CN106478437A - A kind of preparation method of γ aminovaleric acid ester derivant - Google Patents
A kind of preparation method of γ aminovaleric acid ester derivant Download PDFInfo
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- CN106478437A CN106478437A CN201610853376.6A CN201610853376A CN106478437A CN 106478437 A CN106478437 A CN 106478437A CN 201610853376 A CN201610853376 A CN 201610853376A CN 106478437 A CN106478437 A CN 106478437A
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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
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a kind of preparation method of γ aminovaleric acid ester derivant,, with N t-butyloxycarbonyl amino 4,4 biphenyl R alanine ester for initiation material, reactions steps include reduction, oxidation, witig reaction and hydro-reduction for it.It is an advantage of the invention that：Process route is brief, fixes a chiral centre in the feed, reduces the generation of chiral impurity；Primary amine is protected, prevents the generation of oxidation impurities；Palladium carbon or ruthenium catalyst tie ligand is applied to carry out the reduction of ethylene linkage, chiral selectivity is high, and reaction yield is high, is suitable for scale industrial production.
Description
Technical field
The present invention relates to the preparation method of gamma-amino pentanoate derivative, specifically, it is related to a kind of (2R, 4S) -4- ammonia
The preparation method of base -5- (biphenyl -4- base) -2 methyl valeric acid carbethoxy hydrochloride.
Background technology
Sacubitril is an effective ingredient medicine of cardiotonic agents entresto, an enkephalinase inhibitor, it
And Valsartan, the compound preparation of angiotensin ii receptor blocker composition, in order to the painstaking effort of heart failure patient of reducing risks
Pipe death and hospitalization chronic heart failure（NYHAII-IV level）Reduce with ejection fraction.The chemistry of Sacubitril is entitled：
(2R, 4S) -5- [4- xenyl -4- (3- carboxypropanoyl) amino] -2 methyl valeric acid ethyl ester.No. CAS：149709-62-6.Knot
Structure is as shown in Equation 1.
Gamma-amino pentanoate derivative, structure as shown in Equation 2, is the important advanced intermediate of Sacubitril, in chirality
It is also easy to produce chiral impurity in the building process of the heart, therefore its quality purity directly affects the quality of final products,
.
Content of the invention
It is an object of the invention to provide a kind of preparation method of gamma-amino pentanoate derivative, it is on sale in a large number with market
N- t-butyloxycarbonyl-amino -4,4- biphenyl-R- alanine ester be initiation material, through reduction, oxidation, witig reaction,
The reaction such as hydro-reduction obtains product (2R, 4S) -4- amino -5- (biphenyl -4- base) -2 methyl valeric acid carbethoxy hydrochloride, relatively
In prior art route, process route is brief, fixes a chiral centre in the feed, reduces the generation of chiral impurity；To primary
Amine is protected, and prevents the generation of oxidation impurities；Palladium carbon or ruthenium catalyst tie ligand is applied to carry out the reduction of ethylene linkage, chiral choosing
Selecting property is high, and reaction yield is high, is suitable for scale industrial production.
The technical solution used in the present invention is：A kind of preparation method of gamma-amino pentanoate derivative, it is with the N- tert-butyl group
Epoxide carbonyl-amino -4,4- biphenyl-R- alanine ester be initiation material, reactions steps include reduction, oxidation, witig reaction,
Hydro-reduction, reaction scheme is：
.
Comprise the following steps that：
The preparation of intermediate I：
N- t-butyloxycarbonyl-amino -4,4- biphenyl-R- alanine ester, under reducing agent effect, ester ester group is reduced to alcohol
Hydroxyl；
The preparation of intermediate II：
Under catalyst action, oxidized dose of oxidation obtains intermediate II to intermediate I；
The preparation of intermediate III：
Intermediate II and 2- triphenylphosphine vinylpropionic acid ethyl ester occur witig reaction to obtain intermediate III；
The preparation of intermediate IV：
Intermediate III carries out catalytic hydrogenation under catalyst action, and ethylene linkage is reduced；
The preparation of finished product：
Intermediate IV obtains hydrochloric acid product salt under ethanolic hydrogen chloride effect.
Preferably, in the preparation process of intermediate I, N- t-butyloxycarbonyl-amino -4,4- biphenyl-R- alanine ester
Mol ratio with reducing agent is 1:1.2～1:2.5.
Preferably, in the preparation process of intermediate I, described reducing agent is the compositionss of sodium borohydride and lithium bromide, boron hydrogen
The compositionss of change potassium and lithium bromide or diisobutyl aluminium hydride；Required reaction dissolvent is oxolane, acetonitrile, toluene or dichloro
Methane.
Preferably, in the preparation process of intermediate II, intermediate I is 1 with the mol ratio of oxidant:2～1:10.
Preferably, in the preparation process of intermediate II, described oxidant is sodium hypochlorite, oxalyl chloride or dimethyl sulfoxide；Institute
Stating catalyst is 2,2,6,6- phenmethylol conversion thewire and potassium bromide；Required reaction dissolvent is oxolane, toluene or dichloro
Methane.
Preferably, in the preparation process of intermediate III, intermediate II and 2- triphenylphosphine vinylpropionic acid ethyl ester mole
Than for 1:1.1～1:2.5.
Preferably, in the preparation process of intermediate III, required reaction dissolvent is oxolane, methyl tertiary butyl ether(MTBE) or isopropyl
Ether, reaction temperature is 20-80 DEG C.
Preferably, in the preparation process of intermediate IV, described catalyst is palladium carbon or diiodo- (paracymene) ruthenium (II) two
Aggressiveness and the compositionss of its part；Required reaction dissolvent is ethanol or methanol；Reaction temperature is 25-80 DEG C；Catalyst feeds intake and joins
Than the 5-10% for reaction substrate.
Preferably, in the preparation process of finished product, intermediate IV：The mol ratio of ethanolic hydrogen chloride is 1:1～1:8.
Preferably, in the preparation process of finished product, reaction temperature is 25-50 DEG C.
It is an advantage of the invention that：Process route is brief, fixes a chiral centre in the feed, reduces the product of chiral impurity
Raw；Primary amine is protected, prevents the generation of oxidation impurities；Application palladium carbon or ruthenium catalyst tie ligand carry out going back of ethylene linkage
Former, chiral selectivity is high, and reaction yield is high, is suitable for scale industrial production.
Specific embodiment
Embodiment 1
The preparation of intermediate I：
Under room temperature, by 36g N- t-butyloxycarbonyl-amino -4,4- biphenyl-R- methyl lactamine and 12.2g lithium bromide are placed in
In 400mL oxolane, stir 30 minutes, add 5.3g sodium borohydride, then react at room temperature, TLC monitoring reaction；Raw material
After reaction completely, evaporated under reduced pressure solvent, add 300mL water, then use ethyl acetate（100mL×3）Extraction；Organic layer is with anhydrous
Sodium sulfate is dried, sucking filtration, evaporated under reduced pressure solvent, adds the making beating of 250mL ether, dry in residue, obtains 28.9g white solid and produces
Product.Yield：88%.
The preparation of intermediate II：
In 300mL dichloromethane, add 28.9g intermediate I, stirring and dissolving, add 1g catalyst 2,2,6,6- tetramethyl
Piperidine oxide, then Deca 20mL kbr aqueous solution, it is cooled to 0 DEG C, subsequent Deca 145g 10% liquor natrii hypochloritises；Drip
Finish, be warming up to room temperature reaction, TLC detection reaction；Reaction finishes, and adds 100mL water, stirring, stratification, water in reactant liquor
Layer dichloromethane（50mL×2）Extraction；Merge organic faciess, use 100mL saturated sodium bisulfite solution, 100mL saturated aqueous common salt
Washing, anhydrous sodium sulfate drying, it is evaporated to dry, obtain 24.4g product.Yield is 85%.
The preparation of intermediate III：
100mL diisopropyl ether, 24.4g intermediate II, stirring and dissolving, Deca 2- triphenylphosphine vinylpropionic acid is added in reaction bulb
The diisopropyl ether of ethyl ester（32.6g/200mL）Solution；Drip and finish, be warming up to 50 DEG C of reactions, TLC monitoring reaction；Raw material reaction finishes, and subtracts
Pressure is evaporated off diisopropyl ether, then uses 300mL ether to pull an oar, filters, and filter cake uses 300mL ether to pull an oar again, merges organic faciess, and decompression is dense
It is reduced to dry 28.6g white solid product.Yield：93%.
The preparation of intermediate IV：
Add 28.6g intermediate IV, 280mL ethanol in hydriding reactor, be stirred at room temperature, nitrogen displacement, add 2.8 g palladium carbons,
Nitrogen displacement, logical hydrogen displacement, logical hydrogen, to 1 MP, is heated to 50 DEG C of reactions, TLC monitoring reaction；Reaction finishes, and is down to room temperature, subtracts
Pressure concentration of reaction solution, add water 400mL, is heated to reflux 0.5 hour, is cooled to room temperature, stirring and crystallizing, sucking filtration, filter cake 300mL second
Alcohol/water making beating, is dried, obtains 28.2g white solid product.Yield：98%.
The preparation of finished product：
Add 28.2g intermediate V in reaction bulb, add 350mL ethanol solution of hydrogen chloride, stirring and dissolving, be heated to 35 DEG C,
Then insulation reaction at 30 ~ 35 DEG C, has solid to separate out, TLC monitoring reaction；Reaction finishes, and is cooled to room temperature, sucking filtration, filter cake
With washing with alcohol, it is dried, obtains 24.6g white solid product.Yield：96%.
Embodiment 2
The preparation of intermediate I：
Under room temperature, by 40g N- t-butyloxycarbonyl-amino -4,4- biphenyl-R- alanine ethyl ester and 13.2g lithium bromide are placed in
In 400mL toluene, stir 30 minutes, add 8.2g potassium borohydride, then react at room temperature, TLC monitoring reaction；Raw material reaction
After completely, evaporated under reduced pressure solvent, add 300mL water, then use ethyl acetate（100mL×3）Extraction；Organic layer anhydrous slufuric acid
Sodium is dried, sucking filtration, evaporated under reduced pressure solvent, adds the making beating of 300mL ether, dry, obtain 30.5g white solid product in residue.
Yield：86%.
The preparation of intermediate II：
In 300mL toluene, add 30.5g intermediate I, stirring and dissolving, add the oxidation of 1g 2,2,6,6- tetramethyl piperidine
Thing, then Deca 25mL kbr aqueous solution, it is cooled to 0 DEG C, subsequent Deca 157g 10% liquor natrii hypochloritises；Drip and finish, heat up
To room temperature reaction, TLC detection reaction；Reaction finishes, and adds 200mL water, stirring, stratification, water layer first in reactant liquor
Benzene（100mL×2）Extraction；Merge organic faciess, use 150mL saturated sodium bisulfite solution, 150mL saturated common salt water washing, anhydrous
Sodium sulfate is dried, and is evaporated to dry, obtains 25.8g product.Yield is 83%.
The preparation of intermediate III：
100mL oxolane, 25.8g intermediate II, stirring and dissolving, Deca 2- triphenylphosphine vinyl third is added in reaction bulb
The oxolane of acetoacetic ester（35.2g/200mL）Solution；Drip and finish, be warming up to 50 DEG C of reactions, TLC monitoring reaction；Raw material reaction is complete
Finish, remove oxolane under reduced pressure, then use 350mL ether to pull an oar, filter, filter cake uses 400mL ether to pull an oar again, merges organic
Phase, is evaporated to dry 31.6g white solid product.Yield：96%.
The preparation of intermediate IV：
Add 31.6g intermediate IV, 400mL methanol in hydriding reactor, be stirred at room temperature, nitrogen displacement, add 3.1g diiodo- (right
P-Cymene) ruthenium (II) dimer, 0.5g ferrocene ligands (R) -1- [(S) -2- dicyclohexyl phosphino- ferrocenyl]-ethyl two
Cyclohexyl phosphine, nitrogen displacement, logical hydrogen displacement, logical hydrogen, to 1 MP, is heated to 50 DEG C of reactions, TLC monitoring reaction；Reaction finishes, fall
To room temperature, concentrating under reduced pressure reactant liquor, add water 500mL, is heated to reflux 0.5 hour, is cooled to room temperature, stirring and crystallizing, sucking filtration, filter cake
With the making beating of 350mL ethanol/water, it is dried, obtains 30.8g white solid product.Yield：97%.
The preparation of finished product：
Add 30.8g intermediate V in reaction bulb, add 450mL ethanol solution of hydrogen chloride, stirring and dissolving, be heated to 35 DEG C,
Then insulation reaction at 30 ~ 35 DEG C, has solid to separate out, TLC monitoring reaction；Reaction finishes, and is cooled to room temperature, sucking filtration, filter cake
With washing with alcohol, it is dried, obtains 26.9g white solid product.Yield：95%.
Embodiment 3
The preparation of intermediate I：
Under room temperature, by 50g N- t-butyloxycarbonyl-amino -4, in 4- biphenyl-R- alanine ethyl ester 500mL oxolane,
Stirring and dissolving, is cooled to -78 DEG C, then the diisobutyl aluminium hydride solution of Deca 162mL 1N, drips and finishes, and reacts at -78 DEG C
2 hours, then heat to room temperature reaction, TLC monitoring reaction；After raw material reaction is complete, add 200mL saturated ammonium chloride solution,
Stirring 30 minutes, removes part oxolane under reduced pressure, adds 200mL water, stirring, then uses ethyl acetate（200mL×3）Extraction
Take；Organic layer anhydrous sodium sulfate drying, sucking filtration, evaporated under reduced pressure solvent, add 300mL methyl tertiary butyl ether(MTBE) to beat in residue
Slurry, dries, obtains 39.4g white solid product.Yield：89%.
The preparation of intermediate II：
In 400mL dichloromethane, add 39.4g intermediate I, stirring and dissolving, add 1.5g catalyst 2,2,6,6- tetramethyl
Phenylpiperidines oxide, then Deca 30mL kbr aqueous solution, it is cooled to 0 DEG C, subsequent Deca 195g 10% liquor natrii hypochloritises；
Drip and finish, be warming up to room temperature reaction, TLC detection reaction；Reaction finishes, and adds 200mL water in reactant liquor, stirs, stratification,
Water layer dichloromethane（100mL×2）Extraction；Merge organic faciess, use 200mL saturated sodium bisulfite solution, 200mL saturated common salt
Water washing, anhydrous sodium sulfate drying, it is evaporated to dry, obtain 32.9g product.Yield is 85%.
The preparation of intermediate III：
200mL methyl tertiary butyl ether(MTBE), 32.9g intermediate II, stirring and dissolving, Deca 2- triphenylphosphine ethylene is added in reaction bulb
The methyl tertiary butyl ether(MTBE) of base ethyl propionate（44g/200mL）Solution；Drip and finish, be warming up to 50 DEG C of reactions, TLC monitoring reaction；Raw material
Reaction finishes, and removes diisopropyl ether under reduced pressure, then uses 500mL ether to pull an oar, filters, and filter cake uses 500mL ether to pull an oar again, is associated with
Machine phase, is evaporated to dry 39.1g white solid product.Yield：94%.
The preparation of intermediate IV：
Add 39.1g intermediate IV, 400mL ethanol in hydriding reactor, be stirred at room temperature, nitrogen displacement, add 3.9 g palladium carbons,
Nitrogen displacement, logical hydrogen displacement, logical hydrogen, to 1 MP, is heated to 50 DEG C of reactions, TLC monitoring reaction；Reaction finishes, and is down to room temperature, subtracts
Pressure concentration of reaction solution, add water 500mL, is heated to reflux 0.5 hour, is cooled to room temperature, stirring and crystallizing, sucking filtration, filter cake 500mL second
Alcohol/water making beating, is dried, obtains 37.7g white solid product.Yield：96%.
The preparation of finished product：
Add 37.7g intermediate V in reaction bulb, add 500mL ethanol solution of hydrogen chloride, stirring and dissolving, be heated to 35 DEG C,
Then insulation reaction at 30 ~ 35 DEG C, has solid to separate out, TLC monitoring reaction；Reaction finishes, and is cooled to room temperature, sucking filtration, filter cake
With washing with alcohol, it is dried, obtains 33.6g white solid product.Yield：96%.
Claims (10)
1. a kind of preparation method of gamma-amino pentanoate derivative, it is with N- t-butyloxycarbonyl-amino -4,4- biphenyl-R-
Alanine ester be initiation material, reactions steps include reduction, oxidation, witig reaction, hydro-reduction it is characterised in that：Specifically
Step is as follows：
The preparation of intermediate I：
N- t-butyloxycarbonyl-amino -4,4- biphenyl-R- alanine ester, under reducing agent effect, ester ester group is reduced to alcohol
Hydroxyl；
The preparation of intermediate II：
Under catalyst action, oxidized dose of oxidation obtains intermediate II to intermediate I；
The preparation of intermediate III：
Intermediate II and 2- triphenylphosphine vinylpropionic acid ethyl ester occur witig reaction to obtain intermediate III；
The preparation of intermediate IV：
Intermediate III carries out catalytic hydrogenation under catalyst action, and ethylene linkage is reduced；
The preparation of finished product：
Intermediate IV obtains hydrochloric acid product salt under ethanolic hydrogen chloride effect.
2. a kind of gamma-amino pentanoate derivative according to claim 1 preparation method it is characterised in that：Intermediate I
Preparation process in, N- t-butyloxycarbonyl-amino -4, the mol ratio of 4- biphenyl-R- alanine ester and reducing agent is 1:1.2
～1:2.5.
3. a kind of gamma-amino pentanoate derivative according to claim 1 and 2 preparation method it is characterised in that：Middle
In the preparation process of body I, described reducing agent is the compositionss of the compositionss, potassium borohydride and lithium bromide of sodium borohydride and lithium bromide
Or diisobutyl aluminium hydride；Required reaction dissolvent is oxolane, acetonitrile, toluene or dichloromethane.
4. a kind of gamma-amino pentanoate derivative according to claim 1 preparation method it is characterised in that：Intermediate
In II preparation process, intermediate I is 1 with the mol ratio of oxidant:2～1:10.
5. a kind of gamma-amino pentanoate derivative according to claim 1 or 4 preparation method it is characterised in that：Middle
In the preparation process of body II, described oxidant is sodium hypochlorite, oxalyl chloride or dimethyl sulfoxide；Described catalyst is 2,2,6,6- tetra-
Methyl piperidine oxide and the compositionss of potassium bromide；Required reaction dissolvent is oxolane, toluene or dichloromethane.
6. a kind of gamma-amino pentanoate derivative according to claim 1 preparation method it is characterised in that：Intermediate
In III preparation process, intermediate II is 1 with the mol ratio of 2- triphenylphosphine vinylpropionic acid ethyl ester:1.1～1:2.5.
7. a kind of gamma-amino pentanoate derivative according to claim 1 or 6 preparation method it is characterised in that：Middle
In the preparation process of body III, required reaction dissolvent is oxolane, methyl tertiary butyl ether(MTBE) or diisopropyl ether, and reaction temperature is 20-80
℃.
8. a kind of gamma-amino pentanoate derivative according to claim 1 preparation method it is characterised in that：Intermediate
In IV preparation process, described catalyst is palladium carbon or the compositionss of diiodo- (paracymene) ruthenium (II) dimer and its part；
Required reaction dissolvent is ethanol or methanol；Reaction temperature is 25-80 DEG C；Catalyst charge ratio is the 5-10% of reaction substrate.
9. a kind of gamma-amino pentanoate derivative according to claim 1 preparation method it is characterised in that：Finished product
In preparation process, intermediate IV：The mol ratio of ethanolic hydrogen chloride is 1:1～1:8.
10. a kind of gamma-amino pentanoate derivative according to claim 1 or 9 preparation method it is characterised in that：Become
In the preparation process of product, reaction temperature is 25-50 DEG C.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107540574A (en) * | 2017-09-19 | 2018-01-05 | 成都西岭源药业有限公司 | The preparation method of R biphenyl Propanolamines |
| CN108047093A (en) * | 2017-11-29 | 2018-05-18 | 南通常佑药业科技有限公司 | A kind of preparation method of xenyl aminopropan aldehyde compound |
| CN110240548A (en) * | 2018-03-09 | 2019-09-17 | 上虞京新药业有限公司 | A kind of preparation method of Cariliprazine intermediate |
| CN111389468A (en) * | 2020-05-09 | 2020-07-10 | 青岛科技大学 | Application of sulfonated BINAP and polyether functionalized ionic liquid integrated chiral catalyst in asymmetric hydrogenation reaction |
| CN111450880A (en) * | 2020-05-09 | 2020-07-28 | 青岛科技大学 | Sulfonated BINAP and polyether functionalized ionic liquid integrated chiral catalyst |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107540574A (en) * | 2017-09-19 | 2018-01-05 | 成都西岭源药业有限公司 | The preparation method of R biphenyl Propanolamines |
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| CN111389468A (en) * | 2020-05-09 | 2020-07-10 | 青岛科技大学 | Application of sulfonated BINAP and polyether functionalized ionic liquid integrated chiral catalyst in asymmetric hydrogenation reaction |
| CN111450880A (en) * | 2020-05-09 | 2020-07-28 | 青岛科技大学 | Sulfonated BINAP and polyether functionalized ionic liquid integrated chiral catalyst |
| CN111389468B (en) * | 2020-05-09 | 2022-11-29 | 青岛科技大学 | Application of sulfonated BINAP and polyether functionalized ionic liquid integrated chiral catalyst in asymmetric hydrogenation reaction |
| CN111450880B (en) * | 2020-05-09 | 2022-11-29 | 青岛科技大学 | Sulfonated BINAP and polyether functionalized ionic liquid integrated chiral catalyst |
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Application publication date: 20170308 |