CN104447451A - New preparation method of oseltamivir intermediate - Google Patents
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- 0 CCC(CC)OC(C(C(*)C1)Sc2ccc(C)cc2)[C@](*)C1[N+]([O-])=O Chemical compound CCC(CC)OC(C(C(*)C1)Sc2ccc(C)cc2)[C@](*)C1[N+]([O-])=O 0.000 description 4
- PMFBSYXYXWOFJQ-LKGAJIBZSA-N CCOC(C(C[C@H]([C@@H](C)C1)[N+]([O-])=O)C1Sc1ccc(C)cc1)=O Chemical compound CCOC(C(C[C@H]([C@@H](C)C1)[N+]([O-])=O)C1Sc1ccc(C)cc1)=O PMFBSYXYXWOFJQ-LKGAJIBZSA-N 0.000 description 1
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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 compou nd synthesis field, be specifically related to a kind of new preparation process of Oseltamivir intermediate.
Background technology
The molecular formula of Oseltamivir is C
16h
28n
2o
4, chemistry is by name: (3R, 4R, 5S)-4-ethanamide-5-amido-3-(1-third 2-ethoxyethyl acetate)-1-tetrahydrobenzene-1-carboxylic acid, ethyl ester, and structural formula is as follows:
Developed by Gilead company of the U.S. and Switzerland Roche (Roche) company joint research and development, with its phos-phate forms patent medicine, commodity are called Tamiflu, within 1999, go on the market in Switzerland, within 2002, get permission in Discussion on Chinese Listed, being the most effective medicine of anti-avian influenza of generally acknowledging at present, 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 take shikimic acid as raw material (Angew.Chem.Int.Ed.2006; 45; 7330); its synthetic route is as follows: namely first from shikimic acid; through over-churning, ketal protection, Mesylation, acidic condition, selective reduction, ring in molecule, is become to generate epoxy intermediate, then from epoxy intermediate through nitrine open loop, acetylated and nitrine reduction; altogether through 11 steps, the total recovery of 20% obtains Oseltamivir.The shortcoming of the method is the use of more unsafe sodiumazide and the intermediate containing sodiumazide, and raw material shikimic acid is derived from traditional Chinese medicine extraction simultaneously, and the place of production is only for China and south east asia, and limited source, cannot meet extensive demand.Although Roche company had carried out many improvement to this synthetic route afterwards, total recovery still cannot significantly improve, and cost is higher, was difficult to tackle the extensive demand under contingency condition, so, develop new, Oseltamivir synthetic method is extremely urgent efficiently.
2009, (the Angew.Chem.Int.Ed.2009 such as Hayashi, 48,1304) synthetic method succinctly and is efficiently reported, they successively achieve the structure of Oseltamivir hydrogenation of six carbocyclic skeleton and the transformation to group on skeleton of asymmetric organocatalysis only by three times " one kettle way ", general line only needs primary column chromatography, finally obtain Oseltamivir with the yield synthesis of nearly 57%, create the highest total recovery of Oseltamivir synthesis up to now, there is potential industrial prospect.
But employ more unsafe sodiumazide equally in this route, therefore, substituting the use of the higher sodiumazide of above-mentioned danger with safety, succinct, efficient method, is realize the industrialized guarantee of this route further.
Summary of the invention
Term definition
" shown in formula II compound " is (3S, 4R, 5R)-4-tertiary butyl-1-ethyl-5-nitro-3-(pentane-3-hydroxyl)-2-(p-tolyl sulphur) hexanaphthene-Isosorbide-5-Nitrae-dicarbapentaborane acid esters.
" shown in formula III compound " is (1R, 2S, 6R)-4-(ethoxy carbonyl)-6-nitro-2-(pentane-3-base oxo)-3-(p-tolyl sulfo-) hexahydrobenzoic acid.
" shown in formula IV compound " is (3S, 4R, 5R)-ethyl 4-(hydroxyCarbamoyl)-5-nitro-3-(pentane-3-base oxo)-2-(p-tolyl sulfo-) cyclohexyl carbonic ether.
" shown in formula V compound " is (3S, 4R, 5R)-ethyl 4-(acetyl oxygen formamyl)-5-nitro-3-pentane-3-base oxo)-2-(p-tolyl sulfo-) cyclohexyl carbonic ether.
The technical problem to be solved in the present invention is to provide the novel method of the synthesis Oseltamivir that raw material is easy to get, route is short, easy and simple to handle, reaction conditions is gentle.
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
Be dissolved in alcoholic solvent by compound shown in formula II, By Hydrolysis At Room Temperature obtains compound shown in structural formula III in acid condition:
(2) hydroxylamination reaction
Compound shown in formula III is dissolved in solvent, Jiang Wen Zhi ?20 ?5 DEG C, add Vinyl chloroformate, organic amine reaction, more at room temperature add azanol reagent react, obtain compound shown in structural formula IV:
(3) acetylization reaction
After compound dissolution with solvents shown in formula IV, add acylating reagent, room temperature reaction prepares compound shown in structural formula V:
(4) Lossen Chong Pai ?acetylization reaction
By compound dissolution shown in formula V in tetrahydrofuran (THF), add organic amine and water, after heating reflux reaction, in system, add diacetyl oxide, continue to be obtained by reacting compound shown in structural formula VI:
Shown in formula II, compound is according to Angew.Chem.Int.Ed.2009, and 48,1304, disclosed method preparation.
Step 1) described in acid be hydrochloric acid, acetic acid, sulfuric acid, trifluoroacetic acid etc.;
Described alcoholic solvent is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol etc.
Step 2) described solvent is methylene dichloride, chloroform, tetrahydrofuran (THF), methyl tertiary butyl ether, acetone, toluene etc.;
Described azanol reagent is azanol, the aqueous solution of oxammonium hydrochloride or alcoholic solution, and wherein, described alcoholic solvent is selected from: methyl alcohol, ethanol, glycerine etc.;
Described organic amine is triethylamine, DBU, DIPEA, DMAP, N-methylmorpholine.
Step 3) described solvent is methylene dichloride, chloroform, tetrahydrofuran (THF), methyl tertiary butyl ether, acetone, toluene etc.;
Described acylating reagent is aceticanhydride, Acetyl Chloride 98Min., thionyl chloride, DNFB etc.
Step 4) described organic amine is selected from: DBU, DIPEA, TEA.
Wherein, t-Bu is the tertiary butyl, and Ac is ethanoyl, NO
2for nitro, DBU is 1,8-diazabicylo 11 carbon-7-alkene.
In one embodiment, described hydroxylamination reaction, acetylization reaction, Lossen rearrangement-acetylization reaction can one pot carry out, its concrete steps are:
(1) acid hydrolytic reaction
By compound shown in formula II in acid condition By Hydrolysis At Room Temperature obtain compound shown in structural formula III:
(2) hydroxylamination, acetylize, Lossen rearrangement-acetylize one pot reaction
Compound shown in formula III is dissolved in halogenated hydrocarbon solvent, Jiang Wen Zhi ?20 ?5 DEG C, add Vinyl chloroformate, organic amine reaction terminate after; add azanol reagent room temperature reaction again; after feedstock conversion is complete, in system, add acylating reagent, after completion of the reaction; concentrating under reduced pressure; crude product is dissolved in tetrahydrofuran (THF), adds organic amine and water, after heating reflux reaction; in system, add acetic anhydride, continue to be obtained by reacting compound shown in structural formula VI.
Present invention also offers compound shown in compound and formula (VI) shown in formula (IV)
Overall yield of the present invention respectively in one pot under reaction conditions the compound yield shown in formula II I and structural formula VI calculate, overall yield can reach: 79%.
The present invention has compound shown in compound intermediate structural formula II from document; through hydrolysis, hydroxylamination, acetylize, lossen rearrangement-acetylize; the simple operation of totally four steps; synthesize anti-avian influenza medicine Oseltamivir intermediate; wherein, hydroxylamination, acetylize, lossen rearrangement-acetylize can one pot carry out.
The preparation method of Oseltamivir intermediate used in the present invention, effectively prevent and use dangerous higher sodiumazide, adopts one kettle way easy and simple to handle, makes the industrialization of this route have larger feasibility and prospect; Whole piece route agents useful for same after improvement is cheap and easy to get, simple to operate, is a kind of Oseltamivir synthetic route of simple, efficient, environmental protection.
Embodiment
Embodiment 1
The preparation of compound shown in formula III
Compound (the 510.0mg shown in formula II is added in the reaction flask of 50mL, 1.0mmol) dissolve with methyl alcohol 10mL, add 2mL 2mol/L hydrochloric acid, stirring at room temperature, react after about 6 hours, TLC follows the tracks of reaction to the rear stopped reaction of raw materials of compound disappearance shown in structural formula II, and rotary evaporation is except desolventizing, obtain compound shown in substantially pure structural formula III, yield 98%.
Embodiment 2
The preparation of compound shown in formula IV
(the 453mg of compound shown in formula III, 1.0mmol) dissolve with 20mL methylene dichloride, be cooled to 0 DEG C, add Vinyl chloroformate (109mg, 1.0mmol) with triethylamine (202mg, room temperature reaction 1 hour is risen to gradually after 2.5mmol) reacting half an hour, rotary evaporation is except desolventizing, add hydroxylamine hydrochloride (104mg, 1.5mmol) with methyl alcohol 20mL, stirring at room temperature, react stopped reaction after about 4 hours, rotary evaporation is except desolventizing, about 30mL water is added in system, separate organic phase, add the dilute hydrochloric acid of 5mL 1N, methylene dichloride (20mL × 3) extracts, merge organic phase, anhydrous sodium sulfate drying, compound shown in the substantially pure formula IV that rotary evaporation obtains except desolventizing, 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 V
By (the 454mg of compound shown in formula IV, 1.0mmol) be dissolved in 10mL methylene dichloride, add triethylamine (166 μ L again, 1.2mmol), acetic anhydride 4mL, room temperature reaction is about stopped reaction after half an hour, and rotary evaporation obtains compound shown in substantially pure formula V, 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 VI
(the 510mg of compound shown in formula V, 1.0mmol) dissolve with THF (20mL), add DBU (183mg, 1.2mmol) and water (18mg, 1mmol) heating reflux reaction 3 hours, stopped reaction, is cooled to room temperature, adds diacetyl oxide 2mL, room temperature reaction 1 hour, rotary evaporation removing organic solvent, obtains the compound shown in formula VI, yield 86%.
Embodiment 5
The preparation of compound shown in formula VI
The 10mL methylene dichloride of compound shown in formula III dissolves, be cooled to 0 DEG C, add Vinyl chloroformate (131mg, 1.2mmol) with triethylamine (242mg, room temperature reaction 1 hour is risen to gradually after 3.0mmol) reacting half an hour, rotary evaporation is except desolventizing, add hydroxylamine hydrochloride (104mg, 1.5mmol) with methyl alcohol 20mL, room temperature reaction is after about 4 hours, acetic anhydride 4mL is added in system, room temperature reaction is about stopped reaction after half an hour, rotary evaporation obtains crude product V, crude product V THF (20mL) dissolves, add DBU (183mg, 1.2mmol) with water (18mg, 1mmol), heating reflux reaction 3 hours, stopped reaction, be cooled to room temperature, add acetic anhydride 2mL, room temperature reaction 1 hour, rotary evaporation is except desolventizing and reagent, add 30mL ethyl acetate again to dissolve, use 10mL1mol/L hydrochloric acid respectively, saturated sodium-chloride is respectively washed once, anhydrous sodium sulfate drying, compound shown in substantially pure formula VI is obtained after concentrating under reduced pressure, yield 79%.
Claims (11)
1. a new preparation process for Oseltamivir intermediate, it comprises the following steps:
(1) by the compound dissolution shown in structural formula II in alcoholic solvent, acid adding By Hydrolysis At Room Temperature obtains compound shown in structural formula III:
(2) compound shown in structural formula III is dissolved in solvent, Jiang Wen Zhi ?20 ?5 DEG C, add Vinyl chloroformate, organic amine reaction, more at room temperature add azanol reagent react, obtain compound shown in structural formula IV:
(3) be dissolved in solvent by compound shown in structural formula IV, add acylating reagent, room temperature reaction prepares compound shown in structural formula V:
(4) by compound dissolution shown in structural formula V in tetrahydrofuran (THF), add organic amine and water, after heating reflux reaction, in system, add acetic anhydride, continue to be obtained by reacting compound shown in structural formula VI:
2. synthetic method according to claim 1, step (1) described alcoholic solvent is methyl alcohol, ethanol, Virahol, described acid be hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid one or more.
3. synthetic method according to claim 1, step (2) described solvent is selected from: methylene dichloride, chloroform, tetrahydrofuran (THF), methyl tertiary butyl ether, acetone, toluene, described azanol reagent is azanol, the aqueous solution of oxammonium hydrochloride or alcoholic solution, and described organic amine is triethylamine, DBU, DIPEA, DMAP, N-methylmorpholine; Wherein, described alcoholic solvent is selected from: methyl alcohol, ethanol, glycerine.
4. synthetic method according to claim 1; step (3) described solvent is selected from: methylene dichloride, chloroform, tetrahydrofuran (THF), methyl tertiary butyl ether, acetone, toluene; described acylating reagent is selected from: aceticanhydride, Acetyl Chloride 98Min., thionyl chloride, DNFB.
5. synthetic method according to claim 1, step (4) described organic amine is selected from: DBU, DIPEA, TEA.
6. synthetic method according to claim 1, it is characterized in that the reaction of step (2), step (3) and step (4) can without separation and purification, one pot is carried out.
7. the preparation method of compound shown in structural formula IV, comprise: compound shown in structural formula III is dissolved in solvent, Jiang Wen Zhi ?20 ?5 DEG C, add Vinyl chloroformate, organic amine reaction, react under adding azanol reagent room temperature again, obtain compound shown in structural formula IV:
8. according to claim 7, described solvent is selected from: methylene dichloride, chloroform, tetrahydrofuran (THF), methyl tertiary butyl ether, acetone, toluene; Described alcoholic solvent is selected from: methyl alcohol, ethanol, glycerine; Described azanol reagent is azanol, oxammonium hydrochloride, its aqueous solution or alcoholic solution.
9. the preparation method of compound shown in structural formula V, comprising: be dissolved in solvent by compound shown in structural formula IV, add acylating reagent, room temperature reaction prepares compound shown in structural formula V:
10. according to claim 9, described solvent is selected from: methylene dichloride, chloroform, tetrahydrofuran (THF), methyl tertiary butyl ether, acetone, toluene; Described acylating reagent is selected from: aceticanhydride, Acetyl Chloride 98Min., thionyl chloride, DNFB.
Compound shown in compound and formula (VI) shown in 11. formulas (IV):
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109627180A (en) * | 2018-12-29 | 2019-04-16 | 博瑞生物医药（苏州）股份有限公司 | The preparation method of Oseltamivir phosphate |
| CN113024489A (en) * | 2019-12-25 | 2021-06-25 | 上海奥博生物医药技术有限公司 | Preparation method of oseltamivir synthesis process impurity |
| CN113321581A (en) * | 2021-06-29 | 2021-08-31 | 浙江得乐康食品股份有限公司 | Shikimate compound, shikimate compound and preparation method thereof |
| 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 |
| 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 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109627180A (en) * | 2018-12-29 | 2019-04-16 | 博瑞生物医药（苏州）股份有限公司 | The preparation method of Oseltamivir phosphate |
| CN109627180B (en) * | 2018-12-29 | 2021-07-30 | 博瑞生物医药（苏州）股份有限公司 | Preparation method of oseltamivir phosphate |
| CN113024489A (en) * | 2019-12-25 | 2021-06-25 | 上海奥博生物医药技术有限公司 | Preparation method of oseltamivir synthesis process impurity |
| CN113321581A (en) * | 2021-06-29 | 2021-08-31 | 浙江得乐康食品股份有限公司 | Shikimate compound, shikimate compound and preparation method thereof |
| 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 |
| 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 |
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