CN105152980A - Chiral preparation method for N-t-butyloxycarboryl-(4S)-(p-phenyl phenyl methyl)-4-amino-(2R)-methylbutyric acid - Google Patents
Chiral preparation method for N-t-butyloxycarboryl-(4S)-(p-phenyl phenyl methyl)-4-amino-(2R)-methylbutyric acid Download PDFInfo
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a chiral preparation method for N-t-butyloxycarboryl-(4S)-(p-phenyl phenyl methyl)-4-amino-(2R)-methylbutyric acid. The chiral preparation method comprises the following step: enabling a compound (1) and hydrogen to react in the presence of Pd/C and (S-phenylethylamine), thereby preparing a compound (2-a) as shown in the specification. The chiral preparation method is simple in reaction condition, easy to operate, easy in obtaining reagents, and applicable to industrial production, the cost can be lowered as an expensive chiral catalyst is not used, and both the reaction efficiency is improved and the product purity is ensured.
Description
Technical field
The present invention relates to the chiral method for preparing of a kind of N-tertbutyloxycarbonyl-(4S)-(to phenylphenylmethyl)-4-amino-(2R)-methylbutyric.
Background technology
The mixture that LCZ696 is made up of sacubitril (i.e. AHU-377) and valsartan, be first be also a unique medicine surmounting standard care medicine enalapril (enalapril) evident in efficacy in clinical trial, and show higher security; It is also a kind of pioneering economic benefits and social benefits angiotensin receptor-enkephalinase inhibitor (ARNI) simultaneously; there is unique binding mode; protectiveness neuroendocrine system (the NP system of heart can be strengthened; natriuretic peptide system); and suppress harmful system (RAAS system; renin-angiotensin-aldosterone system), be believed to the strain reducing failure heart.This medicine is researched and developed by Novartis, obtains FDA approval on July 7th, 2015, and for the heart failure patient that ejection fraction reduces, reduce cardiovascular death and heart failure and to be in hospital risk, commodity are called Entresto.
Shown in formula (2-a), compound is the intermediate of synthesis AHU-377, and chemical name is: N-tertbutyloxycarbonyl-(4S)-(to phenylphenylmethyl)-4-amino-(2R)-methylbutyric, and structural formula is as follows:
A kind of synthetic method about N-tertbutyloxycarbonyl-(4S)-(to phenylphenylmethyl)-4-amino-(2R)-methylbutyric is disclosed in patent CN101516831, specifically comprise and (i-a) is reacted with chiral catalyst, obtain (ii-a) and (ii-b); Use two kinds of chiral catalysts the ratio of diastereomer can be brought up to more than 88:12 in the method, but the price of these two kinds of chiral catalysts is all very expensive, considerably increases reaction cost, is unsuitable for suitability for industrialized production, reaction scheme is as follows:
Summary of the invention
For solving problems of the prior art, the invention provides the chiral method for preparing of N-tertbutyloxycarbonyl-(4S)-(to phenylphenylmethyl)-4-amino-(2R)-methylbutyric that a kind of selective cost is low, purity is good.
The object of the present invention is to provide the chiral method for preparing of N-tertbutyloxycarbonyl-(4S)-(to phenylphenylmethyl)-4-amino-(2R)-methylbutyric shown in a kind of formula (2-a), comprise, compound (1) reacts with hydrogen and prepares compound (2-a) under Pd/C and (S)-phenylethylamine participate in:
The mole dosage of described (S)-phenylethylamine is preferably the 0.7-1.5 of compound (1) mole dosage doubly, is more preferably 1.0 times of compound (1) mole dosage.
The available 10%Pd/C of described palladium charcoal (Pd/C), the quality of described 10%Pd/C is the 5%-10% of compound (1) quality;
The pressure of described hydrogen is 1.0-10.0bar (1atm=1.033bar), preferred 1.0-6.0bar, more preferably 3.5-4.0bar;
The temperature of described reaction is 25 DEG C-solvent reflux temperature, preferably 40 DEG C-solvent reflux temperature, more preferably 40 DEG C-60 DEG C, and described solvent reflux temperature is different because of the solvent difference selected;
Described reaction is carried out under organic solvent participates in, and the conventional organic solvents such as such as alcoholic solvent, ether solvent, varsol or esters solvent, described organic solvent is preferably methyl alcohol, ethanol, ethyl acetate or tetrahydrofuran (THF), is more preferably ethanol.
Pale solid is obtained after described reaction terminates, described pale solid need carry out following aftertreatment: the mineral acid (be 1 work as gauge with the charging capacity of compound (1)) adding appropriate water, appropriate organic solvent and be no less than 1 equivalent stirs, then cross and filter insolubles and obtain filtrate, filtrate leaves standstill, layering, collected organic layer, the solvent finally removing organic layer obtains product; Described organic solvent can be the conventional organic solvents such as halogenated hydrocarbon solvent, esters solvent, ether solvent or alkane solvents, preferably methylene dichloride, ethyl acetate or tetrahydrofuran (THF) etc.; Described mineral acid is preferably hydrochloric acid or sulfuric acid.
Described compound (2-a) is purified with the mixed solvent of ethyl acetate/heptane, and the volume ratio of described ethyl acetate/heptane is 1:2-1:10, and preferably 1:4-1:6, is more preferably 1:4.
Wherein, the synthesis of compound (1) can referenced patent US5217996.
Researchist in research process first with compound (1) for raw material, carry out hydrogenation and split two-step reaction preparing compound (2-a), wherein hydrogenation carries out under Pd/C catalysis, and resolution reaction is with (S)-phenylethylamine for resolution reagent, and route is as follows:
Result of study shows, after hydrogenation, compound (2-a) is 73.34:26.66 with the ratio of compound (2-b), compound (2-a) and the ratio of compound (2-b) can be brought up to 95.03:4.97 after fractionation, although the method reduces cost to a certain extent, its total recovery only has 61.4%.In order to improve the chiral purity of reaction yield and product further, inventors performed a large amount of experiments, and find unexpectedly, when hydrogenation and resolution reaction merge into (reaction scheme provided by the invention) when step is carried out, reaction yield significantly improves; And when the pressure of hydrogen is 3.5-4.0bar, temperature of reaction is 40 DEG C-60 DEG C, using (S)-phenylethylamine as resolution reagent, (S) when the mole dosage of-phenylethylamine is 1.0 times of compound (1), reaction effect is best, diastereomer (2-a) is 97.62:2.38 with the ratio of (2-b), yield 95.7%; Even can by diastereomer (2-a) after being further purified by ethyl acetate/heptane (volume ratio 1:4) mixed solvent: the ratio of (2-b) brings up to 99.97:0.03, hardly containing compound (2-b), total recovery is up to 88.1%.
Reaction conditions of the present invention is simple to operation, and agents useful for same is easy to get, and while avoiding using expensive chiral catalyst to reduce costs, improves reaction yield, in turn ensure that the purity of product, be applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the HPLC collection of illustrative plates of compound (2-a), the position that retention time is about 12min is compound (2-a), the position that retention time is about 15min is compound (2-b), (2-a) not containing other impurity: (2-b)=97.62:2.38, and in product.
Fig. 2 is the HPLC collection of illustrative plates of compound (2-a), the position that retention time is about 12min is compound (2-a), the position that retention time is about 15min is compound (2-b), (2-a): (2-b)=99.97:0.03.
Fig. 3 is the HPLC collection of illustrative plates of compound (2), the position that retention time is about 12min is compound (2-a), the position that retention time is about 15min is compound (2-b), (2-a): (2-b)=73.34:26.66.
Fig. 4 is the HPLC collection of illustrative plates of compound (2-a), the position that retention time is about 12min is compound (2-a), the position that retention time is about 15min is compound (2-b), (2-a): (2-b)=95.03:4.97.
Embodiment
Below in conjunction with embodiment, the invention will be further described, but protection content of the present invention is not limited only to these embodiments.
In the following example, method therefor if no special instructions, is ordinary method.Reagent of the present invention can be obtained by commercially available purchase.
Embodiment 1
Get compound (1) (20.0g, 1.0 equivalents) be dissolved in ethanol (50ml), add (S)-phenylethylamine (5.9g, 1.0 equivalents), 10%Pd/C (2.0g), reaction solution is placed in 40 DEG C of oil bath heated and stirred under the hydrogen pressure of 4.0bar and reacts 2.5 hours, then be cooled to room temperature, system is gray suspension, direct filtration, obtain pale solid, be placed in reaction flask, add water (20ml), methylene dichloride (80ml), hydrochloric acid (6mol/L, 10ml), stirring at room temperature 1 hour, cross and filter Pd/C, system separatory subsequently, collect dichloromethane layer, anhydrous sodium sulfate drying, filter, pressure reducing and steaming solvent, obtain white solid 20.1g.HPLC detects, and diastereomer ratio is (2-a): (2-b)=97.62:2.38.
Purify with 100ml ethyl acetate/heptane (1:4) recrystallization, obtain white solid 18.5g.HPLC detects, and diastereomer ratio is (2-a): (2-b)=99.97:0.03.
The HPLC collection of illustrative plates of the compound (2-a) that Fig. 1 obtains before showing the method crystallization, the position that retention time is about 12min is compound (2-a), the position that retention time is about 15min is compound (2-b), as shown in the figure, containing a small amount of compound (2-b) in product, and not containing other impurity.
Fig. 2 shows the HPLC collection of illustrative plates with the compound (2-a) obtained after ethyl acetate/heptane (volume ratio 1:4) recrystallization, the position that retention time is about 12min is compound (2-a), the position that retention time is about 15min is compound (2-b), as shown in the figure, after recrystallization, hardly containing compound (2-b) in product.
Embodiment 2
Get compound (1) (500g, 1.0 equivalents) be dissolved in ethanol (1300ml), add (S)-phenylethylamine (148g, 1.0 equivalents), 10%Pd/C (50g), reaction solution is placed in 40 DEG C of oil bath heated and stirred under the hydrogen pressure of 4.0bar and reacts 2.5 hours, then be cooled to room temperature, system is gray suspension, direct filtration, obtain pale solid, be placed in reaction flask, add water (500ml), methylene dichloride (2000ml), hydrochloric acid (6mol/L, 250ml), stirring at room temperature 1 hour, cross and filter Pd/C, system separatory subsequently, collect dichloromethane layer, anhydrous sodium sulfate drying, filter, pressure reducing and steaming solvent, obtain white solid 484.8g.HPLC detects, and diastereomer ratio is (2-a): (2-b)=97.69:2.31.
Purify with 2500ml ethyl acetate/heptane (1:4) recrystallization, obtain white solid 452.2g.HPLC detects, and diastereomer ratio is (2-a): (2-b)=99.97:0.03.
Embodiment 3
Getting compound (1) (20.0g) is dissolved in ethanol (50ml), add 10%Pd/C (2.0g), under the hydrogen pressure of 3.5bar, reaction solution is placed in 40 DEG C of oil bath heated and stirred 2 hours, then be cooled to room temperature, cross and filter Pd/C, pressure reducing and steaming solvent, obtains compound as white solid (2) (21.0g).HPLC detects, compound (2-a): (2-b)=73.34:26.66.
By above-claimed cpd (2) (21.0g, 1.0 equivalents) be dissolved in 210ml ethanol, (S)-phenylethylamine (6.3g is slowly added under stirring at room temperature, 1.0 equivalents), system gradually adularescent solid is separated out, stir after 2 hours, filter, filter cake 105ml washing with alcohol.Filter cake after washing is placed in reaction flask, add water (20ml), methylene dichloride (80ml), hydrochloric acid (6mol/L, 10ml), stirring at room temperature 1 hour, system separatory, collects dichloromethane layer, anhydrous sodium sulfate drying, filter, pressure reducing and steaming solvent, obtains white solid 12.9g.HPLC detects, and diastereomer ratio is (2-a): (2-b)=95.03:4.97.
The HPLC collection of illustrative plates of the compound (2) that Fig. 3 obtains after showing hydrogenation, the position that retention time is about 12min is compound (2-a), the position that retention time is about 15min is compound (2-b), as shown in the figure, after hydrogenation, containing more compound (2-b) in product.
The HPLC collection of illustrative plates of the compound (2-a) obtained after (S)-phenylethylamine fractionation that Fig. 4 shows, the position that retention time is about 12min is compound (2-a), the position that retention time is about 15min is compound (2-b), as shown in the figure, after splitting, the ratio of compound (2-a) increases.
Embodiment 4
Compound (2-a) is prepared according to the method for embodiment 1, be 1 equivalent with the consumption of compound (1), change pressure and the hydrogenation temperature of hydrogen in resolution reagent, the consumption of (S)-phenylethylamine, hydrogenation respectively, observe the change of these factors to the impact of yield before product crystallization, and the ratio of diastereomer before monitoring crystallization, as shown in the table:
As shown above, the change of (S)-phenylethylamine amount has considerable influence to the yield before product crystallization, does not have much affect to the ratio of diastereomer; But when the equivalent of (S)-phenylethylamine is more than 1.0, also can not there is too large change in reaction yield; Continue the amount increasing (S)-phenylethylamine, unnecessary part is as liquid waste disposal.In addition, operate by the method for embodiment 1, when replacing (S)-phenylethylamine with the conventional resolution reagent such as L-Phe, L-Leu, L-PROLINE methyl esters, the solid of minute quantity can only be separated out or separate out without solid at all, therefore, researchist selects (S)-phenylethylamine as optimal selection, and the mole dosage of (S)-phenylethylamine is decided to be the 0.7-1.5 of compound (1) mole dosage doubly.
In experimentation, researchist finds, the pressure of hydrogen in reaction and temperature of reaction almost do not affect the ratio of diastereomer after reaction, but larger to the time effects of reaction; When hydrogen pressure is more than 4.0bar, when temperature of reaction is more than 60 DEG C, the change in reaction times is also little, consider the cost of High Temperature High Pressure, researchist is pressure 3.5-4.0bar the most at last, and temperature 40 DEG C-60 DEG C is as most preferred reaction conditions, and particular case is as shown in the table:
Embodiment 5:
Prepare compound (2-a) according to the method for embodiment 1, get each 20.1g of the product before crystallization and test for recrystallization, the ratio of its diastereomer is (2-a): (2-b)=97.62:2.38.Change the volume ratio of ethyl acetate/heptane, research uses the ethyl acetate/heptane recrystallization of different ratios on the impact of diastereomer ratio, the results are shown in following table:
| Ethyl acetate/heptane volume ratio | Crystallization after product weight | After crystallization (2-a): (2-b) |
| 1:2 | 5.5g | 99.97:0.03 |
| 1:4 | 18.5g | 99.97:0.03 |
| 1:6 | 18.9g | 98.51:1.49 |
| 1:8 | 19.8g | 97.85:2.15 |
| 1:10 | 20.1g | 97.62:2.38 |
Claims (10)
1. the chiral method for preparing of N-tertbutyloxycarbonyl-(4S)-(to phenylphenylmethyl)-4-amino-(2R)-methylbutyric shown in a formula (2-a), it is characterized in that, described method comprises compound 1 and reacts with hydrogen under Pd/C and (S)-phenylethylamine participate in
2. method according to claim 1, is characterized in that, the mole dosage of described (S)-phenylethylamine is 0.7-1.5 times of compound 1 mole dosage.
3. method according to claim 2, is characterized in that, the mole dosage of described (S)-phenylethylamine is 1.0 times of compound 1 mole dosage.
4., according to the arbitrary described method of claim 1-3, it is characterized in that, described Pd/C is 10%Pd/C, and the quality of described 10%Pd/C is the 5%-10% of compound (1) quality.
5., according to the arbitrary described method of claim 1-4, it is characterized in that, the pressure of described hydrogen is 1.0-10.0bar, and the temperature of described reaction is 25 DEG C-solvent reflux temperature.
6. method according to claim 5, is characterized in that, the pressure of described hydrogen is 3.5-4.0bar, and temperature of reaction is 40 DEG C-60 DEG C.
7., according to the arbitrary described method of claim 1-6, it is characterized in that, described method also comprises: the mixed solvent of the reaction product ethyl acetate/heptane of claim 1 is carried out purifying.
8. method according to claim 7, it is characterized in that, described purification process for: described in claim 1 reaction terminate after obtain pale solid, add appropriate water, appropriate organic solvent and mineral acid to stir, then cross and filter insolubles and obtain filtrate, filtrate leaves standstill, layering, and collected organic layer, the solvent finally removing organic layer obtains product.
9. method according to claim 7, is characterized in that, in described mixed solvent, the volume ratio of ethyl acetate/heptane is 1:2-1:10.
10. method according to claim 9, is characterized in that, in described mixed solvent, the volume ratio of ethyl acetate/heptane is 1:4.
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Cited By (6)
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| CN106699604A (en) * | 2017-01-09 | 2017-05-24 | 四川同晟生物医药有限公司 | Sacubitril and preparation method of midbody of sacubitril |
| WO2017098430A1 (en) | 2015-12-10 | 2017-06-15 | Novartis Ag | New process and intermediates |
| WO2018007919A1 (en) | 2016-07-05 | 2018-01-11 | Novartis Ag | New process for early sacubitril intermediates |
| WO2018033866A1 (en) | 2016-08-17 | 2018-02-22 | Novartis Ag | New processes and intermediates for nep inhibitor synthesis |
| WO2018116203A1 (en) | 2016-12-23 | 2018-06-28 | Novartis Ag | New process for early sacubitril intermediates |
| CN109400504A (en) * | 2018-12-11 | 2019-03-01 | 重庆三圣实业股份有限公司 | The isolation and purification method of LCZ696 intermediate diastereoisomer |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017098430A1 (en) | 2015-12-10 | 2017-06-15 | Novartis Ag | New process and intermediates |
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| WO2018007919A1 (en) | 2016-07-05 | 2018-01-11 | Novartis Ag | New process for early sacubitril intermediates |
| WO2018033866A1 (en) | 2016-08-17 | 2018-02-22 | Novartis Ag | New processes and intermediates for nep inhibitor synthesis |
| WO2018116203A1 (en) | 2016-12-23 | 2018-06-28 | Novartis Ag | New process for early sacubitril intermediates |
| CN106699604A (en) * | 2017-01-09 | 2017-05-24 | 四川同晟生物医药有限公司 | Sacubitril and preparation method of midbody of sacubitril |
| CN106699604B (en) * | 2017-01-09 | 2019-01-01 | 四川同晟生物医药有限公司 | One seed sand library is than bent and its intermediate preparation method |
| CN109400504A (en) * | 2018-12-11 | 2019-03-01 | 重庆三圣实业股份有限公司 | The isolation and purification method of LCZ696 intermediate diastereoisomer |
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