CN106905264B - A method of synthesis A Zhalawei intermediate - Google Patents
A method of synthesis A Zhalawei intermediate Download PDFInfo
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- CN106905264B CN106905264B CN201710237869.1A CN201710237869A CN106905264B CN 106905264 B CN106905264 B CN 106905264B CN 201710237869 A CN201710237869 A CN 201710237869A CN 106905264 B CN106905264 B CN 106905264B
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- C07—ORGANIC CHEMISTRY
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- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/04—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with air or molecular oxygen
- C07D301/06—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with air or molecular oxygen in the liquid phase
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- C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
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Abstract
The invention discloses a kind of synthesis A Zhalawei intermediate (1S, 2R) the method for-1- epoxy ethyl-2- PhenethyIamino t-butyl formate, include the following steps: step 1, with 2- nitro-benzylamine asymmetric reduction aminating reaction is occurred into for 1- phenyl-3- butene-2 -one under the effect of chiral amino alcohol catalyst 1, obtains (S)-3- amino-4-phenyl-1- butylene；Step 2, (S) -3- amino-4-phenyl -1- butylene is reacted into protection amino with di-tert-butyl dicarbonate and obtains (S) -3-N- t-butoxycarbonyl amino -4- phenyl -1- butylene；Step 3, with the oxygen in air epoxidation reaction is occurred into for (S) -3-N- t-butoxycarbonyl amino -4- phenyl -1- butylene under the action of chiral helicene phenolic ketone iron complex catalyst 2, obtain (1S, 2R) -1- epoxy ethyl -2- PhenethyIamino t-butyl formate.A Zhalawei important intermediate (1S provided by the invention, 2R) the synthetic method raw material of -1- epoxy ethyl -2- PhenethyIamino t-butyl formate is cheap and easy to get, reaction condition is mild, it is easy to operate, combined coefficient is high, suitable for industrialized production, a new approach is provided to prepare A Zhalawei and intermediate.
Description
Technical field
The invention belongs to organic preparation technical fields, and in particular to a kind of A Zhalawei intermediate (1S, 2R) -1- epoxy second
The synthetic method of base -2- PhenethyIamino t-butyl formate.
Background technique
Sulfuric acid A Zhalawei (formula A) is developed by Bristol-Myers Squibb Co., the U.S., and in June, 2003 is for the first time in the U.S.
Listing, the sharp Chinese mugwort appropriate (REYATAZ) of trade name.Sulfuric acid A Zhalawei is current anti-AIDS drug most important in the world, should
Drug can continue potent inhibition AIDS virus, therefore, only need to take 1 time daily, adverse reaction is few, with other anti HIV-1 virus
Infection medicine is compared, also have absorb rapidly, drug resistance is low, medication is convenient, to the Small side effects of fat metabolism, in duration of medication
Not the advantages that not interfering normal diet.Research with other antiretroviral drugs it is also shown that be combined, treatment inhibition of HIV infection effect
Fruit is more preferable.
The preparation method of sulfuric acid A Zhalawei is it has been reported that mainly with formula (I) compound (1S, 2R) -1- epoxy second
Base -2- PhenethyIamino t-butyl formate and 2- [4- (2- pyridyl group) benzyl]-hydrazine carboxylic acid's tert-butyl ester are raw material, through open loop, water
Solution, aminolysis and at the reactions such as salt preparation.
Synthetic route are as follows:
Formula (I) compound (1S, 2R) -1- epoxy ethyl -2- PhenethyIamino t-butyl formate is synthesis sulfuric acid A Zhala
The key compound of Wei, there are two chiral centres for chiral epoxy compound tool, and structure is complicated, and synthesis difficulty is higher, to sulfuric acid
The synthesis of A Zhalawei has great importance.At present about formula (I) compound (1S, 2R) -1- epoxy ethyl -2- benzene second
The report of carbamate, chemical synthesis process are mainly with the chiral ortho dihydric alcohol containing protected amino
Beginning raw material is made through the reactions such as class, partial hydrolysis and ethylene oxide.
Synthetic route are as follows:
The synthetic method is not related to the building of chiral centre, and starting material is containing there are two the amino of chiral centre to be protected
Chiral ortho dihydric alcohol, which is difficult to synthesize, be difficult to obtain, and price is more expensive, is unsuitable for large-scale production.
Chinese patent CN103468757 and CN104911224 is using compound B as starting material, by the ketone carbonyl in compound B
Base obtains formula using reactions such as cyclization at chiral amino alcohol C, chiral amino alcohol C by the method asymmetric reduction of enzymatic
(I) compound.
This method is related to the building of a chiral centre, and initial compounds B is the amino ketones containing a chiral centre, should
Compound is also difficult to synthesize, and is difficult to obtain, and price is also more expensive；In addition, the synthetic method need to be in the catalysis of biological reducing enzyme
Lower progress, general biological enzyme are not readily available, and therefore, also limit the industrial applications prospect of this method.
Summary of the invention
The technical problem to be solved by the present invention is to overcome existing preparation formula (I) compound (1S, 2R) -1- epoxy ethyl -
Raw material is not easy to obtain, is expensive, being unable to lacking for industrial-scale production in the technology of 2- PhenethyIamino t-butyl formate report
It falls into, a kind of side of effective preparation formula (I) compound (1S, 2R) -1- epoxy ethyl -2- PhenethyIamino t-butyl formate is provided
Method, this method raw material is cheap and easy to get, reaction condition is mild, easy to operate, combined coefficient is high, environmentally friendly, is suitble to scale raw
It produces.
Technical solution of the present invention is summarized as follows:
Step (1) sends out formula (II) compound 1- phenyl-3- butene-2 -one under the effect of catalyst 1 with 2- nitro-benzylamine
Raw asymmetric reduction aminating reaction, obtains formula (III) compound (S) -3- amino-4-phenyl -1- butylene；Step (2), formula
(III) compound is reacted with di-tert-butyl dicarbonate protects amino to obtain formula (IV) compound (S) -3-N- tertbutyloxycarbonyl ammonia
Base -4- phenyl -1- butylene；With the oxygen in air epoxy occurs for step (3), formula (IV) compound under the action of catalyst 2
Change reaction, obtains formula (I) compound (1S, 2R) -1- epoxy ethyl -2- PhenethyIamino t-butyl formate.
Synthetic route are as follows:
Catalyst 1 in the step (1) is chiral amino alcohol, structure are as follows:
R in catalyst structure1For hydrogen atom, C1~C4Alkyl, nitro, halogen etc..
The catalyst efficiency is very high, and dosage is only the 3~8% of the amount of formula (II) combinations of materials.
Catalyst 2 in the step (3) is chiral helicene phenolic ketone iron complex, structure are as follows:
R in the catalyst structure2For hydrogen atom, C1~C4Alkyl, halogen etc..
The catalyst is more efficient, and dosage is only the 2~5% of the amount of formula (IV) combinations of materials.
Formula (I) compound (1S, the 2R) -1- epoxy ethyl -2- PhenethyIamino t-butyl formate prepared with this technique
Three steps are needed, using cheap non-chiral compound as starting material, construct two chiral centres, total recovery is changed up to 65% or more
Purity is learned up to 98%, optical purity is up to 98% or more.
Specific embodiment
Below with reference to specific embodiment is implemented, the present invention is further illustrated.It should be understood that these embodiments are merely to illustrate this
It invents rather than limits the scope of the invention.
Raw material used in embodiment or reagent are commercially available in addition to special instruction.
The preparation of 1 formula of embodiment (III) compound (S) -3- amino-4-phenyl -1- butylene
By 10mmol1- phenyl-3- butene-2 -one, 10mmol 2- nitro-benzylamine, 2.0gMolecular sieve and 20mL dichloro
Methane is added in reaction flask, is uniformly mixed.System temperature is risen to 60~70 DEG C, and is stirred to react 3h under this temperature, is stopped
It only heats, is down to 30~40 DEG C to system temperature, by 1 (R of 0.5mmol catalyst1=Cl) and the addition of 20mL methylene chloride, it maintains
System temperature is further continued for being stirred to react 4h at 30~40 DEG C, stops reaction, filters off after coolingThe solid matters such as molecular sieve,
20mL 4N HCl is added into filtrate at room temperature, is stood after stirring 1h, separates organic layer, washed with 5mL 4N HCl, merges water
Water layer pH value is transferred to 8.5 with sodium carbonate solid, 50mL methylene chloride is added, separates organic layer by layer, dry with anhydrous sodium sulfate
Decompression boils off solvent afterwards, obtains formula (III) compound, yield 85%, ee value 97.5%.
The preparation of 2 formula of embodiment (III) compound (S) -3- amino-4-phenyl -1- butylene
By 10mmol 1- phenyl-3- butene-2 -one, 10mmol 2- nitroaniline, 2.0gMolecular sieve and 20mL dichloro
Methane is added in reaction flask, is uniformly mixed.System temperature is risen to 60~70 DEG C, and is stirred to react 3h under this temperature, is stopped
It only heats, is down to 35~45 DEG C to system temperature, by 1 (R of 0.6mmol catalyst1=Me) and the addition of 20mL methylene chloride, it maintains
System temperature is further continued for being stirred to react 5h at 35~45 DEG C, stops reaction, filters off after coolingThe solid matters such as molecular sieve,
20mL 4N HCl is added into filtrate at room temperature, is stood after stirring 1h, separates organic layer, washed with 5mL 4N HCl, merges water
Water layer pH value is transferred to 8.5 with sodium carbonate solid, 50mL methylene chloride is added, separates organic layer by layer, dry with anhydrous sodium sulfate
Decompression boils off solvent afterwards, obtains formula (III) compound, yield 81%, ee value 94%.
The preparation of 3 formula of embodiment (IV) compound (S) -3-N- t-butoxycarbonyl amino -4- phenyl -1- butylene
By 10mmol formula (III) compound, 0.7mmol potassium carbonate, 13mmol di-tert-butyl dicarbonate and 30mL tetrahydro furan
It mutters and is added in reaction flask, reacted at room temperature 10 hours after being uniformly mixed.Decompression boils off solvent, and 50mL petroleum is added to residue
Ether, then with 4M HCl tune pH value to 1, filter the solid of precipitation, be dried under reduced pressure to obtain formula (IV) compound, yield 98%.
The preparation of 4 formula of embodiment (I) compound (1S, 2R) -1- epoxy ethyl -2- PhenethyIamino t-butyl formate
2 (the R of butyraldehyde and 0.18mmol catalyst that 6mmol formula (IV) compound, 36mmol are newly distilled2=Me) and
50mL dichloroethanes is added, and dry air is passed through with the flow of 15mL/min, and 6h is stirred to react at 35~45 DEG C, stops anti-
It answers, with saturated sodium bicarbonate solution washing reaction mixture, branch vibration layer merges organic layer with ether aqueous layer extracted, and use is anhydrous
Decompression boils off solvent after sodium sulphate is dry, obtains crude product, and the mixture recrystallization of crude product ethyl acetate and petroleum ether obtains formula
(I) compound, yield 80%, ee value 98.2%.
The preparation of 4 formula of embodiment (I) compound (1S, 2R) -1- epoxy ethyl -2- PhenethyIamino t-butyl formate
2 (the R of butyraldehyde and 0.24mmol catalyst that 6mmol formula (IV) compound, 36mmol are newly distilled2=Cl) and
50mL dichloroethanes is added, and dry air is passed through with the flow of 15mL/min, and 8h is stirred to react at 30~40 DEG C, stops anti-
It answers, with saturated sodium bicarbonate solution washing reaction mixture, branch vibration layer merges organic layer with ether aqueous layer extracted, and use is anhydrous
Decompression boils off solvent after sodium sulphate is dry, obtains crude product, and the mixture recrystallization of crude product ethyl acetate and petroleum ether obtains formula
(I) compound, yield 77%, ee value 95.2%.
Claims (3)
1. a kind of tertiary fourth of A Zhalawei intermediate (1S, 2R) -1- epoxy ethyl -2- PhenethyIamino formic acid as shown in formula (I)
The synthetic method of ester, the reaction equation of the synthetic method are as follows:
It is characterized by comprising the following steps:
Formula (II) compound 1- phenyl-3- butene-2 -one occurs not under the effect of catalyst 1 with 2- nitro-benzylamine step (1)
Asymmetric reduction aminating reaction obtains formula (III) compound (S) -3- amino-4-phenyl -1- butylene；
Step (2), formula (III) compound react protection amino with di-tert-butyl dicarbonate and obtain formula (IV) compound (S) -3-N-
T-butoxycarbonyl amino -4- phenyl -1- butylene；
Step (3), formula (IV) compound occur epoxidation reaction with the oxygen in air under the effect of catalyst 2, obtain formula
(I) compound (1S, 2R) -1- epoxy ethyl -2- PhenethyIamino t-butyl formate；Catalyst 1 in the step (1) is
Chiral amino alcohol, structure are as follows:
Wherein R1For hydrogen atom, C1~C4Alkyl, nitro, halogen；
Catalyst 2 in the step (3) is chiral helicene phenolic ketone iron complex, structure are as follows:
Wherein R2For hydrogen atom, C1~C4Alkyl, halogen.
2. a kind of synthetic method of A Zhalawei intermediate according to claim 1, it is characterised in that: the step
(1) dosage of the catalyst 1 in is only the 3~8% of the amount of formula (II) combinations of materials.
3. a kind of synthetic method of A Zhalawei intermediate according to claim 1, it is characterised in that: the step
(2) dosage of the catalyst 2 in is only the 2~5% of the amount of formula (IV) combinations of materials.
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Citations (4)
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|---|---|---|---|---|
| US4238589A (en) * | 1973-03-05 | 1980-12-09 | Hoffmann-La Roche Inc. | Fluorogenic materials and labeling techniques |
| WO2009136365A1 (en) * | 2008-05-08 | 2009-11-12 | Ranbaxy Laboratories Limited | Process for the preparation of 3,4-epoxy-2-amino-1-substituted butane derivatives and intermediate compounds thereof |
| CN104220451A (en) * | 2012-02-15 | 2014-12-17 | 百时美施贵宝公司 | C-3 cycloalkenyl triterpenoids with HIV maturation inhibitory activity |
| CN104803954A (en) * | 2015-04-30 | 2015-07-29 | 上海应用技术学院 | Preparation method for fosamprenir intermediate |
Family Cites Families (2)
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|---|---|---|---|---|
| US20090270499A1 (en) * | 2008-04-24 | 2009-10-29 | Oxyrane (Uk) Limited | Process for Synthesizing Atazanavir |
| CN103951588B (en) * | 2014-04-30 | 2016-10-05 | 淮海工学院 | A kind of method synthesizing onglyza intermediate N-tertbutyloxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine |
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- 2017-04-12 CN CN201710237869.1A patent/CN106905264B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4238589A (en) * | 1973-03-05 | 1980-12-09 | Hoffmann-La Roche Inc. | Fluorogenic materials and labeling techniques |
| WO2009136365A1 (en) * | 2008-05-08 | 2009-11-12 | Ranbaxy Laboratories Limited | Process for the preparation of 3,4-epoxy-2-amino-1-substituted butane derivatives and intermediate compounds thereof |
| CN104220451A (en) * | 2012-02-15 | 2014-12-17 | 百时美施贵宝公司 | C-3 cycloalkenyl triterpenoids with HIV maturation inhibitory activity |
| CN104803954A (en) * | 2015-04-30 | 2015-07-29 | 上海应用技术学院 | Preparation method for fosamprenir intermediate |
Non-Patent Citations (2)
| Title |
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| 手性铁催化体系在不对称催化中的应用研究;李岩云 等，;《分子催化》;20110228;第25卷(第1期);第90-96页 |
| 还原胺化反应的应用及其机理研究;葛新;《中国博士学位论文全文数据库 工程科技I辑》;20160115;B014-26 |
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