CN111333566A - Preparation method of key intermediate of levomilnacipran - Google Patents
Preparation method of key intermediate of levomilnacipran Download PDFInfo
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- CN111333566A CN111333566A CN201811554064.0A CN201811554064A CN111333566A CN 111333566 A CN111333566 A CN 111333566A CN 201811554064 A CN201811554064 A CN 201811554064A CN 111333566 A CN111333566 A CN 111333566A
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- GJJFMKBJSRMPLA-HIFRSBDPSA-N (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-1-cyclopropanecarboxamide Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)N(CC)CC)C[C@@H]1CN GJJFMKBJSRMPLA-HIFRSBDPSA-N 0.000 title claims abstract description 10
- 229960000685 levomilnacipran Drugs 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 63
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 6
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 3
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 claims description 3
- 229960003750 ethyl chloride Drugs 0.000 claims description 3
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 claims description 3
- BRLQWZUYTZBJKN-VKHMYHEASA-N (-)-Epichlorohydrin Chemical compound ClC[C@H]1CO1 BRLQWZUYTZBJKN-VKHMYHEASA-N 0.000 claims description 2
- JCVHIWLGFNCDAR-UHFFFAOYSA-N 2-bromo-3-methyloxirane Chemical compound CC1OC1Br JCVHIWLGFNCDAR-UHFFFAOYSA-N 0.000 claims description 2
- 239000004593 Epoxy Substances 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- BYXYCUABYHCYLY-UHFFFAOYSA-N isoindole-1,3-dione;potassium Chemical compound [K].C1=CC=C2C(=O)NC(=O)C2=C1 BYXYCUABYHCYLY-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 2
- -1 sodium hydride Chemical compound 0.000 claims 2
- 239000012024 dehydrating agents Substances 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 5
- 208000024714 major depressive disease Diseases 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000004440 column chromatography Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- XNCDYJFPRPDERF-NQQJLSKUSA-N (1s,2r)-2-(aminomethyl)-n,n-diethyl-1-phenylcyclopropane-1-carboxamide;hydrochloride Chemical compound Cl.C=1C=CC=CC=1[C@]1(C(=O)N(CC)CC)C[C@H]1CN XNCDYJFPRPDERF-NQQJLSKUSA-N 0.000 description 2
- 229960000600 milnacipran Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- JCVHIWLGFNCDAR-NFJMKROFSA-N (2R)-2-bromo-3-methyloxirane Chemical compound Br[C@@H]1C(C)O1 JCVHIWLGFNCDAR-NFJMKROFSA-N 0.000 description 1
- DUSSQPOLZOFRAA-UHFFFAOYSA-N 2,3-diethyl-1-phenylcyclopropane-1-carboxamide Chemical compound C(C)C1C(C1(C(=O)N)C1=CC=CC=C1)CC DUSSQPOLZOFRAA-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- GJJFMKBJSRMPLA-DZGCQCFKSA-N levomilnacipran Chemical group C=1C=CC=CC=1[C@]1(C(=O)N(CC)CC)C[C@H]1CN GJJFMKBJSRMPLA-DZGCQCFKSA-N 0.000 description 1
- 229960001926 levomilnacipran hydrochloride Drugs 0.000 description 1
- 229960000638 milnacipran hydrochloride Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000003775 serotonin noradrenalin reuptake inhibitor Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
- C07D209/49—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide and having in the molecule an acyl radical containing a saturated three-membered ring, e.g. chrysanthemumic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Levomilnacipran, chemical name: (1R,2S) -2- (aminomethyl) -N, N-diethyl-1-phenylcyclopropanecarboxamide, the earliest drug developed by the PierreFabre laboratory of france for the treatment of adult major depressive disorder. The invention relates to a method for synthesizing a key intermediate compound (I) of levomilnacipran,
Description
Technical Field
The invention belongs to the fields of medicine technology and pharmaceutical chemistry, and particularly relates to a preparation method of a key intermediate of a levorotatory milnacipran medicine for adult major depressive disorder.
Background
Levomilnacipran, chemical name: (1R,2S) -2- (aminomethyl) -N,NDiethyl-1-phenylcyclopropanecarboxamide, the earliest drug developed by the pierre fabre laboratory of france for the treatment of adult major depressive disorder. The drug is approved as a novel SNRI drug on the market in the United states by the United states Food and Drug Administration (FDA) at 26 D.7.2013, and the trade name is Fetzima. The structural formula is as follows:
the racemate resolution process in the naproxen process does not meet the cost-benefit requirements because half of the product is lost. So in the published patents: CN102300840(a), EP2805936 (a 1), IN201404226(I3), IN201403752(I3), WO2014203277(a2) all adopt a method of directly synthesizing a target product from a chiral center-containing raw material. Wherein the intermediate compounds are key intermediate compounds shown in formula I,
disclosure of Invention
The invention aims to provide a novel preparation method for preparing a levomilnacipran intermediate. It is another object of the present invention to provide a novel process for the preparation of levomilnacipran hydrochloride. The reaction formula is as follows:
a process for the preparation of compound V comprising the steps of:
(1) a compound of the formula I in acetonitrile orN,N-dimethyl formamide with (R) Epichlorohydrin or (A)R) -reaction of bromopropylene oxide to produce the compound of formula II. (R) The molar weight ratio of the epoxy halide to the compound I is (1.1-1.5): 1, preferably 1.1: 1.
(2) A compound of formula II in acetonitrile orN,NReaction of dimethyl formamide with phthalimide potassium salt, PPh3And DDQ to produce the compound of formula III. Wherein the potassium phthalimide salt, PPh3The molar weight ratio of the DDQ to the compound II is (1.5-3): 1, preferably 2:2:2: 1; the reaction solvent is preferably acetonitrile; the reaction temperature is 80-150 ℃; the reaction time is 5-8 hours.
(3) And (3) carrying out hydrolysis reaction on the compound III in the formula under an acidic condition to generate a compound IV in the formula. Wherein the acid is concentrated sulfuric acid, hydrochloric acid, trifluoromethanesulfonic acid, alcoholic solution of hydrogen bromide, etc., preferably concentrated sulfuric acid. The molar ratio of concentrated sulfuric acid to the compound III is (1.5-2) to 1; the reaction solvent is toluene or acetonitrile, preferably acetonitrile; the reaction temperature is 25-50 ℃; the reaction time is 2-4 hours.
(4) A compound of formula IV in acetonitrile orN,N-reaction of dimethylformamide with an alkyl halide in the presence of sodium hydride to produce the compound of formula V. Wherein the molar ratio of the sodium hydride to the compound IV is (1.1-1.5) to 1, preferably 1.1: 1; the reaction solvent is preferably acetonitrile; the alkyl halide is ethyl bromide or ethyl chloride, preferably ethyl bromide; halogen andthe molar ratio of the compound IV is (2-2.2) to 1; the reaction temperature is 25-50 ℃; the reaction time is 6-8 hours.
The mass-volume ratio of the compound to the solvent is 1 (1-20), and the unit is g/mL. I.e., units of compound in g and solvent in mL.
All conditions in the preparation method can be matched at will to obtain the levorotatory milnacipran intermediate compound V, and levorotatory milnacipran hydrochloride can be obtained through further reaction, which is detailed in the embodiment of the invention.
The starting materials and reagents according to the present invention are commercially available.
Detailed description of the preferred embodiment
The present invention is described in more detail below with reference to examples, but the present invention is not limited thereto.
Example one
Acetonitrile (150 mL) was added to a 500mL three-necked flask at room temperature and sodium hydride (6.2g,256.8mmol) was added slowly in portions, and then Compound I (15.0g, 128.4mmol) was added slowly dropwise to the system, and the reaction was carried out at 15 ℃ for 1 h. Slowly added dropwise (R) -bromopropylene oxide (19.3g, 141.2mmol) in acetonitrile (45ml) and after the addition was reacted at room temperature for 2 h. The solvent was concentrated under reduced pressure and purified by column chromatography to obtain compound II with purity of 98.47% and yield of 78.77%.
Example two
A250 mL three-necked flask was charged with 100mL of acetonitrile and compound II (10.0g, 57.7mmol) obtained by a conventional synthesis method, sufficiently stirred to dissolve all the compounds, and then potassium phthalimide (21.4g, 115.5mmol) and PPh were added thereto3(30.3g, 115.5mmol) and DDQ (26.2g, 115.5mmol), controlling the temperature of the system to 80 ℃, reacting for 6h, monitoring the reaction completion by TLC, and stopping the reaction. The reaction mixture was quenched with water (120mL) and the organic phase was extracted with dichloromethane. The solvent was concentrated under reduced pressure and purified by column chromatography to obtain compound III with purity 98.51% and yield 89.51%.
Example three
Compound III (14.0g, 46.3mmol) and acetonitrile (140 mL) were added to a 250 mL three-necked flask, stirred well to dissolve all the compounds, concentrated sulfuric acid (9.2g, 92.6mmol) was added, the reaction was carried out at room temperature for 3 hours, and TLC monitored that the reaction of the starting materials was complete, and the reaction was stopped. Adjusting the pH value of 50% sodium hydroxide aqueous solution to 7-8, performing suction filtration, collecting a filter cake, and purifying by using column chromatography to obtain a compound IV with the purity of 98.80% and the yield of 75.73%.
Example four
To a 250 mL three-necked flask was added compound IV (10.0g, 31.2mmol), bromoethane (7.5g, 68.7mmol), and acetonitrile (100 mL), stirred and the heat turned on, the system temperature was controlled to 70 deg.C, and TLC monitored the completion of the reaction of the starting materials and stopped. The purity of the compound IV obtained by column chromatography purification is 99.03%, and the yield is 80.02%.
Claims (9)
1. A preparation method of a levomilnacipran intermediate is characterized by comprising the following steps:
1) a compound of the formula I is reacted with (I) in acetonitrile in the presence of sodium hydrideR) -reaction of bromoepoxypropane to produce a compound of formula II;
2) a compound of formula II in acetonitrile orN,NReaction of dimethyl formamide with phthalimide potassium salt, PPh3And DDQ to generate a compound shown in a formula III;
3) hydrolyzing the compound III in the formula under an acidic condition to generate a compound IV in the formula;
4) a compound of formula IV in acetonitrile orN,N-reaction with ethyl bromide or ethyl chloride in dimethylformamide in the presence of sodium hydride to give the compound of formula V;
2. the process according to claim 1, wherein the epoxy compound used in the step 1 is: (R) Epichlorohydrin or (A)R) Propylene bromoxide, preferably (A)R) -bromopropylene oxide.
3. Preparation according to claim 1The method adopts acetonitrile orN,N-dimethylformamide, preferably acetonitrile.
4. The method according to claim 1, wherein the potassium salt used in step 2 is a potassium phthalimide salt.
5. The process according to claim 1, wherein the dehydrating agent used in the step 2 is PPh3And the molar ratio of DDQ to the compound II is (1.5-3): 1, preferably 2:2: 1.
6. The method according to claim 1, wherein the organic solvent used in step 3 is toluene or acetonitrile, preferably acetonitrile.
7. The process according to claim 1, wherein the acid used in step 3 is concentrated sulfuric acid, hydrochloric acid, trifluoromethanesulfonic acid, an alcoholic solution of hydrogen bromide, or the like, preferably concentrated sulfuric acid; the molar ratio of the concentrated sulfuric acid to the compound III is (1.5-2): 1.
8. The method according to claim 1, wherein the organic solvent used in step 4 is acetonitrile orN,N-dimethylformamide, preferably acetonitrile.
9. The process according to claim 1, wherein the alkyl halide used in step 4 is ethyl bromide or ethyl chloride, preferably ethyl bromide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811554064.0A CN111333566A (en) | 2018-12-19 | 2018-12-19 | Preparation method of key intermediate of levomilnacipran |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811554064.0A CN111333566A (en) | 2018-12-19 | 2018-12-19 | Preparation method of key intermediate of levomilnacipran |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111333566A true CN111333566A (en) | 2020-06-26 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811554064.0A Pending CN111333566A (en) | 2018-12-19 | 2018-12-19 | Preparation method of key intermediate of levomilnacipran |
Country Status (1)
| Country | Link |
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| CN (1) | CN111333566A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601652A (en) * | 2013-12-09 | 2014-02-26 | 上海现代制药股份有限公司 | Preparation method of milnacipran hydrochloride |
| WO2016071303A1 (en) * | 2014-11-04 | 2016-05-12 | Quimica Sintetica, S.A. | Process for the preparation of (1s,2r)-milnacipran |
-
2018
- 2018-12-19 CN CN201811554064.0A patent/CN111333566A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103601652A (en) * | 2013-12-09 | 2014-02-26 | 上海现代制药股份有限公司 | Preparation method of milnacipran hydrochloride |
| WO2016071303A1 (en) * | 2014-11-04 | 2016-05-12 | Quimica Sintetica, S.A. | Process for the preparation of (1s,2r)-milnacipran |
Non-Patent Citations (1)
| Title |
|---|
| BONNAUD, BERNARD等: "1-Aryl-2-(aminomethyl)cyclopropanecarboxylic acid derivatives. A new series of potential antidepressants", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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Application publication date: 20200626 |