CN105801438A - Synthetic method of mirabegron intermediate - Google Patents

Synthetic method of mirabegron intermediate Download PDF

Info

Publication number
CN105801438A
CN105801438A CN201610222186.4A CN201610222186A CN105801438A CN 105801438 A CN105801438 A CN 105801438A CN 201610222186 A CN201610222186 A CN 201610222186A CN 105801438 A CN105801438 A CN 105801438A
Authority
CN
China
Prior art keywords
mirabegron
water
synthetic method
reaction
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201610222186.4A
Other languages
Chinese (zh)
Inventor
战付旭
张启龙
郑庚修
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Jinan
Original Assignee
University of Jinan
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by University of Jinan filed Critical University of Jinan
Priority to CN201610222186.4A priority Critical patent/CN105801438A/en
Publication of CN105801438A publication Critical patent/CN105801438A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups

Abstract

The invention discloses a synthetic method of a mirabegron intermediate (R)-2-(4-nitrobenzene ethyl amino)-1-phenyl ethanol hydrochloride (M-02) and belongs to the field of drug synthesis. The method comprises steps as follows: (1) R-mandelic acid and pivaloyl chloride produce a mixed anhydride intermediate (I); (2) the mixed anhydride intermediate (I) and 4-nitrobenzene ethylamine are subjected to an acrylation reaction to produce an intermediate (II); (3) a mirabegron intermediate (M-01) is obtained through hydrolysis of the intermediate (II); (4) an amido bond of the intermediate (M-01) is reduced and the mirabegron intermediate (M-02) is obtained. The reaction condition is mild, the yield is high, few impurities exist, the production cost is low, and the method is suitable for mass industrial production.

Description

A kind of synthetic method of Mirabegron intermediate
Technical field
The invention belongs to pharmaceutical synthesis field, relate to a kind of Mirabegron intermediate (R)-2-(4-nitrophenethyl ammonia Base) synthetic method of-1-phenylethanol hydrochlorate.
Background technology
In recent years, hyperactive bladder (Overactive Bladder, OAB) has become a big disease of puzzlement people Disease, has a strong impact on the quality of life of patient, mainly shows as urgent micturition, with or without urge incontinence, be often accompanied by frequent micturition Increase with nocturia.In June, 2012, U.S. FDA have approved mirabegron(Mirabegron, trade name Myrbetriq) it is used for controlling Treating adult's overactive bladder, structural formula is as follows:
。
European patent (EP1440969, EP1559427) relates to a kind of synthesis Mirabegron and intermediate (R)-2-(4-thereof Nitrophenethyl amino) synthetic method of-1-phenylethanol hydrochlorate (M-02), described method synthetic route is as follows:
。
This route first step condensation preparation Mirabegron intermediate (R)-2-hydroxy-n-(4-nitrophenethyl)-2-phenyl Acetamide (M-01) employs expensive EDCI(1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) with HOBt(N-hydroxy benzo triazole), post processing through washing, pickling, alkali cleaning, salt acid elution, and need to be entered with the toluene that toxicity is bigger Row recrystallization.Loaded down with trivial details and the raw a large amount of three wastes of this route post-processing step, and cost is high, and by-product is many.Second step reduction of amide In employ expensive monoborane-tetrahydrofuran solution and 1,3-dimethyl-imidazolinone, and reclaim difficulty, cause production High cost, monoborane-oxolane foul smelling, meet water reaction and acutely and release inflammable gas, explosive peroxidating can be formed Thing, has stimulation to eyes, skin, respiratory system, the most unfriendly to environment.Therefore, a kind of synthetic method of exploitation is simple, produce into This is the lowest, post processing simple and meets the new technology of environmental protection is the key issue that the invention solves the problems that.
The defect existed for above technology, for reducing production cost, it is to avoid use expensive EDCI and HOBt, this Invention provides a kind of reaction condition gentleness, yield is high, impurity is few, production cost is low, applicable large-scale industrial production rice draws The method of shellfish grand intermediate (R)-2-(4-nitrophenethyl amino)-1-phenylethanol hydrochlorate (M-02).
Summary of the invention
The present invention is directed to the deficiency in prior art, it is provided that a kind of Mirabegron intermediate (R)-2-(4-Nitrobenzol second Base amino) synthetic method of-1-phenylethanol hydrochlorate (M-02), its technical scheme is as follows:
S1, substitution reaction: under ice-water bath, be slowly added drop-wise to pivaloyl chloride in the solvent of R-MA, triethylamine, drip Finishing, add water temperature reaction, reaction terminates, and obtains mixed anhydride intermediate (I)；
S2, acylation reaction: under room temperature, be slowly added drop-wise in step S1 obtain the two of mixed anhydride intermediate (I) by 4-Nitrobenzol ethamine In chloromethanes/aqueous solution, drip complete reaction 2 h.Reaction terminates, and adds dilute hydrochloric acid cancellation reaction, and layering, during concentration organic facies obtains Mesosome (II)；
S3, hydrolysis: the intermediate (II) obtained in step 2 is dissolved in solvent, slowly drips NaOH under room temperature water-soluble Liquid, hydrolyzes complete intermediate (M-01), and add water crystallize afterwards, filters, and is dried, obtains intermediate (M-01), productivity 91 ~ 93%.
S4, reduction of amide: by Mirabegron intermediate (M-01), NaBH4It is dissolved in THF, under ice bath, drips Et2O·BF3, Back flow reaction, becomes salt to obtain Mirabegron intermediate (M-02), productivity 90% in isopropanol.
In step S1, described solvent is methylene chloride/water, chloroform/water, acetonitrile/water, DMF/ water, acetone/water combination In one or more, wherein preferred solvent is methylene chloride/water, and wherein the volume content of water is 10% ~ 25%, and preferred volume contains Amount is 15%；R-MA is 1.0:1.8 ~ 2.2 with the mol ratio of pivaloyl chloride, and wherein preferred molar ratio is 1.0:2.0；Reaction Temperature is 25 DEG C ~ 75 DEG C, and wherein preferable temperature is 60 ~ 65 DEG C；Response time is 2 h ~ 6 h, and wherein the preferably time is 3 h.
In step S2, mixed anhydride intermediate (I) is 1.0:0.8 ~ 1.2 with the mol ratio of 4-Nitrobenzol ethamine, the most preferably rubs That ratio is 1.0:0.95.
In step S3, the solvent described in intermediate (M-01) crystallize is in methanol/water, ethanol/water, isopropanol/water combination Much a kind of or multiple, wherein preferred compositions is methanol/water, and methanol is 1.0:5.0 ~ 15.0 with the volume ratio of water；The most preferred Volume ratio is 1.0:10.0.
In step S4, intermediate (M-01) and NaBH4With Et2O·BF3Mol ratio be 1:3:3；Reaction temperature is 50 DEG C ~ 80 DEG C, preferable reaction temperature is 70 DEG C.
The synthesis of the present invention is as follows:
。
Beneficial effects of the present invention:
Pivaloyl chloride and the R-MA that the present invention uses low price, be easy to get reacts generation mixed acid anhydride intermediate (I), then acyl Change, hydrolyze, reduce and obtain intermediate (R)-2-(4-nitrophenethyl amino)-1-phenylethanol hydrochlorate (M-02).The present invention Avoid using expensive EDCI and HOBt, reduce production cost, easy and simple to handle, post processing is simple, impurity is few.Heavily tying During crystalline substance, instead of virose toluene with water and methanol, the product purity obtained is high, and industrial operation feasibility is big, is beneficial to Large-scale industrial production.
Accompanying drawing explanation
Fig. 1 is the liquid chromatogram of the Mirabegron intermediate (M-01) that embodiment 1 obtains.
Fig. 2 is the liquid chromatogram of the Mirabegron intermediate (M-02) that embodiment 1 obtains.
Detailed description of the invention
Embodiment 1:
The preparation of intermediate (I): under mechanical agitation, in 250 mL there-necked flasks add R-MA (12.17 g, 80 Mmol, 1 eq), triethylamine (23.28 mL, 168 mmol, 2.1 eq) and dichloromethane (100 mL).Under ice bath, slowly drip Pivaloyl chloride (19.29 g, 160 mmol, 2.0 eq), maintains temperature of reaction system less than 5 DEG C, drips complete, rise to room Temperature, adds water (15 mL) and is slowly ramped to 60 DEG C of reaction 3 h, and reaction terminates, and is cooled to room temperature, obtains mixed anhydride intermediate (I).
The preparation of intermediate (II): under room temperature, slowly drips 4-Nitrobenzol ethamine (12.61 g, 76 mmol, 0.95 eq) It is added in the methylene chloride/water solution of above-mentioned mixed anhydride intermediate (I), drips complete, room temperature reaction 2 h.Reaction terminates, with 1 Dilute hydrochloric acid (20 mL) washing of mol/L, layering, concentrate organic facies and reclaim dichloromethane, obtain intermediate (II).
The preparation of intermediate (M-01): intermediate (II) is dissolved in methanol (40 mL), slowly drips NaOH under room temperature (1.2 eq) aqueous solution, hydrolyzes complete intermediate (M-02), and add water (400 mL) crystallize afterwards, filters, and is dried, obtains white solid Body 21 g, content 99.10%(HPLC), productivity 92.1%.
The preparation of intermediate (M-02): by intermediate (M-01) (9 g, 30 mmol, 1 eq) and NaBH4(3.45 g, 90 Mmol, 3 eq) it is dissolved in anhydrous THF(60 mL) in, slowly drip Et under ice bath2O·BF3(11.7 mL, 90 mmol, 3 eq, W=46.5%), dripping complete insulation reaction 20 minutes, recover to room temperature, backflow 3-4h, TLC follow the trail of or control in liquid phase and reacted Finish, recover to room temperature, 70% solvent is concentrated in vacuo, reclaim THF, under ice bath, slowly drip the dilute hydrochloric acid (30 mL) of 1 mol/L Cancellation is reacted, then with concentrated NaOH solution, system is adjusted to alkalescence (pH ≈ 9), divides 2-3 extraction by ethyl acetate, and organic facies is with full And NaHCO3Wash, be dried, be concentrated to give grease.
Above-mentioned grease is dissolved in isopropanol at 50 DEG C, slowly drip 12 mol/L concentrated hydrochloric acid (3 mL, 1.2 Eq) separate out white solid, low temperature crystallize 1 h, filter, use isopropanol cleaning product, the hydrochlorate of dry intermediate (M-02), Purity 99.83%(HPLC), productivity 90%.
Although the above-mentioned detailed description of the invention to the present invention is described, but not limit to scope System, one of ordinary skill in the art should be understood that on the basis of technical scheme, and those skilled in the art need not pay Go out various amendments or deformation that creative work can make still within protection scope of the present invention.

Claims (5)

1. the synthetic method of a Mirabegron intermediate, it is characterised in that synthetic route is as follows:
The method specifically comprises the following steps that
S1, substitution reaction: R-MA reacts generation mixed anhydride intermediate (I) in a solvent with pivaloyl chloride；
S2, acylation reaction: mixed anhydride intermediate (I) generates intermediate (II) with 4-Nitrobenzol ethamine generation acylation reaction；
S3, hydrolysis: intermediate (II) occurs hydrolysis, is recrystallized to give Mirabegron intermediate (M-01)；
S4, reduction of amide: the amide bond reduction of Mirabegron intermediate (M-01) is obtained Mirabegron intermediate (M-02).
2. according to the synthetic method of a kind of Mirabegron intermediate described in claim 1, it is characterised in that institute in step S1 The solvent stated is one or more in methylene chloride/water, chloroform/water, acetonitrile/water, DMF/ water, acetone/water combination, Qi Zhongshui Volume content be 10% ~ 25%；R-MA is 1.0:1.8 ~ 2.2 with the mol ratio of pivaloyl chloride；Reaction temperature is 25 DEG C ~ 75 ℃；Response time is 2 h ~ 6 h.
3. according to the synthetic method of a kind of Mirabegron intermediate described in claim 1, it is characterised in that mixed in step S2 Acid anhydride intermediate (I) is 1.0:0.8 ~ 1.2 with the mol ratio of 4-Nitrobenzol ethamine.
4. according to the synthetic method of a kind of Mirabegron intermediate described in claim 1, it is characterised in that in Mirabegron Solvent described in mesosome (M-01) recrystallization is one or more in methanol/water, ethanol/water, isopropanol/water combination；Alcohol with The volume ratio of water is 1.0:5.0 ~ 15.0.
5. according to the synthetic method of a kind of Mirabegron intermediate described in claim 1, it is characterised in that intermediate (M- 01), NaBH4With Et2O·BF3Mol ratio be 1:3:3；Reaction temperature is 55 DEG C ~ 75 DEG C.
CN201610222186.4A 2016-04-12 2016-04-12 Synthetic method of mirabegron intermediate Pending CN105801438A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610222186.4A CN105801438A (en) 2016-04-12 2016-04-12 Synthetic method of mirabegron intermediate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610222186.4A CN105801438A (en) 2016-04-12 2016-04-12 Synthetic method of mirabegron intermediate

Publications (1)

Publication Number Publication Date
CN105801438A true CN105801438A (en) 2016-07-27

Family

ID=56460876

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610222186.4A Pending CN105801438A (en) 2016-04-12 2016-04-12 Synthetic method of mirabegron intermediate

Country Status (1)

Country Link
CN (1) CN105801438A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106278909A (en) * 2016-08-12 2017-01-04 浙江华海药业股份有限公司 A kind of post-processing approach of Mirabegron intermediate
CN108727212A (en) * 2018-06-19 2018-11-02 安徽德信佳生物医药有限公司 A kind of synthesis of Mirabegron intermediate (R) -2- hydroxy-ns-(4- nitrophenethyls) -2- phenyl-acetamides

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1575287A (en) * 2001-10-30 2005-02-02 山之内制药株式会社 Alpha-form or beta-form crystal of acetanilide derivative
CN101909440A (en) * 2007-11-14 2010-12-08 瑞科西有限公司 Therapeutic compounds and their use in treating diseases and disorders
CN104230840A (en) * 2014-09-05 2014-12-24 安徽联创药物化学有限公司 Synthesis method of mirabegron

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1575287A (en) * 2001-10-30 2005-02-02 山之内制药株式会社 Alpha-form or beta-form crystal of acetanilide derivative
CN101909440A (en) * 2007-11-14 2010-12-08 瑞科西有限公司 Therapeutic compounds and their use in treating diseases and disorders
CN104230840A (en) * 2014-09-05 2014-12-24 安徽联创药物化学有限公司 Synthesis method of mirabegron

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JUNJI NNANAGA等: "SYNTHESIS OF NEW CHIRAL AMINODIOLS AND THEIR USE FOR THE ASYMMETRIC REDUCTION OF KETONES AS LITHIUM LIUMINUM HYDRIDE MODIFIERS", 《MEMOIRS OF THE FACULTY OF SCIENCE, KYUSHU UNIVERSITY SER.C》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106278909A (en) * 2016-08-12 2017-01-04 浙江华海药业股份有限公司 A kind of post-processing approach of Mirabegron intermediate
CN106278909B (en) * 2016-08-12 2022-07-15 浙江华海药业股份有限公司 Post-treatment method of mirabegron intermediate
CN108727212A (en) * 2018-06-19 2018-11-02 安徽德信佳生物医药有限公司 A kind of synthesis of Mirabegron intermediate (R) -2- hydroxy-ns-(4- nitrophenethyls) -2- phenyl-acetamides
CN108727212B (en) * 2018-06-19 2020-11-27 安徽德信佳生物医药有限公司 Synthesis of mirabegron intermediate (R) -2-hydroxy-N- (4-nitrophenylethyl) -2-phenylacetamide

Similar Documents

Publication Publication Date Title
CN108047077B (en) Preparation method of oseltamivir chiral impurity
CN114805314A (en) Synthesis method of Ensaitevir
CN105801438A (en) Synthetic method of mirabegron intermediate
CN109824547A (en) A kind of synthetic method of double different protected amino acids
CN105273023B (en) A kind of preparation method of 5 '-O-L- valinate hydrochlorides of cytarabine
CN107814754A (en) A kind of preparation method of lauroyl arginine ethyl ester hydrochloride
CN106946724B (en) The synthetic method of monoamine base inhibitor class intermediate 2- acetylaminohydroxyphenylarsonic acid 2- benzyl malonic acid mono ethyl ester
CN103880756B (en) The preparation method of a kind of Azilsartan intermediate
CN106279155A (en) Impurity reference substance of tadanafil and preparation method thereof
CN106187818B (en) A kind of method for preparing cancer therapy drug Vorinostat
EP2714691B1 (en) Process for the preparation of 2-amino-9-((2-phenyl-1,3-dioxan-5-yloxy)methyl)-1h-purin-6(9h)-one compound useful in the preparation of valganciclovir
JP5618306B2 (en) Novel synthesis of substituted 4-amino-pyrimidines
CN103923135B (en) A kind of deuterated 5-hydroxyl color D-glucosamine glycoside derivates and preparation method thereof
CN104557793B (en) The synthetic method of a kind of Carfilzomib intermediate and intermediate thereof
JP2015526507A (en) Method for purifying fluvoxamine free base and method for producing high purity fluvoxamine maleate using the same
CN102731408A (en) Azilsartan intermediate and preparation method thereof
EP3260442B1 (en) Process for preparation of optically pure n-substituted-3-methoxypropionic acid derivatives
CN110628839A (en) Method for green and efficient preparation of L-selenium methyl selenocysteine
CN104910068A (en) 2-cyano isonicotinic acid hydrazide 1.5 p-toluenesulfonate synthetic method
JP2017510593A (en) Preparation method of levothyroxine and levothyroxine salt
CN105085595B (en) A kind of method of deacylation base protection 2,6 halosubstituted purine nucleosides of synthesis
CN104496843B (en) Method for synthesizing ubenimex
CN105017063B (en) 5- amino -2,4,6- triiodo isophthalic acid derivatives and its salt, hydrate or solvate
CN111808040B (en) Synthesis method of multi-configuration 2-oxo-oxazolidine-4-carboxylic acid compounds
CN102659639A (en) Preparation technology of leonurine

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20160727

RJ01 Rejection of invention patent application after publication