CN105646285A - Vilanterol intermediate, preparation method and application thereof - Google Patents
Vilanterol intermediate, preparation method and application thereof Download PDFInfo
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- CN105646285A CN105646285A CN201410720451.2A CN201410720451A CN105646285A CN 105646285 A CN105646285 A CN 105646285A CN 201410720451 A CN201410720451 A CN 201410720451A CN 105646285 A CN105646285 A CN 105646285A
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Abstract
The invention provides a new Vilanterol intermediate compound 2. According to the invention, primary amino is introduced into a compound 5 through Delepine reaction, then di-tert-butyl dicarbonate is employed for amino protection, and the strategy greatly improves the yield and atom utilization rate. On the other hand, cheap and easily available urotropin is adopted in the invention to lower the cost, thus being easy for industrial large-scale production. Compared with the prior art, the yield of the method involved in the invention is increased to 65% by three-step reaction, also use of expensive di-tert-butyl iminodicarboxylate and cesium carbonate is avoided, the cost is reduced, the operation is simple, and the conditions are mild. Therefore, the method is suitable for industrial preparation of Vilanterol and its key intermediate (5R)-5-(2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl)-1, 3 oxazolidine-2-one. (formula of compound 2).
Description
Technical field
The present invention relates to preparation method's technical field of Wei Lanteluo and key intermediate (5R)-5-thereof (2,2-dimethyl-4H-1,3-benzo dioxine-6-base)-1,3 azoles alkane-2-ketone.
Background technology
Beta-2-adrenoreceptor agonists be clinical on the medicine of the treatment asthma that is most widely used and chronic obstructive pulmonary disease. In existing market, the available the longest acting duration of beta-2-adrenoreceptor agonists is 12 hours, which results in and need to be administered twice every day. In recent ten years, the beta-2-adrenoreceptor agonists that exploitation has high effect, highly selective, rapid-action, long action time, every day are administered once causes showing great attention to of pharmaceutical industries. Three toluylic acid Wei Lanteluo are a kind of Novel ultralong effect beta-2-adrenoreceptor agonists developed by Glaxo Group Ltd, have bronchiectatic activity.
The chemical name of Wei Lanteluo is 4-{ (1R)-2-[(6-{2-[(2,6-dichloro benzyl) oxygen base] oxyethyl group } own base) amino]-1-hydroxyethyl }-2-(methylol) phenol, its structural formula is as follows:
The synthetic route of Wei Lanteluo is mainly:
(5R)-5-(2,2-dimethyl-4H-1,3-benzo dioxine-6-base)-1,3 azoles alkane-2-ketone are important intermediates of preparation Wei Lanteluo. The synthesis of this intermediate at present mainly contains two kinds of methods:
1: the patent WO2014041565 delivered with reference to LaurusLabs company limited, its synthetic route is mainly as follows:
The method shortcoming is obvious, and starting raw material is the bromo-2-methylolphenol of 4-, and price comparison is expensive, and ensuing two-step reaction condition is harsh, it is necessary to low temperature-75 DEG C, and product rate is not high. Very significant discomfort closes large-scale industrial production.
2: reference J.Med.Chem.2010,53,4522-4530 and patent WO2003024439, synthetic route is as follows:
This route take salicylic aldehyde as raw material, synthesizes final intermediate through seven steps, but has single step reaction, the reaction of the bromo-1-of 2-(2,2-dimethyl-4H-1,3-benzo dioxine-6-base) second ketone and imines di-tert-butyl dicarboxylate, product rate is lower, only has 58%; The price comparison of imines di-tert-butyl dicarboxylate and cesium carbonate is expensive simultaneously, and cost is higher;And next step also wants acidolysis to fall a tertiary butoxy carbonyl, atom utilization is lower.
Obviously a kind of synthetic route being suitable for suitability for industrialized production is more needed.
Summary of the invention
The object of the present invention is exactly for above-mentioned the deficiencies in the prior art, it is provided that a kind of new Wei Lanteluo intermediate, utilizes this Intermediate Preparation Wei Lanteluo cost low, is beneficial to suitability for industrialized production.
Another object of the present invention is just to provide described Wei Lanteluo new intermediate preparation method and application thereof.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
A new Wei Lanteluo intermediate, as shown in the formula compound 2:
The chemical name of compound 2 is 2-(3-methylol-4-hydroxy phenyl)-2-carbonylethyl t-butyl carbamate.
The preparation method of formula 2 compound, the method is in solvent medium, and alkali is deposited in case, protects the amino of formula 6 compound to be formed with tert-Butyl dicarbonate:
In the preparation of above-mentioned formula 2 compound, the mixed solvent of reaction solvent most preferably tetrahydrofuran (THF) and water (volume ratio 1:1). Alkali is sodium bicarbonate most preferably, and during reaction, alkali is excessive, it is preferable that 4-8 molar equivalent, it is most preferred that 6 molar equivalents (in compound 6). Tert-Butyl dicarbonate is 1.0-1.1 molar equivalent (in compound 6). Temperature of reaction is not particularly limited, normal-temperature reaction.
Further, described formula 6 compound is in the presence of an organic, by formula 5 compound and urotropine, De Erbin reaction occurs, more acidified hydrolysis obtains:
In the preparation of above-mentioned formula 6 compound, De Erbin reaction solvent is preferably acetic ester, such as one or its mixing of ethyl acetate, isopropyl acetate; The alcohol class of C1-C4, such as one or its mixing of methyl alcohol, ethanol, Virahol, it is more preferable to ethyl acetate. Urotropine is excessive, it is preferable that 1.0-2.0 molar equivalent, it is more preferable to 1.1 molar equivalents, and concentrated hydrochloric acid is excessive, it is preferable that 5 molar equivalents (all in compound 5). Temperature of reaction is not particularly limited, normal-temperature reaction.
In the preparation of above-mentioned formula 6 compound, in acidic hydrolysis process, the alcohol class of the preferred C1-C4 of solvent, such as one or its mixing of methyl alcohol, ethanol, Virahol, it is more preferable to ethanol. Acid is concentrated hydrochloric acid preferably, and concentrated hydrochloric acid is excessive, it is preferable that 1.0-8.0 molar equivalent, it is more preferable to 5 molar equivalents (all in compound 5). Temperature of reaction is not particularly limited, normal-temperature reaction.
Further, described formula 5 compound take acetic acid as solvent, compound 4 reduction is obtained with sodium borohydride:
Further, described formula 4 compound is when Lewis acid, and salicylic aldehyde 3 and bromoacetyl bromide generation friedel-crafts acylation obtain:
The application of formula 2 compound when preparing Wei Lanteluo, key intermediate (the 5R)-5-(2,2-dimethyl-4H-1,3-benzo dioxine-6-base)-1 of Wei Lanteluo is obtained by two-step reaction, 3 azoles alkane-2-ketone, method is as follows:
(5R) preparation method of-5-(2,2-dimethyl-4H-1,3-benzo dioxine-6-base)-1,3 azoles alkane-2-ketone (formula 1 compound), comprises the steps:
1) in solvent medium, catalyzer is deposited in case, and 2,2-Propanal dimethyl acetal and compound 2 react to obtain formula 7 compound:
In a solvent, 2) formula 7 compound is carried out asymmetric reduction and obtain formula 8 compound
3), in organic solvent system, under highly basic effect, the condensation that compound 8 carries out self forms formula 1 compound, i.e. Wei Lanteluo intermediate (5R)-5-(2,2-dimethyl-4H-1,3-benzo dioxine-6-base)-1,3 azoles alkane-2-ketone
The preparation of formula 1 compound, step 1) solvent is preferably from alkyl acetate and chlorinating agent, and alkyl acetate is such as ethyl acetate, isopropyl acetate etc.;Chlorinating agent is such as methylene dichloride etc. The preferred tosic acid monohydrate of catalyzer, the amount of catalyzer is 0.05 molar equivalent (in compound 2) preferably. 2,2-Propanal dimethyl acetal is excessive, it is preferable that 1.1-3.0 molar equivalent, it is more preferable to 2 molar equivalents (all in compound 2). Preferred 10-50 DEG C of temperature of reaction, it is most preferred that 45 DEG C. Step 2) reduction reaction preferably in tetrahydrofuran solvent, taking (R)-Me-CBS as catalyzer, with the tetrahydrofuran solution of the 1 of borine mole, compound 7 is carried out asymmetric reduction. Step 3) said highly basic is organic bases, it is preferable that potassium tert.-butoxide.
The useful effect of the present invention:
1) the present invention introduces primary amino by De Erbin reaction in compound 5, then carries out this strategy of protection of amino with tert-Butyl dicarbonate, substantially increases product rate and atom utilization. And in the prior art, compound 5 cesium carbonate as alkali when, first by the substitution reaction with imines di-tert-butyl dicarboxylate, introduce amido di-tert-butyl dicarboxylate, this step product rate is lower, only 58%; A carboxylic acid tert-butyl ester is taken off in acidolysis again, and atom utilizes low, in the process of acidolysis simultaneously, is also easy to slough two carboxylic acid tert-butyl esters and causes product rate lower. On the other hand, the present invention adopts urotropine cheap and easy to get to instead of imines di-tert-butyl dicarboxylate expensive in prior art literature and cesium carbonate, reduces cost, is easy to industrial mass production.
2) the inventive method is compared with prior art, has significant advantage. Prior art reaction scheme three step product rate is 48% (wherein a step is column chromatography purification), and three-step reaction receipts rate of the present invention is 65%, and avoids using expensive imines di-tert-butyl dicarboxylate and cesium carbonate, reduces cost.
3) starting raw material in corresponding prior art each stage, the method of the present invention is simple to operate, mild condition, cost is low, and receipts rate is also improved, it is that a kind of being applicable to synthesizes Wei Lanteluo and key intermediate (5R)-5-(2,2-dimethyl-4H-1 thereof, 3-benzo dioxine-6-base) industrial method of-1,3 azoles alkane-2-ketone.
Below in conjunction with the embodiment of embodiment, the present invention will be further described.
Embodiment
The synthetic route of reaction is as follows:
The preparation of embodiment 1:5-(2-acetyl bromide)-Benzaldehyde,2-hydroxy 4
Nitrogen protection; under ice bath; aluminum chloride 164g (5eq) is distributed in DCM600mL (20 times amount), slowly drips and add bromoacetyl bromide 99.4g (2eq), after 20min dropwises; temperature rises to room temperature; reaction 1h, drips in this mixture and adds salicylic aldehyde 30g, and 20min dropwises; dripping and finish, at 35 DEG C, reaction is spent the night. Adding frozen water in reaction solution, separation organic layer, after washing, drying, vacuum concentration is done. With DCM and normal hexane recrystallization, filtering to obtain product 36.5g, product rate about has 61%.1HNMR (400MHz, CDCl3): �� 11.52 (s, 1H), 9.99 (s, 1H), 8.30 (s, 1H), 8.17 (d, 1H, J=8Hz), 7.10 (d, 1H, J=8Hz), 4.39 (s, 2H); MS (-ESI) m/z240 [M-H]-
The bromo-1-of the embodiment 2:2-[preparation of 4-hydroxyl-3-(methylol)-phenyl second-1-ketone 5
The acetic acid (10 times amount) that the compound 4 of 40.0g is dissolved in 400mL, under ice bath, adds sodium borohydride 6.8g (1.1eq) in batches, finishes, and room temperature reaction 1h, TLC display reacts completely. Vacuum concentration removes major part acetic acid, and water neutralizes with sodium bicarbonate after diluting, and EA extracts, organic phase washed with water and brine It, and after anhydrous sodium sulfate drying, vacuum concentration is dry to obtain crude product pale powder.White powder 32g is obtained, product rate 80% after washing and starching with DCM backflow.
1HNMR (400MHz, DMSO-d6): �� 10.53 (s, 1H), 7.99 (s, 1H), 7.79 (d, 1H, J=8Hz), 6.87 (d, 1H, J=8Hz), 4.75 (s, 2H), 4.50 (s, 2H); MS (+ESI) m/z267 [M+Na]+
The embodiment 3:2-amino-1-[preparation of the hydrochloride (6) of 4-hydroxyl-3-(methylol)-phenyl second-1-ketone
Being joined by the compound 5 of 10.0g in the ethyl acetate of 200mL, add urotropine (1.1eq) 6.2g, room temperature reaction 1h, TLC display reacts completely. Filter, it is white powder 15.6g after filter cake vacuum-drying. Being dissolved in 150mL ethanol by above-mentioned white powder, add concentrated hydrochloric acid (5eq) 17.5mL, room temperature reaction spends the night, and is done by reaction solution vacuum concentration, obtains pale powder 16.0g (mixture), directly throws in next step.
1HNMR (400MHz, DMSO-d6): �� 10.89 (s, 1H), 8.40 (s, 2H), 7.98 (d, 1H, J=2Hz), 7.70 (dd, 1H, J=8Hzand2Hz), 7.02 (d, 1H, J=8Hz), 4.49 (s, 2H), 4.43 (s, 2H); MS (+ESI) m/z182 [M+H]+
The preparation of embodiment 4:2-(3-methylol-4-hydroxy phenyl)-2-carbonylethyl t-butyl carbamate (2)
By upper step product, namely compound 6 (hydrochloride) 16.0g joins in the water of 150mLTHF and 150mL, adds 20.6gNaHCO3(5eq), drip to add and it is dissolved with 9.8gBoc2The solution of the 30mLTHF of O, 20min dropwises. Room temperature reaction 1h, TLC display reacts completely. Adding water, with EA extraction, organic phase washed with water and brine It, after anhydrous sodium sulfate drying, vacuum concentration is done and to be obtained pressed powder crude product, then obtains white powder 8.7g, two step product rates 76% after the DCM backflow of 1-2 times amount is washed and starched.
1HNMR (400MHz, DMSO-d6): �� 10.35 (dr, 1H), 7.94 (s, 1H), 7.75 (d, 1H, J=8Hz), 6.95 (t, 1H, J=4Hz), 6.85 (t, 1H, J=8Hz), 4.49 (s, 2H), 4.35 (d, 1H, J=4Hz), 1.39 (s, 9H); MS (ES+) m/z304 [M+Na]+
The preparation of embodiment 5:2-(2,2-dimethyl-4H-1,3-benzo dioxine-6-base)-2-carbonylethyl t-butyl carbamate (7)
The compound 2 of 7.0g is dissolved in the DCM (10 times amount) of 70mL, add the p-methyl benzenesulfonic acid (0.05eq) of catalytic amount, lower of backflow adds 2,2-Propanal dimethyl acetal (2eq) is dissolved in the solution of 2 times amount DCM, 40min dropwises, reaction 1h, TLC display reacts completely. Reaction solution is used saturated NaHCO3Washing three times, after organic phase anhydrous sodium sulfate drying, vacuum concentration obtains yellow oil. With isopropyl ether and normal heptane recrystallization, obtain white powder 6.7g, product rate 83%.
1HNMR (400MHz, CDCl3): �� 7.77 (dd, 1H, J=8Hzand2Hz), 7.65 (s, 1H), 6.86 (d, 1H, J=8Hz), 5.51 (dr, 1H), 4.87 (s, 2H), 4.56 (d, 2H, J=4Hz), 1.56 (s, 6H), 1.47 (s, 9H); MS (ES+) m/z344 [M+Na]+
Embodiment 6:(2R) preparation of-2-(2,2-dimethyl-4H-1,3-benzo dioxine-6-base)-2-Hydroxy-ethylamino t-butyl formate (8)
Being joined by 0.78mL catalyzer in the anhydrous THF of 10mL, nitrogen protection, lower of ice bath adds BH3.THF, 20min dropwises. Lower of ice bath adds the solution that 2.5g compound 7 is dissolved in the anhydrous THF of 20mL, and 50min dropwises, and rises to room temperature reaction 0.5h, and TLC display reacts completely.With methyl alcohol cancellation reaction under ice bath, after reaction solution vacuum concentration, adding water, with EA extraction, organic phase washed with water and brine It, after anhydrous sodium sulfate drying, vacuum concentration obtains the faint yellow oily matter of 2.8g. White powder 2.2g, product rate 88% is obtained with sherwood oil after washing and starching.
1HNMR (400MHz, CDCl3): �� 7.13 (dd, 1H, J=8Hzand2Hz), 6.99 (s, 1H), 6.79 (d, 1H, J=8Hz), 4.92 (dr, 1H), 4.71-4.74 (m, 1H), 3.42 (d, 1H, J=12Hz), 3.20-3.25 (m, 1H), 1.53 (s, 6H), 1.44 (s, 9H); MS (+ESI) m/z346 [M+Na]+
Embodiment 7:(5R) preparation of-5-(2,2-dimethyl-4H-1,3-benzo dioxine-6-base)-1,3 azoles alkane-2-ketone (1)
Under nitrogen protection, 1.8g compound 8 is dissolved in the DMF of 15mL, at 10-15 DEG C, adds potassium tert.-butoxide 0.7g (1.1eq) in batches, after room temperature reaction 1h, TLC detection reaction is complete. Adding frozen water, adularescent solid precipitates out, and after stirring at room temperature 3h, takes out filter, and filtration cakes torrefaction obtains white powder 1.0g, product rate 72% (purity 99.6%, ee99.2%).
1HNMR (400MHz, CDCl3): �� 7.15 (dd, 1H, J=8Hzand4Hz), 7.02 (s, 1H), 6.83 (d, 1H, J=8Hz), 6.09 (br, 1H), 5.52 (t, 1H, J=8Hz), 4.84 (s, 2H), 3.92 (t, 1H, J=8Hz), 3.53 (t, 1H, J=8Hz), 1.53 (s, 6H); MS (+ESI) m/z250 [M+H]+��
Claims (14)
1. as shown in the formula compound 2:
2. the preparation method of formula 2 compound, the method is in solvent medium, and alkali is deposited in case, protects the amino of formula 6 compound to obtain with tert-Butyl dicarbonate:
3. the preparation method of formula 2 compound as claimed in claim 2, it is characterised in that: described solvent is the tetrahydrofuran (THF) of 1:1 volume ratio and the mixed solvent of water.
4. the preparation method of formula 2 compound as claimed in claim 2, it is characterised in that: described alkali is sodium bicarbonate, and consumption is the 4-8 molar equivalent of compound 6.
5. the preparation method of formula 2 compound as claimed in claim 2, it is characterised in that: described formula 6 compound is in the presence of an organic, by formula 5 compound and urotropine, De Erbin reaction occurs, more acidified hydrolysis obtains:
6. the preparation method of formula 2 compound as claimed in claim 5, it is characterised in that: De Erbin reaction solvent is ethyl acetate, the one of isopropyl acetate or its mixing, the one of methyl alcohol, ethanol, Virahol or its mixing.
7. the preparation method of formula 2 compound as claimed in claim 5, it is characterised in that: concentrated hydrochloric acid consumption is formula 5 compound 5 molar equivalent.
8. the preparation method of formula 2 compound as claimed in claim 5, it is characterised in that: described formula 5 compound take acetic acid as solvent, compound 4 reduction is obtained with sodium borohydride:
9. the preparation method of formula 2 compound as claimed in claim 5, it is characterised in that: described formula 4 compound is when Lewis acid, and salicylic aldehyde 3 and bromoacetyl bromide generation friedel-crafts acylation obtain:
10. the preparation method of (5R)-5-(2,2-dimethyl-4H-1,3-benzo dioxine-6-base)-1,3 azoles alkane-2-ketone, comprises the steps:
1) in solvent medium, catalyzer is deposited in case, and 2,2-Propanal dimethyl acetal and compound 2 react to obtain formula 7 compound:
In a solvent, 2) formula 7 compound is carried out asymmetric reduction and obtain formula 8 compound
3), in organic solvent system, under highly basic effect, the condensation that compound 8 carries out self forms formula 1 compound, i.e. Wei Lanteluo intermediate (5R)-5-(2,2-dimethyl-4H-1,3-benzo dioxine-6-base)-1,3 azoles alkane-2-ketone
11. (5R)-5-(2 as claimed in claim 10,2-dimethyl-4H-1,3-benzo dioxine-6-base) preparation method of-1,3 azoles alkane-2-ketone, it is characterised in that: step 1) solvent is selected from ethyl acetate, isopropyl acetate and methylene dichloride.
12. (5R)-5-(2 as claimed in claim 10,2-dimethyl-4H-1,3-benzo dioxine-6-base)-1, the preparation method of 3 azoles alkane-2-ketone, it is characterized in that: step 1) catalyzer is tosic acid monohydrate, the consumption of catalyzer is formula 2 compound 0.05 molar equivalent.
13. (5R)-5-(2 as claimed in claim 10,2-dimethyl-4H-1,3-benzo dioxine-6-base)-1, the preparation method of 3 azoles alkane-2-ketone, it is characterized in that: step 2) in tetrahydrofuran solvent, taking (R)-Me-CBS as catalyzer, with the tetrahydrofuran solution of the 1 of borine mole, compound 7 is carried out asymmetric reduction.
The preparation method of 14. (5R)-5-as claimed in claim 10 (2,2-dimethyl-4H-1,3-benzo dioxine-6-base)-1,3 azoles alkane-2-ketone, it is characterised in that: step 3) described in highly basic be potassium tert.-butoxide.
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Cited By (4)
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| CN109574982A (en) * | 2019-01-22 | 2019-04-05 | 安徽德信佳生物医药有限公司 | A kind of method of solid acid catalysis synthesis Vilantro intermediate |
| CN109574817A (en) * | 2019-01-22 | 2019-04-05 | 安徽德信佳生物医药有限公司 | A method of Vilantro intermediate is synthesized in the mixed solvent |
| CN112250660A (en) * | 2020-10-22 | 2021-01-22 | 常州亚邦制药有限公司 | Preparation method of salbutamol sulfate impurity |
| CN114736186A (en) * | 2022-05-13 | 2022-07-12 | 安徽德信佳生物医药有限公司 | Method for synthesizing vilanterol intermediate from tert-butyl carbamate |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109574982A (en) * | 2019-01-22 | 2019-04-05 | 安徽德信佳生物医药有限公司 | A kind of method of solid acid catalysis synthesis Vilantro intermediate |
| CN109574817A (en) * | 2019-01-22 | 2019-04-05 | 安徽德信佳生物医药有限公司 | A method of Vilantro intermediate is synthesized in the mixed solvent |
| CN109574982B (en) * | 2019-01-22 | 2020-11-27 | 安徽德信佳生物医药有限公司 | Method for synthesizing vilanterol intermediate under catalysis of solid acid |
| CN109574817B (en) * | 2019-01-22 | 2021-09-14 | 安徽德信佳生物医药有限公司 | Method for synthesizing vilanterol intermediate in mixed solvent |
| CN112250660A (en) * | 2020-10-22 | 2021-01-22 | 常州亚邦制药有限公司 | Preparation method of salbutamol sulfate impurity |
| CN114736186A (en) * | 2022-05-13 | 2022-07-12 | 安徽德信佳生物医药有限公司 | Method for synthesizing vilanterol intermediate from tert-butyl carbamate |
| CN114736186B (en) * | 2022-05-13 | 2023-08-08 | 安徽德信佳生物医药有限公司 | Method for synthesizing Violet Luo Zhongjian body from tert-butyl carbamate |
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