CN105732568B - A kind of synthetic method of Atorvastatin calcium chiral intermediate - Google Patents
A kind of synthetic method of Atorvastatin calcium chiral intermediate Download PDFInfo
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Abstract
The invention discloses a kind of synthetic methods of Atorvastatin calcium chiral intermediate, belong to the synthesis technical field of medicine intermediate.Technical scheme of the present invention main points are：
Description
Technical field
The invention belongs to the synthesis technical fields of medicine intermediate, and in particular to a kind of Atorvastatin calcium chiral intermediate
Synthetic method.
Background technology
Atorvastatin calcium is the potent lipid-lowering medicine that Pfizer Inc. released in 1997.Atorvastatin calcium is can be with
The drug of T-CHOL and triglycerides is reduced simultaneously, belongs to 3- hydroxy-3-methyls-glutaryl-CoA-reductase inhibitors.By
It is treated while Atorvastatin calcium is suitable for T-CHOL and triglyceride Two indices increase, american heart in 2008
Meeting, palsy association exist《The secondary prevention guide of Ischemic Stroke and transient ischemic attack》In emphasize using statins
Intensive Lipid-lowing and keypoint recommendation Atorvastatin calcium, this has just more established it for the big medicine of big kind and long market cycle
Position.Atorvastatin calcium since two thousand two, occupies global well selling medicine umber one position always.Atorvastatin calcium is complete within 2014
13,000,000,000 dollars of ball sales volume is the big kind drug in the undisputed whole world.
(4R-Cis) -6- aminoethyl -2,2- dimethyl -1,3- dioxane-hecanoic acid t-butyl ester is synthesis Atorvastatin
The crucial chiral intermediate of calcium will use inflammable and explosive butyl lithium reagent, instead at present in the chemical synthesising technology of the intermediate
It answers condition more harsh, especially to use the potassium cyanide of severe toxicity, in addition periodic acid used is expensive, from industrialization angle
It says, working condition is harsh, and cost is higher；It is said from environmental, it is seriously polluted, therefore the kind is done by original technique have very greatly
Big difficulty seriously hinders the industrialization process of the product.
In terms of the chiral intermediate living things catalysis synthetic technology, biological enzyme specificity is strong, and products obtained therefrom ee values are high, are better than
Chemical method chiral resolution by the chiral intermediate for the high ee values that biological enzyme obtains, reduces the difficulty of removal chiral impurity,
And biological enzyme substantially reduces the synthesis technology of product, avoids dangerous or high toxic material and expensive compounds
It uses, makes operation more terse, cost is substantially reduced, and pollutant emission is less, more meets the requirement of Green Chemistry.Atropic at present
It cuts down there are two types of statin calcium chiral intermediate living things catalysis synthetic methods, one kind is to rely on alcohol dehydrogenase NADP using Bacillus acidi lactici (height)
(H)-dependent alcohol dehydrogenase (LBADH) enzymatic, another applies 2-deoxy-D-ribose -5-
Phosphate aldolase catalysis deoxyribose phosphate aldolase (DERA).LBADH enzymatics foreign countries have document report
Road, but coenzyme (NADP+) is needed with LBADH enzymatics, technical program is complicated, and the coenzyme country does not produce, import price
Costliness, cost is higher, so this enzymatic is only applicable to laboratory level research, it can not further industrialized production.In recent years
Come, have a small amount of report with DERA enzymatics, compared to LBADH enzymes, the DERA enzymatics efficiency and yield are high, and do not need to be auxiliary
Enzyme.But the DERA enzymes of current document report are mainly extracted from wild mushroom, and extraction procedure is complicated, and yield is relatively low, and enzyme is not easy
It preserves, easily inactivates, it is difficult to adapt to industrialized production.
Invention content
The technical problem to be solved by the present invention is to provide a kind of raw material is cheap and easy to get, route is easy to operate, it is reproducible and
The synthetic method of the higher Atorvastatin calcium chiral intermediate of yield.
It is of the invention to adopt the following technical scheme that solve above-mentioned technical problem, a kind of Atorvastatin calcium chiral intermediate
Synthetic method, it is characterised in that the specific steps are：
A, 1,1,4,4- tetramethoxy -2- butylene is prepared by furans and bromine in methyl alcohol；
B, 1,1,4,4- tetramethoxies -2- butylene is under the action of potassium permanganate and weak acid pyrovinic acid or p-methyl benzenesulfonic acid
Oxidation generation 1,1- dimethoxy acetaldehyde；
C, it is anti-under the catalytic action of catalyst anhydrous alumina with nitromethane addition to occur for 1,1- dimethoxys acetaldehyde
1,1- dimethoxy -2- hydroxyl -3- nitropropanes should be generated；
D, 1,1- dimethoxys -2- hydroxyls -3- nitropropanes be dehydrated under the action of the concentrated sulfuric acid obtain 1,1- dimethoxys -
3- nitro -2- propylene；
E, using glacial acetic acid as solvent, 1,1- dimethoxy -3- nitro -2- propylene is in the catalytic action of catalyst polyphosphoric acids
Lower hydrolysis obtains 3- nitro -2- methacrylaldehyde；
F, 3- nitros -2- methacrylaldehyde, alkylol and dicthenone are in tetra isopropyl oxygen titanium and S- xenol mixed catalysts
Catalytic action under obtain (5S) -7- nitro -5- hydroxyl -3- oxo -6- heptene acid alkyl esters, wherein alkylol for isopropanol or
The tert-butyl alcohol；
G, (5S) -7- nitros -5- hydroxyls -3- oxos -6- heptene acid alkyl ester is in the catalytic action of catalyst sodium borohydride
It is lower to obtain (3R, 5S) -7- nitro -3,5- dihydroxy -6- heptene acid alkyl esters through carbonyl reduction；
H, (3R, 5S) -7- nitros -3,5- dihydroxy -6- heptene acid alkyl ester is in the catalysis of catalyst pyridine hydrobromate
Effect is lower and (4R-Cis) -6- nitre vinyl -2,2- dimethyl -1,3- dioxane-caproic acid Arrcostab is obtained by the reaction in acetone；
I, (4R-Cis) -6- nitre vinyl -2,2- dimethyl -1,3- dioxane-caproic acid Arrcostab catalyst palladium carbon/
Under the catalytic action of hydrazine hydrate or reduced iron powder/glacial acetic acid through double bond addition and nitro restore to obtain (4R-Cis) -6- aminoethyls -
2,2- dimethyl -1,3- dioxane-caproic acid Arrcostab.
It further limits, the detailed process of step A is：Furans and methanol are added in reaction vessel, under nitrogen protection
In -50 DEG C of dropping liquid bromine reaction 3h, 0 DEG C is then heated to the reaction was continued 2h, be warmed to room temperature after reaction, with unsaturated carbonate hydrogen
The pH that sodium solution adjusts reaction solution is 7-8, and decompression steams methanol, then be extracted with ethyl acetate, and organic phase saturated sodium-chloride is molten
Organic phase is separated after liquid washing, then steams ethyl acetate and obtains 1, Isosorbide-5-Nitrae, 4- tetramethoxy -2- butylene.
It further limits, the detailed process of step B is：1,1,4,4- tetramethoxy -2- butylene is added in reaction vessel
And toluene, potassium permanganate and pyrovinic acid or p-methyl benzenesulfonic acid are added, under nitrogen protection in 80 DEG C of reactions, TLC monitoring
Raw material, which is removed under reduced pressure after the reaction was complete, adds in chloroform after toluene, then with saturated sodium carbonate solution adjust reaction solution pH be it is neutral,
Organic phase is separated, chloroform is evaporated off and obtains 1,1- dimethoxy acetaldehyde.
It further limits, the detailed process of step C is：By 1,1- dimethoxys acetaldehyde, nitromethane in reaction vessel
It is added in DMF with catalyst anhydrous alumina, is heated to 130 DEG C of reactions under nitrogen protection, is down to room temperature after reaction,
Reaction solution is filtered, saturated nacl aqueous solution is added in, then extracted with dichloromethane after concentrating filter liquor, organic phase obtains after solvent is evaporated off
To 1,1- dimethoxy -2- hydroxyl -3- nitropropanes.
It further limits, the detailed process of step D is：In 0-5 DEG C by 1,1- dimethoxy -2- hydroxyls in reaction vessel
The toluene alkane solution of base -3- nitropropanes instills the concentrated sulfuric acid, drips rear temperature rising reflux and reacts and separate moisture, after reaction
It is neutral that the pH of reaction solution is adjusted with triethylamine, after toluene is evaporated off, adds in saturated nacl aqueous solution, then extracted with chloroform, organic
Mutually after saturated nacl aqueous solution washs with anhydrous magnesium sulfate it is dry, filter, remove solvent under reduced pressure and obtain 1,1- dimethoxys -3-
Nitro -2- propylene.
It further limits, the detailed process of step E is：By 1,1- dimethoxy -3- nitro -2- propylene in reaction vessel
It is placed in solvent glacial acetic acid with catalyst polyphosphoric acids, reaction is stirred at room temperature, ice water is added in into reaction solution after reaction makes
Polyphosphoric acids all decomposes, and is then extracted with dichloromethane, organic phase filters after being dried over anhydrous sodium sulfate, filtrate steaming removal solvent
After obtain 3- nitro -2- methacrylaldehyde.
It further limits, the detailed process of step F is：In bottle container is reacted by 3- nitro -2- methacrylaldehyde, alkylol and
Tetra isopropyl oxygen titanium (Ti (O-i-Pr)4) be added in THF solution with S- xenols (S- (-) BINOL) mixed catalyst, in nitrogen
The THF solution of dicthenone is added dropwise under gas shielded in -78 DEG C, temperature is kept to continue to be stirred to react after dripping, after reaction
It is warmed to room temperature, filtering reacting liquid is washed, extract, solvent is evaporated off obtains (5S) -7- nitro -5- hydroxyl -3- oxo -6- heptenoic acids
Arrcostab, wherein alkylol are isopropanol or the tert-butyl alcohol.
It further limits, the detailed process of step G is：In reaction vessel (5S) -7- nitro -5- hydroxyls are added in 10 DEG C
The THF solution of base -3- oxo -6- heptene acid alkyl esters and the THF solution of sodium borohydride keep temperature to be stirred to react, reaction knot
THF is evaporated off after beam, adds saturated nacl aqueous solution, is then extracted with dichloromethane, after organic phase is dried with anhydrous slufuric acid ammonium
It filters, (3R, 5S) -7- nitro -3,5- dihydroxy -6- heptene acid alkyl esters is obtained after filtrate steaming removal solvent.
It further limits, the detailed process of step H is：In reaction vessel by (3R, 5S) -7- nitro -3,5- dihydroxy -
6- heptene acid alkyl ester is added in the mixed solution of absolute ethyl alcohol and acetone, is added catalyst pyridine hydrobromate, is heated to
55-60 DEG C of insulation reaction, after reaction cooling are precipitated white solid, filter, and filter cake wash with absolute ethyl alcohol and must after drying
To (4R-Cis) -6- nitre vinyl -2,2- dimethyl -1,3- dioxane-caproic acid Arrcostab.
It further limits, the detailed process of step I is：By (4R-Cis) -6- nitre vinyl -2,2- dimethyl -1,3- two
Six rings of oxygen-caproic acid Arrcostab and catalyst palladium carbon/hydrazine hydrate or reduced iron powder/glacial acetic acid are added in reaction vessel, with methanol
Or target product (4R-Cis) -6- aminoethyl -2,2- dimethyl -1,3- is made as solvent reaction in the mixed solution of second alcohol and water
Dioxane-caproic acid Arrcostab.
Synthetic route in the synthetic method of Atorvastatin calcium chiral intermediate of the present invention is：
It is dangerous, acute that the process route of the present invention not only avoids butyl lithium in chemical synthesis, potassium cyanide and periodic acid etc.
The use of malicious, expensive drug, and since the use of tetra isopropyl oxygen titanium and S- xenol mixing chiral catalysts makes production
The ee of product, which is worth to, to be effectively improved.The step B of the present invention carrys out oxyalkylene using potassium permanganate and weak acid compound, can be effective
Avoid that ozone is inconvenient for use, the incomplete shortcoming of reaction；Step D can simplify experimental implementation using the concentrated sulfuric acid, avoid acidity
Acetic anhydride and the pyridine of alkalinity make the shortcomings that complicated for operation as mixed catalyst due to needing stringent control feed ratio；Step
Rapid F avoids the use than relatively hazardous organic zinc reagent, and product yield and optical voidness using dicthenone and alkylol
Degree all improves a lot；Step H uses pyridine hydrobromide salt as catalyst, because it can be according to the change of pH in reaction process
Change, dissociated or combined, reactions change is suitable for, therefore reaction can be effectively improved than p-methyl benzenesulfonic acid is used alone
Yield；Step I restores nitro and alkene simultaneously using reduced iron powder ice acetic acid, avoids and pressurizes in autoclave
Reaction.The synthetic method raw material is cheap and easy to get, and route is easy to operate, and reproducible and yield is very high, is suitble to industrialized production.
Specific embodiment
The above of the present invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright range.
Embodiment 1
In 2000mL in the reaction bulb of mechanical agitation and thermometer, furans 50g (0.735mol) and methanol are added in
1000mL is placed under the conditions of -50 DEG C, and nitrogen is protected after displacing air, bromine 240g (1.5mol) is slowly added dropwise, after dripping
3h is reacted, 0 DEG C is warming up to the reaction was continued 2h, be warmed to room temperature, adjusted with 1000mL saturated sodium bicarbonate solutions anti-after reaction
The pH for answering liquid is 7-8, and decompression steams remaining methanol, then with ethyl acetate 1000mL extractions reaction solution three times, merges organic phase again
It is washed with saturated nacl aqueous solution, separates organic phase, compound 1, Isosorbide-5-Nitrae, 4- tetramethoxy -2- fourths are obtained after steaming ethyl acetate
Alkene 75g.
Embodiment 2
Compound 1,1,4,4- tetramethoxy -2- fourths are added in 1000mL is with the reaction bulb of mechanical agitation and thermometer
Alkene 70g and toluene 500mL, adds potassium permanganate 15g and pyrovinic acid 7g, is heated to 80 DEG C under nitrogen protection, TLC monitoring
The reaction was complete for raw material, and chloroform 600mL is added in after removing solvent toluene under reduced pressure, in being with saturated solution of sodium carbonate adjusting reaction solution pH
Property, organic phase is separated, chloroform is evaporated off and obtains compound 1,1- dimethoxy acetaldehyde 32g.
Embodiment 3
Compound 1,1,4,4- tetramethoxy -2- fourths are added in 1000mL is with the reaction bulb of mechanical agitation and thermometer
Alkene 70g and toluene 500mL, adds potassium permanganate 15g and p-methyl benzenesulfonic acid 10g, is heated to 80 DEG C under nitrogen protection,
The reaction was complete for TLC monitoring raw material, and chloroform 600mL is added in after removing toluene under reduced pressure, and reaction solution pH is adjusted with saturated solution of sodium carbonate
For neutrality, organic phase is separated, chloroform is evaporated off and obtains compound 1,1- dimethoxy acetaldehyde 35g.
Embodiment 4
In reaction bulbs of the 1000mL with mechanical agitation and thermometer, by 1,1- dimethoxy acetaldehyde 30g (0.3mol),
Nitromethane 19g (0.3mol) and anhydrous alumina 3g (0.03mol) is added in DMF 500mL, and nitrogen protection is heated to 130
DEG C, after reaction, room temperature is down to, filters reaction solution, add in the saturated nacl aqueous solution of 500mL after concentrating filter liquor, then use
600mL dichloromethane extraction reaction solution twice, merges organic phase, 1,1- dimethoxy -2- hydroxyl -3- nitre is obtained after solvent is evaporated off
Base propane 43g.
Embodiment 5
It, will be dissolved with 1,1- under the conditions of 0-5 DEG C in reaction bulbs of the 500mL with mechanical agitation, thermometer and water knockout drum
The toluene solution 250mL of dimethoxy -2- hydroxyl -3- nitropropanes 30g (0.18mol) is slowly dropped into dissolved with concentrated sulfuric acid 35g
(0.36mol) is warming up to and is refluxed reaction 4h, pays attention to dividing water in reaction process, the reaction was complete for TLC monitoring raw material, with three second
Amine adjusts reaction solution pH as neutrality, after toluene is evaporated off, adds in saturated nacl aqueous solution 300mL, then extract two with chloroform 300mL
It is secondary, merge organic phase, then washed once with saturated nacl aqueous solution, with anhydrous magnesium sulfate it is dry, filter, remove solvent under reduced pressure and obtain
To 1,1- dimethoxy -3- nitro -2- propylene 31g.
Embodiment 6
In 500mL reaction bulbs, 1,1- dimethoxy -3- nitros -2- propylene 30g and polyphosphoric acids 3g are added to ice second
In sour 200mL, 8h is stirred at room temperature, adds in ice water 100mL into reaction solution after reaction, and polyphosphoric acids is made all to decompose,
Then with dichloromethane 300mL extractions three times, dried after merging organic phase with anhydrous sodium sulfate, filter, obtained after solvent is evaporated off
3- nitro -2- methacrylaldehyde 17g.
Embodiment 7
In 1000mL reaction bulbs, 3- nitro -2- methacrylaldehyde 20g (0.2mol), tert-butyl alcohol 30g (0.4mol), chirality
Catalyst tetra isopropyl oxygen titanium (Ti (O-i-Pr)4) 4g and S- xenols (S- (-) BINOL) 4g add in THF200mL in, be placed in-
Under the conditions of 78 DEG C, nitrogen protection is slowly added to the THF 200mL dissolved with dicthenone 17g (0.2mol), temperature is kept after dripping
Degree continues to be stirred to react 5h, is slowly increased to room temperature, filtering reacting liquid after reaction, filtrate uses saturated nacl aqueous solution again
300mL is washed, and separates organic phase, and water phase extracts three times through dichloromethane 200mL, merges organic phase, be spin-dried for organic phase and obtain again
(5S) -7- nitro -5- hydroxyl -3- oxo -6- heptene isopropyl propionate 31g, optical purity reach 99.5%ee after testing.
Embodiment 8
In 1000mL reaction bulbs, 3- nitro -2- methacrylaldehyde 20g (0.2mol), isopropanol 24g (0.4mol), chirality
Catalyst tetra isopropyl oxygen titanium (Ti (O-i-Pr)4) 4g and S- xenols (S- (-) BINOL) 4g adds in THF 200mL, put
Under the conditions of -78 DEG C, nitrogen protection is slowly added to the THF 200mL dissolved with dicthenone 17g (0.2mol), is protected after dripping
It holds temperature to continue to be stirred to react 5h, is slowly increased to room temperature, filtering reacting liquid after reaction, filtrate uses saturated nacl aqueous solution again
300mL is washed, and separates organic phase, and water phase extracts three times through dichloromethane 200mL, merges organic phase, be spin-dried for organic phase and obtain again
(5S) -7- nitro -5- hydroxyl -3- oxo -6- heptene isopropyl propionate 29g, optical purity reach 99.5%ee after testing.
Embodiment 9
In reaction bulbs of the 500mL with thermometer, the tertiary fourth of (5S) -7- nitro -5- hydroxyl -3- oxo -6- heptenoic acids
Ester 30g (0.11mol) is added in tetrahydrofuran 300mL, and reaction temperature is set as 10 DEG C, is slowly added to dissolved with NaBH4 9g
The tetrahydrofuran solution 50mL of (0.23mol) keeps temperature to be stirred to react 4h, stops stirring when TLC detection raw materials disappear, steams
Except solvents tetrahydrofurane, saturated nacl aqueous solution 100mL is added, then with dichloromethane 100mL extractions three times, is merged organic
Phase is dried with anhydrous slufuric acid ammonium, (3R, 5S) -7- nitro -3,5- dihydroxy -6- heptenoic acid uncles is obtained after solvent is steamed after filtering
Butyl ester 24g.
Embodiment 10
(3R, 5S) -7- nitro -3,5- dihydroxy -6- heptene tert-butyl acrylates 26g is sequentially added in 500mL there-necked flasks
(0.1mol), absolute ethyl alcohol 300mL and acetone 35g (0.5mol) are stirred to complete molten rear addition catalyst pyridine hydrobromate 5g,
Heating is precipitated white solid, filters, filter cake ice absolute ethyl alcohol 20mL in 55-60 DEG C of insulation reaction 4h, after reaction cooling
Washing obtains (4R-Cis) -6- nitre vinyl -2,2- dimethyl-1,3-dioxane-hecanoic acid t-butyl ester 27g after filter cake drying.
Embodiment 11
In the 500mL reaction bulbs with thermometer, (4R-Cis) -6- nitre vinyl -2,2- dimethyl -1,3- dioxies
Six rings-hecanoic acid t-butyl ester 30g (0.1mol) is added in methanol (200mL), the palladium carbon (3.2g) that content is 10% is added, in nitrogen
Under the conditions of gas shielded, hydrazine hydrate (32g) is slowly added dropwise, it is 20-25 DEG C that reaction temperature is kept during being added dropwise, and has a large amount of bubbles
Occur, the reaction was complete for the reaction was continued 2h after being added dropwise, TLC monitoring raw material, filters reaction solution and removes catalyst palladium carbon, distills out
Part methanol cools down material, and product is precipitated in there-necked flask, filters out product, be washed with a small amount, and wet cake is put in surface plate
On, (4R-Cis) -6- aminoethyls -2,2- dimethyl-1,3-dioxane-hecanoic acid t-butyl ester 28g is obtained after drying.
Embodiment 12
In the 500mL reaction bulbs with thermometer and condenser pipe, (4R-Cis) -6- nitre vinyl -2,2- dimethyl -
1,3- dioxane-hecanoic acid t-butyl ester 30g (0.1mol) is added in the mixed liquor of ethyl alcohol (200mL) and water (100mL), then is added
Enter reduced iron powder (6g, 0.1mol), be heated to 100 DEG C after acetic acid (10mL) is added dropwise, the reaction was complete for TLC monitoring raw material, and filtering is anti-
Liquid is answered, filtrate is through steaming second alcohol and water, and into residue, addition toluene (200mL) is recrystallized, and filters solid,
(4R-Cis) -6- aminoethyl -2,2- dimethyl -1,3- dioxane-hecanoic acid t-butyl ester 27g is obtained after filter cake drying.
Basic principle, main features and advantages embodiment above describes the present invention, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe the originals of the present invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (1)
1. a kind of synthetic method of Atorvastatin calcium chiral intermediate, it is characterised in that the specific steps are：
A, 1 is prepared by furans and bromine, Isosorbide-5-Nitrae, 4- tetramethoxy -2- butylene, detailed process is in methyl alcohol：In reaction vessel
Furans and methanol are added in, under nitrogen protection in -50 DEG C of dropping liquid bromine reaction 3h, then heats to 0 DEG C the reaction was continued 2h, reaction
After be warmed to room temperature, the pH that reaction solution is adjusted with saturated sodium bicarbonate solution is 7-8, and decompression steams methanol, then with acetic acid second
Ester extracts, and organic phase separates organic phase after being washed with saturated nacl aqueous solution, then steams ethyl acetate and obtain 1, Isosorbide-5-Nitrae, 4- tetramethyls
Oxygroup -2- butylene；
B, 1,1,4,4- tetramethoxies -2- butylene aoxidizes under the action of potassium permanganate and weak acid pyrovinic acid or p-methyl benzenesulfonic acid
1,1- dimethoxy acetaldehyde is generated, detailed process is：1,1,4,4- tetramethoxy -2- butylene and first are added in reaction vessel
Benzene adds potassium permanganate and pyrovinic acid or p-methyl benzenesulfonic acid, under nitrogen protection in 80 DEG C of reactions, TLC monitoring raw materials
It is removed under reduced pressure after the reaction was complete and chloroform is added in after toluene, then it is neutral to adjust the pH of reaction solution with saturated sodium carbonate solution, is separated
Organic phase is evaporated off chloroform and obtains 1,1- dimethoxy acetaldehyde；
C, addition reaction life occurs under the catalytic action of catalyst anhydrous alumina with nitromethane for 1,1- dimethoxys acetaldehyde
Into 1,1- dimethoxy -2- hydroxyl -3- nitropropanes, detailed process is：By 1,1- dimethoxys acetaldehyde, nitre in reaction vessel
Methylmethane and catalyst anhydrous alumina are added in DMF, are heated to 130 DEG C of reactions under nitrogen protection, are dropped after reaction
To room temperature, reaction solution is filtered, adds in saturated nacl aqueous solution, then extracted with dichloromethane after concentrating filter liquor, organic phase is evaporated off
1,1- dimethoxy -2- hydroxyl -3- nitropropanes are obtained after solvent；
D, 1,1- dimethoxys -2- hydroxyls -3- nitropropanes are dehydrated under the action of the concentrated sulfuric acid obtains 1,1- dimethoxy -3- nitre
Base -2- propylene, detailed process are：In the 0-5 DEG C of first by 1,1- dimethoxy -2- hydroxyl -3- nitropropanes in reaction vessel
Benzene alkane solution instills the concentrated sulfuric acid, drips rear temperature rising reflux and reacts and separate moisture, is adjusted react with triethylamine after reaction
The pH of liquid is neutrality, after toluene is evaporated off, adds in saturated nacl aqueous solution, then extracted with chloroform, organic phase is molten through saturated sodium-chloride
After liquid washing with anhydrous magnesium sulfate it is dry, filter, remove solvent under reduced pressure and obtain 1,1- dimethoxy -3- nitro -2- propylene；
E, using glacial acetic acid as solvent, 1,1- dimethoxy -3- nitro -2- propylene water under the catalytic action of catalyst polyphosphoric acids
Solution obtains 3- nitro -2- methacrylaldehyde, and detailed process is：It 1,1- dimethoxy -3- nitro -2- propylene and will be urged in reaction vessel
Agent polyphosphoric acids is placed in solvent glacial acetic acid, and reaction is stirred at room temperature, and ice water is added in into reaction solution after reaction makes poly
Phosphoric acid all decomposes, and is then extracted with dichloromethane, and organic phase filters after being dried over anhydrous sodium sulfate, after filtrate steaming removal solvent
To 3- nitro -2- methacrylaldehyde；
F, 3- nitros -2- methacrylaldehyde, alkylol and dicthenone urging in tetra isopropyl oxygen titanium and S- xenol mixed catalysts
(5S) -7- nitro -5- hydroxyl -3- oxo -6- heptene acid alkyl esters are obtained under change effect, wherein alkylol is isopropanol or tertiary fourth
Alcohol, detailed process are：By 3- nitro -2- methacrylaldehyde, alkylol and tetra isopropyl oxygen titanium in bottle container is reacted（Ti(O-i-
Pr)4）With S- xenols（S-(-)BINOL）Mixed catalyst is added in THF solution, under nitrogen protection in -78 DEG C of dropwise additions
The THF solution of dicthenone keeps temperature to continue to be stirred to react, is warmed to room temperature after reaction, filtering reacting liquid after dripping
It is washed, extract, solvent is evaporated off obtains (5S) -7- nitro -5- hydroxyl -3- oxo -6- heptene acid alkyl esters, product yield and light
It is all very high to learn purity, wherein alkylol is isopropanol or the tert-butyl alcohol；
G, (5S) -7- nitros -5- hydroxyls -3- oxo -6- heptene acid alkyl esters pass through under the catalytic action of catalyst sodium borohydride
Carbonyl reduction obtains (3R, 5S) -7- nitro -3,5- dihydroxy -6- heptene acid alkyl esters, and detailed process is：In reaction vessel
The THF solution and the THF of sodium borohydride for adding in (5S) -7- nitro -5- hydroxyl -3- oxo -6- heptene acid alkyl esters in 10 DEG C are molten
Liquid keeps temperature to be stirred to react, THF is evaporated off after reaction, adds saturated nacl aqueous solution, is then extracted with dichloromethane
Take, organic phase with anhydrous slufuric acid ammonium dry after filter, obtained after filtrate steaming removal solvent (3R, 5S) -7- nitros -3,5- dihydroxy -
6- heptene acid alkyl esters；
H, (3R, 5S) -7- nitros -3,5- dihydroxy -6- heptene acid alkyl ester is in the catalytic action of catalyst pyridine hydrobromate
(4R-Cis) -6- nitre vinyl -2,2- dimethyl -1,3-dioxolane-caproic acid Arrcostab, specific mistake is obtained by the reaction in lower and acetone
Cheng Wei：(3R, 5S) -7- nitro -3,5- dihydroxy -6- heptene acid alkyl ester is added in into absolute ethyl alcohol and acetone in reaction vessel
Mixed solution in, add catalyst pyridine hydrobromate, be heated to 55-60 DEG C of insulation reaction, after reaction cooling analysis
Go out white solid, filter, filter cake is washed with absolute ethyl alcohol and obtains (4R-Cis) -6- nitre vinyl -2,2- diformazans after drying
Base -1,3- dioxolanes-caproic acid Arrcostab；
I, (4R-Cis) -6- nitre vinyl -2,2- dimethyl -1,3- dioxolanes-caproic acid Arrcostab is in catalyst palladium carbon/hydration
It restores through double bond addition and nitro to obtain (4R-Cis) -6- aminoethyls -2,2- under the catalytic action of hydrazine or reduced iron powder/glacial acetic acid
Dimethyl -1,3-dioxolane-caproic acid Arrcostab, detailed process are：By (4R-Cis) -6- nitre vinyl -2,2- dimethyl -1,
3- dioxolanes-caproic acid Arrcostab and catalyst palladium carbon/hydrazine hydrate or reduced iron powder/glacial acetic acid are added in reaction vessel, with
The mixed solution of methanol or second alcohol and water reacts obtained target product (4R-Cis) -6- ammonia second as solvent at a certain temperature
Base -2,2- dimethyl -1,3- dioxolanes-caproic acid Arrcostab.
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