily liquid, wherein the yield is as follows: 57.0 percent. The nmr spectrum is shown in fig. 2.
And C: synthesis of Compound C
Figure BDA0002800719090000071
Taking the crude product (1.67g, 10mmol) of the 2-hydroxymethyl-3, 5-dimethyl-4-methoxypyridine obtained in the step B, adding 10 ml of toluene, cooling to 0-5 ℃ in ice water bath, and slowly dropwise adding SOCl2Toluene solution (1.5 ml SOCl)2+1.5 ml of toluene), precipitating a solid in the reaction solution, after 1 hour, dropwise adding, keeping the temperature and stirring for 1 hour, monitoring by TLC, and completing the reaction. Filtration and washing of the filter cake with toluene and suction drying gave 1.75g (7.95mmol) of compound C (2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride) in yield: 79.5 percent. The nmr spectrum is shown in fig. 3.
And (3) carrying out HPLC separation detection on the prepared compound B and compound C, wherein the conditions of the HPLC separation detection are as follows: mobile phase: [ 0.18g of potassium dihydrogenphosphate and 1.38g of dipotassium hydrogenphosphate in 1000mL of water, pH adjusted to 7.5 with phosphoric acid ]: acetonitrile 70: 30, of a nitrogen-containing gas; detection wavelength: 264 nm; flow rate: 1.0 mL/min; column temperature: 30 ℃; sample introduction amount: 20 μ L.
The obtained HPLC profiles are shown in FIGS. 4 to 5, and the mass data of the compound B and the compound C are shown in Table 1 based on FIGS. 4 and 5.
TABLE 1
Figure BDA0002800719090000072
Figure BDA0002800719090000081
Note: the retention time of the impurity A and the impurity D is 3.4 min; the retention time of impurity B was 8.5;
the retention time of impurity E was 8.4; the retention time of the impurity C is 4.7 min; the retention time of impurity F was 4.9 min.
Fractions from impurity a were collected for further structural characterization with nuclear magnetic (as shown in fig. 6) and mass spectral data as follows:1H NMR(300MHz,CDCl3)δ7.46(s,2H),4.00(s,3H),2.05(s,6H).HRMS(ESI,M/Z):Calculated for[M-X]+:154.09,[M-X-H+Na]+:176.07，found:154.0859，176.0683。
thus, it is suggested that the structural formula is:
Figure BDA0002800719090000082
fractions of impurity B were collected for further structural characterization with nuclear magnetic (as shown in fig. 7) and mass spectral data as follows:1H NMR(300MHz,CDCl3)δ8.22(s,2H),3.79(s,3H),2.24(s,6H).HRMS(ESI,M/Z):Calculated for[M]+:137.0841,found:137.1076。
thus, it is suggested that the structural formula is:
Figure BDA0002800719090000083
fractions of impurity C were collected for further structural characterization with nuclear magnetic (as shown in fig. 8) and mass spectral data as follows:1H NMR(300MHz,CDCl3)δ7.99(s,2H),2.11(s,6H).HRMS(ESI,M/Z):Calculated for[M]+:123.0684,found:123.0916。
thus, it is suggested that the structural formula is:
Figure BDA0002800719090000091
as can be seen from the results of table 1: in the preparation process of the omeprazole intermediate, various process impurities are generated, so that the purity of the 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride serving as the intermediate is not high, and the content of the impurities is high, and it can be expected that if the intermediate is prepared into an omeprazole product without repeated purification to control the content of the process impurities, the quality of an omeprazole raw material drug is inevitably influenced, and the safety and the effectiveness of the omeprazole drug are influenced.
The invention discovers and separates the omeprazole process impurities with the structures shown in the formulas I, III and IV for the first time through specific separation conditions, and the discovery of the process impurities enriches the impurity spectrum of the omeprazole raw material medicine, and is beneficial to the impurity analysis of the omeprazole intermediate and the omeprazole raw material medicine. From example 1, it can be found that the preparation of omeprazole intermediate 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride by the existing method can generate more process impurities, and the separation and identification of the process impurities are beneficial to the improvement of the synthesis process of the omeprazole intermediate and the omeprazole bulk drug, thereby being beneficial to further perfecting the quality standard and control of the omeprazole bulk drug and improving the quality level of the bulk drug.
Example 2 preparation of impurity I
Figure BDA0002800719090000092
1g of 3, 5-dimethyl-4-methoxypyridine nitroxide was placed in a three-necked flask, 0.2mL of chloroform and 0.5mL of water were added for dissolution, and 0.68mL of dimethyl sulfate was slowly added dropwise. Reacting for 3 hours at 80 ℃ under the protection of argon.
And (3) post-treatment: the reaction solution obtained above is cooled to room temperature, then 4mL of water and 4mL of chloroform are added for extraction, the organic phases are combined, and the mixture is dried in a rotary manner, DCM: MeOH ═ 20: 1 (volume ratio) column chromatography to obtain an impurity I.1H NMR(300MHz,CDCl3)δ7.46(s,2H),4.00(s,3H),2.05(s,6H).HRMS(ESI,M/Z):Calculated for[M-X]+:154.09,[M-X-H+Na]+:176.07，found:154.0859，176.0683。
Example 3 preparation of impurity III
Figure BDA0002800719090000101
Reacting ZrCl4(815mg, 3.5mmol) was dissolved in dry tetrahydrofuran (35mL),adding NaBH in batches at room temperature under nitrogen atmosphere4(500mg, 13.2mmol) and stirring for 10 minutes to obtain a reaction solution A; dissolving 3, 5-dimethyl-4-methoxypyridine nitroxide (500mg, 3.3mmol) in dry tetrahydrofuran (15mL) to obtain reaction solution B; adding the reaction solution B into the reaction solution A at 0-5 ℃, heating to room temperature, and stirring for reaction. TLC monitored the reaction progress. After the reaction is finished, cooling to 0 ℃, and dropwise adding dilute hydrochloric acid to quench the reaction. The tetrahydrofuran was distilled off under reduced pressure, and the aqueous layer was extracted with ethyl acetate (30 mL. times.3), and the organic phase layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After the organic phase is dried by spinning, the column chromatography is carried out by using ethyl acetate/petroleum ether, thus obtaining 360mg of impurity III with the yield of 80 percent.1H NMR(300MHz,CDCl3)δ8.22(s,2H),3.79(s,3H),2.24(s,6H).HRMS(ESI,M/Z):Calculated for[M]+:137.0841,found:137.1076。
Example 4 preparation of impurity IV
Figure BDA0002800719090000102
Impurity III (360mg, 2.6mmol) was dissolved in 5mL of toluene, 0.26mL of 10M concentrated hydrochloric acid was added, the mixture was refluxed for 12 hours, the reaction was stopped by TLC, the temperature was reduced, the toluene layer was washed with a sodium bicarbonate solution, washed with a saturated saline solution, and dried over anhydrous sodium sulfate. Spin-drying, and performing ethyl acetate/petroleum ether column chromatography to obtain impurity III, 271mg, and yield 85%.1H NMR(300MHz,CDCl3)δ7.99(s,2H),2.11(s,6H).HRMS(ESI,M/Z):Calculated for[M]+:123.0684,found:123.0916。
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. An omeprazole process impurity, which is characterized by having a structure shown in formula (1):
Figure FDA0002800719080000011
wherein R is H or methyl.
2. A preparation method of omeprazole process impurities is characterized by comprising the following steps: 3, 5-dimethyl-4-methoxypyridine nitroxide shown in formula II in ZrCl4In the presence of (A), carrying out reduction reaction with a reducing agent to obtain 3, 5-dimethyl-4-methoxypyridine shown in a formula III;
the reaction formula is as follows:
Figure FDA0002800719080000012
3. the process for the preparation of omeprazole process impurities according to claim 2, wherein the reducing agent is NaBH4(ii) a And/or the presence of a gas in the gas,
the solvent of the reduction reaction is tetrahydrofuran.
4. The process for the preparation of omeprazole process impurities according to claim 2 wherein the 3, 5-dimethyl-4-methoxypyridine nitrogen oxide and ZrCl are present4The molar ratio of (A) to (B) is 1: 0.9-1.2; and/or the presence of a gas in the gas,
the molar ratio of the 3, 5-dimethyl-4-methoxypyridine nitrogen oxide to the reducing agent is 1: 2-6; and/or the presence of a gas in the gas,
the ratio of the 3, 5-dimethyl-4-methoxypyridine nitrogen oxide to the solvent for the reduction reaction is 1g: 50-150 mL.
5. A process for the preparation of omeprazole process impurities according to claim 2 wherein the temperature of the reduction reaction is 0-40 ℃.
6. A process for the preparation of omeprazole process impurities according to any of claims 2-5 comprising the steps of: reacting the ZrCl4Dissolving in dry tetrahydrofuran, adding NaBH in portions under nitrogen atmosphere4Stirring for 5-15 min to obtain reaction liquid A; dissolving the 3, 5-dimethyl-4-methoxypyridine oxynitride in dry tetrahydrofuran to obtain a reaction solution B; and adding the reaction liquid B into the reaction liquid A at the temperature of 0-5 ℃, heating to 15-30 ℃, and stirring for reaction to obtain the catalyst.
7. A process for the preparation of omeprazole process impurities according to any of claims 2-5 further comprising the steps of: demethylating the 3, 5-dimethyl-4-methoxypyridine under an acidic condition to obtain 3, 5-dimethyl-4-hydroxypyridine shown in a formula IV;
the reaction formula is as follows:
Figure FDA0002800719080000021
8. a process for the preparation of omeprazole process impurities according to claim 7 wherein the acid used in the demethylation reaction is hydrochloric acid, preferably concentrated hydrochloric acid at a concentration of 8-12 mol/L; and/or the presence of a gas in the gas,
the solvent used in the demethylation reaction is toluene.
9. The preparation method of omeprazole process impurities according to claim 8, wherein the ratio of 3, 5-dimethyl-4-methoxypyridine to toluene is 1g:8-20 mL; and/or the presence of a gas in the gas,
the ratio of the 3, 5-dimethyl-4-methoxypyridine to the hydrochloric acid is 1g to 0.5-1.0 mL.
10. The process for the preparation of omeprazole process impurities according to claim 7 wherein the reaction temperature of demethylation is 90-120 ℃ and the reaction time is 8-16 hours.
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Publication number Priority date Publication date Assignee Title
CA2225863A1 (en) * 1997-05-06 1998-11-06 Pdi-Research Laboratories, Inc. Synthesis of pharmaceutical useful pyridine derivatives
WO2018214867A1 (en) * 2017-05-24 2018-11-29 上海和誉生物医药科技有限公司 N-(azaaryl)cyclolactam-1-carboxamide derivative, preparation method therefor, and use thereof
CN107652268A (en) * 2017-08-01 2018-02-02 广州加德恩医药有限公司 The preparation method of 4 5-Hydroxyomeprazoles

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Inventor after: Wang Qiwei

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Application publication date: 20210212