CN101973988B - Method for preparing pioglitazone - Google Patents
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- CN101973988B CN101973988B CN2010102948142A CN201010294814A CN101973988B CN 101973988 B CN101973988 B CN 101973988B CN 2010102948142 A CN2010102948142 A CN 2010102948142A CN 201010294814 A CN201010294814 A CN 201010294814A CN 101973988 B CN101973988 B CN 101973988B
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Abstract
The invention relates to a method for preparing pioglitazone. The method comprises the following steps of: treating an amino compound IV (4-[2-(5-ethyl-2-pyridyl) ethoxy] phenylamine) by using hydrobromic acid and sodium nitrite, adding acrylic acid and cuprous oxide for reaction to obtain a bromide III (2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-ethoxy] phenyl} acrylic acid); reacting the bromide III and ammonium dithiocarbamate to obtain sulfothiazolidine diketone II (5-{4-[2-(5-ethyl-2-pyridyl)-ethoxy] benzyl}-2-thiocarbonyl-4-thiazolidone); and adding hydroxylamine hydrochloride for condensation, and hydrolyzing with hydrochloric acid to obtain the pioglitazone I (5-{4-[2-(5-ethyl-2-pyridyl)-ethoxy] benzyl}-2,4-thiazolidinedione). According to the technical scheme, the operation is simple, and the reaction is easy to control; and the yield of the product can reach 62 percent, the quality is good, and the purity reaches 99.5 percent (HPLC).
Description
Technical field
The present invention relates to a kind of preparation method who treats the type ii diabetes medicine, relate to a kind of preparation method of pyrroles's row ketone in particular.
Background technology
Pyrroles's row ketone is by Japan military field KCC Development and Production, is used for improving and controlling blood sugar, is treatment type ii diabetes medicine.
Pyrroles's row ketone, Chinese: 5-{4-[2-(5-ethyl-2-pyridine)-oxyethyl group]-phenyl }-2,4-U 25560 hydrochloride, white or off-white color crystalline powder, molecular structural formula is following:
Disclose the technology for preparing pyrroles's row ketone at patent WO2009133576,4-[2-(5-ethyl-2-pyridyl) oxyethyl group] aniline (amino-complex IV) reacts with Sodium Nitrite and hydrochloric acid, methyl acrylate, and with the thiocarbamide cyclization, hydrolysis prepares pyrroles's row ketone.This technological shortcoming mainly is that yield is on the low side, is merely 31.3%.
Indian patent IN2002MA00647, IN2005MU01255 and IN2006MU01795 also disclose similar patent, and different is when reacting with methyl acrylate is the Hydrogen bromide that adopts.
X＝Cl，Br
Disclose among the patent WO2006035459 and utilized amino-complex IV, Sodium Nitrite, hydrochloric acid and methyl acrylate reaction, with the thiocarbamide cyclization, pyrroles's row ketone, total recovery 24.2% are synthesized in hydrolysis.Disclose amino-complex IV at patent CN86100411 and handled with hydrobromic acid solution, sodium nitrite solution successively, added vinylformic acid first vinegar, Red copper oxide again, stirring reaction to do not have gas produce bromide.Bromide, thiocarbamide cyclization get the imido grpup compound, finally prepare pyrroles's row ketone, yield 43.6% through hydrolysis.Similar preparation method also is provided in patent WO2004024059, is feedstock production pyrroles row ketone with amino-complex IV, yield 34.7%.
The technology general shortcoming of these preparations pyrroles row ketone is that the cyclization yield is low, and between 20～45%, preparation cost is high in amino-complex IV molar yield.
In view of the restriction and the shortcoming of above-mentioned prior art processes, need improve, develop a route of environmental protection safe technology cheaply.
Summary of the invention
The application's goal of the invention is the shortcoming to prior art, and a kind of preparation pyrroles row ketone method that adopts the high yield of novel method for synthesizing is provided.
Design is handled with Hydrogen bromide, Sodium Nitrite with amino-complex IV, add vinylformic acid, Red copper oxide react bromide III; Bromide III and ammonium dithiocarbamate react sulfo-U 25560 II; Add the oxammonium hydrochloride condensation, get pioglitazone I behind the hydrochloric acid hydrolysis.
Technical scheme of the present invention comprises:
A kind of preparation method of pyrroles's row ketone, said method comprises:
(a) with bromide 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] phenyl of the amino-complex 4-shown in structural formula IV [2-(5-ethyl-2-pyridyl) oxyethyl group] aniline preparation shown in structural formula II I } vinylformic acid;
In the step of described preparation bromide; 4-[2-(5-ethyl-2-pyridyl) oxyethyl group] aniline was handled 1～2 hour for 0～5 ℃ with Hydrogen bromide, Sodium Nitrite in organic alcohol, added vinylformic acid, Red copper oxide at 30～80 ℃ of reactions acquisition in 2～6 hours 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] phenyl vinylformic acid;
(b) with the sulfo-thiazolidinedione compound of the preparation of the bromide shown in structural formula II I shown in structural formula II;
In the step of described preparation sulfo-thiazolidinedione compound; The bromide III of step (a) preparation is regulated PH=6～7 with alkali in water; Add ammonium dithiocarbamate, add hydrochloric acid then and close ring acquisition in 1～4 hour 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl at 60～100 ℃-2-thiocarbonyl group-4-thiazolidone;
(c) with the purpose product pioglitazone of the preparation of the sulfo-thiazolidinedione compound shown in structural formula II shown in structural formula I;
In the step of described preparation pioglitazone; The sulfo-thiazolidinedione compound II of step (b) preparation is added the oxammonium hydrochloride condensation; Add hydrochloric acid hydrolysis then and obtain 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl-2; The 4-U 25560, promptly trade name is the purpose product of pioglitazone.
The preparation method of above-mentioned a kind of pyrroles's row ketone is characterized in that:
The employed organic alcohol of step (a) is set to methyl alcohol, ethanol or Virahol; The mass ratio of amino-complex IV and organic alcohol is:
Amino-complex IV: organic alcohol=1: 3～10.
The preparation method of above-mentioned a kind of pyrroles's row ketone is characterized in that:
Mol ratio is in the step (a):
Amino-complex: Sodium Nitrite: vinylformic acid: Red copper oxide=1: 1～1.2: 5～10: 0.08～0.12.
The preparation method of above-mentioned a kind of pyrroles's row ketone is characterized in that:
Mol ratio is in the step (b):
Bromide III: ammonium dithiocarbamate=1: 1～1.2.
The preparation method of above-mentioned a kind of pyrroles's row ketone is characterized in that:
Mol ratio is in the step (c):
Sulfo-thiazolidinedione compound: oxammonium hydrochloride=1: 1.2～2.0.
Reaction process is:
Technical scheme of the present invention has following advantage:
1. operation is simple, and reaction is easy to control;
2. quality product is better, and yield can reach 62%, and purity reaches 99.5%.
Embodiment:
The present invention is further explained the present invention in order better to explain in conjunction with following examples, but the scope that the scope that the present invention requires to protect is not limited to represent among the embodiment.
Embodiment 1
(a) preparation of bromide III: magnetic agitation, TM and reflux condensing tube are installed in the there-necked flask of 1000ml; Add 24.2g (0.10mol) 4-[2-(5-ethyl-2-pyridyl) oxyethyl group] aniline (amino-complex IV); Add 150ml methyl alcohol and 21.9g (0.13mol) Hydrogen bromide (48%); At 0～5 ℃ of 50ml aqueous solution that drips 7.6g (0.11mol) Sodium Nitrite; Be incubated 1 hour, add 50.4g (0.59mol) vinylformic acid, 1.43g (0.01mol) Red copper oxide 50 ℃ of reactions 2 hours.After reaction finishes, get 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] phenyl } vinylformic acid (bromide III);
(b) preparation of sulfo-thiazolidinedione compound II: the bromide III of step (a) preparation is added sodium-acetate adjusting pH value=6.8～7.0; 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] phenyl the sodium-salt aqueous solution of vinylformic acid (bromide III); Ethyl acetate extraction; Water adds 12.1g (0.11mol) ammonium dithiocarbamate (commercial goods) reaction; Add hydrochloric acid (30%) adjusting pH value to 1.0～1.2 then and closed ring 3 hours at 70 ℃, solid filtering gets 26.5g 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl }-2-thiocarbonyl group-4-thiazolidone (sulfo-thiazolidinedione compound II); In amino-complex IV, yield 71.2%.
(c) preparation of pioglitazone I: the sulfo-thiazolidinedione compound II of step (b) preparation is added 500ml water, add 10.4g (0.15mol) oxammonium hydrochloride 15～20 ℃ of condensations.React after 3 hours, add 120g hydrochloric acid (30%) 68～70 ℃ of hydrolysis reaction 4 hours, cooling is crossed and is filtered the 23.3g bullion.Bullion adds the DMF heating for dissolving, reduces to room temperature adding acetone and separates out 22.1g elaboration 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl }-2,4-U 25560 (pioglitazone I); Content 99.5 (HPLC); In amino-complex IV, yield 62.1%.
Embodiment 2
(a) preparation of bromide III: magnetic agitation, TM and reflux condensing tube are installed in the there-necked flask of 1000ml; Add 24.2g (0.10mol) 4-[2-(5-ethyl-2-pyridyl) oxyethyl group] aniline (amino-complex IV); Add 58ml ethanol and 21.9g (0.13mol) Hydrogen bromide (48%); At 0～5 ℃ of 50ml aqueous solution that drips 6.9g (0.10mol) Sodium Nitrite; Be incubated 2 hours, add 43.0g (0.5mol) vinylformic acid, 1.14g (0.008mol) Red copper oxide 30 ℃ of reactions 6 hours.After reaction finishes, get 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] phenyl } vinylformic acid (bromide III);
(b) preparation of sulfo-thiazolidinedione compound II: the bromide III of step (a) preparation is added sodium-acetate adjusting pH value=6.8～7.0; 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] phenyl the sodium-salt aqueous solution of vinylformic acid (bromide III); Ethyl acetate extraction; Water adds the reaction of 11.0g (0.10mol) ammonium dithiocarbamate; Add hydrochloric acid (30%) adjusting pH value to 1.0～1.2 then and closed ring 4 hours at 60 ℃, solid filtering gets 23.9g 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl }-2-thiocarbonyl group-4-thiazolidone (sulfo-thiazolidinedione compound II); In amino-complex IV, yield 64.3%.
(c) preparation of pioglitazone I: the sulfo-thiazolidinedione compound II of step (b) preparation is added 500ml water, add 8.3g (0.12mol) oxammonium hydrochloride 15～20 ℃ of condensations.React after 3 hours, add 120g hydrochloric acid (30%) 68～70 ℃ of hydrolysis reaction 4 hours, cooling is crossed and is filtered the 18.4g bullion.Bullion adds the DMF heating for dissolving, reduces to room temperature adding acetone and separates out 16.1g elaboration 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl }-2,4-U 25560 (pioglitazone I); Content 99.6 (HPLC); In amino-complex IV, yield 45.2%.
Embodiment 3
(a) preparation of bromide III: magnetic agitation, TM and reflux condensing tube are installed in the there-necked flask of 1000ml; Add 24.2g (0.10mol) 4-[2-(5-ethyl-2-pyridyl) oxyethyl group] aniline (amino-complex IV); Add 194ml Virahol and 21.9g (0.13mol) Hydrogen bromide (48%); At 0～5 ℃ of 50ml aqueous solution that drips 8.3g (0.12mol) Sodium Nitrite; Be incubated 1 hour, add 86.1g (1.0mol) vinylformic acid, 1.72g (0.012mol) Red copper oxide 80 ℃ of reactions 2 hours.After reaction finishes, get 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] phenyl } vinylformic acid (bromide III);
(b) preparation of sulfo-thiazolidinedione compound II: the bromide III of step (a) preparation is added sodium-acetate adjusting pH value=6.8～7.0; 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] phenyl the sodium-salt aqueous solution of vinylformic acid (bromide III); Ethyl acetate extraction; Water adds the reaction of 12.1g (0.11mol) ammonium dithiocarbamate; Add hydrochloric acid (30%) adjusting pH value to 1.0～1.2 then and closed ring 1 hour at 100 ℃, solid filtering gets 19.6g 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl }-2-thiocarbonyl group-4-thiazolidone (sulfo-thiazolidinedione compound II); In amino-complex IV, yield 52.7%.
(c) preparation of pioglitazone I: the sulfo-thiazolidinedione compound II of step (b) preparation is added 500ml water, add 10.4g (0.15mol) oxammonium hydrochloride 15～20 ℃ of condensations.React after 3 hours, add 120g hydrochloric acid (30%) 68～70 ℃ of hydrolysis reaction 4 hours, cooling is crossed and is filtered the 17.4g bullion.Bullion adds the DMF heating for dissolving, reduces to room temperature adding acetone and separates out 16.3g elaboration 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl }-2,4-U 25560 (pioglitazone I); In amino-complex IV, yield 46.0%.
Embodiment 4
(a) preparation of bromide III: magnetic agitation, TM and reflux condensing tube are installed in the there-necked flask of 1000ml; Add 24.2g (0.10mol) 4-[2-(5-ethyl-2-pyridyl) oxyethyl group] aniline (amino-complex IV); Add 150ml methyl alcohol and 21.9g (0.13mol) Hydrogen bromide (48%); At 0～5 ℃ of 50ml aqueous solution that drips 7.6g (0.11mol) Sodium Nitrite; Be incubated 1 hour, add 50.4g (0.59mol) vinylformic acid, 1.43g (0.01mol) Red copper oxide 50 ℃ of reactions 2 hours.After reaction finishes, get 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] phenyl } vinylformic acid (bromide III);
(b) preparation of sulfo-thiazolidinedione compound II: the bromide III of step (a) preparation is added sodium-acetate adjusting pH value=6.8～7.0; 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] phenyl the sodium-salt aqueous solution of vinylformic acid (bromide III); Ethyl acetate extraction; Water adds the reaction of 13.2g (0.12mol) ammonium dithiocarbamate; Add hydrochloric acid (30%) then and regulate pH value to 1.0～1.2 at 70 ℃ of pass rings, solid filtering gets 25.7g 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl }-2-thiocarbonyl group-4-thiazolidone (sulfo-thiazolidinedione compound II); In amino-complex IV, yield 69.1%.
(c) preparation of pioglitazone I: the sulfo-thiazolidinedione compound II of step (b) preparation is added 500ml water, add 13.9g (0.20mol) oxammonium hydrochloride 15～20 ℃ of condensations.React after 3 hours, add 120g hydrochloric acid (30%) 68～70 ℃ of hydrolysis reaction 4 hours, cooling is crossed and is filtered the 22.8g bullion.Bullion adds the DMF heating for dissolving, reduces to room temperature adding acetone and separates out 21.7g elaboration 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl }-2,4-U 25560 (pioglitazone I); Content 99.7 (HPLC); In amino-complex IV, yield 60.9%.
Embodiment 5
In the bromide III preparation, add 242g (1mol) 4-[2-(5-ethyl-2-pyridyl) oxyethyl group] aniline (amino-complex IV), add 900ml methyl alcohol; Get 220g elaboration 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl at last }-2,4-U 25560 (pioglitazone I); Content 99.6 (HPLC); In amino-complex IV, yield 61.79%.All the other are with embodiment 1.
Embodiment 6
In the bromide III preparation, add 242g (1mol) 4-[2-(5-ethyl-2-pyridyl) oxyethyl group] aniline (amino-complex IV), add 1500ml ethanol; Get 192.8g elaboration 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl at last }-2,4-U 25560 (pioglitazone I); Content 99.5 (HPLC); In amino-complex IV, yield 54.16%.All the other are with embodiment 2.
Embodiment 7
In the bromide III preparation, add 242g (1mol) 4-[2-(5-ethyl-2-pyridyl) oxyethyl group] aniline (amino-complex IV), add the 2400ml Virahol; Get 208.2g elaboration 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl at last }-2,4-U 25560 (pioglitazone I); Content 99.4 (HPLC); In amino-complex IV, yield 58.49%.All the other are with embodiment 3.
Embodiment 8
In the bromide III preparation, add 242g (1mol) 4-[2-(5-ethyl-2-pyridyl) oxyethyl group] aniline (amino-complex IV), add 2400ml methyl alcohol; Get 216.7g elaboration 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl at last }-2,4-U 25560 (pioglitazone I); Content 99.6 (HPLC); In amino-complex IV, yield 60.87%.All the other are with embodiment 4.
Claims (5)
1. the preparation method of pyrroles's row ketone is characterized in that branch makes following steps:
(a) with bromide 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] phenyl of the amino-complex 4-shown in structural formula IV [2-(5-ethyl-2-pyridyl) oxyethyl group] aniline preparation shown in structural formula II I } propionic acid;
In the step of described preparation bromide; 4-[2-(5-ethyl-2-pyridyl) oxyethyl group] aniline was handled 1～2 hour for 0～5 ℃ with Hydrogen bromide, Sodium Nitrite in organic alcohol, added vinylformic acid, Red copper oxide at 30～80 ℃ of reactions acquisition in 2～6 hours 2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] phenyl propionic acid;
(b) with the sulfo-thiazolidinedione compound of the preparation of the bromide shown in the structural formula II I shown in structural formula II;
In the step of described preparation sulfo-thiazolidinedione compound; The bromide III of step (a) preparation is regulated PH=6～7 with alkali in water; Add ammonium dithiocarbamate, add hydrochloric acid then and close ring acquisition in 1～4 hour 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl at 60～100 ℃-2-thiocarbonyl group-4-thiazolidone;
(c) with the purpose product pyrroles row ketone of the preparation of the sulfo-thiazolidinedione compound shown in structural formula II shown in structural formula I;
In the step of described preparation pyrroles row ketone; The sulfo-thiazolidinedione compound II of step (b) preparation is added the oxammonium hydrochloride condensation; Add hydrochloric acid hydrolysis then and obtain 5-{4-[2-(5-ethyl-2-pyridyl)-oxyethyl group] benzyl-2; The 4-U 25560, promptly trade name is the purpose product of pyrroles's row ketone;
Reaction process is:
2. according to the preparation method of the described a kind of pyrroles's row ketone of claim 1, it is characterized in that the employed organic alcohol of step (a) is set to methyl alcohol, ethanol or Virahol; The mass ratio of amino-complex IV and organic alcohol is:
Amino-complex IV: organic alcohol=1: 3～10.
3. according to the preparation method of the described a kind of pyrroles's row ketone of claim 1, it is characterized in that mol ratio is in the step (a):
Amino-complex: Sodium Nitrite: vinylformic acid: Red copper oxide=1: 1～12: 5～10: 0.08～0.12.
4. according to the preparation method of the described a kind of pyrroles's row ketone of claim 1, it is characterized in that mol ratio is in the step (b): bromide III: ammonium dithiocarbamate=1: 1～1.2.
5. according to the preparation method of the described a kind of pyrroles's row ketone of claim 1, it is characterized in that mol ratio is in the step (c): sulfo-thiazolidinedione compound: oxammonium hydrochloride=1: 2～2.0.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1459450A (en) * | 2002-05-21 | 2003-12-03 | 杭州华东医药（集团）公司生物工程研究所 | Preparation method of 5-[4-[2-(5-ethyl-2-pyridine)ethoxy] benzylidene]-2,4thiazolidine diketone |
| WO2005049610A1 (en) * | 2003-10-28 | 2005-06-02 | Sandoz Ag | Process for preparing thiazolidinediones |
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- 2010-09-28 CN CN2010102948142A patent/CN101973988B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1459450A (en) * | 2002-05-21 | 2003-12-03 | 杭州华东医药（集团）公司生物工程研究所 | Preparation method of 5-[4-[2-(5-ethyl-2-pyridine)ethoxy] benzylidene]-2,4thiazolidine diketone |
| WO2005049610A1 (en) * | 2003-10-28 | 2005-06-02 | Sandoz Ag | Process for preparing thiazolidinediones |
Non-Patent Citations (2)
| Title |
|---|
| 崔军民等.噻唑烷二酮类药物吡格列酮盐酸盐的合成研究.《应用化工》.2010,第39卷(第1期),第80~82页. * |
| 钮因安等.盐酸吡格列酮合成路线图解.《中国医药工业杂志》.2007,第38卷(第1期),第70~72页. * |
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