CN108373423A - Preparation method of the one planting sand library than bent Valsartan compound and/or eutectic key intermediate sand library than bent calcium - Google Patents
Preparation method of the one planting sand library than bent Valsartan compound and/or eutectic key intermediate sand library than bent calcium Download PDFInfo
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- CN108373423A CN108373423A CN201810402315.7A CN201810402315A CN108373423A CN 108373423 A CN108373423 A CN 108373423A CN 201810402315 A CN201810402315 A CN 201810402315A CN 108373423 A CN108373423 A CN 108373423A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
Preparation method the present invention relates to a planting sand library than bent Valsartan compound and/or eutectic key intermediate sand library than bent calcium.Preparation method of the sand library provided by the invention than bent calcium; using (R; E) 5 ([1; 1' xenyls] 4 bases) 4 ((tertbutyloxycarbonyl) amino) 2 methylpent, 2 olefin(e) acids are hydrogenated, are esterified, acylation reaction; Sha Ku is obtained than bent calcium, preparation method provided by the invention industrial production easy to operate, at low cost, suitable.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, are related to a kind of preparation method of pharmaceutical intermediate, more particularly to husky library is than bent
The preparation method of Valsartan compound and/or eutectic key intermediate sand library than bent calcium.
Background technology
Sha Ku is than the chemical name of bent Valsartan calcium sodium：Six-[3- ((1S, 3R) -1- biphenyl -4- ylmethyl -3- ethoxies
Base carbonyl -1- Butylcarbamoyls) propionic acid-(S) -3'- methyl -2'- (valeryl { 2 "-(tetrazolium -5- bases anion) biphenyl -
4'- ylmethyls } amino) butyric acid] 16 sodium list calcium, 15 water complex, for our company exploitation Novartis marketed drug sand library than bent
The analogue of Valsartan sodium (LCZ696).
Sha Ku is than the angiotensin receptor enkephalinase inhibitor that bent Valsartan sodium (LCZ696) is Novartis's exploitation
(ARNi), FDA approvals are obtained in 2015.07.08, for the Patients with Chronic Heart Failure that ejection fraction reduces, the heart can be reduced
Vascular death and heart failure are hospitalized risk.LCZ696 is Sacubitril (AHU-377) and Valsartan with 1:The oversubscription that 1 ratio is formed
Sub- complex compound, it is aobvious compared to existing medicine with unique enkephalinase and angiotensin receptor double action mechanism
Big advantage is shown, which is known as over one of the most important progress that cardiovascular field during the decade obtains.
Constituent one of of the libraries ratio Qu Weisha Sha Ku than bent Valsartan calcium sodium and husky library than bent Valsartan sodium (LCZ696),
Its chemical name is 4- ((the amyl- 2- yls of (2S, 4R) -1- ([1,1'- xenyls] -4- bases) -5- ethyoxyl -4- methyl -5- oxos)
Amino) -4- ketobutyric acids, free acid and calcium salt structural formula are：
The husky library of published synthesis is than in the method for bent Valsartan calcium sodium and Sha Ku ratio song Valsartan sodium (LCZ696), needing
Sha Ku is used than bent or its calcium salt (CN200680001733.0, CN201510758232.8), since its calcium salt forms has more
Good stability, more conducively preserves, use is also more convenient.
In the prior art, has more document report, wherein Novartis is in China than bent or its calcium salt synthesis for Sha Ku
Patent CN200780034141.3 reports following synthetic route.
The route reaction step is long, needs using expensive rhodium or ruthenium class chiral catalyst and special ligand, the patent
Disclosed in hydrogen scheme added using conventional palladium carbon, stereoselectivity is poor, needs multiple refined, is unfavorable for amplifying.
Chinese patent CN201610247438.9, CN201510317119.6, CN201510890026.2 report sand
Library but is all using first making the scheme for switching to calcium salt after sodium salt than the preparation of bent calcium, and step is long, and efficiency is low, is unfavorable for industry
Metaplasia is produced.
Therefore, the husky library of preparation that is easy to operate, at low cost, being more suitable for industry amplification is developed than the method for bent calcium very must
It wants.The present invention meets such demand.
Invention content
The purpose of the present invention is to provide a kind of preparation sand libraries easy to operate, at low cost, being more suitable for industry amplification than bent
The method of calcium.It is specific as follows：Preparation method of the one planting sand library than bent calcium, which is characterized in that preparation method includes the following steps：
Compound I generates husky library than bent calcium in the presence of calcic alkali, with acylation reaction.
Optionally, the calcic alkali is one or more in calcium hydroxide, calcium monohydrogen phosphate, calcium carbonate.
Optionally, the molar ratio of the calcic alkali and compound I are calcic alkali：Compound I=(0.5~5)：1, preferably
(1~3)：1.
Optionally, the preparation method further includes purification step, and purification system is the mixing of organic solvent and water, volume
Than for organic solvent：Water=1：(0.5~5), preferably 1：(1~3).Wherein organic solvent is selected from alcohols, ketone, acetonitrile or four
It is one or more in hydrogen furans, the wherein preferred methanol of alcohols, ethyl alcohol, the preferred acetone of ketone.
Optionally, the compound I is prepared with the following method：
Compound III passes through esterif iotacation step prepare compound I by step of hydrogenation prepare compound II, compound II.
Optionally, include purification step in the step of hydrogenation, purification system is the mixed of isopropyl acetate and petroleum ether
Bonding solvent, volume ratio are isopropyl acetate：Petroleum ether=1：(0.5~5), preferably 1：(1~3).
Optionally, include purification step in the esterif iotacation step, using petroleum ether mashing purified compound I.
The present invention also provides above-mentioned preparation method in the husky library of synthesis than bent Valsartan calcium sodium or sand library than bent Valsartan sodium or
Sha Ku is than the purposes in other salt composites of bent Valsartan and/or eutectic.
Technical scheme of the present invention has the advantages that：
1, it in step of hydrogenation, is recrystallized using isopropyl acetate/petroleum ether, the compound II ((2R, 4S)-being prepared
5- ([1,1'- xenyl] -4- bases) -4- ((tertbutyloxycarbonyl) amino) -2- methvl-pentanoic acids) purity height, it is at low cost；
2, in esterif iotacation step, select petroleum ether as the solvent of purifying mashing, high income, purity is high, and cost is lower, rear to locate
Reason is easier；
3, in acylation step, using calcic alkali, Sha Ku can be directly obtained than bent calcium, have process few, it is at low cost, it is easy to be easy
Operation, avoids prior art and makes sodium salt and change into that calcium salt protocol step is long, and efficiency is low again the advantages that being conducive to industrialized production
The problems such as.Coordinate suitable purification system, husky library of the HPLC purity higher than 99% can be obtained than bent calcium, be used directly for preparing
Sha Ku is than bent Valsartan calcium sodium or husky library than bent Valsartan sodium or husky library than other salt composites of bent Valsartan and/or eutectic.
Specific implementation mode：
Below with reference to embodiment, the present invention is described in further detail, and the embodiment of the present invention is merely to illustrate this
The technical solution of invention, not limitation of the present invention, it is all according to any this field made by present disclosure etc.
With displacement, all belong to the scope of protection of the present invention.
The structure of compound be nuclear magnetic resonance (1H NMR) or MS determine.
Nuclear Magnetic Resonance (1H NMR) be Bruker AVANCE-400, nuclear magnetic resonance (1H NMR) displacement (δ) is with million points
One of the unit of (ppm) provide, measurement solvent is DMSO-d6, it is inside designated as tetramethylsilane (TMS), chemical shift is with 10-6
(ppm) it is provided as unit.
With reference to specific embodiment, the present invention is further detailed：
1 compound II of embodiment ((2R, 4S) -5- ([1,1'- xenyls] -4- bases) -4- ((tertbutyloxycarbonyl) amino) -
2- methvl-pentanoic acids) preparation
(R, E) -5- ([1,1'- xenyls] -4- bases) -4- ((tertbutyloxycarbonyl) ammonia is added under stirring in hydrogenation vessel
Base) -2- methyl-amyl- 2- olefin(e) acids (compound III) (75g, 0.20mol), 10% palladium carbon (Pd/C) (3.0g) and ethyl alcohol 750ml,
It is passed through hydrogen and pressurize (1.0MPa, 25 DEG C) is reacted 20 hours.Filtering, is concentrated to dryness, be added the isopropyl acetate of proper proportion/
Petroleum ether recrystallizes, and obtains white solid (compound II) after dry, specific data see the table below.1H NMR(DMSO-d6)δ12.01
(s, 1H), 7.63 (d, 2H, J=7.6Hz), 7.56 (d, 2H, J=8.0Hz), 7.47-7.43 (m, 2H), 7.35 (d, 1H, J=
7.2Hz), 7.24 (d, 2H, J=8.0Hz), 6.73 (d, 1H, J=8.8Hz), 3.67-3.66 (m, 1H), 2.68 (d, 2H, J=
6.8Hz),2.45-2.42(m,1H),1.78-1.71(m,1H),1.32(s,9H),1.40-1.32(m,1H),1.06(d,3H,J
=6.8Hz)
| Isopropyl acetate：Petroleum ether ratio (volume ratio) | Mass yield | HPLC | Isomers (2R, 4R) |
| 1：0.5 | 50.2% | 99.8% | 0.18% |
| 1：1 | 58.3% | 99.7% | 0.24% |
| 1：3 | 66.9% | 99.6% | 0.32% |
| 1：5 | 73.8% | 99.1% | 0.45% |
2 compound I of embodiment ((2R, 4S) -5- ([1,1'- xenyls] -4- bases) -4- amino-2-methyls-pentanoic acid hydrochloride
Salt) preparation
(2R, 4S) -5- ([1,1'- xenyls] -4- bases) -4- ((tertbutyloxycarbonyl) ammonia is added under stirring in reaction bulb
Base) -2- methvl-pentanoic acids (compound II) (45g, 0.12mol), ethyl alcohol 225ml, be added dropwise at 5 DEG C thionyl chloride (69.3g,
0.58mol), it finishes, is warming up to 40 DEG C and reacts 4 hours.It is concentrated to dryness, petroleum ether mashing, filtering obtains off-white powder after dry
(compound I) 39.5g, mass yield 87.8%.1H NMR(DMSO-d6)δ8.33(s,3H),7.68-7.64(m,4H),7.49-
7.45(m,2H),7.38-7.36(m,3H),4.01-3.96(m,2H),3.38-3.36(m,1H),3.12-3.08(m,1H),
2.85-2.74 (m, 2H), 1.89-1.83 (m, 1H), 1.66-1.60 (m, 1H), 1.09 (t, 3H, J=12.4Hz), 1.07 (d,
3H, J=5.2Hz) .HPLC 99.8%, isomers≤0.2%.
The husky library of embodiment 3 is than bent calcium (4- (((2S, 4R) -1- ([1,1'- xenyls] -4- bases) -5- ethyoxyl -4- methyl -
The amyl- 2- yls of 5- oxos) amino) -4- ketobutyric acids calcium) and preparation
(2R, 4S) -5- ([1,1'- xenyls] -4- bases) -4- amino-2-methyls-valeric acid are added under stirring in reaction bulb
Hydrochloride (compound I) (36g, 0.10mol), succinic anhydride (9.7g, 0.10mol) and DMF 90ml, at 0-10 DEG C in batches plus
Enter appropriate calcic alkali (one or more mixing), finish, is warming up to 25 DEG C and reacts 4 hours.Add water, be beaten, filtering obtains crude product.
The organic solvent of proper proportion and the mixed system recrystallization of water is added, filtering, obtaining off-white powder after dry, (Sha Ku is than bent
Calcium) ,≤0.1%, other data see the table below isomers.
The husky library of embodiment 4 is than bent calcium (4- (((2S, 4R) -1- ([1,1'- xenyls] -4- bases) -5- ethyoxyl -4- methyl -
The amyl- 2- yls of 5- oxos) amino) -4- ketobutyric acids calcium) and preparation
(2R, 4S) -5- ([1,1'- xenyls] -4- bases) -4- amino-2-methyls-valeric acid are added under stirring in reaction kettle
Hydrochloride (compound I) (3.6kg, 10mol), succinic anhydride (970g, 10mol) and DMF 9L are added portionwise at 0-10 DEG C
The calcium hydroxide of 10mol, finishes, and is warming up to 25 DEG C and reacts to complete.Add water, be beaten, filtering obtains crude product.It is tied again with ethanol/water
The volume ratio of crystalline substance, ethyl alcohol and water is 1:1, filtering obtains off-white powder after dry, and than bent calcium, mass yield is in as husky library
88.6%, HPLC purity are 99.6%, isomers≤0.1%.1H NMR(DMSO-d6) δ 7.97 (d, 1H, J=7.8Hz), 7.62
(d, 2H, J=7.8Hz), 7.55 (d, 2H, J=7.8Hz), 7.44-7.42 (m, 2H), 7.34-7.31 (m, 1H), 7.24 (d,
2H, J=7.8Hz), 3.97 (q, 2H, J=4.4Hz), 3.95-3.93 (m, 1H), 2.76-2.73 (m, 1H), 2.65-2.62 (m,
1H),2.51-2.48(m,1H),2.32-2.25(m,4H),1.77-1.73(m,1H),1.43-1.39(m,1H),1.09(t,
3H, J=4.8Hz), 1.04 (d, 3H, J=7.2Hz) .ESI-MS m/z:412[M-Ca+H]+.
In conclusion preparation method of the sand library provided by the invention than bent calcium, using (2R, 4S) -5- ([1,1'- biphenyl
Base] -4- bases) for -4- amino-2-methyls-valerate hydrochlorate in the presence of calcic alkali, with acylation reaction, prepared by single step reaction
Sha Ku is obtained than bent calcium.Compared to documents CN201610247438.9, CN201510317119.6,
CN201510890026.2 is first acylated, then sodium salt is made, and is finally translated into calcium salt, and that there are steps is long, efficiency is low, is unfavorable for work
The problems such as industry, method and step provided by the invention is simple, efficient, can be with industrialized production.
Claims (10)
1. a planting sand library is than the preparation method of bent calcium, which is characterized in that preparation method includes the following steps：
Compound I generates husky library than bent calcium in the presence of calcic alkali, with acylation reaction.
2. preparation method according to claim 1, which is characterized in that the calcic alkali is calcium hydroxide, calcium monohydrogen phosphate, carbon
It is one or more in sour calcium.
3. preparation method according to claim 1, which is characterized in that the molar ratio of the calcic alkali and compound I be containing
Calcium alkali：Compound I=(0.5~5)：1.
4. preparation method according to claim 3, which is characterized in that the molar ratio of the calcic alkali and compound I be containing
Calcium alkali：Compound I=(1~3)：1.
5. preparation method according to claim 1, which is characterized in that the preparation method further includes purification step, is refined
System is the mixing of organic solvent and water, and volume ratio is organic solvent：Water=1：(0.5~5), wherein organic solvent are selected from alcohol
It is one or more in class, ketone, acetonitrile or tetrahydrofuran.
6. preparation method according to claim 5, which is characterized in that the mixed solvent of the organic solvent and water, body
Product is than being organic solvent：Water=1：(1~3).
7. preparation method according to claim 1, which is characterized in that the compound I is prepared with the following method：
Compound III passes through esterif iotacation step prepare compound I by step of hydrogenation prepare compound II, compound II.
8. preparation method according to claim 7, which is characterized in that include purification step in the step of hydrogenation, essence
System processed is the mixed solvent of isopropyl acetate and petroleum ether, and volume ratio is isopropyl acetate：Petroleum ether=1：(0.5~5),
Preferably 1：(1~3).
9. preparation method according to claim 7, which is characterized in that include purification step in the esterif iotacation step, adopt
With petroleum ether mashing purified compound I.
10. any one of claim 1~9 preparation method is in the husky library of synthesis than bent Valsartan calcium sodium or husky library than bent figured silk fabrics sand
Smooth sodium or husky library are than the purposes in other salt composites of bent Valsartan and/or eutectic.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810402315.7A CN108373423B (en) | 2018-04-28 | 2018-04-28 | Preparation method of Sacubitril-valsartan compound and/or eutectic key intermediate Sacubitril calcium |
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|---|---|---|---|
| CN201810402315.7A CN108373423B (en) | 2018-04-28 | 2018-04-28 | Preparation method of Sacubitril-valsartan compound and/or eutectic key intermediate Sacubitril calcium |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN110818581A (en) * | 2019-11-26 | 2020-02-21 | 株洲千金药业股份有限公司 | Post-treatment method of Sacubitril valsartan sodium intermediate |
| CN110845349A (en) * | 2019-11-26 | 2020-02-28 | 株洲千金药业股份有限公司 | Purification method of Sacubitril valsartan sodium intermediate |
| CN112574132A (en) * | 2019-09-30 | 2021-03-30 | 广东东阳光药业有限公司 | Preparation method of shakubiqu valsartan sodium |
| CN115677521A (en) * | 2022-11-16 | 2023-02-03 | 迪嘉药业集团股份有限公司 | Preparation method of high-purity Shakuba kojie calcium |
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| CN115677521A (en) * | 2022-11-16 | 2023-02-03 | 迪嘉药业集团股份有限公司 | Preparation method of high-purity Shakuba kojie calcium |
| CN115677521B (en) * | 2022-11-16 | 2024-02-02 | 迪嘉药业集团股份有限公司 | Preparation method of high-purity Sha Kuba koji calcium |
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|---|---|
| CN108373423B (en) | 2020-10-23 |
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