CN104745652A - Preparation method of Montelukast intermediate - Google Patents
Preparation method of Montelukast intermediate Download PDFInfo
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- CN104745652A CN104745652A CN201510131434.XA CN201510131434A CN104745652A CN 104745652 A CN104745652 A CN 104745652A CN 201510131434 A CN201510131434 A CN 201510131434A CN 104745652 A CN104745652 A CN 104745652A
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- montelukast
- montelukast intermediate
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Abstract
The invention relates to a preparation method of a Montelukast intermediate. The preparation method is characterized in that a compound 1 is subjected to reduction reaction under the actions of ketoreductase, a hydrogen donor, a coenzyme and a cofactor to generate the Montelukast intermediate, wherein the reduction reaction is carried out in a buffer solution with a pH value of 7.5-8.5; the reaction temperature is 40-50 DEG C; the hydrogen donor is isopropanol; the cofactor is a magnesium ion. The preparation method has the advantages that the Montelukast intermediate can be obtained at a conversion rate of 99% and has optical purity of 99.4%ee; compared with the traditional methods, the method has the effects of reducing the reaction steps and reducing the consumption of a Grignard reagent, so that the method is more suitable for large-scale production.
Description
Technical field
the invention belongs to bio-pharmaceuticals and technical field of biochemical industry, be specifically related to a kind of preparation method of Montelukast intermediate.
Background technology
singulair is a kind of selectivity LTRA (LTRA), and its structural formula is
.Singulair is the LTRA anti-asthmatic medicament taken once current unique a kind of every day, easy administration, and range of application is comparatively wide, and 2004 annual sales amounts reach 2,400,000,000 dollars.
singulair contains chiral hydroxyl group center, existing syntheti c route 1(as shown in Figure 1), it obtains chiral intermediate b by chemical method or biological process reduction precursor compound a, then generates c by b and grignard reagent react, finally synthesizes d(and Montelukast by c) (WO 2010064109).Reduction from a to b can with chemical method as J.Am.Chem.Soc.1996, and 118,2521 and WO 2008/009970, or biological process is as Org.Process Res.Dev.2010,14,193 and WO 2009/042984.The synthetic route that above preparation method's Problems existing comprises (1) a is long; (2) synthesize the processing condition harshness of key intermediate c from b, and need 5 equivalent Grignard reagents (WO 2010064109).
disclose one preferably alternative route (as shown in Figure 2), its first composite structure formula is
intermediate 1, then this intermediate reduction is become Singulair intermediate
.The advantage of this route is that synthetic route is short, only needs 2 equivalent Grignard reagents, without the need to re-using Grignard reagent reaction after chiral centre synthesis.But Problems existing how can reduce to high conversion and turning property of high mapping choosing 1 to obtain Singulair intermediate.Patent WO 2014081616 report utilizes high pressure (hydrogen 40 psi) and expensive metal ruthenium catalyst to react, and energy consumption is large and environment friendly is poor; Enzyme catalysis reduction can solve the problem, and patent WO 2009/042984 has also attempted utilizing ketoreductase reduction 1 to generate Singulair intermediate, although optical purity is greater than 99%, within 24 hours, transformation efficiency only has 67%, is difficult to practical industrialization.
Summary of the invention
technical problem to be solved by this invention is to provide the preparation method of a kind of product optical purity and the high Montelukast intermediate of transformation efficiency.
for solving above technical problem, the present invention takes following technical scheme:
a kind of preparation method of Montelukast intermediate, compound 1 issues the Montelukast intermediate described in the generation of raw reduction reaction in the effect of ketoreductase, hydrogen donor, coenzyme and cofactor, described reduction reaction is carry out in the buffered soln of 7.5 ~ 8.5 at pH, temperature of reaction is 40 DEG C ~ 50 DEG C, wherein, described hydrogen donor is Virahol, and described cofactor is magnesium ion
the structural formula of described compound 1 is:
；
the structural formula of described Montelukast intermediate is:
。
particularly, described coenzyme is NADP.
particularly, described cofactor feeds intake with the form of magnesium chloride.
particularly, described ketoreductase is be the ketoreductase of EW012 purchased from the trade mark of Suzhou Chinese biotechnology of enzymes company limited.
particularly, in initial action system, the concentration of described compound 1 is 0.09 ~ 0.12g/mL, the mass ratio of described ketoreductase, described coenzyme, described cofactor, described compound 1 is 0.018 ~ 0.022:0.0018 ~ 0.0022:0.0038 ~ 0.0042:1, and the volume that feeds intake of described Virahol is 52% ~ 58% of reaction system cumulative volume.
particularly, described buffered soln is trolamine hydrochloride buffer solution.
more specifically, the volumetric molar concentration of described buffered soln is 0.09 mol/ L ~ 0.11mol/L, pH is 7.9 ~ 8.1.
particularly, described reaction is carried out at 43 DEG C ~ 47 DEG C.
particularly, described compound 1 is by step (1) and step (2) synthesis:
step (1), o-bromobenzoic acid methyl esters and methylmagnesium-chloride being added in organic solvent, at-8 DEG C ~-3 DEG C, react 2h ~ 4h, after then adding acetic acid solution cancellation reaction, obtaining adjacent bromobenzene Virahol through washing drying;
step (2), by described adjacent bromobenzene Virahol and compound 2 at dimethyl formamide, N, under the existence of N-dicyclohexylmethylamine, tri-o-tolyl phosphine and dichloro two ammino palladium, react at 95 DEG C ~ 105 DEG C, after having reacted, be cooled to 45 DEG C ~ 55 DEG C, compound 1 described in separating out through washing
wherein, the structural formula of described compound 2 is:
。
more specifically, in initial action system, the amount of substance of described o-bromobenzoic acid methyl esters and described methylmagnesium-chloride is than being 1:1.9 ~ 2.2, and the volumetric molar concentration of described o-bromobenzoic acid methyl esters is 1.9 ~ 2.2mol/L.
more specifically, in step (1), described organic solvent is methylene dichloride.
more specifically, in initial action system, the mass ratio of described adjacent bromobenzene Virahol, described compound 2, described tri-o-tolyl phosphine, described dichloro two ammino palladium is 42 ~ 45:60 ~ 65:0.9 ~ 1.1:1, described dimethyl formamide and described N, the volume ratio of N-dicyclohexylmethylamine is 3 ~ 5:1, and the concentration of described adjacent bromobenzene Virahol is 0.15 ~ 0.2g/mL.
the all commercially available acquisition of reaction reagent in the present invention.
due to the enforcement of above technical scheme, the present invention compared with prior art tool has the following advantages:
the present invention, by reducing to compound 1 with biological process, by the optimization regulated reaction, can obtain Montelukast intermediate, and optical purity reaches 99.4%ee, thus make present method meet industrialized requirement with the transformation efficiency of 99%.
Accompanying drawing explanation
accompanying drawing 1 is synthetic route chart of the prior art;
accompanying drawing 2 is the synthetic route chart substituted.
Embodiment
below in conjunction with specific embodiment, the present invention will be further described in detail, but the present invention is not limited to following examples.The implementation condition adopted in embodiment can require to do further adjustment according to the concrete difference used, and not marked implementation condition is the condition in normal experiment.
embodiment 1: synthetic route is shown in Fig. 2.
step (1), reactant o-bromobenzoic acid methyl esters 43 g(0.2 mol) add in the reactor that 100 mL methylene dichloride are housed, 30 g(0.4 mol are added after being cooled to-5 DEG C) methylmagnesium-chloride, stir the 10% acetic acid solution cancellation reaction adding 100 mL after 3 hours, organic phase is after saturated sodium carbonate solution washing, revolve that evaporate to dryness is dry obtains adjacent bromobenzene Virahol 40 g, HPLC purity 98%.
step (2), by adjacent bromobenzene Virahol 21.5 g(0.1 mol) add compound 2, DMF(dimethyl formamide) 100 mL, N, N-dicyclohexylmethylamine 25 mL, tri-o-tolylphosphine(tri-o-tolyl phosphine) 0.5 g, trans-Diamminedichloropalladium (II) (dichloro two ammino palladium) 0.5 g, be heated to 100 DEG C to reacting completely, be cooled to 50 DEG C to add isopyknic deionized water and make compound 1 separate out 50 g, HPLC purity 95%.
5 g compounds 1 are added in step (3), reactor, 0.1 M pH 8.0 trolamine hydrochloride buffer solution 20 mL, Virahol 25 mL, ketoreductase (purchased from Suzhou Chinese biotechnology of enzymes company limited, trade mark EW012) 0.1 g, NADP 10 mg, magnesium chloride 20 mg, 45 DEG C of stirring reactions 18 hours, HPLC detection substrate transformation efficiency 99.1%, the HPLC purity 99% of product, optical purity 99.4%.
comparative example 1
step (1) and step (2) are with embodiment 1.
5 g compounds 1 are added in step (3), reactor, 0.1 M pH 8.5 phosphoric acid hydrochloric acid buffer solution 50 mL, glucose 5 g, ketoreductase is (purchased from Suzhou Chinese biotechnology of enzymes company limited, trade mark EW012) 0.1 g, Hexose phosphate dehydrogenase (purchased from Suzhou Chinese biotechnology of enzymes company limited, trade mark EW002) 0.1 g, NADP 10 mg, magnesium chloride 20 mg, 40 DEG C of stirring reactions 24 hours, HPLC detection substrate transformation efficiency 90.2%, the optical purity 99.4% of product.
above to invention has been detailed description; its object is to allow the personage being familiar with this art can understand content of the present invention and be implemented; can not limit the scope of the invention with this; the equivalence change that all spirit according to the present invention are done or modification, all should be encompassed in protection scope of the present invention.
Claims (10)
1. the preparation method of a Montelukast intermediate, it is characterized in that: compound 1 issues the Montelukast intermediate described in the generation of raw reduction reaction in the effect of ketoreductase, hydrogen donor, coenzyme and cofactor, described reduction reaction is carry out in the buffered soln of 7.5 ~ 8.5 at pH, temperature of reaction is 40 DEG C ~ 50 DEG C, wherein, described hydrogen donor is Virahol, and described cofactor is magnesium ion
The structural formula of described compound 1 is:
；
The structural formula of described Montelukast intermediate is:
。
2. the preparation method of Montelukast intermediate according to claim 1, is characterized in that: described coenzyme is NADP.
3. the preparation method of Montelukast intermediate according to claim 1, is characterized in that: described ketoreductase is be the ketoreductase of EW012 purchased from the trade mark of Suzhou Chinese biotechnology of enzymes company limited.
4. the preparation method of Montelukast intermediate according to claim 1, it is characterized in that: in initial action system, the concentration of described compound 1 is 0.09 ~ 0.12g/mL, the mass ratio of described ketoreductase, described coenzyme, described cofactor, described compound 1 is 0.018 ~ 0.022:0.0018 ~ 0.0022:0.0038 ~ 0.0042:1, and the volume that feeds intake of described Virahol is 52% ~ 58% of reaction system cumulative volume.
5. the preparation method of Montelukast intermediate according to claim 1, is characterized in that: described buffered soln is trolamine hydrochloride buffer solution.
6. the preparation method of Montelukast intermediate according to claim 5, is characterized in that: the volumetric molar concentration of described buffered soln is 0.09 mol/ L ~ 0.11mol/L, pH is 7.9 ~ 8.1.
7. the preparation method of Montelukast intermediate according to claim 1, is characterized in that: described compound 1 is by step (1) and step (2) synthesis:
Step (1), o-bromobenzoic acid methyl esters and methylmagnesium-chloride being added in organic solvent, at-8 DEG C ~-3 DEG C, react 2h ~ 4h, after then adding acetic acid solution cancellation reaction, obtaining adjacent bromobenzene Virahol through washing drying;
Step (2), by described adjacent bromobenzene Virahol and compound 2 at dimethyl formamide, N, under the existence of N-dicyclohexylmethylamine, tri-o-tolyl phosphine and dichloro two ammino palladium, react at 95 DEG C ~ 105 DEG C, after having reacted, be cooled to 45 DEG C ~ 55 DEG C, compound 1 described in separating out through washing
Wherein, the structural formula of described compound 2 is:
。
8. the preparation method of Montelukast intermediate according to claim 7, it is characterized in that: in initial action system, the amount of substance of described o-bromobenzoic acid methyl esters and described methylmagnesium-chloride is than being 1:1.9 ~ 2.2, and the volumetric molar concentration of described o-bromobenzoic acid methyl esters is 1.9 ~ 2.2mol/L.
9. the preparation method of Montelukast intermediate according to claim 7, is characterized in that: in step (1), and described organic solvent is methylene dichloride.
10. the preparation method of Montelukast intermediate according to claim 7, it is characterized in that: in initial action system, the mass ratio of described adjacent bromobenzene Virahol, described compound 2, described tri-o-tolyl phosphine, described dichloro two ammino palladium is 42 ~ 45:60 ~ 65:0.9 ~ 1.1:1, described dimethyl formamide and described N, the volume ratio of N-dicyclohexylmethylamine is 3 ~ 5:1, and the concentration of described adjacent bromobenzene Virahol is 0.15 ~ 0.2g/mL.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116891879A (en) * | 2023-09-08 | 2023-10-17 | 山东静远药业有限公司 | Synthesis method of buvaracetam key intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009042984A1 (en) * | 2007-09-28 | 2009-04-02 | Codexis, Inc. | Ketoreductase polypeptides and uses thereof |
| CN104293850A (en) * | 2014-08-12 | 2015-01-21 | 江苏恒盛药业有限公司 | Montelukast sodium preparation technology and intermediates |
-
2015
- 2015-03-25 CN CN201510131434.XA patent/CN104745652A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009042984A1 (en) * | 2007-09-28 | 2009-04-02 | Codexis, Inc. | Ketoreductase polypeptides and uses thereof |
| CN101889081A (en) * | 2007-09-28 | 2010-11-17 | 科德克希思公司 | Ketoreductase polypeptides and uses thereof |
| CN104293850A (en) * | 2014-08-12 | 2015-01-21 | 江苏恒盛药业有限公司 | Montelukast sodium preparation technology and intermediates |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116891879A (en) * | 2023-09-08 | 2023-10-17 | 山东静远药业有限公司 | Synthesis method of buvaracetam key intermediate |
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