CN100391938C - Preparation method of phenyl (S)-N-ethyl-N-methyl-3-[1-(dimethyamino)ethyl]-amidoformate (I) and tartrate thereof (II) - Google Patents
Preparation method of phenyl (S)-N-ethyl-N-methyl-3-[1-(dimethyamino)ethyl]-amidoformate (I) and tartrate thereof (II) Download PDFInfo
- Publication number
- CN100391938C CN100391938C CNB200510029393XA CN200510029393A CN100391938C CN 100391938 C CN100391938 C CN 100391938C CN B200510029393X A CNB200510029393X A CN B200510029393XA CN 200510029393 A CN200510029393 A CN 200510029393A CN 100391938 C CN100391938 C CN 100391938C
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- iii
- ethyl
- salt
- 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.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/49—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring having at least two amino groups bound to the carbon skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hospice & Palliative Care (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses (S)-N-ethyl-N-methyl-3[1-(dimethylamino) ethyl]-carbamidbenzoate (I) and preparing method of tartrate (II), which comprises the following steps: reacting compound (III) or salt and phosgene, diphosgene or triphosgene to obtain compound (IV); preparing compound (I) through reacting non-purifying compound (IV) and N-methyl-N-ethyl ammonium; reacting compound (I) and L-(+)-tartaric acid to obtain tartrate (II).
Description
Technical field
The present invention relates to (S)-N-ethyl-N-methyl-3-[1-(dimethylamino) ethyl]-a kind of novel synthesis of phenyl carbamate (1) and tartrate (II) thereof.
Background technology
Alzheimer (be called for short AD) is a kind of because the dead nervous system disease that causes of cranial nerve cell, and it mainly is that patient remembers with cognitive ability and loses behavioral activity generation obstacle in various degree that its symptom shows.
Rivastigmine (Rivastigmine, chemical name (S)-N-ethyl-N-methyl-3-[1-(dimethylamino) ethyl]-phenyl carbamate) (I), and tartrate (II) has following structural formula:
Rivastigmine tartrate (II) is a kind of active drug that is used to alleviate the AD PD, its mechanism of action is the acetylcholinesterase that suppresses in the human brain, improve the content of nervus centralis media vagusstoff, be applicable to slight treatment to the moderate patient, can effectively improve patient's memory, side effect is less.The preparation method of rivastigmine (I) is as described below, but up to the present can't obtain gratifying result.
U.S. Pat 5602176 discloses a kind of method, is the rivastigmine of preparation racemization earlier, again with O, and O '-two pair of toluyl tartrate monohydrate salify, crystallization obtains optically pure (S)-rivastigmine.
World patent WO 2004037771 discloses and adopted the meta-methoxy methyl phenyl ketone is starting raw material prepares racemization by polystep reaction 3-(1-(N, the N-dimethyl amido) ethyl)-phenol, obtain optically pure 3-(1-(S)-(N through resolving and purifying again, the N-dimethyl amido) ethyl)-phenol, and then obtain (S)-rivastigmine with N-methyl-N-ethylamino formyl chloride prepared in reaction.
It is that starting raw material reacts with N-methyl-N-ethylamino formyl chloride earlier that English Patent GB 2409453 discloses the employing m-hydroxy acetophenone, is converted into racemization then and gets rivastigmine, makes optically pure (S)-rivastigmine by fractionation again.
These method for splitting meaning person slatterns (R)-isomer of 50% at least, thereby makes that the total recovery of this method is low, and cost is higher.
Summary of the invention
In order to overcome the defective of prior art; The invention provides a kind of new preparation (S)-N-ethyl-N-methyl-3-[1-(dimethylamino) ethyl]-method of phenyl carbamate (I) and tartrate (II) thereof; The method adopts compound (III) or its salt and phosgene, surpalite or triphosgene to obtain compound (IV) under the alkaline matter effect; The not purified direct and N-methyl-N-ethylamine reaction preparation compound (I) of compound (IV); Compound (I) prepares its tartrate (II) with L-(+)-tartaric acid (V) in reaction; Concrete reaction is as follows
The alkaline matter that is adopted in the reaction is exemplified below: inorganic base (as yellow soda ash, salt of wormwood, sodium amide, sodium hydride, potassium hydride KH); Alkali metal alcohol compound (as sodium methylate, sodium ethylate, potassium tert.-butoxide); Organic bases (as triethylamine, pyridine, quinoline, diisopropyl ethyl amine).The solvent that reaction is adopted is an inert solvent, is exemplified below: as ether (as tetrahydrofuran (THF), ether, glycol dimethyl ether, dioxan); Arene (as benzene,toluene,xylene); Halohydrocarbon (as methylene dichloride, trichloromethane, ethylene dichloride).The temperature of reaction is controlled at 0 ℃ of temperature to solvent boiling point.Adopt any inert solvent, lower alcohols (as methyl alcohol, ethanol, propyl alcohol, butanols) during preparation compound (I); Ethers (as tetrahydrofuran (THF), ether, glycol dimethyl ether, dioxan); Arene (as benzene,toluene,xylene); Halogenated hydrocarbon (as methylene dichloride, trichloromethane, ethylene dichloride); Dimethyl formamide, N,N-DIMETHYLACETAMIDE; Ketone etc.
The reaction of compound (IV) and N-methyl-N-ethylamine preferably adds alkaline matter, is beneficial to the carrying out that react, and the alkaline matter that can add is exemplified below: inorganic base (as yellow soda ash, salt of wormwood, sodium amide, sodium hydride); Alkali metal alcohol compounds (as sodium methylate, sodium ethylate, potassium tert.-butoxide); Organic bases (as triethylamine, pyridine, quinoline, diisopropyl ethyl amine).Reaction solvent adopts any inert solvent such as ether (as tetrahydrofuran (THF), ether, glycol dimethyl ether, dioxan); Arene (as benzene,toluene,xylene); Halohydrocarbon (as methylene dichloride, trichloromethane, ethylene dichloride); Dimethyl formamide, N,N-DIMETHYLACETAMIDE; Acetone etc.
Compound (I) and L-(+)-tartrate (V) prepare compound (II) according to the method for routine.
Compound among the present invention (III) or its salt adopt following reaction to obtain,
Method one:
Compound (3) can adopt well-known method to introduce two methyl on amino, comprising formaldehyde/formic acid, methyl-sulfate system.
Compound (4) is introduced nitro in No. 3 positions of phenyl ring selectivity, adoptable nitration condition is nitric acid/sulfuric acid system, in order optionally to introduce nitro in No. 3 positions of phenyl ring, the temperature that the consumption of the nitrating agent that is added in the control reaction and reaction are adopted, the temperature of reaction is no more than 50 ℃, preferably be no more than 40 ℃, the consumption of different reaction systems, different nitrating agents, the top temperature of being controlled is different.
Nitro in the compound (5) can adopt the conventional reduction method, comprises catalytic hydrogenation and chemical reduction.
The diazotization reaction of compound (6), hydrolysis can adopt conventional method to carry out, and make compound (III), and compound (III) can be converted into alkali salt or hydrochlorate as required.
Method two:
Wherein R is ethanoyl, propionyl, benzoyl or phenylacetyl.
Compound (3) can adopt well-known method to introduce two methyl on amino, comprising formaldehyde/formic acid, methyl-sulfate system.
Compound (4) is optionally introduced acyl group in No. 3 positions of phenyl ring, the acylation condition that can adopt is Acetyl Chloride 98Min., propionyl chloride, Benzoyl chloride, the phenyllacetyl chloride system under Lewis acid or protonic acid exist, preferably Acetyl Chloride 98Min., Benzoyl chloride, phenyllacetyl chloride system; Optionally introduce acyl group on the phenyl ring in order to control to be reflected at, the consumption of employed acylating reagent is controlled at the acylating reagent amount of compound (4) the employing 1.1-10.0 molar weight of 1 molar weight, preferred 1.1-2.0 molar weight in the acylation reaction.
Compound (7) and Baeyer-Villager oxygenant prepared in reaction compound (8) in conventional Baeyer-Villager oxidizing reaction system comprise metachloroperbenzoic acid, trifluoro Peracetic Acid system.
Compound (8) hydrolysis or alcoholysis under alkaline condition make compound (III) or its salt, and compound (HI) can be converted into alkali salt or hydrochlorate as required.
Aforesaid method one is in method two; compound (3) can carry out the substitution reaction of nitro or acyl group earlier; resulting compound reacts with the aminomethylation reagent of routine again; wherein acyl group can be ethanoyl, propionyl, benzoyl or phenylacetyl, and resulting product carries out follow-up reaction.
Method three:
Compound (3) can adopt well-known method to introduce two methyl on amino, comprising formaldehyde/formic acid, methyl-sulfate system.
Compound (4) is introduced sulfonic group in No. 3 positions of phenyl ring, and the sulfonated reagent that can adopt is sulfuric acid system or chlorsulfonic acid system.Optionally introduce sulfonic group on the phenyl ring in order to control to be reflected at, the consumption of the sulfonated reagent that can control in the reaction to be added and the temperature of reaction.
Compound (9) employing fusion under the highly basic effect makes compound (III), and the highly basic that reaction is adopted can be sodium hydroxide and/or potassium hydroxide.Compound (III) can be converted into alkali salt or hydrochlorate as required.
Method four:
Compound (3) is introduced sulfonic group in No. 3 positions of phenyl ring, and the sulfonated reagent that can adopt is sulfuric acid system or chlorsulfonic acid system.Optionally introduce sulfonic group on the phenyl ring in order to control to be reflected at, the consumption of the sulfonated reagent of control reaction and the temperature of reaction.
Compound (11) fusion under the highly basic effect makes compound (12), and the highly basic that reaction is adopted can be sodium hydroxide and/or potassium hydroxide.
Amino in the compound (12) can adopt well-known method to introduce two methyl on amino and obtain compound (III), comprises formaldehyde/formic acid system.
Compound (III) can be converted into alkali salt or hydrochlorate as required.
Synthesis technique of the present invention is selected rationally, need not to carry out complicated resolving and purifying, and raw material sources are convenient, and are simple to operate, are convenient to obtain the chemical yield height, and the optical purity height is a kind of method for preparing compound (I) and tartrate (II) thereof of economy.
Specific embodiment
Further illustrate content of the present invention below in conjunction with embodiment, these embodiment are not to be restriction to the scope of the invention or spirit.
The preparation of embodiment one 3-(1-(S)-(N, N-dimethyl amido) ethyl)-Phenyl Chloroformate 99
With triphosgene (15.9g, 53.5mmol) be dissolved in the 400ml tetrahydrofuran (THF), under cryosel bath cooling, add 3-(1-(S)-(N, the N-dimethyl amido) ethyl)-and sodium phenylate (25g, 133.7mmol), 0 ℃ was stirred 20 minutes, be heated to 55-60 ℃ of reaction four hours then, blow away the residue phosgene with nitrogen, filter out sodium-chlor, concentrate oily liquids (30g).Without purification, directly enter next step reaction.
The preparation of embodiment two rivastigmines
Ice-water bath cooling is dissolved in the 200ml anhydrous diethyl ether with the oily liquids (30g) of gained among the embodiment one down, and this drips of solution is added to triethylamine (18.7mL), methylethyl amine, and (7.9g is 133.7mmol) and in the mixed solution of the anhydrous diethyl ether of 300mL.Continuation was stirred 20 minutes under the frozen water cooling, and room temperature reaction spends the night then.Remove by filter triethylamine hydrochloride, with saturated aqueous common salt (2 * 200mL) washings, anhydrous sodium sulfate drying, concentrate colourless oil liquid, 120-122 ℃ of cut (about 0.5 mmhg) collected in underpressure distillation, rivastigmine (26.8g, two go on foot yields 80%).
The preparation of embodiment three 3-(1-(S)-(N, N-dimethyl amido) ethyl)-Phenyl Chloroformate 99
(3.18g 79.5mmol) is dissolved in the 100mL ethanol, slowly is added dropwise to 3-(1-(S)-(N with sodium hydroxide, the N-dimethyl amido) ethyl)-phenolate hydrochlorate (8g, 39.7mmol) the 100mL ethanolic soln, stirring at room is after 1 hour, concentrates evaporate to dryness second alcohol and water.With the gained solid slowly add to cryosel bathe the refrigerative triphosgene (4.7g, in tetrahydrofuran (THF) 15.9mmol) (120mL) solution, 0 ℃ was stirred 20 minutes, be heated to 55-60 ℃ of reaction four hours then, nitrogen blows away the residue phosgene, filters out sodium-chlor, concentrate oily liquids (9g).Without purification, can be directly and methylethyl amine prepared in reaction rivastigmine (operation steps is with reference to embodiment two).
The preparation of embodiment four 3-(1-(S)-(N, N-dimethyl amido) ethyl)-Phenyl Chloroformate 99
With absolute anhydrous pyridine (8.85g, 110mmol) slowly drop to 0 ℃ trichloromethylchloroformate (19.8g, 14.2mL, 200mmol), drip 3-(1-(S)-(N, N-dimethyl amido) ethyl)-phenol (16.5g then, anhydrous diethyl ether 100mmol) (30mL) solution, after drip finishing, 0 ℃ was stirred 1 hour, was warming up to room temperature reaction then 8 hours.Hydrogen chloride gas and unnecessary phosgene are removed in decompression, add the 200mL anhydrous diethyl ether again, filter, concentrate oily liquids (23g).Without purification, can be directly and methylethyl amine prepared in reaction rivastigmine (operation steps is with reference to embodiment two).
The preparation of embodiment five rivastigmine tartrates
With rivastigmine (2.0g, 8.0mmol) and L-(+)-tartrate (1.2g 8.0mmol) is dissolved in the 5mL methyl alcohol, be heated to 60 ℃, stir to clarify, then solution is cooled to room temperature, add acetone (about 50mL), this system is in+5 ℃ of crystallizatioies that spend the night, leach institute's crystallization body, clean (2 * 10mL), 40 ℃ of vacuum-dryings with acetone, get white crystal rivastigmine tartrate (2.56g, 80%).
Embodiment six (S)-N, the preparation of N-dimethyl-1-phenylethylamine
The ice-water bath cooling down, (100g in (S)-1-phenylethylamine, 0.825mol) dropping formic acid (129g, 2.47mol), add again formaldehyde (162g, 2.06mol), reflux is 12 hours then, be cooled to room temperature, 5M hydrochloric acid transfers to PH=2, and 3 * 250ml ethyl acetate extraction is removed impurity, and water transfers to PH=9-10 with 5M NaOH solution, adopt 3 * 400mL ethyl acetate extraction, organic phase saturated aqueous common salt washed twice, anhydrous sodium sulfate drying, solvent removed in vacuo, underpressure distillation gets colourless transparent liquid (86.1g, 70%).
(S)-N that embodiment seven nitros replace, the preparation of N-dimethyl-1-phenylethylamine
With (S)-N, (30g 201mmol) is dissolved in the 150mL chloroform N-dimethyl-1-phenylethylamine, is added drop-wise in the vitriol oil (52mL) under the ice-water bath cooling, and the control solution temperature at room temperature stirred 20 minutes then below 25 ℃.(15mL, 221mmol) and the mixed acid solution of the vitriol oil (15mL), controlled temperature is about 30~35 ℃ during dropping to drip concentrated nitric acid.After drip finishing reaction solution is cooled to room temperature, continue to stir half an hour, regulate pH value to 9~10 with the NaOH solution of 5N then, (3 * 200mL) extractions are after organic phase merges to use chloroform then, with saturated aqueous common salt (2 * 200mL) washings, anhydrous sodium sulfate drying concentrates, and gets yellow oil (37.1g, 95%, the product content that the position replaced between HPLC showed is 65%).
(S)-N that embodiment eight nitros replace, the preparation of N-dimethyl-1-phenylethylamine
With (S)-N, (20g 134mmol) is dissolved in the CHCl of 50mL to N-dimethyl-1-phenylethylamine
3In, be added drop-wise in the vitriol oil (40mL) under the ice-water bath cooling, keep solution temperature to be lower than room temperature, stirring at room is 20 minutes then.Drip concentrated nitric acid (11mL), keep solution temperature in the dropping process about 30-35 ℃.Drip and finish, reaction system is stirred to room temperature, NaOH solution with 5N is regulated pH value to 9~10, and (3 * 250mL) extractions are after organic phase merges to use chloroform then, with saturated aqueous common salt (2 * 150mL) washings, anhydrous sodium sulfate drying concentrates, and gets yellow oil (23.5g, 90%, the product content that the position replaced between HPLC showed is 63%).
The preparation of embodiment nine 3-(1-(S)-(N, N-dimethyl amido) ethyl)-aniline
(20g 103mmol) is dissolved in the 100mL ethanol, is heated to 50 ℃, drips SnCl with resulting yellow oil among the embodiment eight
2.2H
2(76.5g, (keep temperature of reaction in the dropping process is 50~60 ℃ to hydrochloric acid 339mmol) to O for 5N, 240mL) solution, reacts two hours in 50 ℃ after dropwising again.Decompression steams the part ethanol in the system, transferring pH value with 5N NaOH solution is 9~10, use chloroform (3 * 200mL) extractions then, after organic phase merges, with saturated aqueous common salt (2 * 200mL) washings, anhydrous sodium sulfate drying, concentrate, column chromatography for separation gets faint yellow oily thing 3-(1-(S)-(N, N-dimethyl amido) ethyl)-aniline (9.3g, 55%).
The preparation of embodiment ten 3-(1-(S)-(N, N-dimethyl amido) ethyl)-phenol
With the dense H of 17mL
2SO
4Be dissolved in the 50mL water, the ice-water bath cooling adds 3-(1-(S)-(N, N-dimethyl amido) ethyl)-aniline down, and (8.1g 49.39mmol), maintains the temperature at during dropping below 25 ℃, drips the back and continues stirring at room 30 minutes.Then reaction system is bathed cooling with cryosel, drip Sodium Nitrite (3.9g, 20mL aqueous solution 56.5mmol), keep temperature of reaction system below 5 ℃ during dropping, after dropwising, under cryosel bath cooling, continue to stir 1 hour, get a faint yellow diazonium salt solution.Then, this faint yellow diazonium salt solution is dropped in the mixing solutions of water of 120 ℃ the 30mL vitriol oil and 15mL, controlled temperature is at 120-125 ℃, after dropwising, be cooled to room temperature, being neutralized to pH value with the NaOH solution of 5N is 9~10, with ethyl acetate (2 * 100mL) extractions, saturated aqueous common salt (2 * 50mL) washings, the evaporated under reduced pressure solvent, column chromatography for separation gets faint yellow solid 3-(1-(S)-(N, the N-dimethyl amido) ethyl)-phenol (6.53g, 80%).
The preparation of embodiment 11 3-(1-(S)-(N, N-dimethyl amido) ethyl)-phenolate hydrochlorate
The hydrochloric acid (100mL) that the acetic acid ethyl acetate extract of gained among the embodiment ten is added 1N, stirring at room half an hour, divide water-yielding stratum, organic layer is used hydrochloric acid (50mL) washing of 1N again, combining water layer, concentrate faint yellow solid 3-(1-(S)-(N, N-dimethyl amido) ethyl)-phenolate hydrochlorate (8.0g, 80%).
The preparation of embodiment 12 3-(1-(S)-(N, N-dimethyl amido) ethyl)-sodium phenylate
Take by weighing sodium (0.92g, 40mmol) be dissolved in the absolute dehydrated alcohol of 100mL, 3-(the 1-(S)-(N that adds gained among the embodiment ten then, the N-dimethyl amido) ethyl)-and phenol (6.58g, 39.9mmol), stirring at room half an hour, concentrate, get 3-(1-(S)-(N, N-dimethyl amido) ethyl)-sodium phenylate (7.45g, 100%).
The preparation of (S)-1-phenylethylamine that embodiment ten trinitro-s replace
Take by weighing (S)-1-phenylethylamine 20g (165mmol) and be dissolved in the CHCl of 50mL
3In, the ice-water bath cooling is added dropwise in the 35mL vitriol oil down, keeps temperature below 25 ℃ during dropping, drips and finishes the back stirring at room 20 minutes.Drip the dense HNO of 13.5mL
3(d=1.4) and the formulated nitration mixture of the 13.5mL vitriol oil, controlled temperature is about 30~35 ℃ during dropping.After drip finishing reaction solution is cooled to room temperature, continue to stir half an hour, regulate pH value to 9~10 with the NaOH solution of 5N then, (3 * 200mL) extractions are after organic phase merges to use chloroform then, with saturated aqueous common salt (2 * 200mL) washings, anhydrous sodium sulfate drying concentrates, and gets yellow oil (24.9g, 91%, the product content that the position replaced between HPLC showed is 64%).
(S)-N that embodiment ten tetranitros replace, the preparation of N-dimethyl-1-phenylethylamine
Take by weighing the yellow oil (13.3g of embodiment 13 gained, 80mmol), the ice-water bath cooling down, add formic acid (12.6g, 240mmol) with formaldehyde 15.7g (200mmol), heating reflux reaction 12 hours is cooled to room temperature, hydrochloric acid with 5N transfers to PH to 2~3, (impurity is removed in 3 * 100mL) extractions, and water transfers to PH to 9~10 with the NaOH solution of 5N, and (3 * 200mL) extract to use ethyl acetate again with ethyl acetate, organic phase merges, with the saturated common salt water washing (2 * 500mL), anhydrous sodium sulfate drying, solvent removed in vacuo, get yellow oil (12.4g, 80%).
Embodiment 15 (S)-N, the preparation of the ethanoyl product of N-dimethyl-1-phenylethylamine
Be equipped with in the 250mL round-bottomed flask of condenser and nitrogen inlet one and add aluminum chloride (30.7g, 230mmol), dithiocarbonic anhydride (150mL) and Acetyl Chloride 98Min. (3.8mL, 48mmol), with (S)-N, (5.5g 37mmol) is added to (about 15 minutes) in this mixed solution to N-dimethyl-1-phenylethylamine in batches under stirring, again reactant was stirred 10 minutes, refluxed then two hours.With reactant cooling, be added in the ice and fully stir, with in the NaOH aqueous solution of 5N with system to PH be 12; (3 * 200mL) extractions are after organic phase merges, with saturated aqueous common salt (2 * 100mL) washings with chloroform; anhydrous sodium sulfate drying obtains acetylate (5.66g, 80%).
Embodiment 16 (S)-N, the preparation of the benzoylation product of N-dimethyl-1-phenylethylamine
Be equipped with in the 250mL round-bottomed flask of condenser and nitrogen inlet one and add aluminum chloride (15.4g, 115mmol), dithiocarbonic anhydride (75ml) and Benzoyl chloride (2.1ml, 24mmol), with (S)-N, (2.7g 18mmol) is added in this stirred mixture N-dimethyl-1-phenylethylamine in batches in 15 minutes, again reactant was stirred 10 minutes, refluxed then two hours.With reactant cooling, be added in the ice and fully stir, with in the NaOH aqueous solution of 5N with system to PH be 12; (3 * 200mL) extractions are after organic phase merges, with saturated aqueous common salt (2 * 100mL) washings with chloroform; anhydrous sodium sulfate drying obtains benzoylation product (3.4g, 75%) after drying.
Embodiment 17 (S)-N, the Baeyer-Villager oxidation of the acetylate of N-dimethyl-1-phenylethylamine
(S)-N with gained among the embodiment 16; ethanoyl product (the 6g of N-dimethyl-1-phenylethylamine; 31.4mmol) be dissolved in the methylene dichloride (400mL); the adding SODIUM PHOSPHATE, MONOBASIC (4.46g, 31.4mmol), the ice-water bath cooling is down; add metachloroperbenzoic acid (29.5g; 55%, 94.2mmol), 0 ℃ was stirred 12 hours down.Add saturated Na then
2SO
3Solution (100mL), stirring at room 5 hours.Regulate pH value to 9 with saturated sodium bicarbonate, with chloroform (3 * 200mL) extractions, after organic phase merges, saturated aqueous common salt (2 * 200mL) washings, anhydrous sodium sulfate drying, concentrate, column chromatography for separation, 1,2 and 3-(1-(S)-(N, the N-dimethyl amido) ethyl)-phenylacetic acid ester mixture (5.2g, 80%).
Embodiment 18 (S)-N, the Baeyer-Villager oxidation of the benzoylation product of N-dimethyl-1-phenylethylamine
(S)-N; N-dimethyl-1-phenylethylamine benzoylation product (10.6g; 41.8mmol) be dissolved in the methylene dichloride (500mL), the adding SODIUM PHOSPHATE, MONOBASIC (5.94g, 41.8mmol); the ice-water bath cooling down; the adding metachloroperbenzoic acid (39.3g, 55%, 125.4mmol); 0 ℃ of stirring is spent the night, and adds saturated Na then
2SO
3Solution (120mL) stirred 5 hours under the room temperature.Regulate pH value to 9 with saturated sodium bicarbonate, with chloroform (3 * 300mL) extractions, after organic phase merges, saturated aqueous common salt (2 * 200mL) washings, anhydrous sodium sulfate drying, concentrate, column chromatography for separation, 1,2 and 3-(1-(S)-(N, the N-dimethyl amido) ethyl)-Phenylbenzoic acid ester mixture (5.51g, 49%).
The preparation of embodiment 19 3-(1-(S)-(N, N-dimethyl amido) ethyl)-phenol
(5g 24.7mmol), is dissolved in the tetrahydrofuran (THF) (100mL), adds NaOH (1.48g, water 37mmol) (10mL) solution then to take by weighing 1,2 and 3-(1-(S)-(N, N-dimethyl amido) ethyl)-phenylacetic acid ester mixture of gained among the embodiment 17.Stirring at room 3 hours is used NaHCO then
3Saturated solution is transferred pH value to 9, and ethyl acetate (3 * 150mL) extractions, organic phase merges, saturated aqueous common salt (2 * 150mL) washings, anhydrous sodium sulfate drying concentrates column chromatography for separation, get 3-(1-(S)-(N, N-dimethyl amido) ethyl)-phenol (2.03g, 51%).
The preparation of embodiment 20 3-(1-(S)-(N, N-dimethyl amido) ethyl)-phenol
(7g 26mmol), is dissolved in the tetrahydrofuran (THF) (100mL), adds NaOH (1.48g, water 37mmol) (10mL) solution then to take by weighing 1,2 and 3-(1-(S)-(N, N-dimethyl amido) ethyl)-Phenylbenzoic acid ester mixture of gained among the embodiment 18.Stirring at room 3 hours is used NaHCO then
3Saturated solution is transferred pH value to 9, and ethyl acetate (3 * 150mL) extractions, organic phase merges, saturated aqueous common salt (2 * 150mL) washings, anhydrous sodium sulfate drying concentrates column chromatography for separation, get 3-(1-(S)-(N, N-dimethyl amido) ethyl)-phenol (2.10g, 49%).
Embodiment 21 (S)-N, the sulfonation of N-dimethyl-1-phenylethylamine
Take by weighing (S)-N, (23g 154mmol) is dissolved in the 150mL chloroform N-dimethyl-1-phenylethylamine, and (30.8mL, 462mmol), exothermic heat of reaction, temperature rise to 60 ℃ very soon, drip, and naturally cool to room temperature in 20 minutes to splash into chlorsulfonic acid under the room temperature.With in the reaction solution impouring ice (300g), be warming up to 100 ℃ of heating 1 hour gradually, after being cooled to room temperature, transfer pH value to 12, the water in the system is revolved with the NaOH solution of 5N, use ethanol (500mL) heat to extract then, concentrate mother liquid obtained behind the heat filtering, get pale solid 1,2 and 3-(S)-N, the mixture (30.9g, 80%) of N-dimethyl-1-phenylethylamine sodium sulfonate.
Embodiment 22 (S)-N, the sulfonation of N-dimethyl-1-phenylethylamine
Take by weighing (S)-N, and N-dimethyl-1-phenylethylamine (20g 134mmol) is dissolved in the 150mL chloroform, and logical HCl gas is salifies extremely all, solvent evaporated, and infrared oven dry gets white solid (S)-N, N-dimethyl-1-phenylethylamine hydrochloride (24.9g, 134mmol).
(13.4mL 201mmol) is heated to 140 ℃, and to (the S)-N that wherein adds above-mentioned gained, N-dimethyl-1-phenylethylamine hydrochloride reacted one hour in 140 ℃ behind reinforced the finishing with chlorsulfonic acid.Naturally cool to room temperature, with in the reaction solution impouring ice (300g), be warming up to 100 ℃ of heating 1 hour then gradually, transfer pH value to 12, the water in the system is revolved with the NaOH solution of 5N, use ethanol (500mL) heat to extract then, concentrate mother liquid obtained behind the heat filtering, get pale solid 1,2 and 3-(S)-N, the mixture (30.30g, 90%) of N-dimethyl-1-phenylethylamine sodium sulfonate.
Embodiment 23 (S)-N, the sulfonation of N-dimethyl-1-phenylethylamine
(50g 500mmol) is heated to 180 ℃, adds (S)-N, and (14.9g, 100mmol), reaction solution naturally cools to room temperature 180 ℃ of reactions one hour to N-dimethyl-1-phenylethylamine with the vitriol oil.With in the reaction solution impouring ice (200g), transfer pH value to 12 with the NaOH solution of 5N, the water in the system is revolved, use ethanol (350mL) heat to extract then, concentrate mother liquid obtained behind the heat filtering, get 1,2 and 3-(S)-N, the mixture (21.6g, 86%) of N-dimethyl-1-phenylethylamine sodium sulfonate.
The sulfonation of embodiment 24 (S)-1-phenylethylamine
(12.1g 100mmol) is dissolved in the 150mL chloroform, and (20.0mL, 300mmol), exothermic heat of reaction, temperature rise to 60 ℃ very soon, drip, and naturally cool to room temperature in 20 minutes to splash into chlorsulfonic acid under the room temperature to take by weighing (S)-1-phenylethylamine.With in the reaction solution impouring ice (150g), be warming up to 100 ℃ of heating 1 hour gradually, after being cooled to room temperature, NaOH solution with 5N is transferred pH value to 12, and the water in the system is revolved, and uses ethanol (300mL) heat to extract then, concentrate mother liquid obtained behind the heat filtering, get the mixture (20.5g, 92%) of pale solid 1,2 and 3-(S)-1-phenylethylamine sodium sulfonate.
The sulfonation of embodiment 25 (S)-1-phenylethylamine
Take by weighing (S)-1-phenylethylamine (24.2g 200mmol) is dissolved in the 150mL chloroform, and HCl gas is to whole salifies all, solvent evaporated, infrared oven dry, white solid (S)-1-phenylethylamine hydrochloride (31.5g, 200mmol).
(40.0mL 600mmol) is heated to 140 ℃, adds (S)-1-phenylethylamine hydrochloride of above-mentioned gained, and the reinforced back that finishes naturally cools to room temperature in 140 ℃ of reactions one hour with chlorsulfonic acid.With in the reaction solution impouring ice (350g), be warming up to 100 ℃ of heating 1 hour then gradually, NaOH solution with 5N is transferred pH value to 12, water in the system is revolved, use ethanol (500mL) heat to extract then, concentrate mother liquid obtained behind the heat filtering, get pale solid 1,2 and the mixture (41.1g, 92%) of 3-(S)-1-phenylethylamine sodium sulfonate.
The preparation of embodiment 26 3-(1-(S)-(N, N-dimethyl amido) ethyl)-phenol
With embodiment 21, in 22 and 23 1 of gained, 2 and 3-(S)-N, mixture (the 25.1g of N-dimethyl-1-phenylethylamine sodium sulfonate, 100mmol) and NaOH (40g 1mol) is dissolved in (70mL) in the less water, is heated to 120 ℃ with the water evaporate to dryness, continue to be warming up to 280 ℃, system enters molten state, continues reaction 5 minutes, stops heating, naturally cool to room temperature, add water (200mL), transfer PH to 9, use ethyl acetate (3 * 200mL) extractions then with the 6N hydrochloric acid soln, after organic phase merges, (2 * 200mL) wash, and anhydrous sodium sulfate drying concentrates with saturated aqueous common salt, column chromatography for separation, get 3-(1-(S)-(N, N-dimethyl amido) ethyl)-phenol (7.93g, 48%).
The preparation of embodiment 27 3-(1-(S)-amido ethyl)-phenol
With 1 of gained in embodiment 24 and 25,2 and 3-(S)-1-phenylethylamine sodium sulfonate (22.3g, 100mmol) and NaOH (40g 1mol) is dissolved in (70mL) in the less water, be heated to 120 ℃ with the water evaporate to dryness, continue to be warming up to 280 ℃, system enters molten state again, continues reaction 5 minutes, stop heating, naturally cool to room temperature, add water (200mL), transfer PH to 9 with the 6N hydrochloric acid soln, use ethyl acetate (3 * 200mL) extractions then, after organic phase merges, with saturated aqueous common salt (2 * 200mL) washings, anhydrous sodium sulfate drying, concentrate, column chromatography for separation gets 3-(1-(S)-amido ethyl)-phenol (7.54g, 55%).
The preparation of embodiment 28 3-(1-(S)-(N, N-dimethyl amido) ethyl)-phenol
Take by weighing 3-(1-(the S)-amido ethyl)-phenol (11.0g of gained among the embodiment 27,80mmol), the ice-water bath cooling down, adding formic acid (12.6g, 240mmol) with formaldehyde 15.7g (200mmol), heating reflux reaction 12 hours, be cooled to room temperature, hydrochloric acid with 5N transfers to PH to 2~3, and (impurity is removed in 3 * 100mL) extractions, and water transfers to PH to 9~10 with the NaOH solution of 5N with ethyl acetate, (3 * 200mL) extract to use ethyl acetate again, organic phase merges, and the water washing of usefulness saturated common salt (2 * 500mL), anhydrous sodium sulfate drying, solvent removed in vacuo, get 3-(1-(S)-(N, N-dimethyl amido) ethyl)-phenol (10.4g, 79%).
The preparation of embodiment 29 3-(1-(S)-(N, N-dimethyl amido) ethyl)-phenolate hydrochlorate
With the dense H of 25.5mL
2SO
4Be dissolved in the 75mL water, the ice-water bath cooling adds 3-(1-(S)-(N, N-dimethyl amido) ethyl)-aniline down, and (12.15g 74mmol), maintains the temperature at during dropping below 25 ℃, drips the back and continues stirring at room 30 minutes.Then reaction system is bathed cooling with cryosel, drip Sodium Nitrite (5.85g, 30mL aqueous solution 84.75mmol), keep temperature of reaction system below 5 ℃ during dropping, after dropwising, under cryosel bath cooling, continue to stir 1 hour, get a faint yellow diazonium salt solution.Then, this faint yellow diazonium salt solution is dropped in the mixing solutions of water of 120 ℃ the 30mL vitriol oil and 15mL, controlled temperature is at 120-125 ℃, after dropwising, be cooled to room temperature, being neutralized to pH value with the NaOH solution of 5N is 9~10, and (3 * 200mL) extractions are after organic phase merges with chloroform, with saturated aqueous common salt (2 * 200mL) washings, anhydrous sodium sulfate drying to about 200mL, led to HCl gas 30 minutes with the system vacuum concentration.Concentrate faint yellow solid 3-(1-(S)-(N, N-dimethyl amido) ethyl)-phenolate hydrochlorate (12.7g, 85%).
Claims (10)
1. (S)-N-ethyl-N-methyl-3-[1-(dimethylamino) ethyl]-phenyl carbamate
(I) preparation method, this method adopt structural formula to be
(III) compound or its salt and phosgene, trichloromethylchloroformate or triphosgene are under the alkaline matter effect, and reaction obtains compound in inert solvent
(IV), the not purified direct and N-methyl-N-ethylamine prepared in reaction compound (I) in inert solvent of compound (IV).
2. the method for claim 1, wherein said formula (III) compound or its salt makes through following reaction:
D. compound (6) carries out diazotization reaction with nitrite under acidic conditions, and hydrolysis obtains compound (III) then;
E. as required, compound (III) is transformed into corresponding alkali salt or hydrochlorate.
3. the method for claim 1, wherein said formula (III) compound or its salt makes through following reaction:
A. compound (3) prepared in reaction compound (4) under the aminomethylation condition;
B. compound (4) and acylating reagent the Louis calculate or protonic acid in the presence of prepared in reaction compound (7)
Wherein R is ethanoyl, propionyl, benzoyl or phenylacetyl;
Wherein R is ethanoyl, propionyl, benzoyl or phenylacetyl;
D. compound (8) obtains compound (III) through hydrolysis;
E. as required, compound (III) is transformed into corresponding alkali salt or hydrochlorate.
4. the method for claim 1, wherein said compound (III) or its salt carry out through following reaction,
A. compound (3) reacts under the aminomethylation condition and makes compound (4);
C. compound (9) alkali fusion under sodium hydroxide and/or potassium hydroxide or both any mixture effects obtains compound (III)
D. as required, compound (III) is transformed into corresponding alkali salt or hydrochlorate.
5. the method for claim 1, wherein said compound (III) or its salt carry out through following reaction,
B. compound (11) alkali fusion in the presence of sodium hydroxide and/or potassium hydroxide makes compound (12)
C. compound (12) reacts under the aminomethylation condition and makes compound (III);
D. as required, compound (III) is transformed into corresponding alkali salt or hydrochlorate.
6. as the described method of the arbitrary claim of claim 2-3; wherein said compound (3) introduces nitro with the nitrating agent reaction earlier or acyl group is introduced in the acylating reagent reaction; products therefrom again with the aminomethylation reagent react, wherein acyl group is ethanoyl, propionyl, benzoyl or phenylacetyl.
7. the method for claim 1, wherein said alkaline matter is: the mineral alkali that is selected from yellow soda ash, salt of wormwood, sodium amide, sodium hydride, potassium hydride KH; Be selected from the alkali metal alcohol compound of sodium methylate, sodium ethylate, potassium tert.-butoxide; Or be selected from the organic bases of triethylamine, pyridine, quinoline, diisopropyl ethyl amine.
8. the method for claim 1 is wherein carried out from being reflected at the alkaline matter of compound (IV) preparation compound (I), and described alkaline matter is: the mineral alkali that is selected from yellow soda ash, salt of wormwood, sodium amide, sodium hydride; Be selected from the alkali metal alcohol compound of sodium methylate, sodium ethylate, potassium tert.-butoxide; Or be selected from the organic bases of triethylamine, pyridine, quinoline, diisopropyl ethyl amine.
9. the method for claim 1, wherein be: the ether that is selected from tetrahydrofuran (THF), ether, glycol dimethyl ether, dioxan from the used described inert solvent of reaction of compound (III) preparation compound (IV); Be selected from the aromatic hydrocarbon of benzene,toluene,xylene; Or acetone; And, from the used described inert solvent of reaction of compound (IV) preparation compound (I) be: the lower alcohol that is selected from methyl alcohol, ethanol, propyl alcohol, butanols; Be selected from the ether of tetrahydrofuran (THF), ether, glycol dimethyl ether, dioxan; Be selected from the aromatic hydrocarbon of benzene, toluene, ethylbenzene; Be selected from the halohydrocarbon of methylene dichloride, trichloromethane, ethylene dichloride; Dimethyl formamide; N,N-DIMETHYLACETAMIDE; Or acetone.
10. the method for claim 1, compound (I) can with L-(+)-tartrate (V) prepared in reaction compound (II).
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB200510029393XA CN100391938C (en) | 2005-09-02 | 2005-09-02 | Preparation method of phenyl (S)-N-ethyl-N-methyl-3-[1-(dimethyamino)ethyl]-amidoformate (I) and tartrate thereof (II) |
PCT/CN2006/002246 WO2007025481A1 (en) | 2005-09-02 | 2006-09-01 | Process for preparing (s)-n-ethyl-n-methyl-3-[1-(dimethylamino) ethyl]-phenyl carbamate and tartrate thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNB200510029393XA CN100391938C (en) | 2005-09-02 | 2005-09-02 | Preparation method of phenyl (S)-N-ethyl-N-methyl-3-[1-(dimethyamino)ethyl]-amidoformate (I) and tartrate thereof (II) |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1923801A CN1923801A (en) | 2007-03-07 |
CN100391938C true CN100391938C (en) | 2008-06-04 |
Family
ID=37808476
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB200510029393XA Expired - Fee Related CN100391938C (en) | 2005-09-02 | 2005-09-02 | Preparation method of phenyl (S)-N-ethyl-N-methyl-3-[1-(dimethyamino)ethyl]-amidoformate (I) and tartrate thereof (II) |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN100391938C (en) |
WO (1) | WO2007025481A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105439906A (en) * | 2015-12-08 | 2016-03-30 | 哈药集团三精制药有限公司 | Method for synthesizing rivastigmine hydrogen tartrate |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008124969A1 (en) * | 2007-04-16 | 2008-10-23 | Topharman Shanghai Co., Ltd. | Preparation method of rivastigmine and its intermediates |
US7884121B2 (en) | 2007-06-11 | 2011-02-08 | Apotex Pharmachem Inc. | Process for the preparation of phenylcarbamates |
CN101580482B (en) * | 2009-05-27 | 2014-04-23 | 沈阳药科大学 | Method for preparing rivastigmine hydrogen tartrate and application thereof |
CN102786441B (en) | 2011-05-18 | 2013-11-13 | 浙江海正药业股份有限公司 | Preparation method of rivastigmine, intermediates and preparation method of intermediates |
CN103073456B (en) * | 2011-10-26 | 2014-03-19 | 连云港润众制药有限公司 | Preparation method for rivastigmine intermediate |
CN113951332A (en) * | 2021-10-25 | 2022-01-21 | 安徽省华银茶油有限公司 | Preparation method of edible oleogel based on camellia seed oil |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004037771A1 (en) * | 2002-10-24 | 2004-05-06 | Zentiva, A.S. | A method of production of (-)-(s)-3-[1-(dimethylamino)ethyl]phenyl-n-ethyl-n-methylcarbamate |
GB2409453A (en) * | 2003-12-24 | 2005-06-29 | Generics | Process for the preparation of aminoalkyl phenylcarbamates |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060223826A1 (en) * | 2002-11-19 | 2006-10-05 | Takeda Pharmaceutical Company Limited Intellectual Property Department | Indole derivatives as somatostatin agonists or antagonists |
CN1206210C (en) * | 2003-07-31 | 2005-06-15 | 上海三维制药有限公司 | Ethyl methyl 3-[(1s)-1-(dimethylamino) ethyl] phenyl carbamate and its prepn and medicine use |
GB0329284D0 (en) * | 2003-12-18 | 2004-01-21 | Avecia Ltd | Process |
-
2005
- 2005-09-02 CN CNB200510029393XA patent/CN100391938C/en not_active Expired - Fee Related
-
2006
- 2006-09-01 WO PCT/CN2006/002246 patent/WO2007025481A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004037771A1 (en) * | 2002-10-24 | 2004-05-06 | Zentiva, A.S. | A method of production of (-)-(s)-3-[1-(dimethylamino)ethyl]phenyl-n-ethyl-n-methylcarbamate |
GB2409453A (en) * | 2003-12-24 | 2005-06-29 | Generics | Process for the preparation of aminoalkyl phenylcarbamates |
Non-Patent Citations (2)
Title |
---|
GB-2409453 A 2005.06.29 |
WO-2004037771 A1 2004.05.06 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105439906A (en) * | 2015-12-08 | 2016-03-30 | 哈药集团三精制药有限公司 | Method for synthesizing rivastigmine hydrogen tartrate |
Also Published As
Publication number | Publication date |
---|---|
WO2007025481A1 (en) | 2007-03-08 |
CN1923801A (en) | 2007-03-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100391938C (en) | Preparation method of phenyl (S)-N-ethyl-N-methyl-3-[1-(dimethyamino)ethyl]-amidoformate (I) and tartrate thereof (II) | |
CN113880903B (en) | Preparation method of monabivalir | |
RU2393148C2 (en) | Method for synthesis of (s)-3-[(1-dimethylamino)ethyl]-phenyl-n-ethyl-n-methyl-carbamate | |
CN102503805B (en) | Method for preparing 4-felbinac through rearrangement reaction | |
CN110183357B (en) | Preparation method for preparing Sacubitril intermediate | |
CN101302207B (en) | Preparation of 3-o-alkyl-5,6-o-(1-methyl ethylidine)-l-ascorbic acid and preparation of 5,6-o-(1- methyl ethylidine)-l- ascorbic acid | |
US5900501A (en) | Process for the continuous production of aryl carbonates | |
CN102249921A (en) | 2-(2,3-dimethyl phenyl) diester malonate, preparation method thereof, and application thereof | |
CN116514704B (en) | Rafenacin intermediate and preparation method thereof | |
CN102690194A (en) | Preparation method of 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid | |
CN102477051A (en) | Technology for preparing key intermediate of telbivudine | |
CN102180773B (en) | Method for preparing resveratrol | |
CN101348475B (en) | Novel method for synthesizing orlistat, intermediate compound and preparation thereof | |
CN102516215B (en) | Preparation method of C-glucoside containing saturated cyclohexane structure | |
CN102344431A (en) | Method for preparing nebivolol hydrochloride | |
CN101410369A (en) | Process for the preparation of tamsulosin and related compounds | |
CN101575348A (en) | Method for synthesizing beta-sodium glycero-phosphate | |
CN102731328A (en) | Preparation method of bupropion hydrochloride | |
CN102675294A (en) | Method of synthesizing losartan and losartan intermediates | |
CN106831863A (en) | Montelukast sodium intermediate and its preparation method and application | |
CN101792451A (en) | Full synthesis method of 4'',5''-dihydroxyl-5-methoxyl-[6'',6''-dimethyl pyran (2'',3'':7,8)] Hirtellanine A | |
CN101723841B (en) | Preparation method of 2-amino-5-alkoxy propiophenone | |
ITMI20011772A1 (en) | PROCESS FOR THE PREPARATION OF 2,5-BIS- (2,2,2-TRIFLUOROETOSSI) -N- (2-PIPERIDILMETIL) -BENZAMIDE (FLECAINIDE) | |
CN108383720A (en) | A kind of neighbour's substituted benzoic acid meta position chlorination | |
CN111943950B (en) | Preparation method of rilibatan |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080604 Termination date: 20140902 |
|
EXPY | Termination of patent right or utility model |