CN1966485A - Method for synthesizing shikimic acid derivative - Google Patents

Abstract

The invention provides a synthesis method for new derivatives of shikimic acid using 1-cyclohexene 4-ethyl ketone as starting material, which has the skeleton structure of shikimic acid, through bromination, etherification, bromination, nitrosation, oximation, reduction, acetylation, and reduction to obtain raceme, and resolution into GS-4104 and (+) enantiomers. The invention also provides 10 new shikimic acid derivatives and synthetic methods.

Description

A kind of synthetic method of shikimic acid derivative

Invention field

The present invention relates to the organic medicinal chemistry field, in particular to a kind of synthetic method of new shikimic acid derivative.

Background technology

People such as Itzstein.M.von are at Nature, and 363 (6428): the Design Theory that discloses the sialidase inhibitor that influenza virus duplicates among the 418-423 (1993); Then in WO91/16320 and EP0593204A, disclose again and neuraminidase bonded compound, and claimed to have the interior resisting virus activity.

People such as Choung U.Kim are at J.Am.Chem.Soc.119, among the 681-690 (1997) and people such as JohnC.Rohloff at J.Org.Chem.63, neuraminidase inhibitor (GS-4104 is disclosed respectively among the 4545-4550 (1998), Oseltamivir) two kinds of synthetic methods: i.e. quinic acid method and thick grass acid system have outstanding innovative significance on medicinal career.

Wherein one of method is to be starting raw material with the quinic acid, be through 12 step chemical reactions, and to use expensive chemical reagent borine dimethyl thioether/trimethylammonium methylsulfonic acid trifluoromethyl estersil, and technology is numerous and diverse, and cost is higher.Two of method is a starting raw material with the shikimic acid, be through 16 step chemical reaction, and the explosive hazardous substance sodium azide of twice use, also exist complex operation, the defective that total recovery is lower; And shikimic acid is the extract of natural phant, and its resource is subjected to geography, weather effect bigger.

Goal of the invention

The present invention seeks to design and provide a kind of operational path and synthetic method of new shikimic acid derivative, this method should have raw material be easy to get, safe, technology succinct, cost is lower and total recovery than advantages such as height.

Summary of the invention

The present invention's design and the 1-tetrahydrobenzene-4-ketone ethyl formate that provides employing to have the shikimic acid skeleton structure are starting raw material; through bromo, etherificate, bromo, nitrosification, one-tenth oxime, reduction; acetylize, restore, through split the synthetic method of one of GS-4104 and its enantiomorph (+) 8.

The invention provides ten new compounds, and design its synthetic route and technology, known compound (-) 8, i.e. GS-4104 have been synthesized in checking.

One of synthetic route of the present invention:

Two of synthetic route of the present invention:

Starting raw material 1-tetrahydrobenzene-4-ketone ethyl formate is pressed Anestis L.L., J.Org.Chem. (27) 1438-1439 (1962) preparation.

Advantage of the present invention is: the present invention need not quinic acid or shikimic acid is a starting raw material, and is raw material with the 1-tetrahydrobenzene-4-ketone ethyl formate with shikimic acid skeleton structure.4,5 last two amino more easily preparations in reaction process, and need not to protect hydroxyl or carry out epoxidation, more need not costliness and hazardous chemical.Nine step overall yield of reaction 13.8% are for suitability for industrialized production provides an effective way.

The invention will be further described below by embodiment.It should be understood that the described preparation method of the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.Except as otherwise noted, the percentage ratio among the present invention is weight percentage.

Embodiment one

The preparation of compound 1: in the round-bottomed flask of reflux condensing tube is housed, put into the N-bromosuccinimide (NBS) of 33.6g (0.2mol) exsiccant 1-tetrahydrobenzene-4-ketone ethyl formate and 36g (0.21mol) 99.4%, with flask heating and stirring often on glycerol bath carefully.During heating, the NBS dissolving, it is light yellow that liquid shows.Heated 20 minutes, cooling removes by filter succinimide.Filtrate is used air distillation, steam unreacted 1-tetrahydrobenzene-4-ketone ethyl formate,, collect middle distillate residual high boiling liquid underpressure distillation.The output of compound 1 is 29.5g, yield 65.1%.

Embodiment two

The preparation of compound 2: in the three-necked bottle that reflux condensing tube and division box are housed, drop into 24.7g (0.1mol) compound 1 and cyclopentanol 50ml and potassium hydroxide 8.4g (0.15mol), add the toluene azeotropic that refluxes again and divide water.Produce until substantially anhydrous pearl, boil off toluene, add hydrochloric acid, transfer pH, use ethyl acetate extraction to neutral.Through aftertreatment, the output of compound 2 is 21.6g, yield 85.0%.

Embodiment three

The preparation of compound 3: with compound 2 is that raw material and NBS carry out bromo-reaction, and operating process is with embodiment one, and the output of compound 3 is 24.1g, yield 72.5%.

Embodiment four

The preparation of compound 4: in round-bottomed flask, drop into 33.3g (0.1mol) compound 3, be dissolved in the 50ml water, anhydrous sodium carbonate with the 6g porphyrize is neutralized to weakly alkaline, and 0 ℃ sodium nitrite solution (being made up of 7.5g Sodium Nitrite and 8ml water) is under agitation added in the above-mentioned solution.Round-bottomed flask is carefully heated, and the yellow before this back of liquid turns green in the bottle, is brown at last.Be warming up to 80 ℃, begin to have bubble to emerge, stop this moment heating, extract with ethyl acetate 50ml * 3, steam and remove organic solvent, get compound 4, output is 14.8g, yield 64.6%.

Embodiment five

The preparation of compound 5: get 22.9g (0.1mol) compound 4 and be dissolved in the 110ml 2mol/L sodium hydroxide solution, add the 6.2g oxammonium hydrochloride.Mixture was heated in water-bath 50 minutes, transfer to neutrality with Glacial acetic acid, compound 5 (being ketoxime) is separated out in the cooling bath cooling, gets 31.2g, yield 99.4%.

Embodiment six

The preparation of compound (±) 6: get compound 5 (ketoxime) 31.4g (0.1mol) and be dissolved in the 200ml Glacial acetic acid, controlled temperature is no more than 75 ℃, divides three times and adds zinc powder 30g, reacted again 30 minutes, and the elimination throw out, filtrate is no more than 60 ℃ of vacuum and boils off acetate.

Residue adds 80ml water, feeds H ₂S gas generates until no longer including white ZnS.Filter, remove the ZnS throw out, add hydrochloric acid and become white solid compound 6 hydrochloride 27.6g, yield 82.3%.

Embodiment seven

The preparation of compound (±) 7: get in compound 6 hydrochloride 33.6g (0.1mol) the adding 500ml water and make it dissolving; be heated to 50 ℃ and add aceticanhydride 40ml; add the solution that the 40g sodium-acetate is dissolved in 100ml water after stirring evenly immediately; high degree of agitation 30 minutes; the frozen water cooling; leach product, washing, dry compound 7 (acetylate) 28.5g, the yield 83.3% of getting.

Embodiment eight

The preparation of compound (±) 8 (racemic modification): get 34.2g (0.1mol) compound 7 and add Raney's nickel 5g, ethanol 100ml and hydrazine hydrate 50ml, normal pressure feeds H ₂, stirring 8 hours under the room temperature, the elimination catalyzer boils off solvent, uses ethyl alcohol recrystallization again, gets racemic modification (±) 8, output 28.1g, yield 90.0%.

Embodiment nine

The preparation of compound (+) 8 (dextrorotatory form): get 62.4g (0.2mol) racemic modification (±) 8, be dissolved in ethanol, add 1-(-)-tartrate 16.5g (0.11mol) salify.Crystallisation by cooling 24 hours, filter compound (+) 8 (-)-tartrate, water-soluble furnishing alkalescence is extracted with ethyl acetate 100ml * 3.Concentrating under reduced pressure gets crude product, gets compound (+) 8 through ethyl alcohol recrystallization, output 28.7g, yield 46.0%.

Embodiment ten

The preparation of compound (+) 6 and (-) 6: get 60.0g (0.2mol) racemic modification (±) 6 and be dissolved in ethanol, add 1-(-)-tartrate 16.5g (0.11mol) salify, crystallisation by cooling 24 hours, filter (+) 6 (-)-tartrate.It is water-soluble, and furnishing alkalescence is used ethyl acetate extraction, and concentrating under reduced pressure, recrystallization get (+) 6, output 27.5g, yield 45.8%; In the mother liquor behind above-mentioned elimination (+) 6 (-)-tartrate, add 16.5g (0.11mol) d-(+)-tartrate salify, operation in like manner obtains (-) 6, output 27.2g, yield 45.3%.

Checking example one

The preparation of compound (-) 8 (levo form): get filtrate after getting embodiment nine elimination compound (+) 8 (-)-tartrates, drop into d-(+)-tartrate 16.5g (0.11mol), make salify, crystallisation by cooling 24 hours, filter compound (-) 8d (+)-tartrate, water-soluble back alkalize, extract with ethyl acetate 100ml * 3, concentrating under reduced pressure gets crude product, adds 85% phosphoric acid salify, gets compound (-) 8 phosphoric acid salt through ethyl alcohol recrystallization, output 35.3g, yield 43.0%, mp:203-204 ℃, [α] _D-39.3 ° of (Cl, H ₂O), detect consistent through infrared spectra, mass spectrum, specific optical rotation and chiral column HPLC with the GS-4104 reference substance.

Checking example two

The preparation of compound (-) 8 (levo form): get (-) 6 compounds that embodiment ten obtains through acetylize (with reference to embodiment seven) and reduction (with reference to embodiment eight); obtain crude product, add 85% phosphoric acid salify, get compound (-) 8 phosphoric acid salt through ethyl alcohol recrystallization; mp:203-204 ℃, [α] _D-39.2 ° of (Cl, H ₂O), detect consistent through infrared spectra, mass spectrum, specific optical rotation and chiral column HPLC with the GS-4104 reference substance.

Claims (4)

1, a kind of is starting raw material with 1-tetrahydrobenzene-4-ketone ethyl formate, through bromo, etherificate, bromo, nitrosification, oximate, reduction, acetylize and restore racemic modification, then through split the synthetic method of enantiomorph (+) 8 of GS-4104 and it.

2, according to the process of claim 1 wherein that compound 1-8 and enantiomorph ten compounds such as (except that GS-4104) thereof all are new chemical entities and synthetic methods.

3, according to the method for claim 1-2, be starting raw material, after tartrate splits, obtain compound (-) 6 and (+) 6 with compound (±) 6.After acetylize, reduction, obtain the synthetic method of GS-4104 and its enantiomorph (+) 8 respectively.

4, according to the method for claim 1-3, the resolving agent of compound (±) 6 and (±) 8 is that having optically active is the organic acid of representative with d, l tartrate.