CN101538221A - Preparation method of Oseltamivir phosphate - Google Patents
Preparation method of Oseltamivir phosphate Download PDFInfo
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- CN101538221A CN101538221A CN200910047843A CN200910047843A CN101538221A CN 101538221 A CN101538221 A CN 101538221A CN 200910047843 A CN200910047843 A CN 200910047843A CN 200910047843 A CN200910047843 A CN 200910047843A CN 101538221 A CN101538221 A CN 101538221A
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Abstract
The invention discloses a preparation method of Oseltamivir phosphate. The method takes shikimic acid as raw material to prepare Oseltamivir phosphate through thirteen chemical synthesis procedures with yield being at least 41%. The thirteen chemical synthesis procedures comprises the followings: esterification of the raw material, protection of 3, 4-acetone, protection of 5-benaoyl, protection of 3, 4-acetone removal, sulfonylation of 3, 4-dimethyl, selective azide replacement of 3-mesyloxy, reduction of3, 4-azide to amine and adjacent position replacement of ring formation, acetylation of 3, 4-aziridine ring, selective ring opening of 3-pentanol on acetylized aziridine ring, removal of 5-benzoyl protecting group, sulfonylation of 5-methyl, azide replacement of 5-methyl sulfonyl acyloxy, reduction of 5-azido group to amine and salifying with phosphoric acid. Thus the product of the phosphoric acid Oseltamivir phosphate is prepared.
Description
Technical field
The invention belongs to the medicine chemical technology field, relate to the preparation method of medicine, be specifically related to a kind of preparation method of Ro 64-0796/002.
Technical background
The chemical full name of Ro 64-0796/002 (Oseltamivir phosphate) is 4-acetylaminohydroxyphenylarsonic acid 5-amino-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester phosphoric acid salt, is a kind of active drug of preventing and treating bird flu.Before several years, when bird flu brings disaster to human society, the Ro 64-0796/002 of U.S. Gilead company and Switzerland Roche (Luo Shi) company joint research and development exploitation just, commodity are called Tamiflu, the listing of meeting the tendency is under control the bird flu of disaster human society.Many afterwards countries classify Ro 64-0796/002 as national strategy deposit medicine, in case of need.Ro 64-0796/002 is a kind of neuraminidase inhibitor, its medicinal design can be respectively referring to Nature.1993,363,418; WO91/16320; J.Med.Chem.1998,41,2451 and J.Am.Chem.Soc.1997, the record of 119,681. documents, they all help further carrying out the research of Oseltamivir.But up to the present, have the method for only Luo Shi one family of the production that industrial value can pay, single production capacity from Ro 64-0796/002 is not sufficient to tackle the problem (referring to Angew.Chem.Int.Ed.2006,45,7330) in the whole world.It is starting raw material with naturally occurring shikimic acid and quinic acid that the method for Gilead company and Roche (Luo Shi) company cooperative development discloses a kind of, Stereoselective reduction by ketal, introducing 1-ethyl propoxy-lawsuit can roll into a ball, introduce nitrogen-containing functional group with nitrine reagent, allyl amine or TERTIARY BUTYL AMINE, steps such as the stereoselectivity ring-opening reaction of aziridine, the suitability for industrialized production of realization Ro 64-0796/002 (referring to: Org.Process Res.Dev.1999,3,266; Org.Process Res.Dev.2004,8,86; J.Am.Chem.Soc.1997,119,681; J.Org.Chem.1998,63,4545; Angew.Chem.Int.Ed.2006,45,7330; US5763483/1998; WO99/55664; US5886213/1999; WO98/07685; EP1059283/2000), though this method suitability for industrialized production, there are many problems in its synthesis technique.
(1) for example: must use inflammable and explosive chemical---trimethylammonium phosphorus in the synthesis technique of this method, though its production is carried out in can be between hoolivan, but exist potential safety hazard all the time, manufacturing-oriented workman is inevitable in tension, work with nervous diffidence, can not carry out meticulous operation, easily cause the low of production process yield;
(2) for another example: use the very strong reagent of corrodibility---trifluoromethanesulfonic acid (price is also very expensive) in the synthesis technique of this method, the by product that its corrosion produces, not only work has brought difficulty to purifies and separates, and certainly will cause the extra losses of product, influences the yield of production process.
This shows:
Why the yield of the target product of this method is in lower level (17%～27%), can't improve, because technological process exists defective to cause.The insider expects the scientific worker that is correlated with to be studied improvement for this reason, provides a kind of safe, easy row, inexpensive, the preparation method of Ro 64-0796/002 efficiently, to satisfy the needs of the universe to the strategic reserves of control bird flu medicine.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of Oseltamivir, it compared with prior art has safety, easily capable, inexpensive, advantage, and raw material sources is efficiently enriched, can produce on a large scale, thereby can satisfy the needs of the universe the strategic reserves of control bird flu medicine.
Design of the present invention is such:
At first, in view of shikimic acid is very easy to extract from star anise and Ginkgo Leaf, expansion along with domestic star anise cultivated area, the improvement of extraction process, the quality of shikimic acid and output all increase greatly, condition with scale operation is so the present invention's selection is a starting raw material with the shikimic acid.
Be that raw material carries out esterification and obtains the shikimic acid ethyl ester then with the shikimic acid; Carry out the acetonylidene protection again and obtain 3,4-oxygen-isopropylidene shikimic acid ethyl ester; Then make 5 benzoylation protections of aforesaid intermediate product make 3,4-oxygen-isopropylidene-5-oxygen-benzoyl base shikimic acid ethyl ester; Then take off acetonylidene protection (going protection) and make 5-benzoyl shikimic acid ethyl ester; Get intermediate product 5-benzoyl shikimic acid ethyl ester by above four-step reaction, it is intended to finish the benzoyl protection on 5 of the shikimic acids, 3; hydroxyl on 4 recovers (going protection) again; pave road for next step orientation response (going up sulfonylation for 3,4), created condition.3,4 of 5-benzoyl shikimic acid ethyl esters are gone up sulfonyl methaneization and are made 3,4-bis methane sulfonyloxy-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester; Then the replacement of selectivity nitrine makes 3-azido--4-methanesulfonyloxy group-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester on 3; Then the nitrine reducine changes into ring and obtains 5-benzoyloxy-3,4-azabicyclo-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester; Then acetylize makes 3,4-ethanoyl azabicyclo-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester; Then the open loop of 3-amylalcohol makes 4-acetamido-3-ethyl propoxy--5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester; Then 5 are gone protection to take off benzoyl and make 4-acetamido-3-ethyl propoxy--5-hydroxyl-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester; Then 5 are carried out sulfonyl methane and turn into making 4-acetamido-3-ethyl propoxy--5-methanesulfonyloxy group-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester; Then use NaN on 5
3The nitrine replacement obtains 4-acetamido-3-ethyl propoxy--5-azido--1-tetrahydrobenzene-1-carboxylic acid, ethyl ester; Last 5 last nitrine reduction make the Ro 64-0796/002 product with the phosphoric acid salify again.
The present invention conceive exquisite part be the nitrine of allylic (3) regioselectivity and stereoselective methane sulfonate replace and the 3-amylalcohol (insider is traditionally to 3 to acetylethyleneimine, 4 vinyl azabicyclos are called the ethene aziridine) selective opening, the temperature that its substitution reaction and ring-opening reaction need is very low, and yield is very high, thereby is that the yield that improves the finished product has been created condition.
The present invention is achieved in that concrete reactions steps is described below:
(1) is raw material with shikimic acid, carries out esterification hereinafter to be referred as raw material 2 and ethanol and obtain the shikimic acid ethyl ester, hereinafter to be referred as compound 3.
Above-mentioned esterification, in the presence of excess ethyl alcohol and catalyzer, raw material shikimic acid energy 100% is esterified, but because the underpressure distillation operation must cause the loss of compound 3, appropriateness is controlled distillation rate in the underpressure distillation operating process for this reason, helps reducing the entrainment loss of compound 3, the top of this external vacuum distillation apparatus, the retrieving arrangement that setting is made up of Stainless Steel Cloth makes and is carried secretly the droplet of compound 3 or particulate by the ethanol steam to be trapped within Stainless Steel Wire online.After distillation procedure finishes, the solvent (as ethyl acetate) that uses in producing with next step again washes recovery to being trapped in the online compound of Stainless Steel Wire 3, and used solvent can use repeatedly, can also use solvent as next step reaction, enter next step operating system.
By above-mentioned meticulous operation, the loss of compound 3 is reduced to below 1% in a word, thus in the step (1) yield of compound 3 to reach more than 98% be not the thing of a difficulty.
(2) compound 3 is implemented the acetonylidene protection and is obtained 3, and 4-oxygen-isopropylidene shikimic acid ethyl ester is hereinafter to be referred as compound 4.
Earlier step (1) gained compound 3 is dissolved in the ethyl acetate; be made into volumetric molar concentration and be 5.0～10.0% uniform solution; then under the catalysis of tosic acid; make in the compound 33; hydroxyl on the 4-position and 2, the 2-Propanal dimethyl acetal is at room temperature reaction; finish the acetonylidene protection, obtain compound 4.
After above-mentioned reaction finished, the reaction system was earlier with a spot of 5%wt K
2CO
3The aqueous solution carries out alkali cleaning, after water is removed in separation, use anhydrous magnesium sulfate drying again, remove by filter sal epsom, then the organic phase (being above-mentioned reaction system) that has been dried is carried out the underpressure distillation operation, steam and remove ethyl acetate, obtain a kind of yellow transparent liquid, be compound 4, for next step use, its yield is 95%.The protection ratio of the acetonylidene of compound 3 can reach 100% in its tangible experiment, but because system by a plurality of unit operations such as alkali cleaning, dried over mgso, filtration and distillations, the loss of material takes place inevitably, so the yield of compound 4 only is 95%.But when scale operation, by meticulous operation with take suitable recovery measure, its yield is expected to be further enhanced.For example, the water after the alkali cleaning is concentrated centrifugation, to reclaim a small amount of organic phase of wherein carrying secretly; The sal epsom of finishing dry task is concentrated the back solvent wash, be adsorbed on organic phase on the siccative with recovery; Can use the solvent washing strainer equally, and reclaim the entrainment loss that distillation causes with the identical measure of step (1).
(3) compound 4 benzoylations make 3, and 4-oxygen-isopropylidene-5-oxygen-benzoyl base-shikimic acid ethyl ester is hereinafter to be referred as compound 5.
At first compound 4 is dissolved in ethyl acetate or the methylene dichloride, the volumetric molar concentration that is mixed with compound 4 is 4.0～6.0% solution, adds respectively under the ice bath temperature then Dimethylamino pyridine (being called for short DMAP) and triethylamine.The add-on of catalyzer DMAP be compound 4 molar weight 5%; The add-on of triethylamine is 2 times of molar weight of compound 4; Then at room temperature drip Benzoyl chloride again; at room temperature continue reaction 5-6 hour after adding again; finish the carbon 5 key position benzoylations protection on the compound 4, obtain compound 5, wherein the add-on of acylating agent Benzoyl chloride is about 1.3 times of molar weight of compound 4.After reaction finishes, (as if adopting methylene dichloride to make solvent, after then reaction finishes, remove solvent earlier under reduced pressure, be mixed with solution again with ethyl acetate then), the reaction system of generation is that the 1N HCl aqueous solution washes acidity with concentration earlier, is 5%wtK with concentration again
2CO
3The aqueous solution is washed till alkalescence, with saturated nacl aqueous solution washing one time, separates the organic layer that obtains containing compound 5 then, adds anhydrous magnesium sulfate drying again, removes by filter sal epsom, removes ethyl acetate under reduced pressure, obtains compound 5, and yield is 98%.
The organic phase that contains compound 5 that but above-mentioned drying is separating obtained can be directly used in next step reaction.
In addition, find in experiment that replace triethylamine to do alkali with pyridine, its effect is also fine, and does not need the catalysis with DMAP, but the reaction times is slightly longer.
(4) compound 5 takes off acetonylidene (go protection) and makes 5-oxygen-benzoyl base-shikimic acid ethyl ester, hereinafter to be referred as compound 6.
Elder generation is with the ethyl acetate solution of step (3) gained compound 5; remove part ethyl acetate solvent (being intended to improve the volumetric molar concentration of compound 5 in solution) to steam in advance; perhaps compound 5 is dissolved in solvent ethyl acetate; in tetrahydrofuran ester or the acetonitrile; the volumetric molar concentration that is deployed into compound 5 is 10～20% solution; in above-mentioned solution, add dilute hydrochloric acid then; said dilute hydrochloric acid is formed by the equal-volume thin up by commercially available concentrated hydrochloric acid; make compound 5 under the dilute hydrochloric acid effect, take off acetonylidene protection (going protection); make shikimic acid 3; the group of being protected by acetonylidene on the 4 carbon bond positions is hydrolyzed into hydroxy functional group, obtains compound 6.The above-mentioned acetonylidene that takes off is protected used acid, except with the dilute hydrochloric acid, can also use acetic acid, comprises the mixing acid of dilute hydrochloric acid and acetic acid.
Experiment is found: the concentration of de-protected speed and acid is relevant, but the concentration of acid is too big, and side reaction can take place, the formation by product, and this is not wish the thing that takes place, so should not carry out protective reaction with concentrated hydrochloric acid.Would rather be chosen in and carry out relatively mild reaction under the dilute hydrochloric acid effect, can guarantee to obtain single target product---compound 6 like this.
After reaction finishes,, use earlier 5%wt K to gained reaction system
2CO
3In the aqueous solution and deacidification, wash with water again and remove the salt that neutralization produces.Separation obtains organic layer and uses anhydrous magnesium sulfate drying again, removes by filter sal epsom, obtains the exsiccant organic layer, removes ethyl acetate then under reduced pressure, obtains yellow solid.Make with extra care as follows again:, with petroleum ether, suction filtration, obtain filter cake earlier above-mentioned yellow solid, then use sherwood oil: the mixed solvent washing that ethyl acetate=2: 1 is formed, filter and obtain white solid, oven dry, be compound 6, yield is 94～95%.
(5) compound 6 sulfonyl methaneizations make 3, and 4-bis methane sulfonyloxy-5-benzoyloxy-shikimic acid ethyl ester is called for short compound 7, down together.
At first compound 6 is dissolved in ethyl acetate or the methylene dichloride, the volumetric molar concentration that is mixed with compound 6 is 2～4% solution, add methane sulfonyl chloride down earlier at 0 ℃, add catalyzer DMAP again, then (in the ice bath) drips triethylamine under 0 ℃, and constantly the adularescent solid precipitation produces, and the dropping time length reached about 30 minutes, after dropwising, continue reaction 30 minutes again.Acylating agent methane sulfonyl chloride add-on is 5 times of compound 6 molar weights, and DMAP is 0.05 times of compound 6 molar weights, and the add-on of triethylamine is 4 times of compound 6 molar weights.
After reaction finishes, with the reaction system earlier with concentration be the dilute hydrochloric acid washing of 1N to acidity, use 5%wt K again
2CO
3The aqueous solution is washed till alkalescence, at last with saturated sodium-chloride water solution washing extremely neutral (washing at least a time), liquid-liquid separation goes out to contain the organic phase of compound 7, then use anhydrous magnesium sulfate drying, elimination sal epsom obtains the exsiccant organic phase, remove solvent ethyl acetate or methylene dichloride again under reduced pressure, obtain a kind of yellow liquid, promptly compound 7, and yield is 97%.
(6) replacement of compound 7 selectivity nitrine is made 3-azido--4-mesyloxy-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, be called for short compound 8, down together.
At first compound 7 is dissolved in the polar solvent, be mixed with compound 7 volumetric molar concentrations and be 4.0～10% solution, under the ice bath temperature stirs, drip sodium azide aqueous solution and carry out azide reaction then, the dropping time is 30 minutes, dropwises the back and continues reaction 1～2 hour.Above-mentioned said polar solvent is a kind of in DMF, ethanol, DMSO, Virahol, the acetone, or the mixed solvent of being made up of them; Said sodium azide, its add-on are 4～5 times of compound 7 molar weights, adopt excessive sodium azide to be intended to make compound 7 to finish the nitrine substitution reaction in 100% ground.
After reaction finishes, add entry, extract (by comparing V/V=1: 1) with toluene again, obtain containing the toluene organic phase (the unnecessary sodium azide that the purpose that adds entry is to make reaction system and solvent DMF change over to aqueous phase be convenient to separate remove) of compound 8, remove toluene under reduced pressure, crystal is separated out in cooling, and the mixed solvent of forming with sherwood oil and ethyl acetate washs then, and is refining.Wherein the mixed solvent ratio of components is: petrol ether/ethyl acetate=10: 1-5: 1.
Experiment is found: temperature controlling and choice of Solvent have bigger influence to above-mentioned reaction.As the temperature rising byproduct of reaction is increased, reaction is wise under the ice bath temperature so be chosen in; The speed of its reaction of different solvents is also obviously different.Through repeatedly testing relatively, find with DMF and DMSO to be that the solvent effect is best.
Though material loss in follow-up operation, also will be taken place, so the yield of compound 8 only is 95% by a plurality of unit operations such as extraction, reduction vaporization, washings by azide reaction in compound 7 energy 100% ground inevitably.
(7) compound 8 alkalizes into ring again through reduction and obtains 3, and 4-aziridine-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester is called for short compound 9, down together.
The purifying of compound 9: after reaction finishes, at first with the reaction system of above-mentioned gained, remove solvent under reduced pressure (because tetrahydrofuran (THF) or the solubleness of acetonitrile in water are higher, be not suitable for extraction), add saturated sodium chloride solution and ethyl acetate (purpose that adds saturated sodium-chloride water solution is that saturated sodium-chloride water solution has salting out to make organism better enter organic layer) then, carry out liquid-liquid extraction, separate the extracted organic phase that obtains containing compound 9, then remove ethyl acetate under reduced pressure, obtain a kind of liquid of reddish-brown, carry out that column chromatography is refining to obtain a kind of flaxen oily matter, promptly compound 9 again, and yield is 88%.Wherein the ethyl acetate add-on is counted 50～70 times of compound 8 charging capacitys with molar weight, and the two-phase volume ratio of the add-on of saturated nacl aqueous solution when keeping extraction equals 1 and be advisable.
(8) compound 9 acetylizes make 3, and 4-ethanoyl aziridine-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester is called for short compound 10, down together.
At first compound 9 is dissolved in ethyl acetate or the dichloromethane solvent, the volumetric molar concentration that is mixed with compound 9 is 1.5～2.0% solution; Adding by compound 9 volumetric molar concentrations earlier under the ice bath temperature then is 3 times of triethylamines of benchmark, drip by the volumetric molar concentration of compound 9 is 2 times of diacetyl oxides of benchmark again, the dropping time is no less than 15 minutes, dropwise the back and continue reaction 15 minutes, make in the compound 93, hydrogen on the azabicyclo on the 4 key positions is replaced formation 3 by ethanoyl, and 4-ethanoyl-azabicyclo (azabicyclo wherein is an aziridine) makes compound 9 all change into compound 10; After reaction finishes, with the 5%wt wet chemical above-mentioned reaction system is washed to alkalescence (purpose is the acetic acid of unnecessary diacetyl oxide of flush away and generation) earlier, use ethyl acetate extraction again, separate the organic phase that obtains containing compound 10.
The gained organic phase is earlier used anhydrous magnesium sulfate drying, remove by filter sal epsom after, remove ethyl acetate again under reduced pressure, obtain yellow transparent liquid, be compound 10, yield is 98%.
(9) compound 10 open loop under the effect of 3-amylalcohol makes 4-acetamido-3-(1-ethyl propoxy-)-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, is called for short compound 11, down together.
At first compound 10 is dissolved in the solvent 3-amylalcohol; be mixed with the even concentration of rubbing of compound 10 and be 5～7% solution; it is reaction solution; place the reactor of belt stirrer; place ice bath to cool off then; stir; then the mixed solution (the two is 1: 5 Lewis acid solution of forming by volume) with boron trifluoride diethyl etherate and 3-amylalcohol composition is added dropwise in the reaction solution; the dropping time is no less than 15 minutes; dropwise the back and continue reaction 15 minutes; finish in the compound 10 3; ethanoyl aziridine open loop on the 4 key positions; and formation 4-acetamido-3-(1-ethyl propoxy-)-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester 11; as seen the 3-amylalcohol is not only solvent, and exquisite participates in ring-opening reaction, and Here it is in the exquisite here of this utilization Lewis acid.
Lewis acid in the above-mentioned reaction (referring to top said mixed solution) dripping quantity (because of controlling by volume) 0.6 times of the 3-amylalcohol volume that drops into during for the solution of preparation compound 10 than being easier to, so its dripping quantity is represented with volume.
After reaction finishes, the reaction system of gained is used earlier ethyl acetate extraction, obtain extracted organic phase, extremely alkaline with the washing of 5%wt potassium bicarbonate aqueous solution earlier then, again with saturated sodium chloride solution washing one time, the organic layer of telling is used anhydrous magnesium sulfate drying again, elimination sal epsom removes ethyl acetate (extraction agent) and 3-amylalcohol under reduced pressure, obtains 4-acetamido-3-(1-ethyl propoxy-)-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, the intermediates that are called for short compound 11, yield 92%.
(10) compound 11 takes off benzoyl (go protection) and makes 4-acetamido-3-(1-ethyl propoxy-)-5-hydroxyl-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, is called for short compound 12, down with.
At first be solvent with the dehydrated alcohol, it is about 1.0% solution that compound 11 is made into volumetric molar concentration, the reactor that places band to stir; at room temperature add weak base; reacted 5～6 hours, and finished and take off the benzoyl protection in the compound 11 on the 5-carbon bond position, be transformed into compound 12.
After reaction finishes, remove the reaction system of gained under reduced pressure etoh solvent earlier, add ethyl acetate and water extraction (purpose that adds entry is intended to make the weak base class material in the reaction system to change aqueous phase over to) then, tell water, the compound of being carried secretly by water with further recovery for twice with fresh ethyl acetate extraction 12 again, merge organic phase, the organic phase anhydrous magnesium sulfate drying, elimination sal epsom, then remove ethyl acetate under reduced pressure and obtain white solid, use the detergent washing of forming by petrol ether/ethyl acetate=10/1～1/1 (V/V) refining then, suction filtration, be compound 12, yield 90% after the oven dry of gained filter cake.
Wherein said weak base is a kind of in salt of wormwood, yellow soda ash or the ammoniacal liquor, and its add-on equals or be slightly larger than the molar weight of compound 11.
(11) compound 12 makes 4-acetamido-3-(1-ethyl propoxy-)-5-methanesulfonyloxy group-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester through sulfonyl methaneization, is called for short compound 13, down together.
At first compound 12 is dissolved in the dichloromethane solvent, the volumetric molar concentration that is mixed with compound 12 is about 1.5% solution, place reactor, place ice bath again, under the ice bath temperature, add triethylamine then earlier, be added dropwise to methane sulfonyl chloride again, the dropping time is 30 minutes, continues reaction 30 minutes after dropwising again.After reaction finished, the reaction system of gained removed solvent earlier under reduced pressure, added ethyl acetate then and saturated sodium chloride aqueous solution carries out extracting operation, separate and obtain extracted organic phase, then extracted organic phase is washed extremely acidity with the 1N aqueous hydrochloric acid earlier, extremely alkaline with the washing of 5%wt potassium bicarbonate aqueous solution again, isolate organic layer, the organic layer anhydrous magnesium sulfate drying, remove by filter sal epsom, remove ethyl acetate then under reduced pressure, obtain white solid, be compound 13, yield 95%.
Wherein triethylamine and methane sulfonyl chloride add-on are 2 times of compound 12 molar weights.
(12) replacement of compound 13 nitrine makes 4-acetamido-3-(1-ethyl propoxy-)-5-azido--1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, is called for short compound 14, down together.
At first compound 13 is dissolved in and is mixed with in the polar solvent that to contain compound 13 volumetric molar concentrations be about 10% solution and place reactor, add sodium azide and a spot of water again, be heated to and reacted about 90 ℃ 2～3 hours, methanesulfonyloxy group on the carbon 5 key positions of compound 13 is replaced by nitrine, be transformed into compound 14.
After reaction finishes, the reactant of gained is carried out extraction treatment with toluene and water earlier, separate the organic layer that obtains being rich in compound 14, underpressure distillation obtains the reddish-brown solid except that desolvating then.Resulting red solid with petroleum ether, suction filtration, is obtained filter cake, and the mixed solvent of forming with petrol ether/ethyl acetate=10/1 again washs three times at least then, obtains purified compound 14, yield 84%.
Above-mentioned said polar solvent can be a kind of in DMF, ethanol, DMSO, Virahol or the acetone etc., but is good with DMF or DMSO.
(13) compound 14 nitrine reduction, and the phosphorylation salify makes Ro 64-0796/002, abbreviation product 1.
At first compound 14 being dissolved in the volumetric molar concentration that is mixed with compound 14 in solvents tetrahydrofurane or the acetonitrile is the reactor that 2.0% left and right sides solution places the band whipping appts, add less water earlier, add reductive agent then, under 50 ℃, carry out the nitrine reduction reaction, at 50 ℃ of following stirring reaction 10-18 hours, make the azido-(N on the carbon 5 key positions in the compound 14
3) be reduced into amido (NH
2).Said reductive agent is a triphenyl phosphorus; Its consumption is 1.5 times of compound 14 molar weights.After reaction finished, the reaction system of first gained removed solvent under reduced pressure, with ethyl acetate and water extraction, told organic layer then, water layer at least with ethyl acetate extraction once merges organic layer, uses anhydrous magnesium sulfate drying then, elimination sal epsom removes ethyl acetate under reduced pressure, obtains a kind of red liquid.
Then above-mentioned red liquid is placed reactor, add the mixed solvent of forming by ethanol/ethyl acetate=1/1 earlier, reheat is warming up to 50 ℃, will prepare the phosphoric acid mixed solution then in advance and slowly be added dropwise in the reactor, reacts at least 30 minutes, be cooled to 0 ℃ then, suction filtration, filter cake is drained with cold ethanol/ethyl acetate (=1/1) washing again, obtaining a kind of white solid---Ro 64-0796/002 product, yield are 90%.
Wherein said phosphoric acid mixed solution is a kind of by the weight concentration phosphoric acid mixed solution that to be 85% phosphoric acid form with the mixed solvent blend of being made up of ethanol/ethyl acetate=1/1.
In sum as seen: the preparation method of Ro 64-0796/002 provided by the invention has not only overcome the shortcoming of prior art dexterously, and solely ward off small stream and directly solved industrialized technical barrier, can promote to prevent and treat the technical progress of bird flu pharmaceutical industries effectively, the total recovery of its product is minimum also to be reached more than 41%.
Further illustrate content of the present invention below in conjunction with accompanying drawing.
Description of drawings
Fig. 1 is the structural formula and the core process schematic flow sheet of the present invention said " a kind of preparation method of Ro 64-0796/002 " main compound.
Wherein:
2---be the structural formula of raw material shikimic acid, be called for short raw material 2;
3---be the structural formula of shikimic acid ethyl ester, be called for short compound 3, it carries out esterification by raw material 2 and dehydrated alcohol and obtains;
4---be 3, the structural formula of 4-isopropylidene thick grass ethyl ester is called for short compound 4, and it is to protect prepared compound by 3, the 4 key positions realization acetonylidene of compound 3;
5---be 3, the structural formula of 4-oxygen-isopropylidene-5-oxygen-benzoyl base-shikimic acid ethyl ester is called for short compound 5, and it is to protect prepared compound by the 5 key positions realization benzoyl of compound 4;
6---the structural formula of 5-oxygen-benzoyl base-shikimic acid ethyl ester, be called for short compound 6,3,4 key position deprotections of based compound 5 make hydroxyl restore prepared compound again; As seen above four steps belong to the shikimic acid raw material transforms early stage structurally, for following critical structures is transformed prerequisite (its purpose prevents undesirable by product) all set;
7---3, the structural formula of 4-bis methane sulfonyloxy-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic ester ethyl ester is called for short compound 7, and 3,4 key positions of based compound 6 are by the prepared compound of sulfonyl methaneization;
8---the structural formula of 3-azido--4-methanesulfonyloxy group-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, be called for short compound 8,3 key positions of based compound 7 replace prepared compound by the selectivity nitrine;
9---5-benzoyloxy-3, the structural formula of 4-aziridine-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester is called for short compound 9, and the prepared compound of ring is reduced, alkalized in 3,4 key positions of based compound 8 by nitrine;
10---5-benzoyloxy-3, the structural formula of 4-acetylethyleneimine-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester is called for short compound 10, the aziridine of 3,4 key positions of the based compound 9 prepared compound that is acetylation;
11---the structural formula of 4-acetamido-3-(1-ethyl propoxy-)-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, be called for short compound 11,3 of based compound 10,4-ethanoyl aziridine by the 3-amylalcohol at the prepared compound of 3 key position selective openings;
12---the structural formula of 4-acetamido-3-(1-ethyl propoxy-)-5-hydroxyl-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, be called for short compound 12, the 5-benzoyloxy of based compound 11 removes protection (recovery hydroxyl) prepared compound;
13---the structural formula of 4-acetamido-3-(1-ethyl propoxy-)-5-mesyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, be called for short compound 13, the 5-hydroxyl of based compound 12 is by the prepared compound of methylsulfonylization;
14---the structural formula of 4-acetamido-3-(1-ethyl propoxy-)-5-azido--1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, be called for short compound 14, the 5-mesyloxy of based compound 13 is replaced prepared compound by nitrine;
1---4-acetamido-3-(1-ethyl propoxy-)-5-amido-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester phosphoric acid salt, be the structural formula of Ro 64-0796/002, be called for short product 1, the 5-azido-of based compound 14 is reduced into amido, and then with the phosphoric acid salify, make the Ro 64-0796/002 product.
Embodiment
Further illustrate content of the present invention below in conjunction with embodiment, but embodiment does not influence protection scope of the present invention:
The shikimic acid ethyl ester is the preparation of compound 3:
With shikimic acid is that (15.00g 86.13mmol) places 250mL single port flask to raw material 2, adds the 150mL dehydrated alcohol again, stirs, and ice bath drips SOCl down
2(5.13g 43.11mmol), dropwises, and is heated to backflow, under reflux temperature the reaction 5 hours, pressure reducing and steaming ethanol, the cooling obtain the shikimic acid ethyl ester be compound 3 (17.06g, 84.4mmol), yield 98%.
See theoretically, under the condition that excess ethyl alcohol exists, raw material shikimic acid energy 100% is esterified, but in experimentation, owing to also must distill unit operation after the esterification, entrainment loss is unavoidable, so the yield of compound 3 just will inevitably reduce, but when scale operation, can adopt suitable technical measures to reduce material loss, its yield necessarily is expected to improve.
3,4-oxygen-isopropylidene shikimic acid ethyl ester is the preparation of compound 4:
(16.89g 83.55mmol) is added in the 250mL single port flask, adds the ethyl acetate of 150mL earlier with the shikimic acid ethyl ester of gained among the embodiment 1, add 2 again, and the 2-Propanal dimethyl acetal (26.11g, 250.59mmol), add the 150mg tosic acid then, stirring at room 30 minutes.The 5%wt K that adds 20mL
2CO
3The aqueous solution, stir staticly after 5 minutes, divide water-yielding stratum, use the ethyl acetate extraction water one time of 50mL at least again, merge organic layer, add anhydrous magnesium sulfate drying, elimination sal epsom removes ethyl acetate under reduced pressure, obtain yellow transparent liquid 3,4-oxygen-isopropylidene shikimic acid ethyl ester is that (19.23g, 79.37mmol), yield is 95% to compound 4.
Gained compound 4 usefulness nuclear magnetic resonance analyser, polarimeter, mass spectrograph and infrared spectrometer detect, and the result is as follows: [α]
D 20=-30.8 (c 3.0, EtOAc).
1H NMR (CDCl
3) δ 1.30 (t, J=7.1Hz, 3H), 1.41 (s, 3H), 1.46 (s, 3H), 2.20-2.28 (m, 1H), 2.80 (dd, J
1=17.4Hz; J
2=4.6Hz, 1H), 3.84-3.93 (m, 1H), 4.10 (dd, J
1=7.1Hz; J
2=6.8Hz, 1H), 4.22 (q, J=7.1Hz, 2H), 4.73-4.78 (m, 1H), 6.92-6.94 (m, 1H) .MS (m/z, relative intensity) 242 (M
+, 1), 227 (100), 197 (12), 167 (17), 137 (79), 121 (11), 110 (10), 95 (38), 43 (14) .IR (KBr film) 3469,2986,2935,1716,1655,1448,1372,1244,1054,860,754cm
-1.
3,4-oxygen-isopropylidene-5-benzoyl shikimic acid ethyl ester is the preparation of compound 5:
With 3 of gained among the embodiment 2, (6.41g 26.46mmol) places 250mL single port flask to 4-oxygen-sec.-propyl shikimic acid ethyl ester, add the 60mL methylene dichloride, stir, under the ice bath temperature, add triethylamine (5.35g then again, 52.87mmol) and DMAP (161mg, 1.32mmol), (4.84g 34.43mmol) reacted 5 hours to drip Benzoyl chloride, remove methylene dichloride under reduced pressure, the ethyl acetate that adds 100mL is washed till acidity with the 1N HCl aqueous solution earlier then, uses K again
2CO
3The aqueous solution is washed till alkalescence, then with saturated nacl aqueous solution washing one time.The organic layer anhydrous magnesium sulfate drying, elimination sal epsom removes ethyl acetate under reduced pressure and obtains 3,4-oxygen-isopropylidene-5-benzoyl shikimic acid ethyl ester, promptly (8.98g, 25.92mmol), yield is 98% to compound 5.
Gained compound 5 usefulness nuclear magnetic resonance analyser, polarimeter, mass spectrograph and infrared spectrometer detect, and the result is as follows: [α]
D 25=-55.0 (c 3.4, EtOAc).
1H NMR (CDCl
3) δ 1.31 (t, J=7.1Hz, 3H), 1.41 (s, 3H), 1.44 (s, 3H), 2.51 (dd, J
1=17.9Hz; J
2=6.3Hz, 1H), 2.90 (dd, J
1=17.8Hz; J
2=3.5Hz, 1H), 4.23 (q, J=7.0Hz, 2H), 4.39 (dd, J
1=J
2=6.2Hz, 1H), 4.77-4.85 (m, 1H), 5.46 (dd, J
1=11.3Hz; J
2=5.8Hz, 1H), 6.93-6.99 (m, 1H), 7.43 (dd, J
1=J
2=7.5Hz, 2H), 7.52-7.59 (m, 1H), 8.02 (d, J=8.2Hz, 2H) .HRMS (EI) calcd for C
19H
23O
6(M+1): 347.1495.Found:347.1483.IR (KBr film) 3042,2979,1722,1633,1600,1450,1260,1112,1058,1032,858,716cm
-1.
Embodiment 4
5-oxygen-benzoyl base-shikimic acid ethyl ester is the preparation of compound 6:
With 3 of gained among the embodiment 3; 4-oxygen-isopropylidene-5-benzoyl shikimic acid ethyl ester is compound 5 (8.98g; 25.92mmol) place 250mL single port flask; add the 20mL ethyl acetate earlier; add the dilute hydrochloric acid that the water by 5mL concentrated hydrochloric acid and 5mL is mixed with again, then stirring reaction 6 hours at room temperature.
After reaction finished, elder generation added the 80mL ethyl acetate with the dilution of system appropriateness, added 50mL water then with the most of hydrochloric acid of flush away, after water is removed in separation, used 5%wt K again
2CO
3Aqueous solution neutralization, the separated and collected organic layer.Then organic layer anhydrous magnesium sulfate drying, elimination sal epsom, decompression is removed ethyl acetate and is obtained yellow solid.Yellow solid earlier use petroleum ether, and behind the suction filtration, filter cake is used sherwood oil again: the mixed solvent of ethyl acetate=form at 2: 1 washs; the refining white solid that obtains, oven dry obtains 5-oxygen-benzoyl base-shikimic acid ethyl ester; be that (7.47g, 24.39mmol), yield is 94% to compound 6.
3,4-bis methane sulfonyloxy-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester is the preparation of compound 7:
With the 5-oxygen-benzoyl base shikimic acid ethyl ester of gained among the embodiment 4 is compound 6 (7.47g; 24.39mmol) place 500mL single port flask; add the 150mL ethyl acetate; stir; the volumetric molar concentration that is mixed with compound 6 is about 2% solution, add again methane sulfonyl chloride (14.58g, 127.28mmol); add then DMAP (150mg, 1.22mmol).Ice bath drips triethylamine down, and (10.30g 101.79mmol), has a large amount of white solids to produce, and the dropping time is 30 minutes, dropwises the back and continues reaction 30 minutes.After reaction finishes,, add 1N HCl washing earlier, use 5%wt K again to acid to gained reaction system
2CO
3The aqueous solution is washed till alkalescence, washes one time with saturated sodium-chloride water solution at last.The organic layer anhydrous magnesium sulfate drying, elimination sal epsom, the decompression remove ethyl acetate, obtain yellow liquid 3,4-bis methane sulfonyloxy-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester be compound 7 (10.94g, 23.66mmol), yield 97%.
3-azido--4-methanesulfonyloxy group-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester is the preparation of compound 8:
With 3 of gained among the embodiment 5,4-bis methane sulfonyloxy-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester is that (10.94g 23.66mmol) places 250ml single port flask to compound 7, adds 80mLDMF, and the ice bath cooling is stirred down.(6.42g 98.75mmol) is dissolved in 16mL water, is mixed with sodium azide aqueous solution, drips sodium azide aqueous solution and goes in the flask, and the dropping time is 30 minutes, dropwises and continues reaction 1 hour with sodium azide.Reaction finishes the back and adds toluene and water extraction, separates and removes aqueous solution impurity in the reaction system, separates the organic layer that obtains being rich in organic compound 8, and then with saturated sodium-chloride water solution washing organic layer one time, obtain flaxen organic layer, toluene is removed in decompression, obtains brown liquid.Place for some time and then separate out solid.Add petroleum ether, obtain yellow solid, suction filtration, filter cake are used petroleum ether again, and be refining.The oven dry obtain faint yellow solid 3-azido--4-methanesulfonyloxy group-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester be compound 8 (9.20g, 22.47mmol), yield 95%.
Mp?90.3-90.7℃，[α]
D 25＝-27.1(c?2.8，EtOAc).
1H?NMR(CDCl
3)δ1.30(t，J＝7.1Hz，3H)，2.48-2.61(m，1H)，3.07(s，3H)，3.21(dd，J
1＝18.0Hz；J
2＝6.0Hz，1H)，4.24(q，J＝7.1Hz，2H)，4.36-4.46(m，1H)，4.97(dd，J
1＝10.0Hz；J
2＝8.1Hz，1H)，5.34-5.48(m，1H)，6.76-6.81(m，1H)，7.46(dd，J
1＝J
2＝7.8Hz，2H)，7.54-7.62(m，1H)，8.11(d，J＝8.3Hz，2H).MS(m/z，relativeintensity)367(M
+-N
3，5)，336(1)，308(1)，285(1)，257(1)，245(2)，217(2)，199(2)，180(6)，163(4)，152(14)，124(5)，105(100)，77(15).IR(KBr?film)2979，2940，2133，1720，1658，1600，1450，1342，1263，1168，1119，1011，969，711，513cm
-1.Anal.calcd?for?C
17H
19N
3O
7S：C，49.87；H，4.68；N，10.26.Found：C，50.21；H，4.38；N，9.98.
5-benzoyloxy-3,4-aziridine-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, i.e. preparation of compound 9:
3-azido--4-mesyloxy-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester with gained among the embodiment 6, be compound 8 (5.00g, 12.21mmol) place 500mL single port flask, add 250mL tetrahydrofuran (THF) (THF) earlier, stir, under the ice bath temperature, add triphenyl phosphorus (3.53g then, 13.46mmol), reacted 2 hours, (3.71g is 36.66mmol) with 25mL water to add triethylamine again.Continuing stirring reaction spends the night.
After reaction finishes, remove THF under reduced pressure, add ethyl acetate and the saturated nacl aqueous solution of 100mL, extraction, separate the organic phase that obtains being rich in compound 9, then ethyl acetate is removed in decompression, obtains brown liquid, makes with extra care by column chromatography and obtains faint yellow oily thing 5-benzoyloxy-3,4-aziridine-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, be compound 9 (3.09g, 10.75mmol), yield 88%.
5-benzoyloxy-3,4-acetylethyleneimine-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, i.e. preparation of compound 10:
5-benzoyloxy-3 with gained among the embodiment 7,4-aziridine-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, promptly (3.09g 10.75mmol) places 150mL single port flask to compound 9, add the 60ml ethyl acetate again, stir, under the ice bath temperature, add then triethylamine (3.26g, 32.22mmol), drip diacetyl oxide (2.20g again, 21.55mmol), the dropping time is 15 minutes, dropwises to continue reaction 15 minutes.After reaction finishes, in gained reaction system, add saturated sodium bicarbonate solution or saturated potassium hydrogen carbonate solution, with the unnecessary diacetyl oxide that neutralizes, tell organic layer, the organic layer anhydrous magnesium sulfate drying, elimination sal epsom, decompression is removed ethyl acetate and is obtained yellow transparent liquid 5-benzoyloxy-3,4-acetylethyleneimine-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, i.e. compound 10 (3.47g, 10.54mmol), yield 98%.
4-acetamido-3-(1-ethyl propoxy-)-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester is the preparation of compound 11:
5-benzoyloxy-3 with gained among the embodiment 8,4-acetylethyleneimine-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, be compound 10 (3.47g, 10.54mmol) place 150mL single port flask, add 20mL 3-amylalcohol, the flask that reaction solution will be housed then moves to and stirs cooling in the ice bath, under the ice bath temperature, with boron trifluoride diethyl etherate (1.97mL, 15.82mmol) mixed solution that is mixed with 10mL 3-amylalcohol drips in reaction solution, the dropping time is 15 minutes, dropwises to continue reaction 15 minutes again.After reaction finishes, add the 100mL ethyl acetate, be washed till alkalescence, tell organic layer, wash one time with saturated sodium-chloride water solution with the 5%wt wet chemical, organic layer anhydrous magnesium sulfate drying then, elimination sal epsom removes ethyl acetate and 3-amylalcohol under reduced pressure.Obtain 4-acetamido-3-(1-ethyl propoxy-)-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester and be compound 11 (4.05g, 9.70mmol), yield 92%.
4-acetamido-3-(1-ethyl propoxy-)-5-hydroxyl-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, i.e. preparation of compound 12:
With 4-acetamido-3-(1-ethyl the propoxy-)-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester of gained among the embodiment 9 is compound 11 (4.05g, 9.70mmol) place 100mL single port flask, add the 60mL dehydrated alcohol again, at room temperature stir into uniform solution, add salt of wormwood (1.47g then, 10.65mmol), reacted 6 hours.After reaction finishes, remove ethanol earlier under reduced pressure, add the 80mL ethyl acetate then and 40mL water carries out extracting and separating, water layer is used the 40mL ethyl acetate extraction one time again, merge organic phase, the organic phase anhydrous magnesium sulfate drying, elimination sal epsom removes ethyl acetate then under reduced pressure, obtains white solid, the mixing solutions washing of using petrol ether/ethyl acetate=4: 1 to form again, suction filtration, the filter cake oven dry obtains 4-acetamido-3-(1-ethyl propoxy-)-5-hydroxyl-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, i.e. compound 12 (2.74g, 8.74mmol), yield 90%.
Mp?131.9-132.2℃，[α]
D 25＝-103.9(c?3.0，EtOAc).
1H?NMR(CDCl
3)δ0.91(t，J＝7.4Hz，6H)，1.29(t，J＝7.1Hz，3H)，1.42-1.62(m，4H)，2.02(s，3H)，2.43(dd，J
1＝18.6Hz；J
2＝5.1Hz，1H)，2.53-2.71(m，1H)，3.33-3.45(m，1H)，3.90-3.98(m，1H)，4.06(br.s，NH，1H)，4.20(q，J＝7.1Hz，2H)，4.23-4.30(m，1H)，6.19-6.21(m，1H)，6.38(s，1H).MS(m/z，relative?intensity)314(M
++1，7)，313(M
+，2)，267(11)，242(13)，226(21)，212(55)，208(39)，197(19)，155(46)，142(100)，138(47)，96(77)，59(12).IR(KBr?film)3490，3335，2969，2917，1703，1642，1544，1465，1374，1309，1250，1105，950cm
-1.Anal.calcd?for?C
16H
27NO
5：C，61.32；H，8.68；N，4.47.Found：C，61.31；H，8.70；N，4.37.
4-acetamido-5-methanesulfonyloxy group-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester is the preparation of compound 13:
With 4-acetamido-3-(1-ethyl the propoxy-)-5-hydroxyl-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester of gained among the embodiment 10 is compound 12 (2.50g, 7.98mmol) place 100mL single port flask, add the 40ml methylene dichloride earlier, stir, under the ice bath temperature, add then triethylamine (1.61g, 15.91mmol), drip methane sulfonyl chloride (1.82g again, 15.89mmol), the dropping time is 30 minutes, dropwises to continue reaction 30 minutes.Reaction removes methylene dichloride under reduced pressure after finishing then, adds the extraction of 50mL ethyl acetate and 25mL saturated nacl aqueous solution again, and separating obtained organic layer is washed till acidity with the 1N HCl aqueous solution, is washed till alkalescence with wet chemical again, uses anhydrous magnesium sulfate drying again.Then remove under reduced pressure ethyl acetate obtain white solid 4-acetamido-5-methanesulfonyloxy group-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester be compound 13 (2.97g, 7.59mmol), yield 95%.
4-acetamido-5-azido--3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester is the preparation of compound 14:
With 4-acetamido-5-methanesulfonyloxy group-3-(1-ethyl the propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester of gained among the embodiment 11 is compound 13 (2.50g, 6.39mmol) place 150mL single port flask, add 25mLDMF and 5mL water earlier, stir, add sodium azide (1.66g then, 25.53mmol), be heated to 90 ℃, reacted 3 hours.Reaction finishes the back and adds 60mL toluene and 60mL water, and extraction separates the organic layer that obtains being rich in compound 14, the organic layer underpressure distillation obtains the reddish-brown solid, add petroleum ether, suction filtration, filter cake washs three times with the mixed solvent of petrol ether/ethyl acetate=be mixed with at 10: 1.Obtain 4-acetamido-5-azido--3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester and be compound 14 (1.82g, 5.38mmol), yield 84%.
Ro 64-0796/002 is the preparation of finished product 1:
With 4-acetamido-5-azido--3-(1-ethyl the propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester of gained among the embodiment 12 is compound 14 (0.80g, 2.36mmol) place 50mL single port flask, add 25mL THF earlier, add 2.5mL water again, add triphenyl phosphorus (9.28g then, 3.54mmol), 50 ℃ of following stirring reactions 16 hours.Reaction removes THF under reduced pressure after finishing, and adds 25mL ethyl acetate and 10mL water, extraction, isolate organic layer, water layer is used the 25mL ethyl acetate extraction one time again, merges organic layer, uses anhydrous magnesium sulfate drying then, elimination sal epsom removes ethyl acetate under reduced pressure, obtains red liquid.Add the mixed solvent of 4mL ethanol/ethyl acetate=1: 1, stir, be heated to 50 ℃.To prepare in advance again (0.33g 2.86mmol) slowly is added dropwise in the reaction solution with the mixed solution that the mixed solvent of 8mL ethanol/ethyl acetate=1: 1 is formed by 85% phosphoric acid.After dropwising, continue reaction 0.5 hour again, be cooled to 0 ℃, suction filtration, filter cake washs by the mixed solvent of forming at 1: 1 with cold ethanol/ethyl acetate, obtains the white solid Ro 64-0796/002, promptly product 1 (0.87g, 2.12mmol), yield 90%.
Product detects with nuclear magnetic resonance analyser, polarimeter, elemental analyser, mass spectrograph, infrared spectrometer, and the result is as follows: Mp 203.3-204.1 ℃ (lit.203-204 ℃), [α]
D 20=-39.1 (c 1, H
2O) lit.[α]
D 20=-39.9 (c 1, H
2O) }.
1HNMR (D
2O) δ 0.84 (t, J=7.2Hz, 3H), 0.89 (t, J=7.3Hz, 3H), 1.29 (t, J=7.1Hz, 3H), 1.40-1.63 (m, 4H), 2.09 (s, 3H), 2.52 (dd, J
1=15.5Hz; J
2=12.2Hz, 1H), 2.97 (dd, J
1=17.1Hz; J
2=4.7Hz, 1H), 3.48-3.66 (m, 2H), 4.06 (dd, J
1=J
2=10.1Hz, 1H), 4.25 (dd, J
1=13.7Hz; J
2=6.7Hz, 1H), 4.34 (d, J=8.3Hz, 1H), 6.86 (s, 1H) .MS (m/z, relative intensity) 314 (M+1+H
+, 7), 295 (1), 267 (11), 254 (11), 242 (13), 226 (21), 212 (55), 197 (19), 184 (19), 166 (10), 155 (46), 142 (100), 110 (20), 96 (77) .HRMS (EI) calcd for C
16H
29N
2O
4(M+H
+): 313.2127.Found:313.2131.IR (KBr, film) 3354,3249,2969,2938,2875,1621,1558,1547,1374,1130,1067,942cm
-1.Anal.calcd forC
16H
31N
2O
8P:C, 46.83; H, 7.61; N, 6.83.Found:46.42; H, 7.68; N, 6.63.
Claims (9)
1. the preparation method of a Ro 64-0796/002, this method are to be raw material with the shikimic acid, it is characterized in that this method comprises following 13 chemosynthesis steps:
(1) earlier the raw material shikimic acid is dissolved in the ethanol, ice bath drips thionyl chloride down then, and heat temperature raising is under reflux temperature esterification 4-6 hour then, obtains the shikimic acid ethyl ester, is called for short compound 3;
(2) will be set by step the shikimic acid ethyl ester of (1) gained be dissolved in the ethyl acetate, add 2 earlier, the 2-Propanal dimethyl acetal adds the tosic acid of catalytic amount again, the stirring at room reaction obtains 3,4-oxygen-isopropylidene shikimic acid ethyl ester is called for short compound 4;
(3) earlier will be set by step the compound 4 of (2) gained be dissolved in methylene dichloride or the ethyl acetate, the triethylamine that adds 2 times of mol ratios then, reaction makes 3 with Benzoyl chloride under to the catalysis of Dimethylamino pyridine again, and 4-oxygen-isopropylidene-5-oxygen-benzoyl base shikimic acid ethyl ester is called for short compound 5;
(4) will be set by step the compound 5 of (3) gained under the effect of diluted acid, in ethyl acetate, remove the acetonylidene protecting group, make 5-oxygen-benzoyl base shikimic acid ethyl ester, be called for short compound 6;
(5) make solvent with methylene dichloride or ethyl acetate, under the effect of triethylamine, will be set by step the compound 6 of (4) gained make 3 with the methane sulfonyl chloride effect, 4-bis methane sulfonyloxy-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester is called for short compound 7;
(6) will be set by step the compound 7 of (5) gained in polar solvent, make 3-azido--4-methanesulfonyloxy group-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester with the sodium azide reaction, be called for short compound 8;
(7) will be set by step the compound 8 of (6) gained under the effect of phosphorus reductive agent, carry out reduction reaction, cyclisation obtains 5-benzoyloxy-3 under the effect of alkali then, 4-aziridine-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester is called for short compound 9;
(8) in methylene dichloride or the ethyl acetate, will be set by step the compound 9 of (7) gained under the effect of amine, carry out acetylization reaction and make 5-benzoyloxy-3 with aceticanhydride or Acetyl Chloride 98Min., 4-acetylethyleneimine-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester is called for short compound 10;
(9) be solvent with the 3-amylalcohol, step makes 4-acetamido-3-(1-ethyl propoxy-)-5-benzoyloxy-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester by compound 10 open loop under Lewis acid effect of (8) gained, is called for short compound 11;
(10) will be set by step the compound 11 of (9) gained be dissolved in the ethanol, under the weak base effect, take off benzoyl and make 4-acetamido-3-(1-ethyl propoxy-)-5-hydroxyl-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, be called for short compound 12;
(11) will be set by step the compound 12 of (10) gained under the effect of amine, make 4-acetamido-5-methanesulfonyloxy group-3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester with the methane sulfonyl chloride reaction, be called for short compound 13;
(12) compound 13 with step (11) gained makes 4-acetamido-5-azido--3-(1-ethyl propoxy-)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester with the sodium azide reaction in polar solvent, is called for short compound 14;
(13) at first make the azido-in the compound 14 of step (12) gained under the effect of phosphorus reductive agent, be reduced into amino, in oxo solvent, make Ro 64-0796/002 again, be called for short finished product 1 with the phosphoric acid salify.
2. by the described preparation method of claim 1, it is characterized in that said acid in the step (4) is a kind of in hydrochloric acid, phosphoric acid, sulfuric acid, the acetic acid or the mixing acid be made up of them.
3. by the described preparation method of claim 1, it is characterized in that said polar solvent in step (6) and (12) is a kind of in DMF, ethanol, DMSO, Virahol, the acetone or the mixed solvent be made up of them.
4. by the described preparation method of claim 1, it is characterized in that said phosphorus reductive agent is a triphenyl phosphorus in step (7) and (13).
5. by the described preparation method of claim 1, it is characterized in that said alkali in the step (7) is a kind of in triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, saleratus, salt of wormwood, the yellow soda ash.
6. by the described preparation method of claim 1, it is characterized in that said amine in step (8) and (11) is Trimethylamine 99, triethylamine, diisopropylethylamine, a kind of in Dimethylamino pyridine, the pyridine.
7. by the described preparation method of claim 1, it is characterized in that a kind of in boron trifluoride diethyl etherate, zinc chloride, tin chloride, aluminum chloride, iron(ic) chloride, zinc bromide, the magnesium bromide of said Lewis acid in the step (9).
8. by the described preparation method of claim 1, it is characterized in that said weak base in the step (10) is a kind of in salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate, the ammoniacal liquor.
9. by the described preparation method of claim 1, it is characterized in that said oxo solvent in the step (13) is a kind of in methyl alcohol, ethanol, Virahol, ethyl acetate, the acetone or the mixed solvent be made up of them.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910047843A CN101538221A (en) | 2009-03-19 | 2009-03-19 | Preparation method of Oseltamivir phosphate |
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| CN102267961A (en) * | 2010-06-02 | 2011-12-07 | 上海迪赛诺医药发展有限公司 | Method for preparing ethyl (3R,4R,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-1-cyclohexene-1-formate |
| CN103224464A (en) * | 2013-04-15 | 2013-07-31 | 张健存 | Cyclohexene derivative or its pharmaceutically acceptable salt and application thereof |
| CN103833570A (en) * | 2014-03-19 | 2014-06-04 | 浙江师范大学 | Synthesis method of oseltamivir |
| CN106278928A (en) * | 2016-08-10 | 2017-01-04 | 宜昌东阳光长江药业股份有限公司 | A kind of synthetic method of oseltamivir phosphate isomer impurities |
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| CN102267961A (en) * | 2010-06-02 | 2011-12-07 | 上海迪赛诺医药发展有限公司 | Method for preparing ethyl (3R,4R,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-1-cyclohexene-1-formate |
| CN102267961B (en) * | 2010-06-02 | 2013-10-02 | 上海迪赛诺医药发展有限公司 | Method for preparing ethyl (3R,4R,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-1-cyclohexene-1-formate |
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| CN103224464B (en) * | 2013-04-15 | 2016-05-04 | 广州市恒诺康医药科技有限公司 | Cyclohexene analog derivative or its pharmaceutically acceptable salt and uses thereof |
| CN103833570A (en) * | 2014-03-19 | 2014-06-04 | 浙江师范大学 | Synthesis method of oseltamivir |
| CN103833570B (en) * | 2014-03-19 | 2015-05-27 | 浙江师范大学 | Synthesis method of oseltamivir |
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| CN106278928B (en) * | 2016-08-10 | 2018-01-02 | 宜昌东阳光长江药业股份有限公司 | A kind of synthetic method of Oseltamivir phosphate isomer impurities |
| CN108218697A (en) * | 2017-11-16 | 2018-06-29 | 北京融英医药科技有限公司 | A kind of synthetic method of Tamiflu key intermediate |
| CN108218697B (en) * | 2017-11-16 | 2020-06-05 | 北京融英医药科技有限公司 | Synthetic method of tamiflu key intermediate |
| CN113677658A (en) * | 2019-03-14 | 2021-11-19 | 纳尔逊·曼德拉大学 | Flow synthesis method for producing oseltamivir |
| CN111253276A (en) * | 2020-03-30 | 2020-06-09 | 宜昌东阳光长江药业股份有限公司 | Preparation method of oseltamivir phosphate |
| CN111253276B (en) * | 2020-03-30 | 2021-01-08 | 宜昌东阳光长江药业股份有限公司 | Preparation method of oseltamivir phosphate |
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| CN113444065A (en) * | 2021-06-29 | 2021-09-28 | 浙江得乐康食品股份有限公司 | Shikimic acid sulfonated substance and preparation method thereof |
| CN114539088A (en) * | 2022-02-28 | 2022-05-27 | 浙江工业大学 | Preparation method of oseltamivir |
| CN114539088B (en) * | 2022-02-28 | 2023-06-23 | 浙江工业大学 | Preparation method of oseltamivir |
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