CN104447451B - New preparation method of oseltamivir intermediate - Google Patents
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- CN104447451B CN104447451B CN201410641021.1A CN201410641021A CN104447451B CN 104447451 B CN104447451 B CN 104447451B CN 201410641021 A CN201410641021 A CN 201410641021A CN 104447451 B CN104447451 B CN 104447451B
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Abstract
The invention provides a new method for preparing an intermediate (VI) of oseltamivir shown in a formula (I). Starting from a known intermediate (II) reported in a document, chiral acetyl ammonia is built based on a key lossen rearrangement reaction step to obtain a known oseltamivir intermediate structure in the document, so that the use operation of the dangerous sodium azide is avoided, and the high reaction yield is maintained. The method has the advantages that operation is safe and convenient, cheap raw materials are cheap and available. The formula is shown in the specification.
Description
Technical field
The present invention relates to compound synthesis field is and in particular to a kind of new preparation process of Oseltamivir intermediate.
Background technology
The molecular formula of Oseltamivir is c16h28n2o4, chemical entitled: (3r, 4r, 5s) -4- acetamide -5- amido -3- (1-
Third 2-ethoxyethyl acetate) -1- cyclohexene -1- carboxylic acid, ethyl ester, structural formula is as follows:
By gilead company of the U.S. and the joint research and development exploitation of Switzerland roche (Roche) company, with its phos-phate forms patent medicine,
Trade name Tamiflu, in Switzerland's listing, is approved in Discussion on Chinese Listed, is that the anti-avian influenza generally acknowledged at present has the most for 1999 for 2002
The medicine of effect, is also national strategy deposit medicine.Therefore its synthesis is extremely important.
The synthetic route of gilead company of the U.S. and roche company of Switzerland cooperative research and development is with shikimic acid as raw material
(angew.chem.int.ed.2006,45,7330), its synthetic route is as follows: i.e. first from shikimic acid, through over-churning, contracting
Ketone protection, Mesylation, acidic condition, selective reduction, intramolecular cyclization generates epoxy intermediate, then from epoxy intermediate warp
Nitrine open loop, acetylated and nitrine reduction, altogether through 11 steps, 20% total recovery obtains Oseltamivir.The method lack
Point is the use of more unsafe sodium azide and the intermediate containing sodium azide, and raw material shikimic acid carries from Chinese medicine simultaneously
Take, the place of production only limits China and south east asia, limited source is it is impossible to meet extensive demand.Although roche company is later to this
Synthetic route has carried out many improvement, but total recovery still cannot significantly improve, relatively costly it is difficult to reply contingency condition under
Extensive demand, so, development is new, efficient Oseltamivir synthetic method is extremely urgent.
2009, hayashi etc. (angew.chem.int.ed.2009,48,1304) report one succinct and efficient
Synthetic method, they successively achieve the Oseltamivir six of asymmetric organocatalysis only by three times " one kettle way "
The structure of carbocyclic skeleton and the transformation to group on skeleton, general line only needs to primary column chromatography, finally with nearly 57% receipts
Rate synthesis obtains Oseltamivir, creates the highest total recovery of Oseltamivir synthesis so far, before having potential industrialization
Scape.
But, equally employ more unsafe sodium azide in this route, therefore, with safety, succinct, efficient method
Substitute the use of the higher sodium azide of above-mentioned danger, be to realize the industrialized guarantee of this route further.
Content of the invention
Term defines
" compound shown in formula " be (3s, 4r, 5r) -4- tert-butyl group -1- ethyl -5- nitro -3- (pentane -3- hydroxyl) -
2- (p- tolyl sulphur) hexamethylene -1,4- dicarbapentaborane acid esters.
" compound shown in formula " be (1r, 2s, 6r) -4- (ethoxy carbonyl) -6- nitro -2- (pentane -3- base oxo) -
3- (p- tolyl is thio) hexahydrobenzoid acid.
" compound shown in formula " is (3s, 4r, 5r)-ethyl 4- (hydroxyCarbamoyl) -5- nitro -3- (pentane -3- base
Oxo) -2- (p- tolyl is thio) cyclohexyl carbonic ester.
" compound shown in formula " be (3s, 4r, 5r)-ethyl 4- (acetyl oxygen carbamoyl) -5- nitro -3- pentane -
3- base oxo) -2- (p- tolyl is thio) cyclohexyl carbonic ester.
The technical problem to be solved in the present invention is to provide the conjunction that raw material is easy to get, route is short, easy and simple to handle, reaction condition is gentle
Become the new method of Oseltamivir.
For solving this technical problem, the technical solution used in the present invention is:
A kind of Oseltamivir intermediate, shown in formula (vi), the synthetic method of compound, comprises the steps:
(1) acid hydrolytic reaction
Compound shown in formula is dissolved in alcohols solvent, Hydrolysis At Room Temperature obtains structural formula shownization in acid condition
Compound:
(2) hydroxylamination reaction
Compound shown in formula is dissolved in solvent, is cooled to 20 5 DEG C, add ethyl chloroformate, organic amine reaction, then
Add azanol reagent reacting at room temperature, obtain compound shown in structural formula:
(3) acetylization reaction
By compound shown in formula with, after solvent dissolving, adding acylating reagent, room temperature reaction prepares structural formula institute
Show compound:
(4) lossen resets acetylization reaction
Compound shown in formula is dissolved in oxolane, adds organic amine and water, after heating reflux reaction, to system
Middle addition acetic anhydride, continues reaction and obtains compound shown in structural formula:
Compound shown in formula ii according to angew.chem.int.ed.2009,48,1304, the preparation of disclosed method.
Step 1) described in acid be hydrochloric acid, acetic acid, sulfuric acid, trifluoroacetic acid etc.；
Described alcohols solvent is methyl alcohol, ethanol, normal propyl alcohol, isopropanol, n-butanol, tert-butyl alcohol etc..
Step 2) described solvent be dichloromethane, chloroform, oxolane, methyl tertiary butyl ether(MTBE), acetone, toluene etc.；
Described azanol reagent is azanol, the aqueous solution of hydroxylamine hydrochloride or alcoholic solution, and wherein, described alcoholic solvent is selected from: first
Alcohol, ethanol, glycerine etc.；
Described organic amine is triethylamine, dbu, dipea, dmap, n- methylmorpholine.
Step 3) described solvent be dichloromethane, chloroform, oxolane, methyl tertiary butyl ether(MTBE), acetone, toluene etc.；
Described acylating reagent is aceticanhydride, chloroacetic chloride, thionyl chloride, DNFB etc..
Step 4) described organic amine is selected from: dbu, dipea, tea.
Wherein, t-bu is the tert-butyl group, and ac is acetyl group, no2For nitro, dbu is 1,8- diazabicylo 11 carbon -7-
Alkene.
In one embodiment, the reaction of described hydroxylamination, acetylization reaction, lossen rearrangement-acetylization reaction can
Carried out with one pot, it concretely comprises the following steps:
(1) acid hydrolytic reaction
By compound shown in formula, Hydrolysis At Room Temperature obtains compound shown in structural formula in acid condition:
(2) hydroxylamination, acetylation, lossen rearrangement-acetylation one pot reaction
Compound shown in formula is dissolved in halogenated hydrocarbon solvent, is cooled to 20 5 DEG C, add ethyl chloroformate, organic amine
After reaction terminates, add azanol reagent room temperature reaction, after raw material has converted, add acylating reagent in system, reacted
Bi Hou, reduced pressure concentration, crude product is dissolved in oxolane, adds organic amine and water, after heating reflux reaction, in system
Add acetic anhydride, continue reaction and obtain compound shown in structural formula.
Present invention also offers compound shown in formula (iv) and compound shown in formula (vi)
Gross production rate of the present invention compound yield shown in structural formula iii and structural formula vi under reaction condition in one pot respectively
Calculated, gross production rate can reach: 79%.
The present invention has compound shown in compound intermediate structural formula from document, through hydrolysis, hydroxylamination, second
Acylated, lossen rearrangement-acetylation, the simple operation of totally four steps, synthesize anti-avian influenza medicine Oseltamivir intermediate,
Wherein, hydroxylamination, acetylation, lossen rearrangement-acetylation can one pot carry out.
The preparation method of Oseltamivir intermediate used in the present invention, effectively prevent using dangerous higher nitrine
Change sodium, using one kettle way easy and simple to handle so that the industrialization of this route has bigger feasibility and prospect；Whole piece after improvement
Route agents useful for same is cheap and easy to get, simple to operate, is a kind of simple, efficient, Oseltamivir synthetic route of environmental protection.
Specific embodiment
Embodiment 1
The preparation of compound shown in formula
The compound (510.0mg, 1.0mmol) shown in formula ii and methyl alcohol 10ml dissolving is added in the reaction bulb of 50ml,
Add 2ml 2mol/l hydrochloric acid, be stirred at room temperature, after reacting about 6 hours, it is former that tlc follows the tracks of compound shown in structural formula for the reaction
Material stops reaction after disappearing, and rotary evaporation removes solvent, obtains compound shown in essentially pure structural formula, yield
98%.
Embodiment 2
The preparation of compound shown in formula
Compound shown in formula iii (453mg, 1.0mmol) uses 20ml dichloromethane to dissolve, and is cooled to 0 DEG C, adds chloro-carbonic acid
Ethyl ester (109mg, 1.0mmol) and triethylamine (202mg, 2.5mmol) reaction half an hour after be gradually increased to room temperature reaction 1 hour,
Rotary evaporation removes solvent, adds hydroxylamine hydrochloride (104mg, 1.5mmol) and methyl alcohol 20ml, is stirred at room temperature, and reacts about 4 hours
Stop reaction afterwards, rotary evaporation removes solvent, adds about 30ml water in system, separates organic phase, adds dilute salt of 5ml 1n
Acid, dichloromethane (20ml × 3) extracts, and merges organic phase, anhydrous sodium sulfate drying, it is basic that rotary evaporation removing solvent obtains
Upper pure compound shown in formula, yield 92%.
1hnmr (400mhz, cdcl3) 8.02 (s, 1h), 7.38 (d, j=8.0hz, 2h), 7.07 (d, j=8.0hz,
2h), 4.70-4.80 (m, 1h), 4.05-4.17 (m, 1h), 4.02 (t, j=3.2hz, 1h), 3.85-3.97 (m, 1h), 3.74
(m, 1h), 3.52 (m, 1h), 3.13 (quintet, j=4.8hz, 1h), 2.76 (dt, j=13.2,3.6hz, 1h), 2.68
(dt, j=13.2,3.6hz, 1h), 2.31 (s, 3h), 2.28 (q, j=13.2hz, 1h), 2.09 (br, 1h), 1.28-1.48
(m, 2h), 1.21 (t, j=7.2hz, 3h), 1.03-1.18 (m, 2h), 0.76 (t, j=7.2hz, 3h), 0.63 (t, j=
7.2hz,3h)；
hrms(esi)491.1831[(m+na)+].
Embodiment 3
The preparation of compound shown in formula
Compound shown in formula iv (454mg, 1.0mmol) is dissolved in 10ml dichloromethane, add triethylamine (166 μ l,
1.2mmol), acetic anhydride 4ml, stops reaction after room temperature reaction about half an hour, rotary evaporation obtains shown in essentially pure formula
Compound, yield 99%.
1hnmr (400mhz, cdcl3) 7.38 (d, j=8.0hz, 2h), 7.07 (d, j=8.0hz, 2h), 4.70-4.80
(m, 1h), 4.05-4.17 (m, 1h), 4.02 (t, j=3.2hz, 1h), 3.86-3.98 (m, 1h), 3.75 (m, 1h), 3.54 (m,
1h), 3.17 (quintet, j=4.8hz, 1h), 2.76 (dt, j=13.2,3.6hz, 1h), 2.68 (dt, j=13.2,
3.6hz, 1h), 2.31 (s, 3h), 2.28 (q, j=13.2hz, 1h), 2.17 (s, 3h), 1.28-1.48 (m, 2h), 1.23 (t, j
=7.2hz, 3h), 1.03-1.18 (m, 2h), 0.76 (t, j=7.2hz, 3h), 0.63 (t, j=7.2hz, 3h)；
hrms(esi)533.1937[(m+na)+].
Embodiment 4
The preparation of compound shown in formula
Compound shown in formula v (510mg, 1.0mmol) use thf (20ml) dissolve, add dbu (183mg, 1.2mmol) and
Water (18mg, 1mmol) heating reflux reaction 3 hours, stops reaction, is cooled to room temperature, adds acetic anhydride 2ml, and room temperature reaction 1 is little
When, rotary evaporation removes organic solvent, obtains the compound shown in formula, yield 86%.
Embodiment 5
The preparation of compound shown in formula
The 10ml dichloromethane of compound shown in formula iii dissolves, and is cooled to 0 DEG C, addition ethyl chloroformate (131mg,
1.2mmol) and it is gradually increased to room temperature reaction 1 hour after triethylamine (242mg, 3.0mmol) reaction half an hour, rotary evaporation removes
Solvent, adds hydroxylamine hydrochloride (104mg, 1.5mmol) and methyl alcohol 20ml, and room temperature reaction, after about 4 hours, adds vinegar in system
Acid anhydrides 4ml, stops reaction after room temperature reaction about half an hour, rotary evaporation obtains crude product, and crude product is molten with thf (20ml)
Solution, adds dbu (183mg, 1.2mmol) and water (18mg, 1mmol), heating reflux reaction 3 hours, stops reaction, be cooled to room
Temperature, adds acetic anhydride 2ml, room temperature reaction 1 hour, rotary evaporation removes solvent and reagent, adds 30ml ethyl acetate again molten
Solution, is respectively washed once with 10ml1mol/l hydrochloric acid, saturated sodium-chloride, anhydrous sodium sulfate drying respectively, obtains basic after reduced pressure concentration
Upper pure compound shown in formula, yield 79%.
Claims (4)
1. a kind of new preparation process of Oseltamivir intermediate, it comprises the following steps:
(1) compound shown in structural formula is dissolved in alcohols solvent, acid adding Hydrolysis At Room Temperature obtains structural formula shownization
Compound:
(2) compound shown in structural formula is dissolved in solvent, is cooled to -20～5 DEG C, add ethyl chloroformate, organic amine anti-
Should, then add azanol reagent reacting at room temperature, obtain compound shown in structural formula:
(3) compound shown in structural formula is dissolved in solvent, adds acylating reagent, room temperature reaction prepares structural formula institute
Show compound:
(4) compound shown in structural formula is dissolved in oxolane, adds organic amine and water, after heating reflux reaction, to
Add acetic anhydride in system, continue reaction and obtain compound shown in structural formula:
Alcohols solvent wherein described in step (1) is methyl alcohol, ethanol or isopropanol, and described acid is trifluoroacetic acid；
The described solvent of step (2) is dichloromethane or chloroform, and described azanol reagent is azanol, the aqueous solution of hydroxylamine hydrochloride or alcohol
Solution, described organic amine is triethylamine, and described alcoholic solvent is methyl alcohol or ethanol；
The described solvent of step (3) is dichloromethane or chloroform, and described acylating reagent is aceticanhydride；
The described organic amine of step (4) is selected from: dbu, dipea, tea.
2. preparation method according to claim 1 is it is characterised in that the reaction of step (2), step (3) and step (4) can
To purify without isolation, one pot is carried out.
3. the preparation method of compound shown in structural formula, is dissolved in solvent including by compound shown in structural formula, be cooled to-
20～5 DEG C, add ethyl chloroformate, organic amine reaction, add reaction under azanol reagent room temperature, obtain structural formula shownization
Compound:
Wherein said solvent is selected from: dichloromethane or chloroform；Described azanol reagent is azanol, the aqueous solution of hydroxylamine hydrochloride or alcohol
Solution；Described alcoholic solution is selected from: methyl alcohol or ethanol.
4. compound shown in formula (iv) and compound shown in formula (v):
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| CN113336738A (en) * | 2021-06-29 | 2021-09-03 | 浙江得乐康食品股份有限公司 | Shikimic acid ether compound and preparation method thereof |
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Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |
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