CN105348197A - Preparation method of lorcaserin hydrochloride - Google Patents
Preparation method of lorcaserin hydrochloride Download PDFInfo
- Publication number
- CN105348197A CN105348197A CN201510816483.7A CN201510816483A CN105348197A CN 105348197 A CN105348197 A CN 105348197A CN 201510816483 A CN201510816483 A CN 201510816483A CN 105348197 A CN105348197 A CN 105348197A
- Authority
- CN
- China
- Prior art keywords
- reaction
- preparation
- green card
- racemization
- card look
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of medicinal chemistry, and specifically discloses a preparation method of lorcaserin hydrochloride namely (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. The preparation method is characterized in that 4-chlorophenethylamine as a raw material is successively subjected to acylation and amino protection, allyl substitution, Friedel-Crafts alkylation, resolution and salifying to obtain lorcaserin hydrochloride. The preparation method of lorcaserin hydrochloride has the advantages of high yield, low cost, simple operation and the like, and is an economic and industrializable synthesis method.
Description
Technical field
The present invention relates to pharmaceutical synthesis field.Be specifically related to the preparation method of hydrochloric acid green card look woods (I).
Background technology
Hydrochloric acid green card look woods (LorcaserinHydrochloride, I), chemistry (R)-8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzo-aza Lv azepine hydrochloride salt by name.On June 27th, 2012, hydrochloric acid green card look woods is by FDA (Food and Drug Adminstration) (FDA) approval listing, and this is after FDA ratified orlistat from 1999, the first diet pill ratified over 13 years.For obesity or the super severe one of adult status's index (BMI) >27, and patient has a disease (as hypertension, type ii diabetes or hyperlipidemia) relevant to body weight at least.Green card look woods, while fat-reducing, can also improve heart rate, blood pressure and low-density lipoprotein cholesterol level.Its specificity target spot is 5-HT
2C, have very strong effect for appetite control.The structural formula of hydrochloric acid green card look woods is as follows:
At present, the preparation of hydrochloric acid green card look woods is obtained by the fractionation of racemization green card look woods mostly, and reaction scheme is as follows:
As from the foregoing, racemization green card look woods (II) is the key intermediate of synthetic hydrochloric acid green card look woods, and the synthesis technique of domestic and international technician to racemization green card look woods has carried out large quantifier elimination, mainly defines following several routes:
Route one:
US2003225057 report synthetic method be with 2-(4-chloro-phenyl-) ethamine for raw material, obtain racemization green card look woods (II) by six-step processes such as trifluoroacetic acid anhydride acylation, iodo, N-allylation, Heck coupling, reduction, hydrolysis.There is the shortcomings such as operational path is long, atom utilization is low, total recovery (3.7%) is low in this route.In addition, two (pyridine) tetrafluoro boronation iodine (IPy of expensive iodination reagent is used in reaction
2bF
4) and metallic palladium reagent, production cost is high.
Route two:
US20090143576 reports with 2-(4-chloro-phenyl-) ethanol for starting raw material, obtains racemization green card look woods (II) through bromination, amination, chlorination, Fu-Ke (Friedel – Crafts) alkylation.Although this route only has four-step reaction, and starting raw material low price, the first step bromination and the reaction of the 3rd one-step chlorination employ the large phosphorus tribromide of corrodibility and sulfur oxychloride, and can produce more waste gas and spent acid, industrial pollution is large; When replacing, side reaction is more simultaneously, and total recovery is on the low side (18.2%).
Route three:
WO2008070111 for starting raw material, carries out condensation with α-amino isopropyl alcohol with 4-chlorobenzene acetic acid, and through reduction of amide, chloro, Fu-Ke alkylation obtains racemization green card look woods (II).The total recovery of this route still can (51.6%), but condensing agent 3,4 used; 5-trimethoxy phenylo boric acid is expensive; reduction of amide borine price used is more expensive and operation has danger, and sulfur oxychloride can produce a large amount of waste gas and spent acid, is unfavorable for environment protection.
Route four:
WO2005019179 adopts 2-(4-chloro-phenyl-) ethamine to be starting raw material, reacts with 2-chlorpromazine chloride, then obtains racemization green card look woods (II) through Friedel-Crafts, reduction.This reaction scheme is shorter, but total recovery only has 32.1%, and in addition, reduction of amide borine used is not only expensive, and operation inconvenience, add production cost.
Route five:
WO2014187768, reacts with allyl bromide 98 for starting raw material with 2-(4-chloro-phenyl-) ethamine, then through Friedel-Crafts, obtains racemization green card look woods (II).This reaction scheme is short, but the first step reaction yield lower (35%), and have two replacement by products to produce, not easily remove; Second step Friedel-Crafts reaction needs to carry out under 125 DEG C of high temperature under condition of no solvent, and aftertreatment is complicated, is not suitable for industrial production.The total recovery of this route only has 34.6%.
Route six:
In contriver's early-stage Study with 2-(4-chloro-phenyl-) ethamine for starting raw material; first be obtained by reacting intermediate V with tert-Butyl dicarbonate (Boc acid anhydrides); IV is obtained by reacting again with allyl bromide 98; IV sloughs Boc protecting group and obtains N-[2-(4-chloro-phenyl-) ethyl] third-2-alkene-1-amine hydrochlorate; racemization green card look woods (II) (document [Org.ProcessRes.Dev. is obtained by reacting finally by Friedel-Crafts; 2015,19 (9): 1263 – 1267]).In 2-(4-chloro-phenyl-) ethamine, the total recovery of this route racemization green card look woods reaches 76.2%, but route is longer, and particularly de-Boc protecting group needs to use the saturated ethyl acetate solution of HCl, produces a large amount of waste gas and spent acid is unfavorable for maintenance of the equipment
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, the novel method of preparation racemization green card look woods (II) that a kind of raw material of research and design is easy to get, easy and simple to handle, reaction yield is high, cost is low.
Preparation method of the present invention comprises:
N-allyl group-N-[2-(4-chloro-phenyl-) ethyl] t-butyl carbamate (IV) carries out Friedel-Crafts alkylation in molecule and obtains racemization green card look woods (II) under catalyst action.
Wherein catalyzer is aluminum chloride, boron trifluoride, titanium tetrachloride, tin chloride or zinc chloride.The preferred aluminum chloride of catalyzer.
Reaction solvent is the mixture of one or any two kinds in methylene dichloride, trichloromethane, toluene, oil of mirbane, chlorobenzene, orthodichlorobenzene.The preferred chlorobenzene of reaction solvent or orthodichlorobenzene.
Reaction can be carried out in room temperature, and preferred temperature of reaction is 50 ~ 150 DEG C.Preferred temperature of reaction is 90 ~ 120 DEG C.
The mol ratio of IV and catalyzer is preferably 1:1.5 ~ 1:4.The mol ratio of IV and catalyzer is more preferably 1:2 ~ 1:3.
Also frit reaction can be carried out under solvent-free when temperature is at 110 ~ 130 DEG C.
Two-step reaction in preparation in early stage is reduced to single step reaction by the present invention, shorten reactions steps, avoid the use of hydrogen chloride gas, eliminate a step aftertreatment, and total recovery is close even higher.
Based on above-mentioned reaction, the invention also discloses the method that one prepares hydrochloric acid green card look woods (I), comprising:
With N-allyl group-N-[2-(4-chloro-phenyl-) ethyl] t-butyl carbamate (IV) for starting raw material, under catalyst action, carry out Friedel-Crafts alkylation in molecule obtain racemization green card look woods (II), after II tartrate splits, salify obtains hydrochloric acid green card look woods (I).
The preparation method of racemization green card look woods (II) provided by the invention, reagent used is cheap and easy to get, simple to operate, convenient post-treatment.In 2-(4-chloro-phenyl-) ethamine, total recovery is up to 79.3%.Compared with route six, present invention reduces synthetic route, avoid the use of HCl gas, reduce the generation of spent acid waste gas, be conducive to equipment protection, be a kind of economy, be more suitable for industrialized synthetic method.
Embodiment
Embodiment 1
(1) preparation of (4-chlorobenzene ethyl) t-butyl carbamate (V)
By 2-(4-chloro-phenyl-) ethamine (50.0g, 321.3mmol) be placed in 1L three-necked bottle, add 200mL methylene dichloride, stirring and dissolving, at 0 DEG C, drip Boc acid anhydrides (77.1g, 353.3mmol) be dissolved in the solution of 300mL methylene dichloride gained, separate out a large amount of white solid, finish, rise to room temperature, add catalytic amount DMAP, solution graduates into achromaticity and clarification, stirring reaction about 5h (TLC monitoring reacts completely), pour in 400mL water, separate organic layer, water layer dichloromethane extraction twice (200mL × 2), merge organic phase, successively with water and saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, suction filtration, filtrate reduced in volume is to dry, obtain white solid 80.9g, yield 98.5%.mp:60-63℃。
1H-NMR(300MHz,CDCl
3):δ＝7.30-7.27(2H,m,ArH),7.14(2H,d,J＝8.3Hz,ArH),3.36(2H,t,J＝6.6Hz,CH
2),2.78(2H,t,J＝7.0Hz,CH
2),1.44(9H,s,CH
3).
(2) preparation of N-allyl group-N-(4-chlorobenzene ethyl) t-butyl carbamate (IV)
Intermediate V (20.0g, 78.2mmol) is added in 500mL three-necked bottle, adds 250mL toluene, stirring and dissolving, then add K
2cO
3(14.0g, 101.3mmol), KOH (13.1g, 233.5mmol), allyl bromide 98 (14.2g, 117.3mmol) with tetra-n-butyl ammonium bromide (2.52g, 7.82mmol), be heated to Inner temperature 80 DEG C reaction, TLC monitoring reacts completely, and stops heating, is cooled to room temperature, add frozen water 200mL, separate organic layer, aqueous layer with ethyl acetate extracting twice (100mL × 2), merge organic layer, successively with water, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying.Suction filtration, filtrate reduced in volume obtains yellow oil 22.8g, and yield 98.6%, directly drops into the next step.
1H-NMR(300MHz,CDCl
3)δ7.25(2H,d,J＝8.0Hz,ArH),7.11(2H,d,J＝7.5Hz,ArH),5.89-5.61(1H,m,CH),4.99-5.24(2H,m,CH
2),3.75(2H,s,CH
2),3.35(2H,t,J＝7.2Hz,CH
2),2.78(2H,t,J＝7.3Hz,CH
2),1.44(9H,s,CH
3).
(3) preparation of racemization green card look woods (II)
Get aluminum trichloride (anhydrous) (27.1g, 203.2mmol) to be ground into powder, add in 500mL three-necked bottle, add chlorobenzene (100mL), stir in suspension, ice bath is cooled to 0 ~ 5 DEG C.Get after intermediate compound IV (20.0g, 67.6mmol) chlorobenzene (50mL) dissolves and be slowly added dropwise in above-mentioned suspension, finish, nitrogen protection, be warming up to after 110 DEG C of reaction 1 ~ 2h, TLC detection reaction complete, be cooled to room temperature.Slowly pour in 150g mixture of ice and water, cancellation is reacted.The dilute hydrochloric acid of 1mol/L regulates pH=1 ~ 2, extraction, divide water-yielding stratum, organic layer extracts once (100mL) with water again, combining water layer, wash twice (100mL+50mL) by ethyl acetate, water layer 30% sodium hydroxide solution regulates pH=10 ~ 12, extraction into ethyl acetate (200mL+150mL), combined ethyl acetate layer, saturated nacl aqueous solution washes twice (200mL × 2), anhydrous sodium sulfate drying.Suction filtration, concentrating under reduced pressure obtains racemization green card look woods 10.8g, is yellow oil, yield 81.6%.
1H-NMR(300MHz,CDCl
3):δ＝7.16-7.11(1H,m,ArH),7.08(1H,dd,J＝8.0,2.1Hz,ArH),7.00(1H,d,J＝8.0Hz,ArH),3.13-2.81(6H,m,CH
2),2.77-2.63(1H,m,CH),1.33(3H,d,J＝7.3Hz,CH
3).
MS(ESI,70eV):m/z＝196.0[M+H]
+.
(4) (R)-8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-3-benzo-aza
the preparation of L-(+)-tartrate (III)
Racemization green card look woods (II) (10.0g, 51.1mmol) is placed in 100mL three-necked bottle, adds acetone (40mL), stirring and dissolving post-heating to 50 DEG C.By L-(+)-tartrate (1.92g, 12.8mmol) (5mL) soluble in water, slowly be added dropwise in above-mentioned reaction solution, finish, in 50 DEG C of insulated and stirred 3h, add acetone (8mL), naturally cool to room temperature, then be cooled to 5 ~ 10 DEG C of crystallization 5h, suction filtration, cold acetone (10mL) washing leaching cake obtains white solid, and 40 DEG C of vacuum-dryings obtain crude product 5.3g.By crude product and mixed solvent (70mL, acetone: water=3:1, v/v) mix, reflux, to clarification, slowly cools to 0 DEG C ~ 5 DEG C, insulation 5h, suction filtration, cold acetone (10mL) washing leaching cake, 40 DEG C of vacuum-dryings obtain white powder crystal 4.6g, HPLC purity 99.9%, ee value 99.8%.In racemization green card look woods (II), yield 33.2%.
(5) preparation of hydrochloric acid green card look woods (I)
Intermediate III (4.5g, 16.6mmol) is dissolved in the water (10mL), adds 20%K
2cO
3solution adjusts pH to 8 ~ 9.Extraction into ethyl acetate (20mL+20mL).Merge organic layer, with saturated common salt water washing (15mL × 2), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains micro-yellow oil 3.2g, yield 98.4%.
By above-mentioned oily matter (3.2g, 16.3mmol) be dissolved in dehydrated alcohol (10mL), stir the ethyl acetate solution of the saturated HCl of lower slowly instillation to pH=1 ~ 2, drip process control temp and be no more than 20 DEG C, after stirring at room temperature 1h, remove solvent under reduced pressure and obtain hydrochloric acid green card look woods crude product.In crude product, add methyl tertiary butyl ether (15mL), room temperature making beating 1h, suction filtration, 40 DEG C of vacuum-dryings, obtain white crystal 3.6g, yield 91.3%, HPLC purity 99.9%, ee value 99.8%.
1H-NMR(300MHz,DMSO-d
6):δ＝9.61(2H,bs,HCl),7.29-7.21(3H,m,ArH),3.55-3.45(1H,m,CH
2),3.33-3.18(3H,m,CH
2),3.01(1H,dd,J＝15.7,7.1Hz,CH),2.91-2.83(2H,m,CH
2),1.34(3H,d,J＝7.2Hz,CH
3).
13C-NMR(75MHz,DMSO-d
6):δ＝145.4,138.1,131.5,126.4,126.0,114.5,50.1,44.5,34.1,30.8,17.5.
MS(ESI,70eV):m/z＝196.1[M+H]
+.
Embodiment 2
The preparation of racemization green card look woods (II)
Get aluminum trichloride (anhydrous) (22.5g, 168.7mmol) to be ground into powder, add in 500mL three-necked bottle, add 1,2-dichlorobenzene (90mL), stir in suspension, ice bath is cooled to 0 ~ 5 DEG C.Get after intermediate compound IV (20.0g, 67.6mmol) 1,2-dichlorobenzene (50mL) dissolves and be slowly added dropwise in above-mentioned reaction solution, finish; nitrogen protection, is warming up to 120 DEG C of reactions, reaction 1 ~ 2h; after TLC detection reaction completes, stop heating, be cooled to room temperature.Slowly pour in 150g mixture of ice and water, cancellation is reacted.PH=1 ~ 2 are regulated with 1mol/L dilute hydrochloric acid, divide water-yielding stratum, organic layer extracts once (100mL) with water again, combining water layer, ethyl acetate washes twice (100mL × 2), and water layer 30% sodium hydroxide solution regulates pH=10 ~ 12, extraction into ethyl acetate twice (200mL+100mL), combined ethyl acetate layer, saturated nacl aqueous solution washes twice (200mL × 2), anhydrous sodium sulfate drying.Suction filtration, concentrated filtrate, obtaining racemization green card look woods 10.6g, is yellow oil, yield 80.1%.
Embodiment 3
The preparation of racemization green card look woods (II)
Get aluminum trichloride (anhydrous) (13.5g, 101.2mmol) to be ground into powder, add in 250mL tri-mouthfuls of reaction flasks, add chlorobenzene (50mL), stir in suspension, ice bath is cooled to 0 ~ 5 DEG C.Get after intermediate compound IV (10.0g, 33.8mmol) chlorobenzene (30mL) dissolves and be slowly added dropwise in above-mentioned suspension, finish; nitrogen protection, is warming up to 100 DEG C of reactions, after TLC detection reaction completes (about about 2h); stop heating, be cooled to room temperature.Slowly pour in 100mL mixture of ice and water, cancellation is reacted.Dilute hydrochloric acid regulates pH=1 ~ 2, extraction, divide water-yielding stratum, organic layer extracts (50mL) with water again, combining water layer, with n-hexane twice (50mL × 2), water layer 30% sodium hydroxide solution regulates pH=10 ~ 11, extraction into ethyl acetate (100mL × 2), combined ethyl acetate layer, saturated nacl aqueous solution washes twice (100mL × 2), anhydrous sodium sulfate drying.Suction filtration, concentrated filtrate, obtaining racemization green card look woods 5.2g, is yellow oil, yield 78.6%.
Embodiment 4
The preparation of racemization green card look woods (II)
Get aluminum trichloride (anhydrous) (13.5g, 101.2mmol) to be ground into powder, add in 250mL tri-mouthfuls of reaction flasks, add toluene 60mL, stir in suspension, ice bath is cooled to about 5 DEG C.Get after intermediate compound IV (10.0g, 33.8mmol) toluene (30mL) dissolves and be slowly added dropwise in reaction solution, finish; 90 DEG C of reactions are warming up under nitrogen protection; after about 1h (TLC detection reaction completes), stop heating, be cooled to room temperature.Slowly pour in 90mL mixture of ice and water, cancellation is reacted.Dilute hydrochloric acid regulates pH=1 ~ 2, extraction, divide water-yielding stratum, organic layer extracts (100mL) with water again, combining water layer, ethyl acetate washes twice (60mL × 2), 30% sodium hydroxide solution regulates pH=10 ~ 11, extraction into ethyl acetate (100mL+50mL), combined ethyl acetate layer, saturated nacl aqueous solution washes twice (100mL × 2), anhydrous sodium sulfate drying.Suction filtration, concentrated filtrate, obtaining racemization green card look woods 5.0g, is yellow oil, yield 75.6%.
Embodiment 5
The preparation of racemization green card look woods (II)
Aluminum trichloride (anhydrous) (31.6g, 237.0mmol) is ground into powder, is placed in 250mL tri-mouthfuls of reaction flasks; under stirring, add intermediate compound IV (20.0g, 67.6mmol); finish, under nitrogen protection, be warming up to 115 DEG C; react under molten state; after TLC detection reaction completes, stop heating, be cooled to about 80 DEG C; slowly pour in 200g mixture of ice and water, cancellation is reacted.20% sodium hydroxide regulates pH=10 ~ 11, extraction into ethyl acetate (200mL+150mL), combined ethyl acetate layer, saturated nacl aqueous solution washes twice (200mL × 2), anhydrous sodium sulfate drying.Suction filtration, concentrated filtrate, obtaining racemization green card look woods 9.7g, is yellow oil, yield 73.3%.
Claims (10)
1. prepare a method for racemization green card look woods (II), comprise the following steps:
Wherein catalyzer is aluminum chloride, boron trifluoride, titanium tetrachloride, tin chloride or zinc chloride.
2. the process of claim 1 wherein that catalyzer is aluminum chloride.
3. the process of claim 1 wherein that reaction solvent is the mixture of one or any two kinds in methylene dichloride, trichloromethane, toluene, oil of mirbane, chlorobenzene, orthodichlorobenzene.
4. the method for claim 3, wherein reaction solvent is chlorobenzene or orthodichlorobenzene.
5. the process of claim 1 wherein that temperature of reaction is 50 ~ 150 DEG C.
6. the method for claim 5, wherein temperature of reaction is 90 ~ 120 DEG C.
7. the process of claim 1 wherein that the mol ratio of IV and catalyzer is 1:1.5 ~ 1:4.
8. the method for claim 7, wherein the mol ratio of IV and catalyzer is 1:2 ~ 1:3.
9. the process of claim 1 wherein solvent-free under in 110 ~ 130 DEG C of frit reactions.
10. prepare a method for hydrochloric acid green card look woods (I), comprising:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510816483.7A CN105348197B (en) | 2015-11-23 | 2015-11-23 | A kind of preparation method of hydrochloric acid green card color woods |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510816483.7A CN105348197B (en) | 2015-11-23 | 2015-11-23 | A kind of preparation method of hydrochloric acid green card color woods |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105348197A true CN105348197A (en) | 2016-02-24 |
| CN105348197B CN105348197B (en) | 2018-07-03 |
Family
ID=55324283
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510816483.7A Active CN105348197B (en) | 2015-11-23 | 2015-11-23 | A kind of preparation method of hydrochloric acid green card color woods |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105348197B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106496122A (en) * | 2016-08-31 | 2017-03-15 | 安徽省润生医药股份有限公司 | A kind of preparation method and its usage of hydrochloric acid green card color woods |
| CN110950802A (en) * | 2019-12-25 | 2020-04-03 | 江西博雅欣和制药有限公司 | Synthesis process of intermediate of weight-reducing drug lorcaserin hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102329268A (en) * | 2011-10-25 | 2012-01-25 | 天津药物研究院 | Preparation method for 7-chlorine-5-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepine |
| WO2014187768A1 (en) * | 2013-05-20 | 2014-11-27 | Lek Pharmaceuticals D.D. | Novel synthetic processes to 8-chloro-3-benzo[d]azepine via friedel-crafts alkylation of olefin |
-
2015
- 2015-11-23 CN CN201510816483.7A patent/CN105348197B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102329268A (en) * | 2011-10-25 | 2012-01-25 | 天津药物研究院 | Preparation method for 7-chlorine-5-oxo-2,3,4,5-tetrahydro-1H-1-benzoazepine |
| WO2014187768A1 (en) * | 2013-05-20 | 2014-11-27 | Lek Pharmaceuticals D.D. | Novel synthetic processes to 8-chloro-3-benzo[d]azepine via friedel-crafts alkylation of olefin |
Non-Patent Citations (1)
| Title |
|---|
| QIHUA ZHU，ET AL.: "Novel Synthesis of Antiobesity Drug Lorcaserin Hydrochloride", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106496122A (en) * | 2016-08-31 | 2017-03-15 | 安徽省润生医药股份有限公司 | A kind of preparation method and its usage of hydrochloric acid green card color woods |
| CN110950802A (en) * | 2019-12-25 | 2020-04-03 | 江西博雅欣和制药有限公司 | Synthesis process of intermediate of weight-reducing drug lorcaserin hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105348197B (en) | 2018-07-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104086379B (en) | The synthetic method of the clean intermediate of Da Gelie | |
| CN107056675B (en) | A kind of synthetic method of silodosin and its intermediate | |
| CN102311355B (en) | Preparation method of rofecoxib | |
| CN111454137A (en) | Synthetic method for improving yield of 5-chloro-1-indanone | |
| CN106459014A (en) | Method of preparation for ledipasvir and derivative thereof, and intermediate compound for preparation of ledipasvir | |
| CN102367260A (en) | Synthesis method of 2-aminopyrimidine-5-boric acid | |
| CN105348197A (en) | Preparation method of lorcaserin hydrochloride | |
| CN105367497B (en) | A kind of slimming drugs hydrochloric acid green card color woods and its preparation method of intermediate | |
| CN105777584B (en) | The preparation method of alanine derivatives | |
| CN106032380A (en) | Industrial production method of midazolam | |
| CN109651238A (en) | A kind of new method preparing picosulfate sodium | |
| CN111116493B (en) | Method for preparing Apabetalone, intermediate and preparation method of intermediate | |
| CN105753735B (en) | Preparation method of high-efficiency low-toxicity vasopressin antagonist | |
| CN114702425A (en) | Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate | |
| CN113429379A (en) | LH-1801 intermediate and preparation method and application thereof | |
| CN104672180B (en) | Chiral preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate | |
| CN107325078B (en) | Preparation method of cilostazol | |
| CN106699605A (en) | Methylation method of lacosamide intermediate | |
| CN101723955B (en) | Method for preparing olanzapine | |
| CN111499575B (en) | Method for preparing lorcaserin | |
| ZA200503239B (en) | Process for production of an acetylenic compound | |
| CN105461634A (en) | Preparation method of enzalutamide | |
| CN104151276A (en) | Preparation method of metabolic impurity of dronedarone hydrochloride | |
| CN109851549B (en) | 5-hydrogen-benzo [ b ] carbazole and related derivatives and synthetic method thereof | |
| CN106748862A (en) | A kind of preparation method for promoting gastroenteritic power medicine Itopride Hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |