CN105541750B - A kind of preparation method of Mirabegron analysis of control product - Google Patents
A kind of preparation method of Mirabegron analysis of control product Download PDFInfo
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- CN105541750B CN105541750B CN201610151005.3A CN201610151005A CN105541750B CN 105541750 B CN105541750 B CN 105541750B CN 201610151005 A CN201610151005 A CN 201610151005A CN 105541750 B CN105541750 B CN 105541750B
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- C07—ORGANIC CHEMISTRY
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The present invention relates to a kind of preparation method for being used to analyze the reference substance of the Mirabegron quality of production, comprise the steps of：(1) under solvent and acid condition, in hydrogen atmosphere, under catalyst action, compound B reacts to obtain compound C；(2) in solvent and acid condition, under condensing agent effect, compound C and compound D are condensed to yield compound A.The reaction scheme that this method shortens relative to prior art.
Description
Technical field
The invention belongs to the field of pharmaceutical synthesis, is related to a kind of β -3 adrenoceptor agonists (β -3adrenergic
Agonist) in Mirabegron preparation process caused impurity preparation method.
Background technology
Mirabegron trade name Myrbetriq, developed by Japanese Astellas (Astellas) drugmaker, in 2011
, on September listed for 16 in Japan, and molecular formula is：C21H24N4O2S, chemistry are entitled：(R) -2- (2- amino -1,3- thiazole-4-yls) -
4'- [2- [(2- hydroxyl -2- phenethyls) amino] ethyl] phenyl acetamide.Structural formula is：
Mirabegron is a kind of β -3 adrenoceptor agonists of high selectivity, June 28 in 2012 Nikkei U.S. food
Drug Administration (FDA) ratifies to be used to treat adult's overactive bladder.
EP1559427, EP1440969 etc. report that the synthetic method of Mirabegron is：With to D- mandelic acids (compound F)
It is raw material with 4- nitro phenyl ethylamines (compound G), under condensing agent effect, is condensed to yield intermediate (R) -2- hydroxy-ns-[2-
(4- nitrobenzophenones) ethyl] phenyl acetamide (compound H), then by reduction of amide, nitro reduce, then with thiazolamine-
4- acetic acid (compound D) carries out being condensed to yield Mirabegron (compound E), and specific synthetic route is as shown in Scheme 1：
During Mirabegron is synthesized, a kind of property and the closely similar accessory substance of Mirabegron, i.e. 2- can be produced
(2- amino -1,3-thiazoles -4- bases) -4'- [2- (PhenethyIamino) ethyl] phenyl acetamide (compound A), it is difficult to by tying again
The conventional methods such as crystalline substance are removed.Therefore during synthesising target compound, for the purpose of monitoring product quality, always need
Pure compound A is wanted as reference substance, to analyze the purity of target product.
CN103641792 reports the synthetic method of the accessory substance：With phenylacetic acid (compound J) and 4- nitro phenyl ethylamines
(compound G) is raw material, by condensation reaction, reduction of amide, nitro reduce, then with thiazolamine -4- acetic acid (compound D)
Carry out being condensed to yield compound A, specific synthetic route is as shown in Scheme 2：
This method, using the method similar to synthesis Mirabegron, obtains compound A using phenylacetic acid as raw material.This method
Synthesis step is longer, and reaction is complicated, and cost is high.Therefore it is that prior art is desired to seek simpler synthetic method.
The content of the invention
It is an object of the invention to provide a kind of new compound A, i.e. 2- (2- amino -1,3-thiazoles -4- bases) -4'-
The synthetic route of [2- (PhenethyIamino) ethyl] phenyl acetamide, to overcome prior art institute application method synthetic route longer
Defect.
According to the present invention, compound A synthetic method comprises the steps as shown in Scheme 3：(1) in solvent and acid
Under the conditions of property, in hydrogen atmosphere, under catalyst action, compound B reacts to obtain compound C；(2) in solvent and acid condition
In, under condensing agent effect, compound C and compound D are condensed to yield compound A.
In step (1), compound B is dissolved in organic solvent I, in acid condition, in hydrogen atmosphere, made by catalyst
Reacted under, obtain compound C.After completion of the reaction, filter, filtrate decompression extracts solvent, adds sodium carbonate, dichloromethane
Or ethyl acetate stirring, liquid separation, organic phase washing, dry, decompression extracts solvent, is recrystallized to give compound C crude products.
Can be used for step (1) organic solvent I can be selected from halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent,
Esters solvent, carboxylic acids solvent, ketones solvent, sulfoxide type solvents.Wherein preferred halogenated hydrocarbons, esters and carboxylic acids solvent, it is more excellent
Select esters and acetic acid, the mixed solvent being most preferably made up of the two.The difficult point of the present invention is, it is necessary to by Liang Zhong functional groups
Convert simultaneously, i.e. by hydroxyl carbon conversion into methylene, nitro is switched into amino.Therefore reaction environment will consider both reactions
Specific feature.Inventor obtains the scheme that can preferably implement by largely groping.
In a kind of specific embodiment, using acetic acid as solvent, moderate amount of sulfuric acid is added, using hydrogen reduction method, with blue Buddhist nun
Nickel or palladium-carbon are catalyst, wherein it is preferred that 10% palladium-carbon.Compound B quality and the volume ratio of organic solvent are 1:10-1:
30, preferably 1:20.In this programme, the mol ratio of compound B and sulfuric acid is very crucial, and preferable scope is 1:1-1:3, it is optimal
Elect 1 as:1.2.Deviate this ratio, reaction yield can be remarkably decreased.The quality of catalyst is compound B 5%-40%, excellent
Select 15-25%, most preferably 20%.Reaction temperature is between 0 DEG C -60 DEG C, preferably 35-45 DEG C, most preferably 38-40 DEG C.Adopt
With this reaction condition, 3-8 hours can be maintained at a constant temperature with reaction system.
In another more preferred embodiment, 3 are pressed with ethyl acetate and acetic acid:1-1.5 volume ratio is made into multiple
Bonding solvent, with 98% concentrated sulfuric acid offer strong acid reaction environment, the mol ratio of compound B and sulfuric acid is 1:0.2-0.5, wherein excellent
Select 0.2-0.3.The dead plaster of compound B moles 60% is added in reaction system.Using the program can use compared with
A small amount of solvent, compound B quality and the volume ratio of compounded organic solvent can be 1:Between 3-10, usual 1:5-9 is i.e.
Enough.Reaction can react 2-10 hours in 30-60 DEG C.It can carry out at a constant temperature.Preferably, can be present
50-60 DEG C of reaction 1-2 hour, 1-2 hours are then reacted below 40 DEG C.Using this embodiment, post processing is relatively simple,
Yield is also higher.After reaction terminates, filtering, decompression, which filters, removes solvent, adds a small amount of 10% sodium carbonate liquor, uses organic solvent
Liquid separation, organic phase is then handled, obtain end-product.
In step (2), in water, under acid condition, in the presence of condensing agent, compound C and compound D are condensed
Reaction, obtains compound A.Alkaline matter is added after completion of the reaction to dissociate, and is filtered, is recrystallized to give compound A.
Wherein, acidic materials used are inorganic acid, preferably hydrochloric acid.Described condensing agent is dicyclohexylcarbodiimide
(DCC), DIC (DIC) and 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides (EDCI), O- (benzos
Triazole -1- bases)-two (dimethylamino) carbon hexafluorophosphates (HBTU), preferably 1- (3- dimethylamino-propyls) -3- ethyls
Carbodiimide (EDCI).Described alkaline matter is inorganic base, preferably sodium hydroxide.Described compound C quality and water
Volume ratio be 1:5-1:20.Preferably 1:15.Described compound C and the mol ratio of acidic materials are 1:1-1:5.Preferably
1:2.3.Described compound C and the mol ratio of condensing agent are 1:1-1:1.5.Preferably 1:1.3.Described compound C is with changing
Compound D mol ratio is 1:1-1:5.Preferably 1:1.3.Described compound C and the mol ratio of alkaline matter are 1:1-1:5.
Preferably 1:3.Described reaction temperature is 0 DEG C -60 DEG C.Preferably 15 DEG C.
The present invention to Mirabegron synthesis technique by optimizing, and from the midbody compound in Mirabegron technique
B starts to synthesize, and obtains Mirabegron impurity compound A.This method is simple to operate, and greatly reduces cost.
Embodiment
The present invention is described in further detail below in conjunction with specific embodiment, but should not be construed as limiting the invention.
Embodiment 1
The preparation of 4- [2- (PhenethyIamino) ethyl] aniline
By 2.0g (6.2mmol) compounds B, 0.4g Pd/C (10%, it is aqueous 68.14%), 0.74g (7.4mmol) dense sulphur
Acid mixes with 40mL glacial acetic acids, is passed through hydrogen, is heated to 38 DEG C of reaction 5h.TLC is detected after completion of the reaction, and filtering, decompression extracts
Solvent, the addition sodium carbonate liquors of 15mL 20%, 10mL ethyl acetate, liquid separation, aqueous phase are extracted with ethyl acetate (10mL × 2), closed
And organic phase, solvent is extracted with saturated common salt water washing, liquid separation, organic phase anhydrous sodium sulfate drying, decompression, crude product passes through post
Chromatography, eluent are that ethyl acetate presses 85 with ethanol:15 volume ratios, yellow solid 0.96g, i.e. compound after being dried
C, yield 65.0%.Embodiment 2
The preparation of 4- [2- (PhenethyIamino) ethyl] aniline
By 2.0g (6.2mmol) compounds B, 0.4g Pd/C (10%, it is aqueous 68.14%), 0.19g (1.9mmol) dense sulphur
Acid, 0.51g dead plasters are added in 12mL double solvents, and double solvents is by 3 with ethyl acetate and acetic acid:1 volume ratio
It is made into, is passed through hydrogen, reacted 2 hours at 55 DEG C, is then down to 30 DEG C of reaction 1.5h.Filtering, decompression extract solvent, add 5mL
10% sodium carbonate liquor, 10mL ethyl acetate, liquid separation, aqueous phase are extracted with ethyl acetate (5mL × 2), merge organic phase, use saturation
Brine It, liquid separation, organic phase anhydrous sodium sulfate drying, decompression extract solvent, and crude product passes through column chromatography for separation, eluent
85 are pressed for ethyl acetate and ethanol:15 volume ratios, yellow solid 1.24g yellow solids after being dried, i.e. compound C, yield
84.0%.
Embodiment 3
The preparation of 2- (2- amino -1,3- thiazole-4-yls) -4'- [2- (PhenethyIamino) ethyl] phenyl acetamide
By 1.24g (5.2mmol) compound C, 1.06g (6.7mmol) thiazolamine -4- acetic acid (compound D),
1.29g (6.7mmol) 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides (EDCI), 1.17g (2.3mmol) concentrated hydrochloric acid are molten
In 19mL water, 15 DEG C of stirring reaction 3h, TLC detections after completion of the reaction, are slowly added to 8ml 2M sodium hydroxide solutions, filtered,
Ethanol water recrystallizes to obtain 1.76g white solids, yield 89.3%.
m.p.239.3-240.2℃
1H NMR(500MHz,Methanol-d4):δ 7.56 (d, J=8.2Hz, 2H), 7.33 (t, J=7.5Hz, 2H),
7.31-7.25 (m, 3H), 7.23 (d, J=8.3Hz, 2H), 6.36 (s, 1H), 3.56 (s, 2H), 3.25 (td, J=8.9,8.3,
4.2Hz, 4H), 2.98 (dt, J=14.1,8.2Hz, 4H)13C NMR(500MHz,Methanol-d4):δ170.23,
169.36,144.39,137.59,136.34,132.04,128.78,128.62,128.38,126.92,120.35,103.73,
48.73,48.68,38.88,31.99,31.43.
1H NMR(500MHz,DMSO-d6):δ 10.16 (s, 1H), 9.07 (s, 2H), 7.57 (d, J=8.2Hz, 2H),
7.34 (t, J=7.5Hz, 2H), 7.29-7.23 (m, 3H), 7.18 (d, J=8.2Hz, 2H), 6.92 (s, 2H), 6.30 (s,
1H), 3.46 (s, 2H), 3.19-3.09 (m, 4H), 2.96 (dd, J=10.2,6.3Hz, 2H), 2.91 (dd, J=10.0,
6.4Hz,2H).13C NMR(500MHz,DMSO-d6):δ168.66,168.43,146.23,138.48,137.70,132.17,
129.34,129.11,129.10,127.24,119.67,103.08,48.24,48.17,40.40,32.03,31.47。
Claims (7)
1. a kind of preparation method of Mirabegron analysis of control product, it is characterised in that specifically include following steps：
(1) compound B is dissolved in organic solvent I, it is in acid condition, anti-by being carried out under catalyst action in hydrogen atmosphere
Should, compound C is obtained, after completion of the reaction, filtering, filtrate decompression extracts solvent, adds sodium carbonate, dichloromethane or ethyl acetate
Stirring, liquid separation, organic phase washing, dry, decompression extracts solvent, is recrystallized to give compound C；(2) in solvent and acid condition
In, in the presence of condensing agent, compound C and compound D are condensed to yield compound A, reaction equation is：
The organic solvent I is acetic acid or presses 3 with ethyl acetate and acetic acid:1-1.5 volume ratio is made into, and institute is provided using sulfuric acid
Sour environment is stated, the catalyst is 10% palladium carbon catalyst；
Organic solvent I is acetic acid, and compound B quality and the volume ratio of acetic acid are 1:10-1:30, compound B and sulfuric acid rub
You are than being 1:1-1:3, the quality of catalyst is compound B 15-25%, between reaction temperature is 0 DEG C -60 DEG C；
Organic solvent I presses 3 with ethyl acetate and acetic acid:When 1-1.5 volume ratio is made into, the mol ratio of compound B and sulfuric acid is
1:0.2-0.5, compound B quality and the volume ratio of organic solvent I are 1:3-10.
2. preparation method according to claim 1, it is characterised in that described when organic solvent I is acetic acid in step (1)
Compound B quality is 1 with the volume ratio of organic solvent I:The mol ratio of 20, compound B and sulfuric acid is 1:1.2 catalyst
Quality is the 20% of compound B, and reaction temperature is 38-40 DEG C.
3. preparation method according to claim 1, it is characterised in that in step (1), organic solvent I with ethyl acetate and
Acetic acid presses 3:When 1-1.5 volume ratio is made into, the mol ratio of compound B and sulfuric acid is 1：0.2-0.3.
4. preparation method according to claim 3, it is characterised in that in step (1), organic solvent I with ethyl acetate and
Acetic acid presses 3:When 1-1.5 volume ratio is made into, the calcium sulfate of compound B moles 60% is added in reaction system.
5. preparation method according to claim 4, it is characterised in that in step (1), organic solvent I with ethyl acetate and
Acetic acid presses 3:When 1-1.5 volume ratio is made into, reacts and react 1-2 hours at 50-60 DEG C, it is small that 1-2 is then reacted below 40 DEG C
When.
6. preparation method according to claim 1, it is characterised in that in the step (2), specifically include following steps：
In water, under acid condition, in the presence of condensing agent, compound C and compound D is subjected to condensation reaction, obtains compound A,
Alkaline matter is added after completion of the reaction to dissociate, and is filtered, is recrystallized to give compound A.
7. preparation method according to claim 6, it is characterised in that inorganic acid, described condensing agent are used in step (2)
For dicyclohexylcarbodiimide (DCC), DIC (DIC) and 1- (3- dimethylamino-propyls) -3- ethyls carbon two
Imines (EDCI), (dimethylamino) the carbon hexafluorophosphates (HBTU) of O- (BTA -1- bases)-two, described basic species
Matter is inorganic base, and described compound C quality and the volume ratio of water are 1:5-1:20, compound C rub with the inorganic acid
You are than being 1:1-1:5, the mol ratio of the compound C and condensing agent are 1:1-1:1.5, the compound C and compound D's rubs
You are than being 1:1-1:5, the mol ratio of the compound C and alkaline matter are 1:1-1:5.
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