CN114736196B - Violet Luo Zhulian and side chain coupling post-treatment purification process - Google Patents
Violet Luo Zhulian and side chain coupling post-treatment purification process Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 invention discloses a purification process for coupling of Violet Luo Zhulian and a side chain, and belongs to the field of drug synthesis. Willand Luo Zhulian 2- [2- (6-Bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene is coupled with the side chain (5R) -5- (2, 2-dimethyl-4H-1, 3-benzodioxan-6-yl) -1, 3-oxazolidin-2-one, excess backbone 2- [2- (6-Bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene is reacted with pyridine derivative to form a salt, and the salt is washed with hot water at 50 ℃. The method has the advantages of mild reaction conditions of salifying by using the pyridine derivative which is low in cost and easy to obtain, simple operation and easy removal of impurities, avoids purification products by a silica gel chromatographic column purification and distillation method, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of synthesis of pharmaceutical intermediates, and relates to a purification process for coupling of Violet Luo Zhulian and side chains.
Background
Veland Luo San phenylacetate (Vilanterol trifenatate) is a long acting β2 receptor agonist developed by the company Glazin Smik (GSK). The compound preparation of the medicine and the fluticasone furoate and the compound preparation of the medicine and the turnip bromide are approved by the FDA in 5 months and 12 months in 2013 respectively, and are used for treating obstructive pulmonary disease and asthma. Wherein, (5R) -3- [6- [2- [ (2, 6-dichlorophenyl) methoxy]Ethoxy group]Hexyl group]-5- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxazolidinone is a key intermediate for the synthesis of vilantro, CAS:503068-36-8, molecular formula: c (C) 28 H 35 Cl 2 NO 6 Molecular weight: 552.49, which is subjected to two steps of reaction to obtain the vilantro, the specific reaction is as follows:
currently, the synthesis of (5R) -3- [6- [2- [ (2, 6-dichlorophenyl) methoxy ] ethoxy ] hexyl ] -5- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxazolidinone is mainly carried out using the following procedure (reference: US 2015239862A):
the route adopts the coupled reaction of vilantt Luo Zhulian 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene and a side chain (5R) -5- (2, 2-dimethyl-4H-1, 3-benzodioxan-6-yl) -1, 3-oxazolidin-2-ketone to obtain (5R) -3- [6- [2- [ (2, 6-dichlorophenyl) methoxy ] ethoxy ] hexyl ] -5- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxazolidinone under the effect of potassium tert-butoxide. Because the vilanabro side chain intermediate (5R) -5- (2, 2-dimethyl-4H-1, 3-benzodioxan-6-yl) -1, 3-oxazolidin-2-one is chiral and requires at least 7 steps of reaction synthesis, it is relatively expensive and an excess of the vilanabro main chain intermediate is typically added in the process to ensure complete conversion of the side chain intermediate. However, the synthesized product (5R) -3- [6- [2- [ (2, 6-dichlorophenyl) methoxy ] ethoxy ] hexyl ] -5- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxazolidone and the main chain raw material are all relatively viscous liquid at normal temperature, and purification by recrystallization is difficult, and meanwhile, the two compounds have relatively high boiling points, the boiling point is about 420.8+/-45.0 ℃ (760 Torr), and the product is easy to decompose at high temperature, so that purification by distillation is difficult. At present, the industry mainly depends on silica gel chromatographic column purification, the production efficiency is limited, and industrialization is difficult to realize.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a process for coupling, post-treatment and purification of a vilantrum Luo Zhulian and a side chain, wherein the vilantrum Luo Zhulian- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene and the side chain (5R) -5- (2, 2-dimethyl-4H-1, 3-benzodioxan-6-yl) -1, 3-oxazolidine-2-ketone are subjected to a coupling reaction, and excessive main chain 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene reacts with pyridine derivatives to form salts, and then the salts are washed by hot water to remove impurities, wherein the specific salification reaction is as follows:
the pyridine derivative is one of pyridine, 2-picolinic acid, 2-hydroxypyridine, 2-aminopyridine, 3-picolinic acid, 3-hydroxypyridine, 3-aminopyridine, 4-picolinic acid, 4-hydroxypyridine and 4-aminopyridine, and preferably 2-picolinic acid, 3-picolinic acid and 4-picolinic acid; after the coupling reaction of the main chain and the side chain is finished, the added pyridine derivative is 10% of the molar quantity of 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene; the pyridine derivative is directly added into a reaction system after the coupling reaction of the main chain and the side chain is finished; the reaction solvent is DMF; the temperature of the hot water is 50 ℃; the reaction time after the pyridine derivative is added is 2 hours.
The invention has the beneficial effects that:
(1) The invention adopts pyridine derivative to wash away excessive main chain 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene after salifying, and the purity of the product can reach more than 99% without purification by silica gel chromatographic column or distillation.
(2) The method is simple to operate, thorough in removal and feasible in large-scale industrial production.
Detailed Description
Example 1:
to a 100L reactor was added (5R) -5- (2, 2-dimethyl-4H-1, 3-benzodioxan-6-yl) -1, 3-oxazolidin-2-one (2.5 kg,10.0 mol) with DMF (20 kg). Potassium tert-butoxide (1.2 kg,10.5 mol) was added to the reaction system in portions at a temperature of less than 30℃for 1 hour, and the mixture was stirred for 1 hour after the addition. 2- [2- (6-Bromohexyloxy) ethoxymethyl was added dropwise at 30-35℃over 1.5 hours]-1, 3-dichlorobenzene (4.2 kg,11.0mol, diluted with 5kg of DMF), stirring at 30-35 ℃ for 2 hours, liquid phase control until complete consumption of (5R) -5- (2, 2-dimethyl-4H-1, 3-benzodioxan-6-yl) -1, 3-oxazolidin-2-one. After that, the process is carried out,4-Pyridinecarboxylic acid (0.135 kg) was added to the reaction system, and stirring was continued at 50℃for 2 hours. Ethyl acetate (25 kg) and water (25 kg) were added to the reaction system, and the mixture was stirred at 50℃for 1 hour. The layers were separated and the organic phase was washed twice with saturated NaCl (10kg+10kg) solution and twice with water (10kg+10kg). The organic phase is added with Na 2 SO 4 (2 kg) drying, filtering, and distilling the filtrate under reduced pressure to remove the solvent to obtain (5R) -3- [6- [2- [ (2, 6-dichlorophenyl) methoxy]Ethoxy group]Hexyl group]-5- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxazolidinone as pale yellow oil (5.1 kg, 92% yield, 99.1% purity in liquid phase, 2- [2- (6-bromohexyloxy) ethoxymethyl group)]-1, 3-dichlorobenzene content < 0.1%).
Example 2:
to a 100L reactor was added (5R) -5- (2, 2-dimethyl-4H-1, 3-benzodioxan-6-yl) -1, 3-oxazolidin-2-one (2.5 kg,10.0 mol) with DMF (20 kg). Potassium tert-butoxide (1.2 kg,10.5 mol) was added to the reaction system in portions at a temperature of less than 30℃for 1 hour, and the mixture was stirred for 1 hour after the addition. 2- [2- (6-Bromohexyloxy) ethoxymethyl was added dropwise at 30-35℃over 1.5 hours]-1, 3-dichlorobenzene (4.2 kg,11.0mol, diluted with 5kg of DMF), stirring at 30-35 ℃ for 2 hours, liquid phase control until complete consumption of (5R) -5- (2, 2-dimethyl-4H-1, 3-benzodioxan-6-yl) -1, 3-oxazolidin-2-one. Thereafter, 4-picolinic acid (0.135 kg) was added to the reaction system and stirring was continued for 1 hour at 50℃by heating. Ethyl acetate (25 kg) and water (25 kg) were added to the reaction system, and the mixture was stirred at 50℃for 1 hour. The layers were separated and the organic phase was washed twice with saturated NaCl (10kg+10kg) solution and twice with water (10kg+10kg). The organic phase is added with Na 2 SO 4 (2 kg) drying, filtering, and distilling the filtrate under reduced pressure to remove the solvent to obtain (5R) -3- [6- [2- [ (2, 6-dichlorophenyl) methoxy]Ethoxy group]Hexyl group]-5- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxazolidinone as a pale yellow oil (5.1 kg, 92% yield, 98.8% purity in liquid phase, 2- [2- (6-bromohexyloxy) ethoxymethyl group)]-1, 3-dichlorobenzene content 0.6%).
Example 3:
(5R) -5- (2, 2-dimethyl-4H-1, 3-Benzodioxan-6-yl) -1, 3-oxazolidin-2-one (250) was added to a 10L reactorg,1.0 mol), DMF (2 kg). Potassium tert-butoxide (120 g,1.05 mol) was added to the reaction system in portions at a temperature of less than 30℃for 1 hour, and the mixture was stirred for 1 hour after the addition. 2- [2- (6-Bromohexyloxy) ethoxymethyl was added dropwise at 30-35℃over 1.5 hours]-1, 3-dichlorobenzene (420 g,1.1mol, diluted with 500g of DMF), stirred at 30-35℃for 2 hours, liquid phase control until complete consumption of (5R) -5- (2, 2-dimethyl-4H-1, 3-benzodioxan-6-yl) -1, 3-oxazolidin-2-one. Thereafter, 4-hydroxypyridine (104 g) was added to the reaction system, and stirring was continued for 2 hours at 50℃with heating. Ethyl acetate (25 kg) and water (25 kg) were added to the reaction system, and the mixture was stirred at 25℃for 1 hour. Ethyl acetate (2.5 kg) and water (2.5 kg) were added to the reaction system, and the mixture was stirred at 25℃for 1 hour. The layers were separated and the organic phase was washed twice with saturated NaCl (1 kg+1 kg) solution and twice with water (1 kg+1 kg). The organic phase is added with Na 2 SO 4 (200g) Drying, filtering, and distilling the filtrate under reduced pressure to remove the solvent to obtain (5R) -3- [6- [2- [ (2, 6-dichlorophenyl) methoxy]Ethoxy group]Hexyl group]-5- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxazolidinone as pale yellow oil (497 g, 91% yield, 98.3% purity in liquid phase, 2- [2- (6-bromohexyloxy) ethoxymethyl)]-1, 3-dichlorobenzene content 0.8%).
Example 4:
to a 10L reactor was added (5R) -5- (2, 2-dimethyl-4H-1, 3-benzodioxan-6-yl) -1, 3-oxazolidin-2-one (250 g,1.0 mol) and DMF (2 kg). Potassium tert-butoxide (120 g,1.05 mol) was added to the reaction system in portions at a temperature of less than 30℃for 1 hour, and the mixture was stirred for 1 hour after the addition. 2- [2- (6-Bromohexyloxy) ethoxymethyl was added dropwise at 30-35℃over 1.5 hours]-1, 3-dichlorobenzene (420 g,1.1mol, diluted with 500g of DMF), stirred at 30-35℃for 2 hours, liquid phase control until complete consumption of (5R) -5- (2, 2-dimethyl-4H-1, 3-benzodioxan-6-yl) -1, 3-oxazolidin-2-one. Ethyl acetate (2.5 kg) and water (2.5 kg) were added to the reaction system, and the mixture was stirred at 50℃for 1 hour. The layers were separated and the organic phase was washed twice with saturated NaCl (1 kg+1 kg) solution and twice with water (1 kg+1 kg). The organic phase is added with Na 2 SO 4 (200g) Drying, filtering, and distilling the filtrate under reduced pressure to remove the solvent to obtain (5R) -3- [6- [2- [ (2, 6-dichlorophenyl) base) Methoxy group]Ethoxy group]Hexyl group]-5- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxazolidinone as pale yellow oil (514 g, 93% yield, 92.6% purity in liquid phase, 2- [2- (6-bromohexyloxy) ethoxymethyl)]-1, 3-dichlorobenzene content 7.3%).
While the foregoing describes the embodiments of the present invention, it should be understood that the present invention is not limited to the embodiments, and that various modifications and changes can be made by those skilled in the art without any inventive effort.
Claims (6)
1. After the coupling reaction of the Violet Luo Zhulian and the side chain, the Violet Luo Zhulian- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene and the side chain (5R) -5- (2, 2-dimethyl-4H-1, 3-benzodioxan-6-yl) -1, 3-oxazolidine-2-ketone are subjected to the coupling reaction, pyridine derivatives are added to react with excessive 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene to form salts, and the salts are removed by heating, wherein the specific salt forming reaction is as follows:
wherein r=4-COOH; 4-OH.
2. A purification process according to claim 1, wherein the pyridine derivative is added in an amount of 10% of the molar amount of 2- [2- (6-bromohexyloxy) ethoxymethyl ] -1, 3-dichlorobenzene.
3. The purification process of claim 1, wherein the heating temperature is 50 ℃.
4. The purification process of claim 1, wherein the pyridine derivative is directly added to the reaction system.
5. A purification process according to claim 1, wherein the reaction solvent is DMF.
6. A purification process according to claim 1, wherein the reaction time after adding pyridine derivatives is 2h.
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