CN101475573A - Anti-influenza medicament oseltamivir phosphate intermediate, synthesizing method and use thereof - Google Patents
Anti-influenza medicament oseltamivir phosphate intermediate, synthesizing method and use thereof Download PDFInfo
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Abstract
The invention relates to Tamiflu intermediates of the following structural formula, and methods for synthesizing the same and the uses of the same. The intermediates can be used for synthesizing Tamiflu drugs more economically with simpler operation.
Description
Technical field
The present invention relates to important intermediate, the preparation method and use of Tamiflu, adopting cheap pyrroles is starting raw material, and entire operation is simple more, safety.
Background technology
In the flu outbreak phase, oral administration prevention and treatment influenza are most convenient and economic method.Relenza is oral invalid, and bioavailability is low, cost an arm and a leg, this just impel people attempt to seek oral effectively, can be at the efficient influenza virus NA inhibitor of gastrointestinal absorption.(a.J.Am.Chem.Soc., 1997,119:681-690 such as Kim in 1997; B.J.Med.Chem., 1998,41,2451-2460) by analysis to sialic acid and NA mixture transition state structures, think if adopt six-membered carbon ring to replace the dihydropyrane ring can increase the firm degree of female ring, the optimum configuration of may easier acquisition strong effectively resisiting influenza virus and good drug effect, and synthesized a series of full carbon six-ring influenza virus NA inhibitor.This idea has finally caused the invention of oral new drug Tamiflu:
Tamiflu-pro-drug Tamiflu.
Tamiflu (be Oseltamivir, IC GS-4071)
50Be lnmol/L (H1N1), its ethyl ester GS-4104 shows oral effective in experimentation on animals, the process clinical study was named in 1999 is Oseltamivir, and as first orally active influenza virus NA inhibitor in Switzerland's Initial Public Offering, be used for prevention and treatment A type and Type B influenza.Tamiflu is the ethyl ester type prodrug of GS-4071, can block the cracking of influenza virus NA to the sialic acid residues on virus infected cell surface, thereby suppresses the release of newborn virion from host cell.Tamiflu has very high Orally active, and generates active GS-4071 through the metabolism of liver esterase in the body, and produces the curative effect that suppresses influenza virus NA.
At present, Tamiflu is produced by Roche company research and development, all is to be starting raw material with the compound that contains six-membered carbon ring, transforms the semi-synthetic that obtains needed chiral centre and configuration and finish through multistep.1997, (a.J.Am.Chem.Soc., 1997,119:681-690 such as Kim; B.J.Med.Chem., 1998,41,2451-2460) when designing and synthesizing Tamiflu, adopting (-)-shikimic acid (shikimic acid) is starting raw material, obtains Tamiflu through route as follows:
In this route, adopted NaN several times
3Be the nucleophilic reaction of reagent, because the explosion hazard that reagent and intermediate exist has brought danger to large-scale commercial production.
1998, Rohloff etc. (J.Org.Chem., 1998,63:4545-4550) adopting comparatively cheap (-)-quininic acid [(-)-quinic acid] is starting raw material, the route map shown in the process has synthesized Tamiflu:
This method can be synthesized the Tamiflu product of kilogram levels.But similar with the route of kim, this route has used NaN same twice
3As reagent.
The Federspiel of Roche company in 1999 etc. (Org.Process Res.Dev., 1999,3:266-274) reported the process modification of some committed steps of suitability for industrialized production Tamiflu.Subsequently, calendar year 2001 Karpf etc. (J.Org.Chem., 2001,66:2044-2051) on the basis of forefathers research, from epoxy compounds A at MgBr
2With allyl amine regioselectivity open loop oxygen, the back utilizes the allyl amine selectivity to open the reaction of azepine triatomic ring again down in OEt catalysis, and the allyl group protection of removing on the nitrogen-atoms by the catalytic reaction of Pd-C at last obtains Tamiflu, and route is as follows:
This route adopts allyl amine to replace NaN for the first time
3Introduce nitrogen-atoms, thus the explosion risk in having avoided producing.
2004, and the Harrington of Roche company etc. (Org.Process Res.Dev., 2004,8:86-91) reported the second industry synthetic route of Tamiflu.This group is still from epoxy compounds A, at MgCl
2Catalysis is protected C with methanesulfonate ester then down with big sterically hindered tert-butylamine regioselectivity open loop oxygen
4Form ethylenimine immediately behind the hydroxyl of-position, with diallyl amine regioselectivity open loop and acetylize, remove protection at last and must arrive Tamiflu under the acid catalysis condition, synthetic route is as follows:
Though the latter has carried out the route improvement, adopted new nitrogenous reagent on price than NaN
3Expensive a lot, and to remove protecting group at last be to use precious metal such as Pd, so production cost raises up.Secondly originate from China because Tamiflu is produced used shikimic acid raw material, the room for promotion of output is little; Today, the Tamiflu throughput of Roche seemed unable to do what one wishes owing to sharply rising for the demand of Tamiflu in bird flu outburst various countries.Therefore, the route of a new tamiflu synthesis of exploitation is necessary that very the raw material that need break away from the one hand for shikimic acid relies on, and must avoid NaN in addition
3Use etc. explosive chemical reagent (or triazo-compound intermediate).
Corey had proposed a new synthetic route (J.Am.Chem.Soc. in 2006,2006,128,6310-6311), at first utilize Asymmetric Diels-Alder Reaction to make up six-membered carbon ring efficiently, aminolysis, iodo make up the chirality lactan, made up cyclohexadiene by twice elimination again, and formed required α, the beta-unsaturated esters of Tamiflu, two steps made up the ternary nitrogen heterocyclic then, finished the synthetic of Tamiflu by amylalcohol open loop, acidifying at last, synthetic route is as follows:
It is raw material that this route adopts cheap small molecules, greatly reduces the synthetic cost, and has also avoided the use sodiumazide in the whole synthetic route, makes the entire operation process safer.
The people such as Jim-Min Fang in Taiwan in 2007 are chiral source (J.Am.Chem.Soc. with the D-wood sugar, 2007,129,11892-11893), at first hydrogenation of six carbocyclic carboxylicesters 8a and 8b have been made up by the Horner-Wadsworth-Emmons reaction, transform by brief several steps and realized the synthetic of Tamiflu, synthetic route is as follows:
This synthetic method author has attempted having changed carboxylicesters and amino into phosphoric acid ester and guanidine radicals substituting group respectively, the derivative 13b that has synthesized Tamiflu, active testing shows that 13b has higher inhibition activity to influenza virus NA, has expanded the compound scope of NA inhibitor so again.
People such as Nina Kann utilized the cyclohexadiene carboxylicesters to form iron carbonyl mixture (Chem.Commun. in 2007,2007,3183-3185), further form allyl cation, make up the amino-carbon chiral centre, again selective epoxidation, nitrine open loop oxygen compound, make up the ternary nitrogen heterocyclic, finished Corey important intermediate synthetic in the Tamiflu synthetic route smoothly, for the synthetic work of Tamiflu is opened up a new route again.
People such as Trost were starting raw material (Angew.Chem.Int.Ed. with the tetrahydrobenzene lactone in 2008; 2008,47,3759-3761); utilizing the catalysis of chirality palladium to open lactone changes; highly selective obtained open-loop products, make up alpha, beta-unsaturated esters; utilize the rhodium ligand catalysis to make up the ternary nitrogen heterocyclic again; the amylalcohol open loop, at last through the conversion of protecting group with remove, finished the synthetic of Tamiflu:
The important intermediate of the more high efficiency synthetic method tamiflu synthesis of people's expectation so that whole synthetic route more economically, is operated simpler.
Summary of the invention
The important intermediate that the purpose of this invention is to provide a kind of Tamiflu.
Purpose of the present invention also provides a kind of synthetic method of important intermediate pin of above-mentioned Tamiflu.
Another object of the present invention provides a kind of purposes of important intermediate of above-mentioned Tamiflu, promptly can be more economically, and operation more simply is used for the tamiflu synthesis medicine.
To the Tamiflu constructional feature, group of the present invention has proposed a kind of important intermediate of new Tamiflu, has the compound of following structural formula:
Wherein, R
1=C
2H
5, OC
2H
5,
Or OH; R
2=H; R
3=H; Perhaps
Or
The Boc=tertbutyloxycarbonyl.
Tamiflu intermediate of the present invention especially recommends to have following structural formula:
Wherein, the Boc=tertbutyloxycarbonyl,
Method of the present invention adopts simple small molecules pyrroles for starting raw material, uses modern more vitochemical high efficiency synthetic methods, and the important intermediate of having synthesized Tamiflu, whole synthetic route operates simplyr more economically, and specifically route is as follows:
Compound 1 is to be that raw material obtains by the Diels-Alder prepared in reaction with pyrroles, people (Weeresakare, G.-M. such as Xu in 2002; Xu, Q.; Rainier, J.-D.Tetrahedron Lett.2002,43,8913-8915.) report had been arranged; Compound 1 sodium borohydride reduction by 2 times of amounts in organic solvent, between-10 ℃-25 ℃ reduced 30 minutes, had realized the selective reduction of alkene bromine, obtained compound
With
Realized the selective reduction of alkene bromine, based on compound 1b.And reduzate Rainier in 2006 reported (Org.Lett.2006,8,459-462.), but substrate and synthetic method and the present invention are all inequality; Compound 1b obtains compound 2 by dihydroxylation reaction, and specifically compound 1b at room temperature stirs with the perosmic anhydride of the N-methylmorpholine oxide compound of 1.5 times of amounts and catalytic amount in organic solvent and obtained compound 2 in 9 hours; Compound 2 obtains compound 3 after the protection of ketone fork, alkaline condition is opened bridged ring, successfully obtaining compound 4 (is target molecule parent nucleus-contain α, the six-membered carbon ring of beta-unsaturated esters), and introduced the required amino of target molecule simultaneously, it also is one of committed step of this synthetic route that alkaline condition is opened bridged ring; The attention of value be the mixture of compound 1b and compound 1a and 1b by dihydroxylation reaction, ketone fork protection glycol, alkaline condition is opened bridged ring also can obtain compound 4 smoothly, this has also improved utilization ratio of raw materials in the inventive method; The present invention splits employed alkali of one step of bridged ring and screens, find hexamethl disilamine base lithium, hexamethl disilamine base sodium, trimethyl carbinol lithium, diisobutyl Lithamide, potassium tert.-butoxides etc. all can be realized the open loop purpose, and the amount of alkali 1eq-5eq all can, alkali number is big more, the reaction times can shorten thereupon, temperature of reaction is controlled at-78 ℃～5 ℃, uses different alkali that temperature of reaction is also had certain influence; Next compound 4 being carried out chemistry splits, at first compound 4 is obtained compound 5 through saponification reaction, again with compound 5 and the condensation of chirality prothetic group, split mechanism by thermodynamics and successfully obtained a pair of diastereomeric compound 6a and 6b, compound 6b is the configuration that needs of the present invention just, and what subsequently compound 6a and compound 6b are removed that prothetic group can high yield obtains a pair of enantiomer compound 4a and compound 4b; Though adopt prothetic group can the high isomer of high yield excessive obtain required isomer, but because the polarity of two enantiomers is very similar, a large amount of preparations can cause the difficulty of separating, consulting document finds, Nagao etc. once reacted from alpha-alkyl-alpha-amino group malonic ester by enzymatic hydrolysis, had synthesized Serine (a.Tetrahedron:Asymmetry, 1997 of chirality alpha-substitution, 8,585; B.Tetrahedron:Asymmetry, 1997,8,3651), the present invention has also attempted such class lytic enzyme, uses and substrate of the present invention, found that, the hydrolysis rate of two kinds of configurations of substrate of the present invention exists evident difference, and wherein a kind of configuration selective hydrolysis becomes acid, utilize the high isomer of kinetic resolution mechanism excessive obtained required optically active compound; Resolved product compound 4b acidic conditions in alcohol removes the protection of ketone fork and obtains compound 8, obtain compound 9 with cyclic sulfite protection glycol again, the open loop of sodiumazide selectivity attack allylic, the important intermediate-compound 10 that has obtained the tamiflu synthesis molecule that successful solid is single-minded; Just can realize the synthetic of Tamiflu molecule, specific embodiments Corey J.Am.Chem.Soc., 2006 through the known conversion of several steps again with this intermediate, 128,6310-6311) and Nina Kann (Chem.Commun., 2007,3183-3185) report had been arranged.
Method of the present invention can further describe as follows: make respectively by following (1), (1)～(2), (1)～(3), the four kinds of steps in (1)～(4):
(1) compound
Do to stir under solvent and the tosic acid room temperature with organic ketone and obtain compound after 5～12 hours
Described
With the mol ratio of tosic acid be 1:0.05～0.2.
(2) in organic solvent,
With alkali mol ratio 1:0.1-5, obtain after 1～3 hour in reaction under-78～10 ℃
Described alkali is hexamethl disilamine base lithium, hexamethl disilamine base sodium, trimethyl carbinol lithium, diisobutyl Lithamide or potassium tert.-butoxide; The recommendation response temperature is-50～0 ℃.
(3) to step (2)
The raceme compound splits: in the organic solvent solvent,
With stirred 0.5～3 hour under the monovalence metal hydroxides room temperature, obtain compound
Described monovalence metal hydroxides is a lithium hydroxide.
(4) will
And under condensing agent [1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride] effect, stirred under the room temperature 1～3 hour, obtain
With
Described
With the mol ratio of condensing agent be 1:1～1.5:1～1.5; Perhaps
Two compounds obtaining of reaction in ethanol respectively again with wait mole to two times of molar weights
Stirred under the room temperature 10～24 hours, and obtained compound
With
Wherein, R
1, R
2, R
3With Boc as previously mentioned.
Tamiflu intermediate of the present invention not only can be used for the tamiflu synthesis medicine, and has successfully opened up the route of a new tamiflu synthesis important intermediate, makes the preparation of Tamiflu become more economically, operates more simple and efficient.
Embodiment
Following example helps to understand the present invention, but is not limited to content of the present invention.
Embodiment 1
(500mg 1.4mmol) is dissolved in the methyl-sulphoxide (7.25mL) compound 1, and cryosel is bathed and add sodium borohydride (110mg down in the methyl-sulphoxide system, 2.9mmol), remove cryostat, rise to room temperature naturally, careful ammonium chloride solution cancellation reaction, ethyl acetate extraction (20mL * 3), the salt washing organic phase of adding, anhydrous sodium sulfate drying, elimination sodium sulfate, decompression removes solvent, and column chromatography for separation gets pure product (285mg, 74%, 1a: 1b=2:1).Compound 1a:
1HNMR (300MHz, CDCl
3): δ 6.39 (bs, 1H), 6.19 (bs, 1H), 4.90 (bs, 1H), 4.68 (bs, 1H), 4.09 (m, 2H), 3.14 (bs, 1H), 2.17 (bs, 1H), 1.55 (bs, 1H), 1.42 (s, 9H), 1.24 (t, J=7.1Hz, 3H).Compound 1b;
1HNMR (300MHz, CDCl
3): δ 6.36 (bs, 2H), 4.94 (bs, 1H), 4.72 (bs, 1H), 4.18 (q, J=7.3Hz, 2H), 2.39-2.31 (m, 2H), 1.46 (bs, 1H), 1.40 (s, 9H), 1.30 (t, J=7.1Hz, 3H).
Embodiment 2
Compound 1a (100mg 0.37mmol) is dissolved in the trimethyl carbinol (3.12mL), add respectively under the room temperature N-oxidation methyl morpholine (66mg, 0.56mmol), perosmic anhydride (0.2mL, 2g/100mL in H
2O 0.016mmol) and distilled water (0.62mmol), stirred 9 hours under the room temperature, system adds sodium sulfite solution 5mL and stirs after 40 minutes, ethyl acetate extraction (10mL * 5), organic phase is washed once with sodium chloride solution, anhydrous sodium sulfate drying, filter, concentrate petrol ether/ethyl acetate=2:1, column chromatography, assign to compound 2 (107mg, 96%). compound 2:
1HNMR (300MHz, CDCl
3): δ 4.32-4.10 (m, 4H), 3.89-3.88 (m, 2H), 3.78 (br, 1H), 2.97-2.90 (m, 1H), 1.98-1.88 (m, 1H), 1.80-1.74 (m, 1H), 1.46 (s, 9H), 1.29 (t, J=7.2Hz, 3H);
13CNMR (100MHz, CDCl
3): δ 172.61,156.67, and 80.77,73.59,70.76,64.64,63.73,61.11,42.75,28.06,27.63,14.07; FT-IR (fim): 3438,2979,2934,1732,1705,1369,1194,1062,900cm
-1ESI-MS (m/z): 324.1 ([M+Na]
+); ESI-HRMS (m/z): calculated value (Calcd for) C
14H
23NO
6([M+Na]
+): 324.1418, measured value (Found): 324.1430.
Embodiment 3
(432mg 1.44mmol) is dissolved in the propione (4.6mL) compound 2, adds the tosic acid (36mg that contains a crystal water under the room temperature, 0.19mmol), stir 12h under the room temperature, add the sodium hydrogen carbonate solution cancellation, ethyl acetate extraction (10mL * 3), organic phase is washed once with sodium chloride solution, and anhydrous sodium sulfate drying filters, concentrate, petrol ether/ethyl acetate=10:1 column chromatography is assigned to compound 3 (501mg, 94%). compound 3:
1HNMR (300MHz, CDCl
3): δ 4.50-4.15 (m, 6H), 2.95 (br, 1H), 1.93 (br, 1H), 1.72-1.47 (m, 5H), 1.45 (s, 9H), 1.29 (t, J=7.0Hz, 3H), 0.91 (t,, J=7.5Hz, 3H), 0.85 (t, J=7,4Hz, 3H);
13CNMR (100MHz, CDCl
3): δ 171.44,154.09, and 114.67,81.33,79.76,78.80,60.97,59.79,58.75,42.47,28.41,28.16,27.99,26.53,14.02,8.51,7.52; FT-IR (fim): 2974,2937,2880,1729,1731,1365,1169cm
-1ESI-MS (m/z): 392.1 ([M+Na]
+); ESI-HRMS (m/z): Calcd for C
19H
31NO
6([M+Na]
+): 392.2044, Found:392.2049.
Embodiment 4
Hexamethl disilamine base lithium (1.74mL under-78 ℃ of argon shields; 1M in toluene; 1.74mmol); add in the tetrahydrofuran (THF) (10mL) of anhydrous and oxygen-free, and compound 3 (321mg, tetrahydrofuran (THF) 0.87mmol) (7mL) drips of solution adds in the above-mentioned solution;-78 ℃ were stirred 2 hours down; naturally rise to zero degrees celsius, restir is 2 hours under the ice bath, adds shrend and goes out; ethyl acetate extraction (10mL * 3); organic phase is washed once with sodium chloride solution, and anhydrous sodium sulfate drying filters; concentrate; petrol ether/ethyl acetate=15:1 column chromatography is assigned to compound (±)-4 (257mg, 80%). compound (±)-4:
1HNMR (300MHz, CDCl
3): δ 6.73 (t, J=3.1Hz, 1H), 5.03 (d, J=9.4Hz, 1H), 4.77-4.74 (m, 1H), 4.37-4.35 (m, 1H), 4.21 (q, J=7.2Hz, 2H), 3.97-3.89 (m, 1H), 2.69 (dd, J=5.1,6.5Hz, 1H), 2.23-2.12 (m, 1H), 1.64 (q, J=7.4Hz, 2H), 1.56 (q, J=7.4Hz, 2H), 1.47 (s, 9H), 1.30 (t, J=7.1Hz, 3H), 0.91 (t, J=7.5Hz, 3H), 0.81 (t, J=7.5Hz, 3H);
13CNMR (100MHz, CDCl
3): δ 166.24,155.45, and 134.77,130.21,113.56,79.70,74.67,72.97,60.90,48.09,30.11,29.62,28.36,25.42,14.15,8.39,7.94; FT-IR (fim): 3454,3360,2974,2937,1715,1506,1365,1242,1167,1068,1014,925,734cm
-1ESI-MS (m/z): 392.1 ([M+Na]
+); ESI-HRMS (m/z): Calcd for C
19H
31NO
6([M+Na]
+): 392.2044, Found:392.2058.
Embodiment 5
(160mg 0.43mmol) is dissolved in the tetrahydrofuran (THF) (4.3mL) compound (±)-4, adds entry (1.3mL), 0 ℃ of adding contains the lithium hydroxide of a crystal water, and (72mg 1.72mmol), is stirred to the system raw material and disappears under the room temperature, 0 ℃ adds the 1N hydrochloric acid soln to system and regulates pH=2-3, ethyl acetate dilution, saturated common salt water washing, anhydrous sodium sulfate drying, filter, concentrate petrol ether/ethyl acetate=2:1 column chromatography, obtain compound (±)-5 (134mg, 98%).
1HNMR (300MHz, CDCl
3): δ 9.34 (br, 1H), 6.85 (s, 1H), 5.10 (d, J=9.0Hz, 1H), 4.78 (s, 1H), 4.37 (d, J=4.3Hz, 1H), 3.95-3.93 (m, 1H), 2.69 (dd, J=5.5,16.7Hz, 1H), 2.21-2.11 (m, 1H), 1.68-1.52 (m, 4H), 1.47 (s, 9H), 0.91 (t, J=7.3Hz, 3H), 0.81 (t, J=7.3Hz, 3H);
13CNMR (100MHz, CDCl
3): δ 170.7,155.3, and 136.9,129.5,113.7,80.0,74.6,72.9,48.0,30.1,29.6,28.3,25.1,8.4,7.9; FT-IR (fim): 3356,2980,2941,1694,1535,1368,1172,1068,928,686cm
-1ESI-MS (m/z): 364.1 ([M+Na]
+); ESI-HRMS (m/z): Calcd for C
17H
27NO
6([M+Na
+): 364.17306.Found:364.17393.
Embodiment 6
Under the room temperature to compound 5 (125mg, 0.37mmol) methylene dichloride (1.9mL) solution in add prothetic group (143mg, 0.74mmol), EDCI (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride) (142mg, 0.74mmol), DMAP (N, the N-4-Dimethylamino pyridine) (19mg, 0.16mmol), stirring 3 hours under the room temperature, system adds the ethyl acetate dilution, washing, saturated common salt washing, anhydrous sodium sulfate drying filters drying, petroleum ether/ethyl ether=2: 1 column chromatographies, get compound 6a (92mg), 6b (92mg), total recovery 96%.Compound 6a:[α]
D 20=-23.8 ° of (c1.03, CHCl
3);
1HNMR (300MHz, CDCl
3): δ 7.36-7.17 (m, 5H), 6.21 (s, 1H), 5.04 (d, J=9.3Hz, 1H), 4.87-4.78 (m, 2H), 4.46-4.29 (m, 3H), and 4.18-4.02 (m, 1H), 3.36 (d, J=10.5Hz, 1H), and 2.85-2.77 (m, 1H), 2.49 (d, J=7.3Hz, 2H), 1.69-1.62 (m, 4H), 1.47 (s, 9H), 0.94-0.85 (m, 6H);
13CNMR (100MHz, CDCl
3): δ 186.2,170.6, and 154.9,134.7,133.9,132.8,129.2,129.0,128.9,127.5,113.6,79.6,74.7,73.0,71.5,60.0,47.8,36.8,30.2,29.6,29.4,28.3,26.4,8.3,8.1; FT-IR (fim): 3452,3333,2925,1699,1498,1367,1240,1170,924cm
-1ESI-MS (m/z): 539.2 ([M+Na]
+); ESI-HRMS (m/z): Calcd for C
27H
36N
2O
6S ([M+Na]
+): 539.21863, Found:539.21926; Compound 6b:[α]
D 20=-77.8 ° (c 0.87, CHCl
3);
1HNMR (300MHz, CDCl
3): δ 7.36-7.19 (m, 5H), 6.07 (s, 1H), 5.06 (d, J=9.0Hz, 1H), 4.81-4.74 (m, 2H), 4.46-4.32 (m, 3H), and 4.18-4.08 (m, 1H), 3.38 (d, J=13.3Hz, 1H), 2.85-2.77 (m, 1H), 2.61-2.39 (m, 2H), 1.67-1.65 (m, 4H), 1.47 (s, 9H), 0.99-0.83 (m, 6H);
13CNMR (100MHz, CDCl
3): δ 185.6,170.3, and 155.0,134.9,133.8,130.9,129.3,129.0,127.4,113.7,79.6,74.7,72.9,71.4,60.3,47.9,37.1,30.3,29.4,28.3,26.6,8.3,8.2; FT-IR (fim): 3452,3333,2925,1699,1498,1367,1240,1170,924cm
-1ESI-MS (m/z): 539.2 ([M+Na]
+); ESI-HRMS (m/z): Calcd for C
27H
36N
2O
6S ([M+Na]
+): 539.21863, Found:539.21798;
Embodiment 7
0 ℃ to compound (-)-6b (83mg adds DMAP (N, N-4-Dimethylamino pyridine) (20mg in methylene dichloride 0.16mmol) (1.9mL) solution, 0.16mmol), dehydrated alcohol (28uL, 0.48mmol), stirring at room 24 hours, the ethyl acetate dilution, washing, saturated common salt washing, anhydrous sodium sulfate drying, filter, concentrate petroleum ether/ethyl ether=15:1 column chromatography, get compound (+)-4 (43mg, 73%); [α]
D 20=+24.3 ° of (c1.08, CHCl
3);
1HNMR (300MHz, CDCl
3): δ 6.73 (t, J=3.1Hz, 1H), 5.03 (d, J=9.4Hz, 1H), 4.77-4.74 (m, 1H), 4.37-4.35 (m, 1H), 4.21 (q, J=7.2Hz, 2H), 3.97-3.89 (m, 1H), 2.69 (dd, J=5.1,6.5Hz, 1H), 2.23-2.12 (m, 1H), 1.64 (q, J=7.4Hz, 2H), 1.56 (q, J=7.4Hz, 2H), 1.47 (s, 9H), 1.30 (t, J=7.1Hz, 3H), 0.91 (t, J=7.5Hz, 3H), 0.81 (t, J=7.5Hz, 3H);
13CNMR (100MHz, CDCl
3): δ 166.24,155.45, and 134.77,130.21,113.56,79.70,74.67,72.97,60.90,48.09,30.11,29.62,28.36,25.42,14.15,8.39,7.94; FT-IR (fim): 3454,3360,2974,2937,1715,1506,1365,1242,1167,1068,1014,925,734cm
-1ESI-MS (m/z): 392.1 ([M+Na]
+); ESI-HRMS (m/z): Calcd forC
19H
31NO
6([M+Na]
+): 392.2044, Found:392.2058.
Embodiment 8
(142mg 0.38mmol) is dissolved in the methyl alcohol (12mL) compound 4, adds tosic acid (15mg) under the room temperature, after the stirring at room 12 hours, system adds the sodium hydrogen carbonate solution cancellation, ethyl acetate extraction (10mL * 3), and organic phase washes with water, sodium chloride solution is washed, anhydrous sodium sulfate drying, filter, concentrate petrol ether/ethyl acetate=2:1 column chromatography, assign to compound (±)-8 (92mg, 80%); Compound 5:
1HNMR (300MHz, CDCl
3): δ 6.72 (s, 1H), 5.34 (d, J=7.5Hz, 1H), 4.43 (s, 1H), 4.21 (q, J=7.2Hz, 2H), 4.30 (s, 1H), 3.83 (br, 1H), 3.50 (br, 2H), 2.59 (dd, J=5.4,7.9Hz, 1H), and 2.36-2.27 (m, 1H), 1.45 (s, 9H), 1.29 (t, J=7.3Hz, 3H);
13CNMR (100MHz, CDCl
3): δ 166.33,155.68, and 137.58,129.83,79.81,69.51,68.28,60.92,48.71,28.31,26.61,14.09; FT-IR (fim): 3390,2978,2931,1715,1519,1367,1249,1167,1017cm
-1ESI-MS (m/z): 324.1 ([M+Na]
+); ESI-HRMS (m/z): Calcd for C
14H
23NO
6([M+Na]
+): 324.1418.Found:324.1424.
Embodiment 9
(37mg 0.10mmol) is dissolved in the methyl alcohol (3.3mL) compound (+)-4, adds tosic acid (4mg) under the room temperature, after the stirring at room 12 hours, system adds the sodium hydrogen carbonate solution cancellation, ethyl acetate extraction (10mL * 3), and organic phase washes with water, sodium chloride solution is washed, anhydrous sodium sulfate drying, filter, concentrate petrol ether/ethyl acetate=2:1 column chromatography, assign to compound (-)-8 (24mg, 80%); [α]
D 20=-35.7 ° of (c0.97, CHCl
3);
1HNMR (300MHz, CDCl
3): δ 6.72 (s, 1H), 5.34 (d, J=7.5Hz, 1H), 4.43 (s, 1H), 4.21 (q, J=7.2Hz, 2H), 4.30 (s, 1H), 3.83 (br, 1H), 3.50 (br, 2H), 2.59 (dd, J=5.4,7.9Hz, 1H), 2.36-2.27 (m, 1H), 1.45 (s, 9H), 1.29 (t,, J=7.3Hz, 3H);
13CNMR (100MHz, CDCl
3): δ 166.33,155.68, and 137.58,129.83,79.81,69.51,68.28,60.92,48.71,28.31,26.61,14.09; FT-IR (fim): 3390,2978,2931,1715,1519,1367,1249,1167,1017cm
-1ESI-MS (m/z): 324.1 ([M+Na]
+); ESI-HRMS (m/z): Calcd forC
14H
23NO
6([M+Na]
+): 324.1418, Found:324.1424.
Embodiment 10
(70mg 0.23mmol) is dissolved in the 1.2mL tetrahydrofuran (THF) compound (±)-8 under the argon shield, and ice bath adds triethylamine (128uL down; 0.92mmol) and thionyl chloride (50uL, 0.69mmol), stirring is 3 hours under the recovery room temperature; add the dilution of 20mL ethyl acetate, organic phase washing (5mL * 2), sodium chloride solution is washed once; anhydrous sodium sulfate drying filters, and concentrates; petrol ether/ethyl acetate=4:1 column chromatography; assign to compound (±)-9 (80mg, 100%)
1HNMR shows that product is a pair of non-corresponding isomer, directly casts the step reaction.
Embodiment 11
(20mg 0.066mmol) is dissolved in the tetrahydrofuran (THF) (0.33mL) compound (±)-8 under the argon shield, and ice bath adds triethylamine (37uL down; 0.27mmol) and thionyl chloride (15uL, 0.20mmol), stirring is 3 hours under the recovery room temperature; add the dilution of 10mL ethyl acetate, organic phase washing (5mL * 2), sodium chloride solution is washed once; anhydrous sodium sulfate drying filters, and concentrates; petrol ether/ethyl acetate=4:1 column chromatography; assign to compound 9 (22mg, 96%)
1HNMR shows that product is a pair of non-corresponding isomer, directly casts the step reaction.
Embodiment 12
(80mg 0.23mmol) is dissolved in N to compound (±)-9 under the room temperature, in the dinethylformamide (2.3mL), add under the room temperature sodiumazide (75mg, 1.15mmol), stirring at room 12 hours, add the dilution of 20mL ethyl acetate, the organic phase ammonium chloride solution is washed (5mL * 2), washing (5mL * 2), sodium chloride solution is washed once, and anhydrous sodium sulfate drying filters, concentrate, petrol ether/ethyl acetate=4:1 column chromatography is assigned to compound (±)-10 (71mg, 95%).
1HNMR (300MHz, CDCl
3): δ 6.76 (s, 1H), 4.85 (br, 1H), 4.22 (q, J=7.1,13.7Hz, 2H), 4.13 (d, J=2.0Hz, 1H), 4.01 (s, 1H), 3.91 (d, J=5.5Hz, 1H), 2.75-2.67 (m, 1H), 2.51-2.45 (m, 1H), 1.46 (s, 9H), 1.31 (t, J=7.1Hz, 3H);
13CNMR (100MHz, CDCl
3): δ 165.6,156.9, and 132.5,131.5,80.6,71.9,61.2,60.8,48.6,28.5,28.2,14.1; FT-IR (fim): 3369,2979,2928,1718,1514,1367,1245,1168,1095,744cm
-1ESI-MS (m/z): 349.1 ([M+Na]
+); ESI-HRMS (m/z): Calcd for C
14H
22N
4O
5([M+Na]
+): 349.14824, Found:349.14790.
Embodiment 13
(22mg 0.063mmol) is dissolved in N to compound 9 under the room temperature, in the dinethylformamide (0.63mL), add under the room temperature sodiumazide (20mg, 0.30mmol), stirring at room 12 hours, add the dilution of 10mL ethyl acetate, the organic phase ammonium chloride solution is washed, washing, sodium chloride solution is washed once, and anhydrous sodium sulfate drying filters, concentrate, petrol ether/ethyl acetate=4:1 column chromatography is assigned to compound (+)-10 (15mg, 73%); [α]
D 20=+116.3 ° of (c1.0, CHCl
3);
1HNMR (300MHz, CDCl
3): δ 6.76 (s, 1H), 4.85 (br, 1H), 4.22 (q, J=7.1,13.7Hz, 2H), 4.13 (d, J=2.0Hz, 1H), 4.01 (s, 1H), 3.91 (d, J=5.5Hz, 1H), 2.75-2.67 (m, 1H), 2.51-2.45 (m, 1H), 1.46 (s, 9H), 1.31 (t, J=7.1Hz, 3H);
13CNMR (100MHz, CDCl
3): δ 165.6,156.9, and 132.5,131.5,80.6,71.9,61.2,60.8,48.6,28.5,28.2,14.1; FT-IR (fim): 3369,2979,2928,1718,1514,1367,1245,1168,1095,744cm
-1ESI-MS (m/z): 349.1 ([M+Na]
+); ESI-HRMS (m/z): Calcd forC
14H
22N
4O
5([M+Na]
+): 349.14824, Found:349.14790.
Embodiment 14
0 ℃ to (±)-10 (43mg, add in methylene dichloride 0.13mmol) (1.3mL) solution triethylamine (54uL, 0.39mmol), methylsulfonyl chloride (20ul, 0.26mmol), 0 ℃ was stirred 30 minutes, added the ethyl acetate dilution, washing, the saturated common salt washing, anhydrous sodium sulfate drying filters, concentrate, petrol ether/ethyl acetate=4:1 column chromatography is got compound (±)-11 (50mg, 95%);
1HNMR (300MHz, CDCl
3): δ 6.83 (s, 1H), 4.90 (s, 2H), 4.40 (s, 1H), 4.25 (q, J=7.0Hz, 2H), 4.13-4.11 (m, 1H), 3.10 (s, 3H), 2.79 (dd, J=5.4,18.2Hz, 1H), 2.45-2.25 (m, 1H), 1.46 (s.9H), 1.33 (t, J=7.2Hz, 3H); ESI-MS (m/z): 427.1 ([M+Na]
+).
Embodiment 15
0 ℃ to (+)-10 (15mg, add in methylene dichloride 0.046mmol) (0.46mL) solution triethylamine (19uL, 0.14mmol), methylsulfonyl chloride (7ul, 0.09mmol), 0 ℃ was stirred 30 minutes, added the ethyl acetate dilution, washing, the saturated common salt washing, anhydrous sodium sulfate drying filters, concentrate, petrol ether/ethyl acetate=4:1 column chromatography is got compound (+)-11 (18mg, 97%); [α]
D 20=+154.3 ° of (c0.8, CHCl
3);
1HNMR (300MHz, CDCl
3): δ 6.83 (s, 1H), 4.90 (s, 2H), 4.40 (s, 1H), 4.25 (q, J=7.0Hz, 2H), 4.13-4.11 (m, 1H), 3.10 (s, 3H), 2.79 (dd, J=5.4,18.2Hz, 1H), 2.45-2.25 (m, 1H), 1.46 (s.9H), 1.33 (t, J=7.2Hz, 3H); ESI-MS (m/z): 427.1 ([M+Na]
+).
Claims (6)
1. Tamiflu intermediate, its feature has following structural formula:
Or
Wherein, R
1=C
2H
5, OC
2H
5,
Or OH;
R
2=H; R
3=H; Perhaps
Or
The Boc=tertbutyloxycarbonyl.
2. as claim 1 Tamiflu intermediate, its feature has following structural formula:
Wherein, the Boc=tertbutyloxycarbonyl,
3. as institute's Tamiflu intermediates preparation in the claim 1, it is characterized in that making respectively with following (1), (1)～(2), (1)～(3), the four kinds of steps in (1)～(4):
(1) compound
Do to stir under solvent and the tosic acid room temperature with organic ketone and obtain compound after 5～12 hours
Described
With the mol ratio of tosic acid be 1:0.05～0.2.
(2) in organic solvent,
With alkali mol ratio 1:0.1-5, obtain after 1～3 hour in reaction under-78～10 ℃
Described alkali is hexamethl disilamine base lithium, hexamethl disilamine base sodium, trimethyl carbinol lithium, diisobutyl Lithamide or potassium tert.-butoxide;
(3) to step (2)
The raceme compound splits: in the organic solvent solvent,
With stirred 0.5～3 hour under the monovalence metal hydroxides room temperature, obtain compound
(4) will
And under condensing agent [1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride] effect, stirred under the room temperature 1～3 hour, obtain
With
Described
With the mol ratio of condensing agent be 1:1～1.5:1～1.5; Perhaps every mole
With
Two compounds that should obtain in ethanol respectively again with wait mole to two times of molar weights
Stirred under the room temperature 10～24 hours, and obtained compound
With
4. the synthetic method of the Tamiflu intermediate described in claim 3 is characterized in that the temperature of reaction described in the step (2) is-50～0 ℃.
5. the synthetic method of the Tamiflu intermediate described in claim 3 is characterized in that the monovalence metal hydroxides described in the step (3) is a lithium hydroxide.
6. the Tamiflu intermediate described in claim 1 is used to prepare the Tamiflu medicine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102464596A (en) * | 2010-11-10 | 2012-05-23 | 南开大学 | One-pot method for preparing crucial intermediate in oseltamivirphosphate synthesizing reaction |
| TWI548615B (en) * | 2011-03-08 | 2016-09-11 | 公益財團法人微生物化學研究會 | Compound, method for producing the same |
| 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 |
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| US6518048B2 (en) * | 2000-04-10 | 2003-02-11 | Hoffmann-La Roche Inc. | Stereo-specific synthesis of shimikic acid derivatives with improved efficiency |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102464596A (en) * | 2010-11-10 | 2012-05-23 | 南开大学 | One-pot method for preparing crucial intermediate in oseltamivirphosphate synthesizing reaction |
| TWI548615B (en) * | 2011-03-08 | 2016-09-11 | 公益財團法人微生物化學研究會 | Compound, method for producing the same |
| 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 |
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