CN116730939A - Preparation method of famoxadone characteristic impurities - Google Patents
Preparation method of famoxadone characteristic impurities Download PDFInfo
- Publication number
- CN116730939A CN116730939A CN202211598583.3A CN202211598583A CN116730939A CN 116730939 A CN116730939 A CN 116730939A CN 202211598583 A CN202211598583 A CN 202211598583A CN 116730939 A CN116730939 A CN 116730939A
- Authority
- CN
- China
- Prior art keywords
- famoxadone
- reaction
- characteristic
- step1
- preparing
- 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
- PCCSBWNGDMYFCW-UHFFFAOYSA-N 5-methyl-5-(4-phenoxyphenyl)-3-(phenylamino)-1,3-oxazolidine-2,4-dione Chemical compound O=C1C(C)(C=2C=CC(OC=3C=CC=CC=3)=CC=2)OC(=O)N1NC1=CC=CC=C1 PCCSBWNGDMYFCW-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 239000005772 Famoxadone Substances 0.000 title claims abstract description 51
- 239000012535 impurity Substances 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- XXRCUYVCPSWGCC-UHFFFAOYSA-N Ethyl pyruvate Chemical compound CCOC(=O)C(C)=O XXRCUYVCPSWGCC-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229940117360 ethyl pyruvate Drugs 0.000 claims abstract description 9
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229940067157 phenylhydrazine Drugs 0.000 claims abstract description 7
- 239000007787 solid Substances 0.000 claims abstract description 7
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims abstract description 6
- 238000006467 substitution reaction Methods 0.000 claims abstract description 5
- 239000012043 crude product Substances 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 8
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 5
- 238000004321 preservation Methods 0.000 claims description 4
- 150000003852 triazoles Chemical class 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000004458 analytical method Methods 0.000 abstract description 3
- 239000012467 final product Substances 0.000 abstract description 3
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000003908 quality control method Methods 0.000 abstract description 2
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940116333 ethyl lactate Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000006315 carbonylation Effects 0.000 description 2
- 238000005810 carbonylation reaction Methods 0.000 description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KRSXGTAVHIDVPM-UHFFFAOYSA-N 2-phenoxyacetophenone Chemical compound C=1C=CC=CC=1C(=O)COC1=CC=CC=C1 KRSXGTAVHIDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000005754 Cyazofamid Substances 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- YXKMMRDKEKCERS-UHFFFAOYSA-N cyazofamid Chemical compound CN(C)S(=O)(=O)N1C(C#N)=NC(Cl)=C1C1=CC=C(C)C=C1 YXKMMRDKEKCERS-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- MPMNUCMJDPWNCV-UHFFFAOYSA-M magnesium;phenoxybenzene;bromide Chemical compound [Mg+2].[Br-].C=1C=[C-]C=CC=1OC1=CC=CC=C1 MPMNUCMJDPWNCV-UHFFFAOYSA-M 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000001475 oxazolidinediones Chemical class 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/44—Two oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of famoxadone characteristic impurities, which comprises the following steps: step1: performing Friedel-crafts reaction on diphenyl ether and ethyl pyruvate to obtain an intermediate; step2: and (3) carrying out substitution reaction on the famoxadone duplex intermediate obtained in Step1 and the solid light ring and phenylhydrazine, and carrying out aftertreatment on the generated crude product to obtain famoxadone characteristic impurities. The preparation method provided by the invention has the advantages that through Friedel-crafts acylation and substitution, the process steps are simple, the reaction condition is mild, the operation is easy, the purity of the final product is more than 99%, the famoxadone characteristic impurity obtained by the preparation method provided by the invention can be used as a reference, the development of famoxadone analysis method is facilitated, the quality control of famoxadone is facilitated, and a reference idea is provided for famoxadone production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of famoxadone characteristic impurities.
Background
The famoxadone is a novel efficient, broad-spectrum and non-systemic bactericide, is developed by Dupont and put into commercialization in 1998 in the form of a mixture (such as cyazofamid), belongs to oxazolidinedione compounds, and is a mitochondrial electron transfer inhibitor. The molecular structure is as follows:
the reported processes are basically that an important intermediate 2- (4-oxyphenyl) ethyl lactate is synthesized by various methods, and then the intermediate reacts with a carbonylation reagent and phenylhydrazine to synthesize the famoxadone. The currently reported synthetic routes mainly include the following three types:
(1) The method uses Grignard reagent to react with 4-phenoxyphenyl magnesium bromide and ethyl pyruvate to obtain 2- (4-oxyphenyl) ethyl lactate, the reaction must isolate water and air, the reaction temperature is-78 ℃, the operation is complex, and the energy consumption is high.
(2) The method uses phenoxyacetophenone as raw material, uses sodium cyanide to add carbonyl, then hydrolyzes and esterifies to obtain 2- (4-oxyphenyl) ethyl lactate, uses sodium cyanide as a highly toxic reagent, and has limited raw material sources.
(3) The method is simple and convenient to operate and easy to obtain raw materials, and is an ideal industrial synthesis route compared with the former two methods.
From the literature reported so far, friedel-crafts reaction is carried out by adopting single Lewis acid, the famoxadone intermediate is inevitably formed in a duplex mode (as above), and the post-treatment is difficult to remove. And then reacts with a carbonylation reagent and phenylhydrazine in the next step, so that characteristic impurities of the famoxadone are generated, and the quality of the final product is affected. The characteristic impurity structure is as follows:
the famoxadone characteristic impurities are used as byproducts in the famoxadone original medicine preparation process, and the famoxadone characteristic impurities are very similar to famoxadone in nature and are difficult to remove, so that the purity and quality of the famoxadone original medicine are seriously influenced. In order to improve the product quality of the famoxadone, the analysis and control of the characteristic impurities are very important, but the control of the quality of the famoxadone needs to detect the impurities, namely the characteristic impurities are needed to be used as a reference substance.
Disclosure of Invention
The invention provides a preparation method of famoxadone characteristic impurities, which solves the problems set forth in the background technology.
The scheme for solving the technical problems is as follows: the preparation method of the famoxadone characteristic impurity comprises the following steps:
step1: performing Friedel-crafts reaction on diphenyl ether and ethyl pyruvate to obtain an intermediate, wherein the reaction formula is as follows:
step2: the famoxadone duplex intermediate obtained in Step1 and the solid light ring are subjected to substitution reaction with phenylhydrazine, and the generated crude product is subjected to aftertreatment to obtain famoxadone characteristic impurities, wherein the reaction formula is as follows:
on the basis of the technical scheme, the invention can be improved as follows.
Further, the molar ratio of Step1 diphenyl ether to ethyl pyruvate is 1: (2.0 to 5.0), preferably the molar amount of ethyl pyruvate is 2.5.
Further, the reaction temperature of Step1 is-30-20 ℃, the reaction dropwise adding time is 1-3h, and the preferable dropwise adding heat preservation time is 2h.
Further, the friedel-crafts reaction of Step1 is carried out in a solvent which is methylene dichloride, and the mass ratio of the solvent to diphenyl ether is (5-10): 1.
further, step2 reaction Step: adding the famoxadone duplex intermediate, triethylamine and phenylhydrazine prepared by Step1 into a reaction container filled with toluene, adding triazole or DCC or CDI, heating to 80 ℃, and then slowly cooling to 45 ℃; and (3) dripping a toluene solution of solid phosgene, and after dripping, carrying out heat preservation reaction until the reaction is complete, and carrying out aftertreatment to obtain the famoxadone characteristic impurity.
Further, the mol ratio of the famoxadone duplex intermediate to the toluene solution of triethylamine, triazole and solid phosgene is 1:4:2.5:0.8.
Further, the solvent is toluene, and the mass ratio of the solvent to the famoxadone intermediate is (4-6): 1.
The beneficial effects of the invention are as follows: the invention provides a preparation method of famoxadone characteristic impurities, which has the following advantages:
the preparation method has the advantages that the preparation method is simple in process steps through Friedel-crafts acylation and substitution, the reaction condition is mild, the operation is easy, the purity of the final product is more than 99%, the famoxadone characteristic impurity obtained by the preparation method provided by the invention can be used as a reference, the development of famoxadone analysis method is facilitated, the quality control of famoxadone is facilitated, and a reference idea is provided for famoxadone production.
The foregoing description is only an overview of the present invention, and is intended to provide a more thorough understanding of the present invention, and is to be accorded the full scope of the present invention. Specific embodiments of the present invention are given in detail by the following examples.
Detailed Description
The principles and features of the present invention are described below with examples given for the purpose of illustration only and are not intended to limit the scope of the invention. The invention is more specifically described by way of example in the following paragraphs. Advantages and features of the invention will become more apparent from the following description and from the claims.
It will be understood that when an element is referred to as being "fixed to" another element, it can be directly on the other element or intervening elements may also be present. When a component is considered to be "connected" to another component, it can be directly connected to the other component or intervening components may also be present. When an element is referred to as being "disposed on" another element, it can be directly on the other element or intervening elements may also be present. The terms "vertical," "horizontal," "left," "right," and the like are used herein for illustrative purposes only.
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 herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
The invention provides a preparation method of famoxadone characteristic impurities, which comprises the following steps:
step1: 150g of methylene chloride (20 mmol) and titanium tetrachloride (22 mmol) are added into a 500mL three-necked flask, stirring and freezing are started, ethyl pyruvate (50 mmol) is started to be added dropwise after the temperature is reduced to-5 ℃ for about 2 hours, and the reaction is continued for 2 hours at the temperature of about-5 ℃. After the reaction is finished, adding acid water for quenching, extracting with dichloromethane, drying, concentrating, and distilling under high vacuum to obtain pale yellow liquid with the yield of 88%, the purity of 94%, and the reaction formula is as follows:
step2: adding the product obtained in the step1, namely the famoxadone duplex intermediate (10 mmol), triethylamine (40 mmol), N, N' -carbonyl diimidazole (25 mmol) and toluene 150mL into a 500mL three-port bottle, heating to 80 ℃, slowly cooling to 45 ℃, dripping a toluene solution of phosgene (8 mmol) as a reinforcement body, and preserving heat for 4 hours after dripping, so that the reaction is complete; adding hydrochloric acid to quench the reaction, directly filtering to obtain a crude product, refining by adopting methanol and water (9:1) to obtain the product, namely the famoxadone characteristic impurity, wherein the yield is 58%, the purity is 99.1%, and the reaction formula is as follows:
LC-MS:579(M+H)；
1H-NMR(400MHz,CDCl3)δ9.55(s,1H),7.36(d,J＝8Hz,2H),7.25-7.23(m,4H),7.06(d,J＝8Hz,2H),6.81(t,J＝12Hz,1H),1.96(s,3H)；
the above description is only of the preferred embodiments of the present invention, and is not intended to limit the present invention in any way; those of ordinary skill in the art will readily implement the invention as described above; however, those skilled in the art will appreciate that many modifications, adaptations, and variations of the present invention are possible in light of the above teachings without departing from the scope of the invention; meanwhile, any equivalent changes, modifications and evolution of the above embodiments according to the essential technology of the present invention still fall within the scope of the present invention.
Claims (7)
1. The preparation method of the famoxadone characteristic impurity comprises the following steps:
step1: performing Friedel-crafts reaction on diphenyl ether and ethyl pyruvate to obtain an intermediate, wherein the reaction formula is as follows:
step2: the famoxadone duplex intermediate obtained in Step1 and the solid light ring are subjected to substitution reaction with phenylhydrazine, and the generated crude product is subjected to aftertreatment to obtain famoxadone characteristic impurities, wherein the reaction formula is as follows:
2. the method for preparing famoxadone as claimed in claim 1, wherein the molar ratio of diphenyl ether to ethyl pyruvate is 1:2.0-5.0, preferably the molar amount of ethyl pyruvate is 2.5.
3. The method for preparing the famoxadone characteristic impurity according to claim 1, wherein the reaction temperature of Step1 is-30-20 ℃, the reaction dropwise adding time is 1-3h, and the preferable dropwise finishing heat preservation time is 2h.
4. The method for preparing the famoxadone characteristic impurity according to claim 1, wherein the friedel-crafts reaction of Step1 is carried out in a solvent, the solvent is dichloromethane, and the mass ratio of the solvent to diphenyl ether is (5-10) to 1.
5. The method for preparing famoxadone as claimed in claim 1, wherein Step2 comprises the steps of: adding the famoxadone duplex intermediate, triethylamine and phenylhydrazine prepared by Step1 into a reaction container filled with toluene, adding triazole or DCC or CDI, heating to 80 ℃, and then slowly cooling to 45 ℃; and (3) dripping a toluene solution of solid phosgene, and after dripping, carrying out heat preservation reaction until the reaction is complete, and carrying out aftertreatment to obtain the famoxadone characteristic impurity.
6. The method for preparing the famoxadone characteristic impurity according to claim 6, wherein the mol ratio of the famoxadone duplex intermediate to the toluene solution of triethylamine, triazole and solid phosgene is 1:4:2.5:0.8.
7. The method for preparing the famoxadone characteristic impurity according to claim 6, wherein the solvent is toluene, and the mass ratio of the famoxadone intermediate to the famoxadone intermediate is (4-6) to 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211598583.3A CN116730939A (en) | 2022-12-12 | 2022-12-12 | Preparation method of famoxadone characteristic impurities |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211598583.3A CN116730939A (en) | 2022-12-12 | 2022-12-12 | Preparation method of famoxadone characteristic impurities |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116730939A true CN116730939A (en) | 2023-09-12 |
Family
ID=87912080
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211598583.3A Pending CN116730939A (en) | 2022-12-12 | 2022-12-12 | Preparation method of famoxadone characteristic impurities |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116730939A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1706802A (en) * | 2005-05-27 | 2005-12-14 | 中国科学院上海有机化学研究所 | Prepn process of 2-ary lactate, naprosyn and ibuprofen |
| CN1733694A (en) * | 2005-08-05 | 2006-02-15 | 中国科学院上海有机化学研究所 | The method for preparing precursor of cycloprothrin |
| CN105541743A (en) * | 2015-12-10 | 2016-05-04 | 上海生农生化制品有限公司 | Bisfamoxadone-like compounds and synthetic method thereof |
| WO2017201846A1 (en) * | 2016-05-27 | 2017-11-30 | 浙江普洛得邦制药有限公司 | Preparation method of antibacterial oxazolidinone medicine and intermediate thereof |
-
2022
- 2022-12-12 CN CN202211598583.3A patent/CN116730939A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1706802A (en) * | 2005-05-27 | 2005-12-14 | 中国科学院上海有机化学研究所 | Prepn process of 2-ary lactate, naprosyn and ibuprofen |
| CN1733694A (en) * | 2005-08-05 | 2006-02-15 | 中国科学院上海有机化学研究所 | The method for preparing precursor of cycloprothrin |
| CN105541743A (en) * | 2015-12-10 | 2016-05-04 | 上海生农生化制品有限公司 | Bisfamoxadone-like compounds and synthetic method thereof |
| WO2017201846A1 (en) * | 2016-05-27 | 2017-11-30 | 浙江普洛得邦制药有限公司 | Preparation method of antibacterial oxazolidinone medicine and intermediate thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109563102A (en) | The manufacturing method of the intermediate of biotin and the manufacturing method of biotin | |
| CN115304547A (en) | Preparation method of 10-methoxyiminostilbene compound | |
| CN112062712A (en) | Preparation method of 2- (5-bromo-3-methylpyridin-2-yl) acetic acid hydrochloride | |
| CN111072697B (en) | Preparation method of 4-phenoxyphenylboronic acid | |
| CN111574444A (en) | Preparation method of bedaquiline | |
| CN116730939A (en) | Preparation method of famoxadone characteristic impurities | |
| CN109942433B (en) | Chemical synthesis method of 3',4',5' -trifluoro-2-aminobiphenyl | |
| CN109535120B (en) | Preparation method of 7-substituted-3, 4,4, 7-tetrahydrocyclobutane coumarin-5-ketone | |
| JP2008239601A (en) | Method for producing lactide compound | |
| CN115231989A (en) | Preparation method of 3, 5-dichlorobenzyl alcohol | |
| CN108822174A (en) | 2 '-EOE- guanosine of novel nucleoside modifier and preparation method thereof | |
| CN107602337B (en) | Preparation method of 1,4-dicyano-2-butene | |
| US20210284595A1 (en) | Spirobiindane derivatives and a process for preparation thereof | |
| IL168110A (en) | Process for production of an acetylenic compound | |
| CN113149926B (en) | Preparation method of 3, 5-disubstituted isoxazole derivative | |
| CN102050786B (en) | Synthesis method of 1-chloroformyl-2-imidazolidineketone | |
| CN113264854B (en) | Synthesis method of tetrahydroxyethyl ethylene diamine tetra-p-toluenesulfonate | |
| KR20190049233A (en) | Method of preparing heptafluoroisopropyl methyl ether | |
| CN108727171B (en) | Preparation method of 4,4' -di (2-bromoacetyl) biphenyl | |
| CN118459383A (en) | Diselenide compound and synthesis method thereof | |
| CN117903059A (en) | Preparation method of ligand compound | |
| CN118063294A (en) | Efficient preparation method of dapagliflozin intermediate | |
| CN116693442A (en) | 4-methoxy pyrrole derivative and synthesis method thereof | |
| CN117683003A (en) | New process for synthesizing englitjing intermediate | |
| CN111574343A (en) | Novel synthesis method of cyclopropylformaldehyde |
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 |