CN106905264A - A kind of method of synthesis A Zhalawei intermediates - Google Patents
A kind of method of synthesis A Zhalawei intermediates Download PDFInfo
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- CN106905264A CN106905264A CN201710237869.1A CN201710237869A CN106905264A CN 106905264 A CN106905264 A CN 106905264A CN 201710237869 A CN201710237869 A CN 201710237869A CN 106905264 A CN106905264 A CN 106905264A
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- formula
- compound
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- butylene
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- PTUXNCQDACBMKP-UHFFFAOYSA-N C=CC(Cc1ccccc1)=O Chemical compound C=CC(Cc1ccccc1)=O PTUXNCQDACBMKP-UHFFFAOYSA-N 0.000 description 1
- OQOQQESCCJVOST-UHFFFAOYSA-N C=CC1(Cc2ccccc2)CC1 Chemical compound C=CC1(Cc2ccccc2)CC1 OQOQQESCCJVOST-UHFFFAOYSA-N 0.000 description 1
- JAKDNFBATYIEIE-LBPRGKRZSA-N CC(C)(C)OC(N[C@@H](Cc1ccccc1)C(CCl)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](Cc1ccccc1)C(CCl)=O)=O JAKDNFBATYIEIE-LBPRGKRZSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
-
- 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 the method for one kind synthesis PhenethyIamino t-butyl formate of A Zhalawei intermediate (1S, 2R) 1 epoxy ethyl 2, comprise the following steps：, there is asymmetric reduction aminating reaction in step 1, obtain the butylene of 4 phenyl of (S) 3 amino 1 in the case where chiral amino alcohol catalyst 1 is acted on by the ketone of 1 phenyl, 3 butylene 2 with 2 nitro-benzylamines；Step 2, the butylene of 4 phenyl of (S) 3 N t-butoxycarbonyl aminos 1 is obtained by the butylene of 4 phenyl of (S) 3 amino 1 and di-tert-butyl dicarbonate reaction protection amino；Step 3, be there is into epoxidation reaction with the oxygen in air in the presence of chiral helicene phenolic ketone iron complex catalyst 2 in the butylene of 4 phenyl of (S) 3 N t-butoxycarbonyl aminos 1, the PhenethyIamino t-butyl formate of (1S, 2R) 1 epoxy ethyl 2 is obtained.A Zhalawei important intermediates (the 1S that the present invention is provided, 2R) the synthetic method raw material of the PhenethyIamino t-butyl formate of 1 epoxy ethyl 2 is cheap and easy to get, reaction condition is gentle, it is easy to operate, combined coefficient is high, it is suitable to industrialized production, a new approach is provided to prepare A Zhalawei and intermediate.
Description
Technical field
The invention belongs to organic preparing technical field, and in particular to a kind of A Zhalawei intermediates (1S, 2R) -1- epoxy second
The synthetic method of base -2- PhenethyIamino t-butyl formates.
Background technology
Sulfuric acid A Zhalawei (formula A), is developed by Bristol-Myers Squibb Co. of the U.S., and in June, 2003 is first in the U.S.
Listing, trade name is sharp to end appropriate (REYATAZ).Sulfuric acid A Zhalawei is current anti-AIDS drug topmost in the world, should
Medicine can continue potent suppression AIDS virus, therefore, only needing to take 1 time daily, adverse reaction is few, with other anti HIV-1 virus
Infection medicine is compared, also with absorbing that rapid, drug resistance is low, medication is convenient, the Small side effects to fat metabolism, during taking medicine
The advantages of not disturbing normal diet.Research with other antiretroviral drugs it is also shown that be combined, treatment inhibition of HIV infection effect
Fruit is more preferably.
The existing document report of the preparation method of sulfuric acid A Zhalawei, mainly with formula (I) compound (1S, 2R) -1- epoxy second
Base -2- PhenethyIaminos t-butyl formate and 2- [4- (2- pyridine radicals) benzyl]-hydrazine carboxylic acid's tert-butyl ester are raw material, through open loop, water
Solution, amine solution and into salt etc. reaction prepare.
Synthetic route is：
Formula (I) compound (1S, 2R) -1- epoxy ethyl -2- PhenethyIamino t-butyl formates are synthesis sulfuric acid A Zhala
The key compound of Wei, the chiral epoxy compound has two chiral centres, and complex structure, synthesis difficulty is higher, to sulfuric acid
The synthesis of A Zhalawei has great importance.Formula (I) compound (1S, 2R) -1- epoxy ethyl -2- benzene second has been related to it at present
The report of carbamate, chemical synthesis process be mainly with the chiral ortho dihydroxylic alcohols containing protected amino as rise
Beginning raw material, is obtained through the reaction such as class, partial hydrolysis and oxirane.
Synthetic route is：
The synthetic method is not related to the structure of chiral centre, and initiation material is to be protected containing two amino of chiral centre
Chiral ortho dihydroxylic alcohols, the compound be difficult synthesis, be difficult to obtain, price costly, is unsuitable for large-scale production.
Chinese patent CN103468757 and CN104911224 with compound B as initiation material, by the ketone carbonyl in compound B
By the method asymmetric reduction of enzymatic into chiral amino alcohol C, chiral amino alcohol C obtains formula to base by the reaction such as cyclization again
(I) compound.
The method is related to a structure for chiral centre, and initial compounds B is, containing an amino ketones for chiral centre, to be somebody's turn to do
Compound also is difficult to synthesis, is difficult to obtain, and price is also costly；In addition, the synthetic method need to be in the catalysis of biological reducing enzyme
Under carry out, general biology enzyme is not readily available, therefore, also limit the industrial applications prospect of the method.
The content of the invention
The technical problems to be solved by the invention be overcome existing preparation formula (I) compound (1S, 2R) -1- epoxy ethyls -
2- PhenethyIaminos t-butyl formate report technology in raw material be not easy to obtain, it is expensive, be unable to industrial-scale production lack
Fall into, there is provided a kind of effective side for preparing formula (I) compound (1S, 2R) -1- epoxy ethyl -2- PhenethyIamino t-butyl formates
Method, the method raw material is cheap and easy to get, reaction condition is gentle, easy to operate, combined coefficient is high, environmentally friendly, is adapted to scale life
Produce.
Technical scheme is summarized as follows：
Step (1), formula (II) compound 1- phenyl -3- butene-2s -one is sent out under the effect of catalyst 1 with 2- nitro-benzylamines
Raw asymmetric reduction aminating reaction, obtains formula (III) compound (S) -3- amino-4-phenyl -1- butylene；Step (2), formula
(III) compound and di-tert-butyl dicarbonate reaction protection amino are that formula (IV) compound (S) -3-N- tertbutyloxycarbonyl ammonia is obtained
Base -4- phenyl -1- butylene；There is epoxy with the oxygen in air in the presence of catalyst 2 in step (3), formula (IV) compound
Change reaction, obtain formula (I) compound (1S, 2R) -1- epoxy ethyl -2- PhenethyIamino t-butyl formates.
Synthetic route is：
Catalyst 1 in described step (1) is chiral amino alcohol, and structure is：
R in catalyst structure1It is hydrogen atom, C1~C4Alkyl, nitro, halogen etc..
The catalyst efficiency is very high, and its consumption is only the 3~8% of the amount of formula (II) combinations of materials.
Catalyst 2 in described step (3) is chiral helicene phenolic ketone iron complex, and structure is：
R in the catalyst structure2It is hydrogen atom, C1~C4Alkyl, halogen etc..
The catalyst is in hgher efficiency, and its consumption is only the 2~5% of the amount of formula (IV) combinations of materials.
Formula (I) compound (1S, the 2R) -1- epoxy ethyl -2- PhenethyIaminos t-butyl formate prepared with this technique
Three steps are needed, with cheap non-chiral compound as initiation material, two chiral centres is constructed, total recovery is changed up to more than 65%
Purity is learned up to 98%, optical purity is up to more than 98%.
Specific embodiment
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
Invention rather than limitation the scope of the present invention.
Raw material used or reagent are commercially available in addition to special instruction in embodiment.
The preparation of embodiment 1 formula (III) compound (S) -3- amino-4-phenyl -1- butylene
By 10mmol1- phenyl -3- butene-2s -one, 10mmol 2- nitro-benzylamines, 2.0gMolecular sieve and 20mL dichloros
Methane is added in reaction bulb, is uniformly mixed.System temperature is risen into 60~70 DEG C, and the lower stirring reaction 3h of temperature herein, is stopped
Only heat, treat that system temperature is down to 30~40 DEG C, by (the R of 0.5mmol catalyst 11=Cl) and the addition of 20mL dichloromethane, maintain
System temperature is further continued for stirring reaction 4h at 30~40 DEG C, stops reaction, is filtered off after coolingThe solid matters such as molecular sieve, room
To 20mL 4N HCl are added in filtrate under temperature, stood after stirring 1h, separate organic layer, washed with 5mL 4N HCl, merge water
Layer, 8.5 are transferred to sodium carbonate solid by water layer pH value, add 50mL dichloromethane, separate organic layer, use anhydrous sodium sulfate drying
Decompression afterwards boils off solvent, obtains formula (III) compound, yield 85%, ee values 97.5%.
The preparation of embodiment 2 formula (III) compound (S) -3- amino-4-phenyl -1- butylene
By 10mmol 1- phenyl -3- butene-2s -one, 10mmol 2- nitroanilines, 2.0gMolecular sieve and 20mL dichloros
Methane is added in reaction bulb, is uniformly mixed.System temperature is risen into 60~70 DEG C, and the lower stirring reaction 3h of temperature herein, is stopped
Only heat, treat that system temperature is down to 35~45 DEG C, by (the R of 0.6mmol catalyst 11=Me) and the addition of 20mL dichloromethane, maintain
System temperature is further continued for stirring reaction 5h at 35~45 DEG C, stops reaction, is filtered off after coolingThe solid matters such as molecular sieve, room
To 20mL 4N HCl are added in filtrate under temperature, stood after stirring 1h, separate organic layer, washed with 5mL 4N HCl, merge water
Layer, 8.5 are transferred to sodium carbonate solid by water layer pH value, add 50mL dichloromethane, separate organic layer, use anhydrous sodium sulfate drying
Decompression afterwards boils off solvent, obtains formula (III) compound, yield 81%, ee values 94%.
The preparation of embodiment 3 formula (IV) compound (S) -3-N- t-butoxycarbonyl amino -4- phenyl -1- butylene
By 10mmol formulas (III) compound, 0.7mmol potassium carbonate, 13mmol di-tert-butyl dicarbonates and 30mL tetrahydrochysene furans
Mutter in addition reaction bulb, be uniformly mixed rear room temperature reaction 10 hours.Decompression boils off solvent, and 50mL oil is added to residue
Ether, then pH value to 1 is adjusted with 4M HCl, the solid that suction filtration is separated out, drying under reduced pressure obtains formula (IV) compound, yield 98%.
The preparation of embodiment 4 formula (I) compound (1S, 2R) -1- epoxy ethyl -2- PhenethyIamino t-butyl formates
By the butyraldehyde and the (R of 0.18mmol catalyst 2 of 6mmol formulas (IV) compound, 36mmol newly distillation2=Me) and
50mL dichloroethanes is added, and dry air is passed through with the flow of 15mL/min, in 35~45 DEG C of stirring reaction 6h, is stopped anti-
Should, with saturated sodium bicarbonate solution washing reaction mixture, branch vibration layer uses ether aqueous layer extracted, merges organic layer, with anhydrous
Decompression boils off solvent after sodium sulphate is dried, and obtains the mixture recrystallization of crude product, crude product ethyl acetate and petroleum ether, obtains formula
(I) compound, yield 80%, ee values 98.2%.
The preparation of embodiment 4 formula (I) compound (1S, 2R) -1- epoxy ethyl -2- PhenethyIamino t-butyl formates
By the butyraldehyde and the (R of 0.24mmol catalyst 2 of 6mmol formulas (IV) compound, 36mmol newly distillation2=Cl) and
50mL dichloroethanes is added, and dry air is passed through with the flow of 15mL/min, in 30~40 DEG C of stirring reaction 8h, is stopped anti-
Should, with saturated sodium bicarbonate solution washing reaction mixture, branch vibration layer uses ether aqueous layer extracted, merges organic layer, with anhydrous
Decompression boils off solvent after sodium sulphate is dried, and obtains the mixture recrystallization of crude product, crude product ethyl acetate and petroleum ether, obtains formula
(I) compound, yield 77%, ee values 95.2%.
Claims (3)
1. A Zhalawei intermediate (1S, 2R) -1- epoxy ethyl -2- PhenethyIamino formic acid tertiary fourth of the one kind as shown in formula (I)
The synthetic method of ester, the reaction equation of the synthetic method is：
It is characterized in that comprising the following steps：
Step (1), formula (II) compound 1- phenyl -3- butene-2s -one is occurred not under the effect of catalyst 1 with 2- nitro-benzylamines
Asymmetric reduction aminating reaction, obtains formula (III) compound (S) -3- amino-4-phenyl -1- butylene；
Step (2), formula (III) compound obtains formula (IV) compound (S) -3-N- with di-tert-butyl dicarbonate reaction protection amino
T-butoxycarbonyl amino -4- phenyl -1- butylene；
There is epoxidation reaction in step (3), formula (IV) compound, that is, formula is obtained under the effect of catalyst 2 with the oxygen in air
(I) compound (1S, 2R) -1- epoxy ethyl -2- PhenethyIamino t-butyl formates；Catalyst 1 in described step (1) is
Chiral amino alcohol, structure is：
Wherein R1It is hydrogen atom, C1~C4Alkyl, nitro, halogen；
Catalyst 2 in described step (3) is chiral helicene phenolic ketone iron complex, and structure is：
Wherein R2It is hydrogen atom, C1~C4Alkyl, halogen.
2. the synthetic method of a kind of A Zhalawei intermediates according to claim 1, it is characterised in that：Described step
(1) consumption of the catalyst 1 in is only the 3~8% of the amount of formula (II) combinations of materials.
3. the synthetic method of a kind of A Zhalawei intermediates according to claim 1, it is characterised in that：Described step
(2) consumption of the catalyst 2 in is only the 2~5% of the amount of formula (IV) combinations of materials.
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