CN1939898B - Chiral synthesis of combined protein deacetylated enzyme inhibitor - Google Patents

Chiral synthesis of combined protein deacetylated enzyme inhibitor Download PDF

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CN1939898B
CN1939898B CN2005100301495A CN200510030149A CN1939898B CN 1939898 B CN1939898 B CN 1939898B CN 2005100301495 A CN2005100301495 A CN 2005100301495A CN 200510030149 A CN200510030149 A CN 200510030149A CN 1939898 B CN1939898 B CN 1939898B
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acid
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histone deacetylase
deacetylase inhibitor
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CN1939898A (en
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段文虎
张土磊
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Shanghai Institute of Materia Medica of CAS
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Abstract

Chiral synthesis of Trichostatin A has better intermediate stability and more product yield. It's simple and cheap.

Description

A kind of chirality total synthesis method of histone deacetylase inhibitor
Technical field
The present invention relates to the synthetic field of medicine, specifically relate to the new chirality total synthesis method of a kind of histone deacetylase inhibitor Trichostatin A.
Background technology
Trichostatin A separated the natural product that obtains by Japanese scientist Tsuji in 1976 from the kind of Streptomyces hygroscopicus, Tsuji finds that this natural product has antifungic action.1985, discovery Trichostatin A such as Yoshida and Morioka had differentiation-inducing action to kinds of tumor cells such as human leukemia, people's neck tumours, cause apoptosis of tumor cells.Nineteen ninety, Yoshida etc. have found that Trichostatin A is strong HDAC (Histidine deacetylase) inhibitor, and Trichostatin A can influence and transcribe and the interference cell cycle, suppress the increment of tumour cell.Simultaneously, Yoshida etc. find that also the Trichostatin A (natural Trichostatin A is the R configuration) of S configuration does not break up two and leads effect, illustrate that it is very necessary that the chirality of carrying out this natural product is synthesized.
1988, Mori (Tetrahedron 1988,44,6013-6020) wait reported unique up to now one piece about the complete synthesis route of Trichostatin A chirality.This route has not only adopted expensive chiral source 3-hydroxy-2-methyl methyl propionate and much more valuable reagent, and the intermediate poor stability, and experimental implementation is strict, and synthesis step is long, and total recovery neither very high (6.1%).
In recent years, a large amount of documents has carried out the research report to the multiple physiologically active of Trichostatin A, has shown the vital role of this natural product, so be necessary to develop a kind of succinct effectively practical synthetic route.
Summary of the invention
The object of the present invention is to provide the chirality total synthesis method of a kind of very promising antitumor natural product Trichostatin A.
It may further comprise the steps:
(1) with paranitrobenzaldehyde and propionic aldehyde and catalyst mix in solvent, room temperature reaction a few hours, obtain two diastereomeric compounds 2aWith 2b
Figure G200510030149520051019D000011
Wherein catalyzer is proline(Pro) or its following derivative, preferred proline(Pro):
Figure G200510030149520051019D000021
Catalyst levels is greater than 0.1 equivalent, preferred 0.2 equivalent;
The propionic aldehyde consumption is greater than 1.0 equivalents, preferred 2.0 equivalents;
The solvent that reacts used can be chloroform, methylene dichloride, tetracol phenixin, 1,2-ethylene dichloride, ether, tetrahydrofuran (THF), glycol dimethyl ether, diethylene glycol dimethyl ether, dioxane, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), hexamethylphosphoramide, methyl acetate, ethyl acetate, methyl alcohol, ethanol, acetonitrile etc. or their mixed solvent, preferred N, dinethylformamide and dimethyl sulfoxide (DMSO), more preferably N, dinethylformamide.
(2) compound 2aWith 2bUnder Louis acid catalysis, obtain compound with ortho ester 3aWith 3b
Figure G200510030149520051019D000022
The ortho ester that reacts used can be trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, tributyl orthoformate, orthoformic acid three benzyl esters, trimethyl orthoacetate, triethly orthoacetate, ortho-acetic acid three propyl ester, ortho-acetic acid tri-n-butyl, ortho-acetic acid three benzyl esters, former propionic acid trimethyl, triethyl orthopropionate, former propionic acid three propyl ester, former propionic acid tri-n-butyl or former propionic acid three benzyl esters etc., preferred trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, tributyl orthoformate, orthoformic acid three benzyl ester, more preferably trimethyl orthoformates;
The Lewis acid that reacts used can be tosic acid, camphorsulfonic acid, boron trifluoride diethyl etherate, titanium tetrachloride, tin tetrachloride, sulfuric acid, hydrochloric acid, nitric acid, iron trichloride, aluminum chloride, Nickel Chloride, cobalt dichloride, ammonium nitrate, ammonium chloride etc., preferred tosic acid and camphorsulfonic acid, more preferably tosic acid.
(3) compound 3aWith 3bRoom temperature reaction in solvent obtains compound with trialkylchlorosilane and a kind of alkali 4aWith 4bCompound 4aWith 4bCan separate fully by column chromatography, obtain required compound 4a
Figure G200510030149520051019D000031
The trialkylchlorosilane that reacts used can be TERT-BUTYL DIMETHYL CHLORO SILANE, tert-butyl diphenyl chlorosilane, chlorotriethyl silane, tri isopropyl chlorosilane etc., preferred TERT-BUTYL DIMETHYL CHLORO SILANE.
The alkali that reacts used can be imidazoles, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N, N dimethylamine base) pyridine, N, accelerine etc., preferred imidazoles and triethylamine, more preferably imidazoles.
(4) compound 4aObtain compound taking off under the acetal protective condition 5
Figure G200510030149520051019D000032
Taking off the acetal protective condition can be sulfuric acid/silica gel system, Iodotrimethylsilane/methylene dichloride system, trifluoroacetic acid/chloroform system, acetic acid/aqueous systems, tosic acid/acetone system, stannous chloride dihydrate/methylene dichloride system, methyl-sulphoxide/water/dioxane system, preferred tosic acid/acetone system.
(5) compound 5Obtain compound through wittig reaction or Horner-Emmons-Wittig reaction 6
The used Wittig reagent of Wittig reaction is following structure:
Figure G200510030149520051019D000034
The used alkyl phosphate of Horner-Emmons-Wittig reaction is following structure:
Figure G200510030149520051019D000041
R wherein 3Can be fatty alkyls such as methyl, ethyl, propyl group, butyl, also can be aromatic bases such as phenyl, naphthyl, can also be benzyl, allyl group etc., preferable methyl and ethyl, more preferably methyl.
(6) compound 6Be reduced to compound 7
Figure G200510030149520051019D000042
Reductive agent in the reaction can be diisobutyl aluminium hydride, red aluminium etc., preferred diisobutyl aluminium hydride.
(7) compound 7Be oxidized to compound 8
Figure G200510030149520051019D000043
Oxygenant in the reaction can be PCC, activated manganese dioxide, Dess-Martin reagent, Swern oxidizing condition and known in the art all can realize the oxidizing condition of this oxidation, preferred PCC and activated manganese dioxide, more preferably PCC.
(8) compound 8Obtain compound through wittig reaction or Horner-Emmons-Wittig reaction again 9
Figure G200510030149520051019D000044
The used Wittig reagent of Wittig reaction is following structure:
The used alkyl phosphate of Horner-Emmons-Wittig reaction is:
Figure G200510030149520051019D000052
R wherein 4Can be fatty alkyls such as identical or different methyl, ethyl, propyl group, butyl, also can be aromatic bases such as phenyl, naphthyl, can also be benzyl, allyl group etc., preferable methyl and ethyl;
(9) compound 9Remove the trialkyl silyl protection and obtain compound 10
The method that removes trialkyl silyl can be selected following reaction system for use: tetrabutyl ammonium fluoride/tetrahydrofuran (THF), hydrofluoric acid/acetonitrile, acetic acid/water/tetrahydrofuran (THF), triethylamine/hydrofluoric acid, hydrochloric acid/ethanol, iodine/methyl alcohol etc., preferred tetrabutyl ammonium fluoride/tetrahydrofuran (THF) and hydrofluoric acid/acetonitrile system, more preferably hydrofluoric acid/acetonitrile system.
(10) compound 10Reduction obtains compound 11
Figure G200510030149520051019D000054
Reductive condition can be selected following reaction system for use: hydrogen/Lindlar catalyzer, sodium disulfide/ethanol, tindichloride/ethanol, iron powder/acetic acid, tin/hydrochloric acid etc., preferred hydrogen/Lindlar catalyst system.
(11) by compound 11Obtain compound 12
Figure DEST_PATH_G200510030149501D00011
The condition of methylating can be selected following reaction system for use: formaldehyde/sodium triacetoxy borohydride, formaldehyde/sodium cyanoborohydride, methyl iodide/own nitrile/salt of wormwood, formaldehyde/formic acid etc., preferred formaldehyde/sodium triacetoxy borohydride system.
(12) compound 12With NH 2The OH reaction obtains compound 13
(13) compound 13Oxidized benzyl position hydroxyl obtains Trichostatin A.
Figure DEST_PATH_G200510030149501D00013
The oxygenant that reacts used can be Manganse Dioxide, DDQ, ceric ammonium nitrate, PCC, NBS etc., preferred DDQ.
The raw material that this method not only adopts cheaply is easy to get, and experimental implementation is simple, and intermediate stability is high, and total recovery (12.9%) also is much higher than existing route.
Embodiment:
Embodiment one: compound 2aWith 2bPreparation:
The 1.51g paranitrobenzaldehyde is dissolved among the 35mLDMF, adds the 230mgL-proline(Pro), add the 1.44mL propionic aldehyde then, stirring at room 7 hours, TLC follows the tracks of and reacts completely.Add 100mL water, ethyl acetate extraction three times merges organic layer, dried over mgso, and vacuum pump is drained solvent, is contained 2aWith 2bCrude product, directly drop into next step.
Compound 2aHydrogen spectrum:
1HNMR(300MHz，CDCl 3)：δ9.802(1H，d，J＝0.9Hz)，8.224(2H，d，J＝6.6Hz)，7.548(2H，d，J＝6.3Hz)，4.974(1H，d，J＝6.0Hz)，3.409(1H，br)，2.774(1H，m)，0.996(3H，d，J＝5.7Hz)。
Embodiment two: compound 3aWith 3bPreparation:
To contain 2aWith 2bCrude product add 30mL methyl alcohol, 3.00g trimethyl orthoformate and 380mg one hydration tosic acid, stirring at room 30 minutes.Add 10mL saturated sodium bicarbonate solution and 100mL water, ethyl acetate extraction three times merges organic layer, and dried over mgso is drained solvent, gets crude product.Obtain compound through the column chromatography purification 3aWith 3bCommon 2.26g ( 1The HNMR analytical proof 3a: 3b=11: 1), two step total recoverys 88.6%.
Compound 3aHydrogen spectrum:
1HNMR(300MHz，CDCl 3)：δ8.202(2H，d，J＝8.7Hz)，7.513(2H，d，J＝8.7Hz)，4.719(1H，d，J＝8.4Hz)，4.313(1H，d，J＝5.7Hz)，3.497(3H，s)，3.416(3H，s)，2.114(1H，m)，0.686(3H，d，J＝7.2Hz)；
Compound 3bHydrogen spectrum:
1HNMR(400MHz，CDCl 3)：δ8.179(2H，d，J＝8.8Hz)，7.497(2H，d，J＝8.8Hz)，5.217(1H，s)，4.302(1H，d，J＝4.4Hz)，3.503(3H，s)，3.463(3H，s)，2.045(1H，m)，0.790(3H，d，J＝7.2Hz)；
MS(EI)m/z(％)：256[M+H]，223(2.0)，152(10)，75(100)，72(67)；
Compound 3aWith 3bThe specific rotatory power of (11: 1) mixture:
[α] D 23-6.94°(c＝3.10，CHCl 3)。
Embodiment three: compound 4aWith 4bPreparation:
With 3.63g 4aWith 4bMixture and 4.28gTBSCl and 2.90g imidazoles be dissolved among the 25mLDMF stirring at room 20 hours.Add 80mL water, ethyl acetate extraction, organic layer are drained after with dried over mgso, are contained 4aWith 4bCrude product.Through column chromatography for separation 4aWith 4b, obtain compound 4a3.75g is faint yellow solid, productive rate 71.4% altogether.
1HNMR(300MHz，CDCl 3)：δ8.173(2H，d，J＝8.7Hz)，7.467(2H，d，J＝8.7Hz)，4.804(1H，d，J＝6.6Hz)，4.152(1H，d，J＝5.4Hz)，3.376(3H，s)，3.365(3H，s)，0.883(9H，s)，0.689(3H，d，J＝6.9Hz)，0.053(3H，s)，-0.236(3H，s)；
MS(EI)m/z(％)：369[M +]，266(35)，240(100)，89(11)；
[α] D 22+35.3°(c＝2.20，CHCl 3)。
Mp?35-36℃。
Embodiment four: compound 5Preparation:
3.85g 4aBe dissolved in 180mL2%TsOHH 2In the O/ acetone (g/mL), stirring at room one hour.Add the saturated NaHCO of 20mL 3Solution, ethyl acetate extraction, organic layer are drained after with dried over mgso, obtain compound 5 3.20g, directly drop into next step reaction.
1HNMR(300MHz，CDCl 3)：δ9.779(1H，d，J＝2.4Hz)，8.218(2H，d，J＝8.7Hz)，7.498(2H，d，J＝8.7Hz)，4.924(2H，d，J＝7.2Hz)，2.704(1H，m)，0.923(3H，d，J＝7.2Hz)，0.858(9H，s)，0.046(3H，s)，-0.217(3H，s)。
Embodiment five: compound 6Preparation:
With the 3.20g compound 5Be dissolved in the anhydrous CH of 100mL with 9.20g reagent A 2Cl 2In, reflux is 20 hours under the argon shield.Solvent evaporated, column chromatography obtains compound 63.60g, two step total recoverys 87.8%.
1HNMR(300MHz，CDCl 3)：δ8.167(2H，d，J＝8.7Hz)，7.427(2H，d，J＝8.4Hz)，6.622(1H，dd，J＝1.2，10.2Hz)，4.623(1H，d，J＝5.4Hz)，3.729(3H，s)，2.748(1H，m)，1.650(3H，d，J＝1.2Hz)，0.946(3H，d，J＝6.3Hz)，0.856(9H，s)，0.035(3H，s)，-0.202(3H，s)；
MS(EI)m/z(％)：378[M +-Me]，336(37)，304(4)，266(100)，240(42)，185(24)，115(14)，89(34)，73(70)，59(7)；
[α] D 23+77.4°(c＝0.575，CHCl 3)。
Embodiment six: compound 7Preparation:
With the 2.06g compound 6Be dissolved in the 30mL dry toluene, be chilled to-70 ℃, in 15 minutes, drip the n-heptane solution of the DIBAL-H of 16mL1mol/L, drip off the back and continue to stir 20 minutes.Add the saturated solution of 20mL sodium-potassium tartrate, rise to room temperature, continue to stir 1 hour, add ethyl acetate extraction, organic layer is drained after with dried over mgso, obtains compound through column chromatography 71.61g, productive rate 84.0%.
1HNMR(300MHz，CDCl 3)：δ8.147(2H，d，J＝9.0Hz)，7.417(2H，d，J＝9.3Hz)，5.235(1H，m，J＝9.9，1.5，1.2Hz)，4.607(1H，d，J＝5.1Hz)，3.953(2H，d，J＝1.2Hz)，2.664(1H，m)，1.433(3H，d，J＝1.5Hz)，0.915(3H，d，J＝6.6Hz)，0.873(9H，s)，0.039(3H，s)，-0.195(3H，s)；
MS(EI)m/z(％)：340，308，292，266(100)，250(6)，226(36)，210(3)，194(2)，163(4)，145(12)，115(14)，73(74)，59(4)；
[α] D 23+30.6°(c＝1.46，CHCl 3)。
Embodiment seven: compound 8Preparation:
With 2.02g 6Be dissolved in the 60mL tetrahydrofuran (THF), add 15g silica gel, ice bath also stirs the solution of the 3.00gPCC of property adding next time in the 30mL tetrahydrofuran (THF), removes ice bath, stirring at room 10 hours.Filter silica gel, revolve behind the filtrate adding 30mL water and steam most tetrahydrofuran (THF), the residue ethyl acetate extraction merges organic layer, with draining after the dried over mgso, obtains compound through column chromatography 81.78g, productive rate 88.6%.
1HNMR(300MHz，CDCl 3)：δ9.393(1H，s)，8.178(2H，d，J＝8.7Hz)，7.433(2H，d，J＝9.0Hz)，6.370(1H，dd，J＝9.9，1.2Hz)，4.715(1H，d，J＝5.1Hz)，2.953(1H，m)，1.520(3H，d，J＝1.2Hz)，1.057(3H，d，J＝6.9Hz)，0.878(9H，s)，0.054(3H，s)，-0.197(3H，s)；
MS(EI)m/z(％)：363[M +]，266(100)，238(27)，155(44)，143(66)，115(21)，75(25)，73(78)，69(17)；
[α] D 23+54.5°(c＝0.725，CHCl 3)。
Embodiment eight: compound 9Preparation:
With 1.42g 8Be dissolved in the anhydrous CH of 25mL with 4.08g reagent B 2Cl 2In, reflux is 20 hours under the argon shield.Solvent evaporated, column chromatography obtains compound 91.50g, productive rate 88.6%.
1HNMR (300MHz, CDCl 3): δ 8.148 (2H, d, J=9.0Hz), 7.402 (2H, d, J=8.4Hz), 7.273 (1H, d, J=15.9Hz), 5.741 (1H, d, J=10.2Hz), 5.740 (1H, d, J=15.0Hz), 4.656 (1H, d, J=4.8Hz), 4.212 and 4.208 (2H altogether, q, J=7.2Hz), 2.787 (1H, m), 1.509 (3H, d, J=0.9Hz), 1.300 (3H, t, J=7.2Hz), 0.996 (3H, d, J=6.9Hz), 0.874 (9H, s), 0.040 (3H, s) ,-0.199 (3H, s);
MS(ESI)：434(M+H)；
[α] D 23+94.2°(c＝0.705，CHCl 3)。
Embodiment nine: compound 10Preparation:
With 690mg 9Be dissolved in the 28.5mL acetonitrile, drip the HF aqueous solution of 1.5mL40% again, stirring at room 12 hours.The NaOH aqueous solution and the 50mL water that add 15mL2mol/L, ethyl acetate extraction merges organic layer, with draining after the dried over mgso, obtains compound 10530mg directly drops into next step reaction.
1HNMR(300MHz，CDCl 3)：δ8.191(2H，d，J＝9.0Hz)，7.495(2H，d，J＝8.7Hz)，7.301(1H，dd，J＝0.6，15.9Hz)，5.799(1H，d，J＝15.3Hz)，5.796(1H，d，J＝10.5Hz)，4.648(1H，d，J＝6.6Hz)，4.197(2H，q，J＝7.2Hz)，2.866(1H，m)，1.673(3H，d，J＝1.2Hz)，1.290(3H，t，J＝7.2Hz)，0.971(3H，d，J＝6.6Hz)；
MS(EI)m/z(％)：320[M+H]，274(7)，168(100)，152(23)，139(34)，122(24)，111(13)，95(81)，79(18)，67(6)，55(5)；
[α] D 23+128°(c＝0.140，CHCl 3)。
Embodiment ten: compound 11Preparation:
With 530mg 10Be dissolved in 18mL methyl alcohol, add 700mg5%Lindlar catalyzer (Pd/CaCO 3/ PbO) and the 0.30mL quinoline, normal temperature and pressure is down with hydrogen catalytic hydrogenation 20 hours.Cross and filter out catalyzer, filtrate is drained the back column chromatography, gets light yellow crystal 420mg, two step overall yields 91.2%.
1HNMR(300MHz，CDCl 3)：δ7.349(1H，dd，J＝15.6，0.9Hz)，7.110(2H，d，J＝8.4Hz)，6.667(2H，d，J＝8.4Hz)，5.842(1H，d，J＝9.6Hz)，5.807(1H，d，J＝15.6Hz)，4.359(1H，d，J＝7.5Hz)，4.207(2H，q，J＝7.2Hz)，2.838(1H，m)，1.771(3H，d，J＝1.2Hz)，1.298(3H，t，J＝7.2Hz)，0.856(3H，d，J＝6.9Hz)；
MS(EI)m/z(％)：289[M +]，271(2)，198(5)，168(14)，149(5)，139(5)，122(100)，94(16)，77(11)；
[α] D 23+177°(c＝0.850，CHCl 3)；
Mp?122-124℃。
Embodiment 11: compound 12Preparation:
With 600mg 11Be dissolved in 25mL1, in the 2-ethylene dichloride, drip the formalin of 0.5mL37%, drip off the back and stirred 10 minutes, add the 1.76g sodium triacetoxy borohydride, stirred 10 hours.Filter insolubles, the filtrate evaporate to dryness is after column chromatography obtains compound 12525mg, productive rate 79.8%.
1HNMR(300MHz，CDCl 3)：δ7.362(1H，d，J＝15.6Hz)，7.207(2H，d，J＝8.7Hz)，6.750(2H，d，J＝7.5Hz)，5.860(1H，d，J＝11.7Hz)，5.814(1H，d，J＝15.9Hz)，4.379(1H，d，J＝7.8Hz)，4.208(2H，q，J＝7.2Hz)，2.955(6H，s)，2.871(1H，m)，1.794(3H，s)，1.300(3H，t，J＝7.2Hz)，0.852(3H，d，J＝6.9Hz)；
MS(EI)m/z(％)：317[M +]，299(55)，226(100)，211(38)，150(73)；
[α] D 23+180°(c＝0.441，CHCl 3)。
Embodiment 12: compound 13Preparation:
(1) preparation of 1.5mol/L azanol/methanol solution:
The 2.34g hydroxylamine hydrochloride is dissolved in the methyl alcohol of 12mL heat, argon shield adds the solution of 2.81g potassium hydroxide in 10mL methyl alcohol down, adds the back and continues to stir 30 minutes.Be cooled to room temperature, filter, obtain 1.5mol/L azanol/methanol solution.
(2) compound 13Preparation:
With 130mg 12Be dissolved in the 2mL methyl alcohol, argon shield adds 5mL1.5mol/L azanol/methanol solution, stirring at room 2.5 hours down.Add saturated sodium bicarbonate solution, ethyl acetate extraction merges organic layer, with draining after the dried over mgso, gets compound 13Crude product, directly drop into next step.
1HNMR(300MHz，CDCl 3)：δ7.228(1H，d，J＝12.6Hz)，7.155(2H，d，J＝8.4Hz)，6.704(2H，d，J＝8.4Hz)，5.779(1H，d，J＝6.9Hz)，5.745(1H，d，J＝13.5Hz)，4.291(1H，d，J＝7.5Hz)，2.904(6H，s)，1.712(3H，s)，0.752(3H，d，J＝6.3Hz)。
Embodiment 13: the preparation of Trichostatin A:
The compound that embodiment 12 is obtained 13Crude product be dissolved in the 5mL dioxane, stir the solution of Dropwise 5 0mgDDQ in the 5mL dioxane down, drip off the back and stirred 10 minutes.Reacting liquid filtering is drained filtrate, and column chromatography obtains Trichostatin A 60mg, two step productive rates 48.4%.
1HNMR(300MHz，CDCl 3)：δ7.846(2H，d，J＝9.0Hz)，7.208(1H，d，J＝15.3Hz)，6.673(2H，d，J＝9.0Hz)，5.963(1H，d，J＝9.3Hz)，5.807(1H，d，J＝15.9Hz)，4.418(1H，m)，3.078(6H，s)，1.910(3H，s)，1.304(3H，d，J＝6.6Hz)；
MS(EI)m/z(％)：302[M +]，287(0.6)，274(3.5)，148(100)；
[α] D 21+106°(c＝0.095，EtOH)。
Compound 3aAnalyze to determine its ee value by the mosher ester:
(1) compound 3aWith (S)-(-)-mosher acid-respons
Reaction flask is put in 30mg (S)-(-)-mosher acid, and oil pump was taken out 30 minutes, added the 1mL anhydrous methylene chloride, added 10mg again 3aSolution in the 0.2mL methylene dichloride, ice bath and argon shield add 50mgDCC and 6mgDMAP down, keep 0 ℃ to stir 2.5 hours, obtain compound 3a(S)-(-)-mosher ester.
(2) compound 3aWith (R)-(+)-mosher acid-respons
Operate same compound 3aReaction with (S)-(-)-mosher acid obtains compound 3a(R)-(+)-mosher ester.
By two mosher esters relatively 1HNMR proves 3aBe approaching optically pure compound.

Claims (11)

1. the preparation method of the histone deacetylase inhibitor shown in the formula 1 may further comprise the steps:
Figure FSB00000100664100011
(1) paranitrobenzaldehyde and 1.0-3.0 equivalent propionic aldehyde are mixed in the solvent, room temperature reaction a few hours under 0.1-0.2 equivalent catalyst action, obtain two diastereomeric compounds 2aWith 2b
Figure FSB00000100664100012
Described catalyzer be selected from proline(Pro),
Figure FSB00000100664100013
Figure FSB00000100664100014
(2) compound 2aWith 2bWith ortho ester HC (OR 1) 3Under Louis acid catalysis, obtain compound 3aWith 3b
Figure FSB00000100664100015
Described ortho ester HC (OR 1) 3Be selected from trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate, tributyl orthoformate, orthoformic acid three benzyl esters;
(3) compound 3aWith 3bWith trialkylchlorosilane R 2Cl and a kind of alkali room temperature reaction in solvent obtain compound 4aWith 4b, compound 4aWith 4bCan separate fully by column chromatography, obtain required compound 4a
Figure FSB00000100664100021
Described trialkylchlorosilane is selected from TERT-BUTYL DIMETHYL CHLORO SILANE, chlorotriethyl silane or tri isopropyl chlorosilane;
(4) compound 4aObtain compound taking off under the acetal protective condition 5
Figure FSB00000100664100022
(5) compound 5Obtain compound through wittig reaction or Horner-Emmons-Wittig reaction 6
The used Wittig reagent of Wittig reaction is:
Figure FSB00000100664100024
The used alkyl phosphate of Horner-Emmons-Wittig reaction is:
Figure FSB00000100664100025
R wherein 3Be methyl, ethyl, propyl group, butyl, phenyl, naphthyl, benzyl or allyl group identical or inequality;
(6) compound 6Be reduced to compound through reductive agent 7
Figure FSB00000100664100031
(7) compound 7Be oxidized to compound 8
(8) compound 8Obtain compound through wittig reaction or Horner-Emmons-Wittig reaction again 9
Figure FSB00000100664100033
The used Wittig reagent of Wittig reaction is:
The used alkyl phosphate of Horner-Emmons-Wittig reaction is:
R wherein 4Be methyl, ethyl, propyl group, butyl, phenyl, naphthyl, benzyl or allyl group identical or inequality;
(9) compound 9Remove the trialkyl silyl protection and obtain compound 10
Figure FSB00000100664100042
(10) compound 10Obtain compound through the reductive agent reduction 11
Figure FSB00000100664100043
(11) by compound 11Methylate and obtain compound 12
Figure FSB00000100664100044
(12) compound 12With NH 2The OH reaction obtains compound 13
(13) compound 13The oxidized Trichostatin A that obtains of benzyl position hydroxyl
Figure FSB00000100664100052
2. the preparation method of histone deacetylase inhibitor according to claim 1, it is characterized in that the used solvent of step (1) is chloroform, methylene dichloride, tetracol phenixin, 1,2-ethylene dichloride, ether, tetrahydrofuran (THF), glycol dimethyl ether, diethylene glycol dimethyl ether, dioxane, N, dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), hexamethylphosphoramide, methyl acetate, ethyl acetate, methyl alcohol, ethanol, acetonitrile or their mixed solvent.
3. the preparation method of histone deacetylase inhibitor according to claim 1 is characterized in that the used Lewis acid of catalysis is tosic acid, camphorsulfonic acid, boron trifluoride diethyl etherate, titanium tetrachloride, tin tetrachloride, sulfuric acid, hydrochloric acid, nitric acid, iron trichloride, aluminum chloride, Nickel Chloride, cobalt dichloride, ammonium nitrate or ammonium chloride in the step (2).
4. the preparation method of histone deacetylase inhibitor according to claim 1, it is characterized in that used alkali is imidazoles, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N in the step (3), the N dimethylamine base) pyridine or N, accelerine.
5. the preparation method of histone deacetylase inhibitor according to claim 1, it is characterized in that taking off in the step (4) the acetal protective condition is sulfuric acid/silica gel system, Iodotrimethylsilane/methylene dichloride system, trifluoroacetic acid/chloroform system, acetic acid/aqueous systems, tosic acid/acetone system, stannous chloride dihydrate/methylene dichloride system or methyl-sulphoxide/water/dioxane system.
6. the preparation method of histone deacetylase inhibitor according to claim 1 is characterized in that the reductive agent in the step (6) is diisobutyl aluminium hydride or red aluminium.
7. the preparation method of histone deacetylase inhibitor according to claim 1 is characterized in that the oxygenant in the step (7) is PCC, activated manganese dioxide, Dess-Martin reagent or Swern reagent.
8. the preparation method of histone deacetylase inhibitor according to claim 1 is characterized in that the method that removes trialkyl silyl in the step (9) selects following reaction system for use: tetrabutyl ammonium fluoride/tetrahydrofuran (THF), hydrofluoric acid/acetonitrile, acetic acid/water/tetrahydrofuran (THF), triethylamine/hydrofluoric acid, hydrochloric acid/ethanol or iodine/methyl alcohol.
9. the preparation method of histone deacetylase inhibitor according to claim 1 is characterized in that reductive condition is selected following reaction system for use in the step (10): hydrogen/Lindlar catalyzer, sodium disulfide/ethanol, tindichloride/ethanol, iron powder/acetic acid or tin/hydrochloric acid.
10. the preparation method of histone deacetylase inhibitor according to claim 1 is characterized in that the condition of methylating is selected following reaction system for use in the step (11): formaldehyde/sodium triacetoxy borohydride, formaldehyde/sodium cyanoborohydride, methyl iodide/own nitrile/salt of wormwood or formaldehyde/formic acid.
11. the preparation method of histone deacetylase inhibitor according to claim 1 is characterized in that applied oxygenant is Manganse Dioxide, DDQ, ceric ammonium nitrate, PCC or NBS in the step (13).
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US4218478A (en) * 1979-01-05 1980-08-19 Ruiko Oiwa Trichostatin as an antiprotozoal agent
EP0331524A2 (en) * 1988-03-04 1989-09-06 Japan Tobacco Inc. Synthesis of trichostatins

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US4218478A (en) * 1979-01-05 1980-08-19 Ruiko Oiwa Trichostatin as an antiprotozoal agent
EP0331524A2 (en) * 1988-03-04 1989-09-06 Japan Tobacco Inc. Synthesis of trichostatins

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