CN101362708B - Synthesis method of tert-butyl-[2-(biphenyl-4-yl)-1-(hydroxymethyl)ethyl] carbamate - Google Patents
Synthesis method of tert-butyl-[2-(biphenyl-4-yl)-1-(hydroxymethyl)ethyl] carbamate Download PDFInfo
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Abstract
The invention discloses a synthesis method of a pharmaceutical intermediate of tertiary butyl-(2-(biphenyl-4-yl)-1-(methylol) ethyl) carbamate, which comprises the steps that: diethyl acetamidornalonate and 4-substituent biphenyl are taken as initial raw materials and undergone six steps of reactions including condensation, decarboxylation, hydrolysis, reduction and acylation to obtain the tertiary butyl-(2-(biphenyl-4-yl)-1-(methylol) ethyl) carbamate. The method of the invention has the advantages of available raw materials, convenient operation, high reaction yield rate, recoverable solvents used in the synthesis course, thereby reducing environmental pollution and greatly reducing production cost; according to test results, the products obtained by the method has reliable quality and stable performance.
Description
(1) technical field
The present invention relates to the compound method of a kind of pharmaceutical intermediate tertiary butyl-[2-(biphenyl-4-yl)-1-(methylol) ethyl] carbamate.
(2) background technology
The tertiary butyl-[2-(biphenyl-4-yl)-1-(methylol) ethyl] carbamate is a kind of important midbody, is widely used in a plurality of fields such as medicine, agricultural chemicals and chemical industry.(European Journal of Medicinal Chemistry 40 (2005) 563-581) such as Antonio Vamavas possess some special knowledge to the midbody compound (III) of this material is synthetic; React in the presence of sodium ethylate by acetamino diethyl malonate and 4-bromomethylbiphenyl and to obtain compound (III); Adopt the method for hydrochloric acid hydrolysis decarboxylation in the document, stronger to equipment corrosion.In addition; The method of reducing document of compound V (European Journal of Medicinal Chemistry 40 (2005) 563-581) adopts expensive lithium aluminum hydride reagent; Need harsh reaction conditionss such as strict anhydrous, anaerobic, production unit is required very high, operational difficulty during aftertreatment; And produce a large amount of hydrogen, there is potential safety hazard.
Method by compound (III) synthetic compound (VIII) does not still have bibliographical information.
(3) summary of the invention
The technical problem that the present invention will solve is to provide a kind of yield height, cost is low, environmental protection pressure is little, the method for synthesizing tertiary butyl-[2-(biphenyl-4-yl)-1-(methylol) ethyl] carbamate of suitable suitability for industrialized production.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
Compound method suc as formula the tertiary butyl shown in (VIII)-[2-(biphenyl-4-yl)-1-(methylol) ethyl] carbamate comprises the steps:
Steps A: the 4-substituted biphenyl shown in kharophen malonic ester shown in the formula (I) and the formula (II) is carried out condensation reaction obtain compound (III) under the effect of alkali metal alcoholate;
Step B: compound (III) obtains compound (IV) through decarboxylic reaction under the effect of mineral alkali;
Step C: compound (IV) obtains compound (V) with Fatty Alcohol(C12-C14 and C12-C18) C through esterification in the presence of acylating reagent;
Step D: compound (V) obtains compound (VI) through reduction reaction under hydroborate-aluminum chloride effect;
Step e: the tert-Butyl dicarbonate shown in compound (VI) and the formula (VII) obtains the tertiary butyl shown in the formula (VIII)-[2-(biphenyl-4-yl)-1-(methylol) ethyl] carbamate through condensation under the alkali effect;
Reaction equation is following:
In formula (I), formula (III) or the formula V, R
1, R
2, R
3Independently be selected from straight or branched alkyl or the benzyl of C1～C6 separately; X is selected from C1, I or OSO in the formula (II)
2R ', said R ' are selected from alkyl or the p-methylphenyl of C1～C5.
Particularly, described compound method is carried out according to following steps:
Steps A: condensation reaction
In Fatty Alcohol(C12-C14 and C12-C18) A, add basic metal, the frozen water cooling is stirred; Basic metal is dissolved fully, add kharophen malonic ester (I), in 20～65 ℃ of reactions 0.5～3 hour; Add 4-substituted biphenyl (II) in 30～60 ℃ of reactions 20～30 hours, add water, the cooling crystallization; Suction filtration, drying obtains compound (III);
Step B: decarboxylic reaction
In reaction vessel, add compound (III), mineral alkali, pure water, Fatty Alcohol(C12-C14 and C12-C18) B, stir, heating reflux reaction 15～30 hours is neutralized to pH=1～2 with acid, stirring and crystallizing, and suction filtration, drying obtains compound (IV);
Step C: esterification
(IV) is dissolved among the Fatty Alcohol(C12-C14 and C12-C18) C with compound, is cooled to below 10 ℃, drips acylating reagent, dropwises temperature rising reflux reaction 20～50 hours, concentrate, and the cooling crystallization, suction filtration, drying obtains compound (V);
Step D: reduction reaction
In aprotic solvent, add aluminum chloride, temperature is controlled at below 5 ℃, adds hydroborate, and the back that stirs adds compound (V), finishes in 20～40 hours in 0～25 ℃ of reaction, obtains compound (VI) through aftertreatment D; Described aftertreatment D adopts following method: under ice-water bath; Slowly drip the shrend reaction of going out, concentrate to steam and remove aprotic solvent, adding first alcohol and water; The consumption of the methyl alcohol that is added is 1～5 times of compound (V) quality; Preferred 1～3 times, the water yield that is added is 3～10 times of aluminum chloride quality, preferred 5～8 times; Finish temperature rising reflux and dissolve clearly, the cooling crystallization, suction filtration, drying obtains compound (VI);
Step e: condensation reaction
Compound (VI) and organic solvent are stirred, under 0～10 ℃, drip alkali and tert-Butyl dicarbonate (VII) simultaneously, dropwise, finished in 12～30 hours, obtain target compound (VIII) through aftertreatment E 0～30 ℃ of reaction; Described aftertreatment E adopts following steps: the suction filtration desalination, and concentrated steaming desolventizes, and adds the extraction of methylene dichloride and water; Organic phase is through anhydrous sodium sulfate drying, and the back is steamed and removed methylene dichloride, and adding consumption is 2～4 times methyl alcohol of compound (VI) quality and the mixed solution of normal heptane (wherein methyl alcohol and normal heptane volume ratio 1:6～10); Heating up, it is clear to dissolve, cooling crystallization, suction filtration; Drying gets target compound (VIII).
Specify in the face of each step reaction down.
Described Fatty Alcohol(C12-C14 and C12-C18) A, Fatty Alcohol(C12-C14 and C12-C18) B, Fatty Alcohol(C12-C14 and C12-C18) C independently are selected from the Fatty Alcohol(C12-C14 and C12-C18) of C1-C5 separately, specifically are selected from one of following: methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, sec-butyl alcohol, the trimethyl carbinol, Pentyl alcohol.
Basic metal described in the steps A is sodium, potassium or lithium, preferred sodium.
The amount of substance that feeds intake in the steps A is than acetamino diethyl malonate (I): basic metal: 4-substituted biphenyl (II): Fatty Alcohol(C12-C14 and C12-C18) A is recommended as 1:1～2:0.7～1.2:8～16, preferred 1:1.1～1.2:0.90～0.95:10～12.
The said reaction conditions of steps A is preferably: add kharophen malonic ester (I) back prior to 30～35 ℃ of reactions 1～1.5 hour, add 4-substituted biphenyl (II) then in 45～50 ℃ of reactions 12～15 hours.
It is one of following that mineral alkali described in the step B specifically can be selected from: Lithium Hydroxide MonoHydrate, Pottasium Hydroxide, sodium hydroxide, cesium hydroxide, calcium hydroxide, Marinco H, preferred sodium hydroxide or Pottasium Hydroxide.
The described acid of step B can be mineral acid or organic acid, and it is one of following that mineral acid can be selected from: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide, preferably sulfuric acid or hydrochloric acid, more preferably hydrochloric acid.It is one of following that organic acid can be selected from: oxalic acid, Phenylsulfonic acid, p-methyl benzenesulfonic acid, acetate, formic acid.
Amount of substance feed intake among the step B than compound (III): mineral alkali: pure water: Fatty Alcohol(C12-C14 and C12-C18) B is recommended as 1:1～2:5～10:5～10, preferred 1:1～1.5:6～8:6～8.
The said reaction times of step B is preferably 10～14 hours.
It is one of following that the described acylating reagent of step C can be selected from: sulfur oxychloride, POCl3, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, two (trichloromethyl) carbonic ether.
Amount of substance feed intake among the said step C than compound (IV): acylating reagent: Fatty Alcohol(C12-C14 and C12-C18) C is recommended as 1:2～7:3～10, preferred 1:3～4:5～8.
The said reaction times of step C is preferably 30～42 hours.
It is one of following that the described aprotic solvent of step D can be selected from: THF, ether, N, dinethylformamide, glycol ether, dme, glycol dimethyl ether, 1,4-dioxane, hexanaphthene, toluene, YLENE.
It is one of following that the described hydroborate of step D is selected from: Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN, lithium borohydride, preferred POTASSIUM BOROHYDRIDE 97MIN.
Amount of substance feed intake among the said step D than compound (V): hydroborate: aluminum chloride: aprotic solvent is recommended as 1:1.2～3:1.2～3:10～15, preferred 1:1.5～2.4:1.5～2.5:12～13.
The said reaction conditions of step D is preferably: feeding intake makes after finishing 20～25 ℃ of reactions 20～25 hours.
It is one of following that the described organic solvent of step e is selected from: THF, methylene dichloride, 1,4-dioxane, N, dinethylformamide, toluene, YLENE, hexanaphthene.
The described alkali of step e can be mineral alkali or organic bases, and it is one of following that mineral alkali specifically can be selected from: yellow soda ash, salt of wormwood, saleratus, sodium hydrogencarbonate, Lithium Hydroxide MonoHydrate, sodium hydroxide, Pottasium Hydroxide, cesium hydroxide, Marinco H, calcium hydroxide.Organic bases is selected from aminated compounds, specifically can be selected from one of following: methylamine, ethamine, n n dimetylaniline, Trimethylamine 99, diethylamine, diisopropyl ethyl amine, triethylamine, TERTIARY BUTYL AMINE, pyridine, 2,6-lutidine, piperidines, morpholine.
Amount of substance feed intake in the said step e than compound (VI): alkali: tert-Butyl dicarbonate (VII): organic solvent is recommended as 1:1～3:1～2.5:3～10, preferred 1:2～2.5:1～1.6:6～8.
The said reaction conditions of step e is preferably: feeding intake makes after finishing 18～28 ℃ of reactions 20～25 hours.
Compared with prior art, beneficial effect of the present invention is embodied in:
A) prepare the synthetic of compound VIII by compound III through synthetic route according to the invention and be not in the news as yet, have that raw material is cheap and easy to get, advantages such as technology maturation, process stabilizing, easy and simple to handle and easy enforcement;
B) the present invention uses hydrolysis decarboxylation under the alkaline condition instead for the decarboxylic reaction of compound III, has reduced corrosion on Equipment.
C) for the method for reducing of compound V, the present invention adopts hydroborate-aluminum chloride system, and the lithium aluminum hydride reagent that uses in the existing technology is not only easy and simple to handle, and production cost reduces greatly, helps suitability for industrialized production.
In a word, synthetic route raw material according to the invention is cheap and easy to get, and advantage such as the maturation that possesses skills, process stabilizing, easy and simple to handle and easy enforcement, has a extensive future.
(4) embodiment
Through specific embodiment, do further bright specifically below to technical scheme of the present invention; But the present invention is not limited to these embodiment.
Synthesizing of embodiment 1 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) methyl-malonate
According to mol ratio is the kharophen methyl-malonate: 4-chloromethyl biphenyl: sodium: ethanol=1:1:1.1:10 reacts as follows:
In having the there-necked flask of drying tube, add ethanol; Be cooled to below 10 ℃; Add the 12.65g sodium Metal 99.5 in batches, treat that sodium Metal 99.5 dissolves the back fully and adds kharophen methyl-malonate 94.58g, add 4-chloromethyl biphenyl 101.34g after 2 hours 20-30 ℃ of reaction; Be warming up to 50-60 ℃ of reaction 20 hours, reaction finishes.Add water, the cooling crystallization, suction filtration, oven dry obtains 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) methyl-malonate, and analyzing content through HPLC is >=98%, yield 82% (in the kharophen methyl-malonate).
Synthesizing of embodiment 2 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate
According to mol ratio is acetamino diethyl malonate: 4-chloromethyl biphenyl: sodium: ethanol=1:1:1.1:10 reacts as follows:
In having the there-necked flask of drying tube, add ethanol; Be cooled to below 10 ℃; Add the 12.65g sodium Metal 99.5 in batches, treat that sodium Metal 99.5 dissolves the back fully and adds acetamino diethyl malonate 108.61g, add 4-chloromethyl biphenyl 101.34g after 2 hours 20-30 ℃ of reaction; Be warming up to 50-60 ℃ of reaction 20 hours, reaction finishes.Add water, the cooling crystallization, suction filtration, oven dry obtains 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate, and analyzing content through HPLC is >=98%, yield 85% (in acetamino diethyl malonate).
Synthesizing of embodiment 3 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate
According to mol ratio is acetamino diethyl malonate: biphenyl-4-ylmethyl methanesulfonates: sodium: ethanol=1:1:1.1:10 reacts as follows:
In having the there-necked flask of drying tube, add ethanol; Be cooled to below 10 ℃; Add the 12.65g sodium Metal 99.5 in batches, treat that sodium Metal 99.5 dissolves the back fully and adds acetamino diethyl malonate 108.61g, add biphenyl-4-ylmethyl methanesulfonates 131.15g after 2 hours 20-30 ℃ of reaction; Be warming up to 50-60 ℃ of reaction 20 hours, reaction finishes.Add water, the cooling crystallization, suction filtration, oven dry obtains 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate, and analyzing content through HPLC is >=98%, yield 83% (in acetamino diethyl malonate).
Synthesizing of embodiment 4 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate
According to mol ratio is acetamino diethyl malonate: biphenyl-4-bromomethylbiphenyl: sodium: ethanol=1:1:0.7:8 reacts as follows:
In having the there-necked flask of drying tube, add ethanol; Be cooled to below 10 ℃; Add the 8.05g sodium Metal 99.5 in batches, treat that sodium Metal 99.5 dissolves the back fully and adds acetamino diethyl malonate 108.61g, add biphenyl-4-bromomethylbiphenyl 123.57g after 2 hours 20-30 ℃ of reaction; Be warming up to 50-60 ℃ of reaction 20 hours, reaction finishes.Add water, the cooling crystallization, suction filtration, oven dry obtains 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate, and analyzing content through HPLC is >=98%, yield 81% (in acetamino diethyl malonate).
Synthesizing of embodiment 5 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate
According to mol ratio is acetamino diethyl malonate: biphenyl-4-bromomethylbiphenyl: sodium: ethanol=1:2:1.2:16 reacts as follows:
In having the there-necked flask of drying tube, add ethanol; Be cooled to below 10 ℃; Add the 13.80g sodium Metal 99.5 in batches, treat that sodium Metal 99.5 dissolves the back fully and adds acetamino diethyl malonate 108.61g, add biphenyl-4-bromomethylbiphenyl 247.14g after 2 hours 20-30 ℃ of reaction; Be warming up to 50-60 ℃ of reaction 30 hours, reaction finishes.Add water, the cooling crystallization, suction filtration, oven dry obtains 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate, and analyzing content through HPLC is >=98%, yield 84% (in acetamino diethyl malonate).
Synthesizing of embodiment 6 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid
According to mol ratio is 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate: sodium hydroxide: water: ethanol=1:1.1:8:8 reacts as follows:
In there-necked flask, add 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate 95.86g, sodium hydroxide 11.00g, water, ethanol, heating reflux reaction 20 hours, reaction finishes.Be cooled to 60 ℃, be neutralized to pH=1-2, the cooling crystallization with technical hydrochloric acid; Suction filtration, oven dry obtains 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid; Analyzing content through HPLC is >=99%, yield 92% (in 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate).
Synthesizing of embodiment 7 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid
According to mol ratio is 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate: sodium hydroxide: water: ethanol=1:1:5:5 reacts as follows:
In there-necked flask, add 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate 95.86g, sodium hydroxide 9.60g, water, ethanol, heating reflux reaction 15 hours, reaction finishes.Be cooled to 60 ℃, be neutralized to pH=1-2, the cooling crystallization with technical hydrochloric acid; Suction filtration, oven dry obtains 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid; Analyzing content through HPLC is >=99%, yield 91% (in 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate).
Synthesizing of embodiment 8 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid
According to mol ratio is 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate: sodium hydroxide: water: ethanol=1:2:10:10 reacts as follows:
In there-necked flask, add 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate 95.86g, sodium hydroxide 19.20g, water, ethanol, heating reflux reaction 30 hours, reaction finishes.Be cooled to 60 ℃, be neutralized to pH=1-2, the cooling crystallization with technical hydrochloric acid; Suction filtration, oven dry obtains 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid; Analyzing content through HPLC is >=99%, yield 96% (in 2-acetylaminohydroxyphenylarsonic acid 2-(biphenyl-4-ylmethyl) ethyl malonate).
Synthesizing of embodiment 9 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride
According to mol ratio is 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid: sulfur oxychloride: methyl alcohol=1:3:8 reacts as follows:
In there-necked flask, add 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid 70.83g and methyl alcohol, be cooled to below 10 ℃, dripping thionyl chloride 89.23g, the control dropping temperature is below 10 ℃, dropwises temperature rising reflux reaction 30 hours, reaction finishes.Concentration of reaction solution, the cooling crystallization, suction filtration, oven dry obtains 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride, and analyzing content through HPLC is >=99%, yield 92% (in 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid).
Synthesizing of embodiment 10 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride
According to mol ratio is 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid: sulfur oxychloride: methyl alcohol=1:2:3 reacts as follows:
In there-necked flask, add 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid 70.83g and methyl alcohol, be cooled to below 10 ℃, dripping thionyl chloride 59.48g, the control dropping temperature is below 10 ℃, dropwises temperature rising reflux reaction 20 hours, reaction finishes.Concentration of reaction solution, the cooling crystallization, suction filtration, oven dry obtains 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride, and analyzing content through HPLC is >=99%, yield 89% (in 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid).
Synthesizing of embodiment 11 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride
According to mol ratio is 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid: sulfur oxychloride: methyl alcohol=1:7:10 reacts as follows:
In there-necked flask, add 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid 70.83g and methyl alcohol, be cooled to below 10 ℃, dripping thionyl chloride 208.19g, the control dropping temperature is below 10 ℃, dropwises temperature rising reflux reaction 50 hours, reaction finishes.Concentration of reaction solution, the cooling crystallization, suction filtration, oven dry obtains 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride, and analyzing content through HPLC is >=99%, yield 95% (in 2-acetylaminohydroxyphenylarsonic acid 3-(biphenyl-4-yl) propionic acid).
Synthesizing of embodiment 12 2-amino-3-(biphenyl-4-yl)-1-propylated hydrochlorate
According to mol ratio is 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride: Peng Qinghuana: aluminum chloride: THF=1:2:2:15 reacts as follows:
In there-necked flask, drop into THF, be cooled to 0～5 ℃, slowly successively add aluminum trichloride (anhydrous) 66.67g and Peng Qinghuana 18.93g; After stirring; Add 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride 72.94g, 20-25 ℃ was reacted 20 hours, and reaction finishes.Reaction solution frozen water cooling slowly drips the shrend reaction of going out, and concentrated steaming desolventizes; Add 150ml methyl alcohol and 400ml water, temperature rising reflux dissolves clear, the cooling crystallization; Suction filtration, drying obtains 2-amino-3-(biphenyl-4-yl)-1-propylated hydrochlorate; Analyzing content through HPLC is >=99%, yield 95% (in 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride).
Synthesizing of embodiment 13 2-amino-3-(biphenyl-4-yl)-1-propylated hydrochlorate
According to mol ratio is 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride: Peng Qinghuana: aluminum chloride: THF=1:1.2:1.2:10 reacts as follows:
In there-necked flask, drop into THF, be cooled to 0～5 ℃, slowly successively add aluminum trichloride (anhydrous) 37.33g and Peng Qinghuana 10.59g; After stirring; Add 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride 72.94g, 20-25 ℃ was reacted 20 hours, and reaction finishes.Reaction solution frozen water cooling slowly drips the shrend reaction of going out, and concentrated steaming desolventizes; Add 73ml methyl alcohol and 190ml water, temperature rising reflux dissolves clear, the cooling crystallization; Suction filtration, drying obtains 2-amino-3-(biphenyl-4-yl)-1-propylated hydrochlorate; Analyzing content through HPLC is >=99%, yield 90% (in 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride).
Synthesizing of embodiment 14 2-amino-3-(biphenyl-4-yl)-1-propylated hydrochlorate
According to mol ratio is 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride: Peng Qinghuana: aluminum chloride: THF=1:3:3:15 reacts as follows:
In there-necked flask, drop into THF, be cooled to 0～5 ℃, slowly successively add aluminum trichloride (anhydrous) 96.01g and Peng Qinghuana 27.25g; After stirring; Add 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride 72.94g, 20-25 ℃ was reacted 40 hours, and reaction finishes.Reaction solution frozen water cooling slowly drips the shrend reaction of going out, and concentrated steaming desolventizes; Add 220ml methyl alcohol and 780ml water, temperature rising reflux dissolves clear, the cooling crystallization; Suction filtration, drying obtains 2-amino-3-(biphenyl-4-yl)-1-propylated hydrochlorate; Analyzing content through HPLC is >=99%, yield 97% (in 2-amino-3-(biphenyl-4-yl) methyl propionate hydrochloride).
Synthesizing of embodiment 15 tertiary butyls-[2-(biphenyl-4-yl)-1-(methylol) ethyl] carbamate
According to mol ratio is 2-amino-3-(biphenyl-4-yl)-1-propylated hydrochlorate: sodium hydroxide: tert-Butyl dicarbonate: THF=1:1.3:1.3:5 reacts as follows:
In there-necked flask, add 2-amino-3-(biphenyl-4-yl)-1-propylated hydrochlorate 65.94g and THF, stir, be cooled to below 10 ℃; Drip 10% sodium hydroxide solution, drip tert-Butyl dicarbonate 70.93g simultaneously, dropwise; 20-25 ℃ was reacted 20 hours, and reaction finishes.Reacting liquid filtering, filtrating concentrating steam and remove THF, use dichloromethane extraction; Extraction liquid concentrates to steam and removes methylene dichloride behind anhydrous sodium sulfate drying, adds methyl alcohol and normal heptane 130ml (pressing v:v=1:6) altogether; Heating up, it is clear to dissolve, cooling crystallization, suction filtration; Drying gets the target compound tertiary butyl-[2-(biphenyl-4-yl)-1-(methylol) ethyl] carbamate.Analyzing content through HPLC is >=99%, yield 85% (in 2-amino-3-(biphenyl-4-yl)-1-propylated hydrochlorate).
Synthesizing of embodiment 16 tertiary butyls-[2-(biphenyl-4-yl)-1-(methylol) ethyl] carbamate
According to mol ratio is 2-amino-3-(biphenyl-4-yl)-1-propylated hydrochlorate: sodium hydroxide: tert-Butyl dicarbonate: THF=1:1:1:3 reacts as follows:
In there-necked flask, add 2-amino-3-(biphenyl-4-yl)-1-propylated hydrochlorate 65.94g and THF, stir, be cooled to below 10 ℃; Drip 10% sodium hydroxide solution, drip tert-Butyl dicarbonate 52.35g simultaneously, dropwise; 20-25 ℃ was reacted 12 hours, and reaction finishes.Reacting liquid filtering, filtrating concentrating steam and remove THF, use dichloromethane extraction; Extraction liquid concentrates to steam and removes methylene dichloride behind anhydrous sodium sulfate drying, adds methyl alcohol and normal heptane 210ml (pressing v:v=1:8) altogether; Heating up, it is clear to dissolve, cooling crystallization, suction filtration; Drying gets the target compound tertiary butyl-[2-(biphenyl-4-yl)-1-(methylol) ethyl] carbamate.Analyzing content through HPLC is >=99%, yield 80% (in 2-amino-3-(biphenyl-4-yl)-1-propylated hydrochlorate).
Synthesizing of embodiment 17 tertiary butyls-[2-(biphenyl-4-yl)-1-(methylol) ethyl] carbamate
According to mol ratio is 2-amino-3-(biphenyl-4-yl)-1-propylated hydrochlorate: sodium hydroxide: tert-Butyl dicarbonate: THF=1:3:2.5:10 reacts as follows:
In there-necked flask, add 2-amino-3-(biphenyl-4-yl)-1-propylated hydrochlorate 65.94g and THF, stir, be cooled to below 10 ℃; Drip 10% sodium hydroxide solution, drip tert-Butyl dicarbonate 130.95g simultaneously, dropwise; 20-25 ℃ was reacted 30 hours, and reaction finishes.Reacting liquid filtering, filtrating concentrating steam and remove THF, use dichloromethane extraction; Extraction liquid concentrates to steam and removes methylene dichloride behind anhydrous sodium sulfate drying, adds methyl alcohol and normal heptane 210ml (pressing v:v=1:10) altogether; Heating up, it is clear to dissolve, cooling crystallization, suction filtration; Drying gets the target compound tertiary butyl-[2-(biphenyl-4-yl)-1-(methylol) ethyl] carbamate.Analyzing content through HPLC is >=99%, yield 90% (in 2-amino-3-(biphenyl-4-yl)-1-propylated hydrochlorate).
Claims (10)
1. suc as formula the compound method of the tertiary butyl shown in (VIII)-[2-(biphenyl-4-yl)-1-(methylol) ethyl] carbamate, it is characterized in that described compound method comprises the steps:
Steps A: the 4-substituted biphenyl shown in kharophen malonic ester shown in the formula (I) and the formula (II) is carried out condensation reaction obtain compound (III) under the alkali metal alcoholate effect;
Step B: compound (III) obtains compound (IV) through decarboxylic reaction under the effect of mineral alkali;
Step C: compound (IV) obtains compound (V) with Fatty Alcohol(C12-C14 and C12-C18) C through esterification in the presence of acylating reagent;
Step D: compound (V) obtains compound (VI) through reduction reaction under hydroborate-aluminum chloride effect;
Step e: the tert-Butyl dicarbonate shown in compound (VI) and the formula (VII) obtains the tertiary butyl shown in the formula (VIII)-[2-(biphenyl-4-yl)-1-(methylol) ethyl] carbamate through condensation under the alkali effect;
Reaction equation is following:
In formula (I), formula (III) or the formula V, R
1, R
2, R
3Independently be selected from straight or branched alkyl or the benzyl of C1～C6 separately; X is selected from C1, I or OSO in the formula (II)
2R ', said R ' are selected from alkyl or the p-methylphenyl of C1～C5.
2. compound method as claimed in claim 1 is characterized in that described compound method specifically carries out according to following steps:
Steps A:
In Fatty Alcohol(C12-C14 and C12-C18) A, add basic metal, the frozen water cooling is stirred; Basic metal is dissolved fully, add kharophen malonic ester (I), in 20～65 ℃ of reactions 0.5～3 hour; Add 4-substituted biphenyl (II) in 30～60 ℃ of reactions 20～30 hours, add water, the cooling crystallization; Suction filtration, drying obtains compound (III); Feed intake amount of substance than kharophen malonic ester (I): basic metal: 4-substituted biphenyl (II): Fatty Alcohol(C12-C14 and C12-C18) A is 1:1～2:0.7～1.2:8～16;
Step B:
In reaction vessel, add compound (III), mineral alkali, pure water, Fatty Alcohol(C12-C14 and C12-C18) B, stir, heating reflux reaction 15～30 hours is neutralized to pH1～2 with acid, the cooling crystallization, and suction filtration, drying obtains compound (IV); Feed intake amount of substance than compound (III): mineral alkali: water: Fatty Alcohol(C12-C14 and C12-C18) B is 1:1～2:5～10:5～10;
Step C:
(IV) is dissolved among the Fatty Alcohol(C12-C14 and C12-C18) C with compound, is cooled to below 10 ℃, drips acylating reagent, dropwises temperature rising reflux reaction 20～50 hours, concentrate, and the cooling crystallization, suction filtration, drying obtains compound (V); Feed intake amount of substance than compound (IV): acylating reagent: Fatty Alcohol(C12-C14 and C12-C18) C is 1:2～7:3～10;
Step D:
In aprotic solvent, add aluminum chloride, temperature is controlled at below 5 ℃, adds hydroborate, and the back that stirs adds compound (V), finishes in 20～40 hours in 0～25 ℃ of reaction, obtains compound (VI) through aftertreatment D; Feed intake amount of substance than compound (V): hydroborate: aluminum chloride: aprotic solvent is 1:1.2～3:1.2～3:10～15;
Step e:
Compound (VI) and organic solvent are stirred, under 0～10 ℃, drip alkali and tert-Butyl dicarbonate (VII) simultaneously, dropwise, finished in 12～30 hours, obtain target compound (VIII) through aftertreatment E 0～30 ℃ of reaction; Feed intake amount of substance than compound (VI): alkali: tert-Butyl dicarbonate (VII): organic solvent is 1:1～3:1～2.5:3～10.
3. compound method as claimed in claim 2 is characterized in that described Fatty Alcohol(C12-C14 and C12-C18) A, Fatty Alcohol(C12-C14 and C12-C18) B, Fatty Alcohol(C12-C14 and C12-C18) C independently are selected from the Fatty Alcohol(C12-C14 and C12-C18) of C1-C5 separately.
4. the method for synthetic biphenol compound as claimed in claim 2 is characterized in that the described basic metal of steps A is sodium, potassium or lithium.
5. the method for synthetic biphenol compound as claimed in claim 2, it is one of following to it is characterized in that the described mineral alkali of step B is selected from: Lithium Hydroxide MonoHydrate, Pottasium Hydroxide, sodium hydroxide, cesium hydroxide, calcium hydroxide, Marinco H.
6. the method for synthetic biphenol compound as claimed in claim 2, it is one of following to it is characterized in that the described acylating reagent of step C is selected from: sulfur oxychloride, POCl3, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, two (trichloromethyl) carbonic ether.
7. the method for synthetic biphenol compound as claimed in claim 2; It is one of following to it is characterized in that the described aprotic solvent of step D is selected from: THF, ether, N; Dinethylformamide, diglyme, glycol dimethyl ether, 1,4-dioxane, hexanaphthene, toluene, YLENE.
8. the method for synthetic biphenol compound as claimed in claim 2, it is one of following to it is characterized in that the described hydroborate of step D is selected from: Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN, lithium borohydride.
9. the method for synthetic biphenol compound as claimed in claim 2, it is one of following to it is characterized in that the described organic solvent of step e is selected from: THF, methylene dichloride, 1,4-dioxane, N, dinethylformamide, toluene, YLENE, hexanaphthene.
10. the method for synthetic biphenol compound as claimed in claim 2; It is one of following to it is characterized in that the described alkali of step e is selected from: yellow soda ash, salt of wormwood, saleratus, sodium hydrogencarbonate, Lithium Hydroxide MonoHydrate, sodium hydroxide, Pottasium Hydroxide, cesium hydroxide, Marinco H, calcium hydroxide, methylamine, ethamine, n n dimetylaniline, Trimethylamine 99, diethylamine, diisopropyl ethyl amine, triethylamine, TERTIARY BUTYL AMINE, pyridine, 2,6-lutidine, piperidines, morpholine.
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| AR092278A1 (en) * | 2012-08-31 | 2015-04-08 | Novartis Ag | PROCESS FOR OBTAINING N-ACILIC DERIVATIVES OF BIFENYL-ALANINE AND RELATED INTERMEDIARIES |
| CN103113247B (en) * | 2013-03-13 | 2014-05-14 | 苏州大学 | Method for preparing amino-acid ester |
| AU2014310569A1 (en) * | 2013-08-21 | 2016-02-18 | Patheon Austria Gmbh & Co Kg | Synthesis of biphenylalaninol via novel intermediates |
| JPWO2015037460A1 (en) * | 2013-09-10 | 2017-03-02 | 住友化学株式会社 | Process for producing optically active 3- (biphenyl-4-yl) -2-[(t-butoxycarbonyl) amino] propan-1-ol |
| CN104725256B (en) * | 2015-02-11 | 2018-03-16 | 威海迪素制药有限公司 | A kind of preparation method of biphenylalanine derivative |
| WO2016199688A1 (en) * | 2015-06-10 | 2016-12-15 | 住友化学株式会社 | Method for producing carbamate compound |
| CN105017082B (en) * | 2015-07-31 | 2017-09-19 | 上海皓元医药股份有限公司 | A kind of preparation method of heart failure medicine Entresto key intermediates (R) tert-butyl group (base of 1 ([1,1` biphenyl] 4 bases) 3 hydroxy propane 2) carbamate |
| CN106467471B (en) * | 2015-08-18 | 2021-02-02 | 上海翰森生物医药科技有限公司 | Preparation method and application of high-optical-purity biphenylalanine and derivatives thereof |
| JP7138106B2 (en) * | 2016-12-23 | 2022-09-15 | ノバルティス アーゲー | A novel method for the initial sacubitril intermediate |
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| CN108383744B (en) * | 2018-02-11 | 2021-05-11 | 浙江工业大学 | Preparation method of 2, 6-dimethyl-tyrosine |
| CN113004161B (en) * | 2021-03-23 | 2023-03-28 | 康化（上海）新药研发有限公司 | Preparation method of (2R, 3R) -3-methyl-3-phenylalanine |
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