CN109053495A - A kind of synthetic method of LCZ696 intermediate - Google Patents
A kind of synthetic method of LCZ696 intermediate Download PDFInfo
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- CN109053495A CN109053495A CN201810809611.9A CN201810809611A CN109053495A CN 109053495 A CN109053495 A CN 109053495A CN 201810809611 A CN201810809611 A CN 201810809611A CN 109053495 A CN109053495 A CN 109053495A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/04—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups
- C07C303/10—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups by reaction with sulfur dioxide and halogen or by reaction with sulfuryl halides
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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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The invention discloses a kind of LCZ696 intermediates: (R)-tert-butyl (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) and carbamate synthetic method, this method is as follows: 1) reacting to obtain intermediate II with substituent group sulfonic acid chloride by raw material BOC-D- tyrosine I；2) it is coupled intermediate II and phenyl grignard reagent to obtain intermediate III；3) intermediate III is obtained into (R)-tert-butyl (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) carbamate IV by potassium borohydride reduction；The method of the invention trifluoromethanesulfanhydride anhydride expensive and hypertoxic come fictitious hosts with cheap p-toluenesulfonyl, while avoided again using expensive metallic catalyst Pd, experimental implementation is simple, and yield is higher, is suitble to amplification production.
Description
Technical field
The present invention relates to the synthesis technical field of medication chemistry more particularly to a kind of husky library is prepared than bent key intermediate
(R) method of-tert-butyl (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) carbamate.
Background technique
It is a kind of economic benefits and social benefits vasotonia that the heavy pound of Novartis's exploitation, which is depressured anti-heart failure new drug LCZ696 (trade name Entresto),
Plain receptor enkephalinase inhibitor, the hypertension drug Valsartan (Valsartan) for combining Novartis and husky library are than bent
(Sacubitril), the treatment of the heart failure patient reduced for ejection fraction, significant in efficacy and side effect is low, has wide
Wealthy market prospects.LCZ696 is Valsartan and Sha Ku than bent sodium-salt hydrate eutectic, and synthesis technology is substantially by Sha Ku ratio
The acidified free rear and Valsartan of bent calcium salt obtains product in sodium hydroxide solution in the form of being hydrated eutectic, due to Valsartan
Partial synthesis technology comparative maturity, thus synthesize focus and just fall in Sha Ku than in knee-piece section.Sha Ku is 4- more entitled than bent chemistry
{ [(2S, 4R) -1- (1,1 '-biphenyl -4- base) -5- ethyoxyl -4- methyl -5- oxo -2- amyl] amino } -4- Oxoacetic Acid,
Its structure is as follows:
Husky library is prepared than there are many synthesis reports before song, wherein J.Med.Chem.1995 1689- of volume 38
Page 1700 report Sha Ku than bent synthetic method:
The route starting material is BOC-D- methyl-P-tyrosine, and coupling reaction needs high using price when synthesizing biphenyl structural
Expensive and hypertoxic trifluoromethanesulfanhydride anhydride will also use the tetrakis triphenylphosphine palladium of larger equivalent as catalyst, and subsequent anti-
EDCI, lithium aluminium hydride and palladium carbon etc. should have been used again, these reagent prices are more expensive, and some processes step operation has
There is certain risk, in addition along with step route is too long, is not suitable for amplification production.
PCT Patent WO2008031567, WO2010136474 and WO2012025501 etc. are reported is by 4- bromo biphenyl
Beginning raw material passes through grignard reaction for chiral epichlorohydrin open loop, then prolongs reaction, hydrolysis and Boc protection reaction through light and obtain
Chiral amino alcohol (R)-tert-butyl (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) carbamate, then passes through
It is oxidized to aldehyde, most obtains Sha Ku than bent through serial reaction afterwards.
This route is the current sand library that synthesizes than bent dominating process route, but route steps are still on the high side；Starting material
Need multistep to synthesize and used the strong acid of larger equivalent in production process and produce a large amount of waste liquid, environmental protection pressure compared with
Greatly；In addition it needs to use noble metal catalyst in chiral reduction step, reacts more difficult manipulation, process costs are higher.At present these
It synthesizes husky library and all there is certain limitation than bent route, technique amplification cost is higher, it is therefore desirable to develop more inexpensive, high
The synthetic method of efficiency, key is to find a kind of low cost, high efficiency synthesizes husky library than bent key intermediate (R)-tert-butyl
(1- ([1,1'- biphenyl] -4-
Base) -3- hydroxy propane -2- base) carbamate preparation route.
Summary of the invention
In view of the above problems, simple, low in cost, suitable work that it is an object of that present invention to provide a kind of process routes
The husky library that industry metaplasia produces is than bent key intermediate: (R)-tert-butyl (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base)
The synthetic method of carbamate.
In order to achieve the above object, The technical solution adopted by the invention is as follows: a kind of LCZ696 intermediate: (R)-tert-butyl
The synthetic method of (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) carbamate；
1) raw material BOC-D- tyrosine I is reacted to obtain intermediate II with substituent group sulfonic acid chloride；
Wherein, RSO2Cl is substituent group sulfonic acid chloride, and base is alkali, and R is methyl, ethyl, phenyl or p-methylphenyl；Substituent group
Sulfonic acid chloride is one of methylsufonyl chloride, ethyl chloride, phenylsulfonylchloride or p-methylphenyl sulfonic acid chloride.
2) it is coupled intermediate II and phenyl grignard reagent to obtain intermediate III；
Wherein, catalyst is catalyst, and MX is magnesium chloride, magnesium bromide or magnesium iodide；Phenyl grignard reagent is phenylchloride
Change one of magnesium, phenyl-magnesium-bromide or phenyl magnesium iodide.
3) intermediate III is obtained into (R)-tert-butyl (1- ([1,1'- biphenyl] -4- base) -3- hydroxyl by potassium borohydride reduction
Base propane -2- base)
Carbamate IV.
In step 1) of the invention, the alkali of selection is organic base, specially triethylamine, diisopropylethylamine, DBU or pyridine
One of；Reaction dissolvent be methylene chloride, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, tetrahydrofuran,
One of 1,4- dioxane, toluene or acetone or several mixtures；Reaction temperature is -10~110 DEG C.
In step 2) of the invention, the catalyst of selection is one in bis- (triphenylphosphine) Nickel Chlorides or Nickel Chloride
Kind；Reaction dissolvent is selected from one of toluene, tetrahydrofuran, 2- methyltetrahydrofuran or Isosorbide-5-Nitrae-dioxane or several mixed
Close object；It can choose in the reaction process of step 3) and ligand or addition ligand triphenylphosphine be not added；Reaction temperature is -15~50
℃。
In step 3) of the invention, reaction dissolvent is the mixed solvent of methanol and tetrahydrofuran；Reaction temperature is -10~80
℃。
The present invention has the advantages that method of the invention is to husky library than bent key intermediate: (R)-tert-butyl (1-
([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) carbamate synthetic route carry out improvement, not only select honest and clean
Valence carrys out the expensive and hypertoxic trifluoromethanesulfanhydride anhydride of fictitious hosts to substituent group sulfonic acid chloride, and cheap nickel has been selected to urge
Agent is avoided using expensive metallic catalyst Pd.Simultaneously, the present invention to the experiment condition in process route such as: it is anti-
Selection, reaction condition, solvent and the catalyst etc. for answering object are all optimized, and experimental implementation is simple, and yield is higher, are suitble to amplification
Production.
Specific embodiment
The present invention is described in further detail combined with specific embodiments below.
Embodiment 1: preparation (R)-tert-butyl (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) carbamic acid
Ester；
1) I a of BOC-D- methyl-P-tyrosine (29.53g, 100mmol), diisopropylethylamine are added in three-necked flask
(19.39g, 150 mmol) and methylene chloride (148mL), are cooled to 0~5 DEG C after mixing evenly, are slowly added dropwise into toluene sulphur
Methylene chloride (50mL) solution of acyl chlorides (22.88g, 120 mmol), is to slowly warm up to react at room temperature after being added dropwise.Reaction knot
Water (148mL) liquid separation is added in beam, and water phase uses methylene chloride (74mL) to extract 2 times again, merges organic phase saturated common salt and washes 1 time
(148mL), sodium sulphate dry, filter concentration, are added petroleum ether mashing, filtering, dry intermediate II a (41.59g, purity
96.2%, yield: 89%).
2) intermediate II a (44.95g, 100mmol) and tetrahydrofuran (225mL) are added in three-necked flask, after stirring and dissolving
Ice salt bath is cooling, and vacuum switches nitrogen 3 times, and bis- (triphenylphosphine) Nickel Chlorides (654mg, 1.0mmol) and triphenylphosphine is added
The tetrahydrofuran solution (105mmol, 105mL) of 1.0M phenyl-magnesium-bromide, -10~0 DEG C of stirring is added dropwise in (525 mg, 2.0mmol)
It is to slowly warm up to react at room temperature after 30 minutes, reaction terminates that dilute hydrochloric acid (2mol/L, 112mL) quenching reaction is added, and mixed liquor is used
Ethyl acetate (112mL) extracts 3 times, merges organic phase and washes 2 times (112mL), and sodium sulphate dries, filters, and after concentration, second is added
Acetoacetic ester and petroleum ether mixed solvent are beaten to obtain intermediate III (30.53g, purity 97.8%, yield: 84%).
3) intermediate III (35.54g, 100mmol) and tetrahydrofuran (178mL) are added in three-necked flask, after mixing evenly
It is added potassium borohydride (5.39g, 100mmol), is heated to 45~50 DEG C, is slowly dropped into methanol (36mL), drips off rear insulation reaction
Overnight.Reaction terminates to be cooled to 10~15 DEG C of addition 0.5mol/L dilute hydrochloric acid (178mL) quenching reactions, and ethyl acetate is added in water phase
(178 mL) is extracted 2 times, is merged organic phase saturated common salt and is washed 2 times (178mL), sodium sulphate is dry, and ethyl alcohol petroleum is used after concentration
The mashing of ether mixed solvent, is filtered, dry, obtains (R)-tert-butyl (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) ammonia
Carbamate IV (30.03g, purity 99.2%, yield: 91%).
Embodiment 2: preparation (R)-tert-butyl (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) carbamic acid
Ester
1) in three-necked flask be added I a of BOC-D- methyl-P-tyrosine (29.53g, 100mmol), triethylamine (15.18g,
150mmol) with tetrahydrofuran (148mL), it is cooled to 0~5 DEG C after mixing evenly, is slowly added dropwise into methylsufonyl chloride
Tetrahydrofuran (50mL) solution of (13.75g, 120mmol), is to slowly warm up to react at room temperature after being added dropwise.Reaction terminates to add
Enter water (148mL) and revolve and remove partial solvent, water phase is added methylene chloride (148mL) and extracts 3 times, merges organic phase saturated salt solution
Wash 1 time (148mL), sodium sulphate dries, filters concentration, be added petroleum ether mashing, filtering, dry intermediate II b (33.91g,
Purity 95.8%, yield: 87%).
2) intermediate II b (37.34g, 100mmol) and 2- methyltetrahydrofuran (187mL), stirring are added in three-necked flask
Ice salt bath is cooling after dissolution, and vacuum switches nitrogen 3 times, and bis- (triphenylphosphine) Nickel Chlorides (654mg, 1.0mmol) and three are added
Phenylphosphine (525mg, 2.0mmol), the tetrahydrofuran solution (105mmol, 105mL) of dropwise addition 1.0M phenyl-magnesium-chloride, -10~0
DEG C stirring 30 minutes after be to slowly warm up to react at room temperature, reaction terminate be added dilute hydrochloric acid (2mol/L, 112mL) quenching reaction, mix
It closes liquid to be extracted 3 times with ethyl acetate (93mL), merges organic phase and wash 2 times (93mL), sodium sulphate dries, filters, and after concentration, adds
Enter ethyl acetate and petroleum ether mixed solvent is beaten to obtain intermediate III (28.89g, purity 97.2%, yield: 79%).
3) intermediate III (35.54g, 100mmol) and tetrahydrofuran (178mL) are added in three-necked flask, after mixing evenly
It is added potassium borohydride (5.39g, 100mmol), is heated to 50~55 DEG C, is slowly dropped into methanol (36mL), 4~6 are reacted after dripping off
Hour.Reaction terminates to be cooled to 10~15 DEG C of addition 0.5mol/L dilute hydrochloric acid (178mL) quenching reactions, and ethyl acetate is added in water phase
(178 mL) is extracted 2 times, is merged organic phase saturated common salt and is washed 2 times (178mL), sodium sulphate is dry, and ethyl alcohol petroleum is used after concentration
The mashing of ether mixed solvent, is filtered, dry, obtains (R)-tert-butyl (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) ammonia
Carbamate IV (29.46g, purity 98.9%, yield: 89%).
Embodiment 3: comparative example: in the case where other conditions are constant, according to the operating method in embodiment 1 to the present invention
Technical solution compare test, obtained result is as shown in the table:
As seen from the above table, first step reactant selected in embodiment 1: paratoluensulfonyl chloride, second step reactant: benzene
Base magnesium bromide, third step reactant: being optimum embodiment when potassium borohydride；When using other substituent groups and phenyl grignard reagent,
Certain variation can all occur for the reaction in each portion and yield, this is because substituent group difference causes compound stability after synthesis to be sent out
A degree of decline has been given birth to, final product (R)-tert-butyl (1- ([1,1'- biphenyl] -4- base) -3- hydroxyl is eventually resulted in
Propane -2- base) carbamate IV purity and yield decline, the cost of whole synthetic route improve.
Embodiment 4: comparative example: in the case where other conditions are constant, according to the operating method in embodiment 1 to the present invention
Technical solution compare test, obtained result is as shown in the table:
As seen from the above table, the organic base of the first step selected in embodiment 1: diisopropylethylamine, second step catalyst:
Bis- (triphenylphosphine) Nickel Chlorides are optimal when the reaction temperature of three steps is respectively 0~5 DEG C, -10~0 DEG C and 45~50 DEG C
Embodiment；It can be seen that working as reaction temperature of the invention, when organic base and catalyst change, also will have a direct impact on final
The yield and purity of product.
It should be noted that above-mentioned is only presently preferred embodiments of the present invention, protection model not for the purpose of limiting the invention
It encloses, any combination or equivalents made on the basis of the above embodiments all belong to the scope of protection of the present invention.
Claims (10)
1. a kind of synthetic method of LCZ696 intermediate, which is characterized in that
1) raw material BOC-D- tyrosine I is reacted to obtain intermediate II with substituent group sulfonic acid chloride；
2) it is coupled intermediate II and phenyl grignard reagent to obtain intermediate III；
3) intermediate III is obtained into (R)-tert-butyl (1- ([1,1'- biphenyl] -4- base) -3- hydroxyl third by potassium borohydride reduction
Alkane -2- base) carbamate IV.
。
2. the synthetic method of LCZ696 intermediate as described in claim 1, which is characterized in that in the step 1), select
Alkali be organic base, specially one of triethylamine, diisopropylethylamine, DBU or pyridine.
3. the synthetic method of LCZ696 intermediate as described in claim 1, which is characterized in that in the step 1), reaction
Solvent be methylene chloride, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, tetrahydrofuran, 1,4- dioxane,
One of toluene or acetone or several mixtures.
4. the synthetic method of LCZ696 intermediate as described in claim 1, which is characterized in that in the step 1), replace
Base sulfonic acid chloride RSO2Cl is one of methylsufonyl chloride, ethyl chloride, phenylsulfonylchloride or p-methylphenyl sulfonic acid chloride.
5. the synthetic method of LCZ696 intermediate as described in claim 1, which is characterized in that in the step 1), reaction
Temperature is -10~110 DEG C.
6. the synthetic method of LCZ696 intermediate as described in claim 1, which is characterized in that in the step 2), select
Catalyst be bis- (triphenylphosphine) one of Nickel Chlorides or Nickel Chloride.
7. the synthetic method of LCZ696 intermediate as described in claim 1, which is characterized in that in the step 2), phenyl
Grignard Reagent is one of phenyl-magnesium-chloride, phenyl-magnesium-bromide or phenyl magnesium iodide.
8. the synthetic method of LCZ696 intermediate as described in claim 1, which is characterized in that in the step 2), reaction
Solvent is selected from one of toluene, tetrahydrofuran, 2- methyltetrahydrofuran or Isosorbide-5-Nitrae-dioxane or several mixtures.
9. the synthetic method of LCZ696 intermediate as described in claim 1, which is characterized in that in the step 2), select
Ligand is triphenylphosphine, and reaction temperature is -15~50 DEG C.
10. the synthetic method of LCZ696 intermediate as described in claim 1, which is characterized in that in the step 3), reaction
Solvent is the mixed solvent of methanol and tetrahydrofuran；Reaction temperature is -10~80 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111253425A (en) * | 2020-02-21 | 2020-06-09 | 常州南京大学高新技术研究院 | Synthesis method of 1, 3-bis [2- (3, 4-epoxycyclohexyl) ethyl ] tetramethyldisiloxane |
| CN112661671A (en) * | 2020-12-22 | 2021-04-16 | 江苏阿尔法药业有限公司 | Preparation method of Sacubitril intermediate |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111253425A (en) * | 2020-02-21 | 2020-06-09 | 常州南京大学高新技术研究院 | Synthesis method of 1, 3-bis [2- (3, 4-epoxycyclohexyl) ethyl ] tetramethyldisiloxane |
| CN111253425B (en) * | 2020-02-21 | 2022-04-29 | 常州南京大学高新技术研究院 | Synthesis method of 1, 3-bis [2- (3, 4-epoxycyclohexyl) ethyl ] tetramethyldisiloxane |
| CN112661671A (en) * | 2020-12-22 | 2021-04-16 | 江苏阿尔法药业有限公司 | Preparation method of Sacubitril intermediate |
| CN112661671B (en) * | 2020-12-22 | 2022-04-22 | 江苏阿尔法药业股份有限公司 | Preparation method of Sacubitril intermediate |
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