CN101391978B - Novel synthetic method of HIV-1 protease inhibitor atazanavir - Google Patents
Novel synthetic method of HIV-1 protease inhibitor atazanavir Download PDFInfo
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Abstract
The invention relates to a new synthetic method of an HIV-1 protease inhibitor, Atazanavir, which adopts a convergent-typed synthetic strategy, introduces a construction unit, methoxycarbonyl-tert-lencyl, as an N atom protecting group in the whole early synthetic stage, and takes the diastereomeric selective reduction of aminoketone as the key and final reaction step of the new process. The method comprises the steps that: the compound of formula V, namely, N-1-[N-(methoxycarbonyl)-L-tert-leucine]-N-2-[4-(2-pyridyl)-phenmethyl]hydrazine, and the compound of formula VI, namely, (S)-1-((S)-4-chlorine-3-carbonyl-1-phenyl butane-2-yl-2-amino)-3, 3-dimethyl-1-carbonyl butane-2-yl-methyl carbamate, are treated with nucleophilic substitution reaction to generate the compound of formula VII, namely, 1-[4-(2-pyridyl)phenyl]-5(S)-2, 5-bis{[N-(methoxycarbonyl)-L-tert-leucineyl] amino}-4-carbonyl-6-phenyl-2-azahexane; and the compound of formula VII is treated with reduction reaction to generate the Atazanavir. The invention has the advantages of less process route steps, easily-controlled reaction conditions, simple and convenient operation, low-price and easily-obtained raw material, high product yield, low cost and being suitable for large-scale production.
Description
Technical field
The present invention relates to a kind of new protease inhibitor atazanavir (Atazanavir, 1-[4-(Pyridin-2-yl) phenyl]-5 (S)-2,5-bis{[N-(methoxycarbonyl)-L-tert-leucinyl] synthetic method of amino}-4 (S)-hydroxy-6-phenyl-2-azahexane).
Background technology
Human immunodeficiency virus (HIV) is the pathogenic agent that causes acquired immune deficiency syndrome (AIDS) (AIDS).In the infectious cycle of HIV virus particle, virus protease is to play the functional enzyme that polyprotein is cut into structural protein.Therefore, be the effective ways that the inhibitor of target becomes the treatment acquired immune deficiency syndrome (AIDS) at virus protease.
Reyataz R is that the azepine of an open chain is intended peptide compounds, is a kind of novel protein enzyme inhibitors.With respect to other proteinase inhibitor, Reyataz R has two remarkable advantages, and at first it is the proteinase inhibitor that unique allowance was taken once in a day, and this will simplify dosage course of treatment greatly; Secondly, Reyataz R does not also show the cholesterol and the triglyceride content that can increase patient, and this is the difficult problem that other all proteinase inhibitor all can run in various degree.The structure of Reyataz R is as follows:
The main process of the synthetic route (route 1) of existing Reyataz R is as follows: with the p-bromobenzaldehyde is raw material; pass through into acetal; the Grignard reagent coupling; reduction amination forms phenylhydrazone; hydro-reduction obtains intermediate N 1-(tertbutyloxycarbonyl)-N-2-[4-(2-pyridyl) Ben Yajiaji]-hydrazine; (S)-1-formyloxy-2-styroyl t-butyl carbamate reacts through Wittig; epoxidation reaction obtains (S)-1-((R)-2-oxyethane)-2-styroyl t-butyl carbamate; this intermediate is obtained the hydrazine intermediate by the front and carries out the reaction of open loop oxygen; the monoethanolamine product that obtains removes protecting group again; under the effect of condensing agent, obtain final product Reyataz R (Guido Bold with methoxycarbonyl Terleu fragment condensation; Alexander Fassler; Hans-Georg Capraro etc.; J.Med.Chem.1998; 41,3387-3401).Among this preparation method, epoxy intermediate is generated through the Wittig reaction by the phenylpropyl alcohol ammonium aldehyde of tertbutyloxycarbonyl protection, even but still have the part racemization at-78 ℃ of following substrates, cause epoxy product enantioselectivity lower, the separation and purification difficulty causes yield not high.And expensive condensing agent TPTU is used in the condensation reaction of final step in this method, and methoxycarbonyl Terleu charging capacity is excessive simultaneously, difficult the recovery, and end product is through silica gel column chromatography, and yield is lower, unsuitable suitability for industrialized production.
Route 1
Through improving, another operational path (route 2) is being raw material to bromophenyl boric acid, through the Suzuki coupling, reduction amination forms phenylhydrazone, hydro-reduction obtains intermediate N 1-(tertbutyloxycarbonyl) N-2-[4-(2-pyridyl) Ben Yajiaji]-hydrazine, another synthetic fragment is from optically pure (2S, 3S)-3,4-dihydroxyl-1-phenyl butane-2-t-butyl carbamate sets out, protect with tertiary butyl dimethyl-silicon ether through primary hydroxyl, secondary hydroxyl is introduced methane sulfonyl, remove steps such as forming epoxy under primary hydroxyl protecting group and the highly basic effect, obtain (S)-1-((R)-2-oxyethane)-2-styroyl t-butyl carbamate, the hydrazine intermediate of this intermediate and above-mentioned preparation carries out the reaction of open loop oxygen, remove protecting group, under the effect of condensing agent, obtain final product Reyataz R (Zhongmin Xu equally with the condensation of methoxycarbonyl Terleu, Janak Singh, Mark D.Schwinden etc., Organic Process Research﹠amp; Development, 2002,6,323-328).This preparation method is identical with former route when making up the basic skeleton of compound; but the chiral epoxy intermediate is set out through the protecting group strategy by 4 step prepared in reaction by the higher chiral diol of price; this route is compared the optical purity that has improved intermediate with former route; but synthesis step is more, and production cost is higher.
Route 2
Summary of the invention
The objective of the invention is to seek that of alternative existing route is easy and simple to handle, yield is higher, cost is lower, be suitable for the synthetic route of suitability for industrialized production Reyataz R.
To achieve these goals, the synthetic method of Reyataz R of the present invention is implemented by following reactions steps.
The epoxy addition that is different from bibliographical information makes up chiral amino alcoholic acid synthesis strategy; the present invention adopt height convergent type strategy and with the keto-amine of height cis-selectivity be reduced to contain (S)-hydroxyl amino alcohol as committed step, promptly with N-methoxycarbonyl-L-Terleu as two critical segments of the protecting group of N-atom through S
N2 reactions connect into ketone methylene radical azepine-dipeptides isostere (aza-dipeptide isostere), obtain (S)-hydroxyl azepine-dipeptides isostere Reyataz R through asymmetric reduction reaction then.At first; with single tertbutyloxycarbonyl hydrazine hydrate is raw material; with the condensation of a part methoxycarbonyl Terleu; form phenylhydrazone with dipyridyl phenyl aldehyde IV reaction after removing protecting group; hydro-reduction obtains key intermediate N-1-[N-(methoxycarbonyl)-L-Terleu base]-N-2-[4-(2-pyridyl)-benzyl] hydrazine V ((S)-methyl 3,3-dimethyl-1-oxo-1-(2-(4-(pyridin-2-yl) benzyl) hydraz--nyl) butan-2-ylcarbamate).Another reaction intermediate is so that (S)-4-chloro-3-carbonyl-1-phenyl butane-2-t-butyl carbamate is a raw material; remove after the protecting group and the condensation of a part methoxycarbonyl Terleu; generate (S)-1-((S)-4-chloro-3-carbonyl-1-phenyl butane-2-base-amino)-3; 3-dimethyl-1-carbonyl butane-2-aminocarbamic acid methyl esters (methyl (S)-1-((S)-4-chloro-3-oxo-1-phenylbutan-2-ylamino)-3; 3-dimethyl-1-oxobutan-2-ylcarbamate) VI; VI is carried out nucleophilic substitution with the intermediate V of preparation as previously mentioned again, and this reaction product is reduced to end product Reyataz R VIII with the reductive agent cis-selectivity again.Route map as shown in Scheme 3.Wherein crucial synthetic fragment methoxycarbonyl Terleu I adopts bibliographical information method preparation (Brian M.Adger, Ulrich C.Dyer, Ian C.Lennon, Peter D.GIFfin and Simon E.Ward.Tetrahedron Lett.1997,38,2153-2154.)
Route 3
The synthetic route of methoxycarbonyl Terleu I is as shown below:
Particularly, synthetic method of the present invention comprises the following steps:
(1) removes protecting group after single tertbutyloxycarbonyl hydrazine hydrate and the condensation of methoxycarbonyl Terleu I and generate the N-methoxycarbonyl-bright aminocarbonyl hydrazine hydrate of uncle L-hydrochloride II.More particularly, in condensation reaction, reaction solvent can be selected N for use, dinethylformamide, methyl-sulphoxide, tetrahydrofuran (THF), dioxane, hexamethylphosphoramide, acetone, acetonitrile, toluene, methylene dichloride, ethylene dichloride or ethyl acetate etc., adopt condensing agent to be selected from 1-ethyl-3-(3-dimethylamine propyl) carbodiimide (EDCI), I-hydroxybenzotriazole (HOBt), 1-hydroxyl-7-azepine benzotriazole (HOAt), dicyclohexylcarbodiimide (DCC), benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU), O-(7-azo benzotriazole-1-oxygen)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HATU), organic bases (triethylamine for example, diisopropyl ethyl amine, pyridine, piperidines, N-methylmorpholine), 0～60 ℃ of temperature range internal reaction 2～24 hours; Then condensation product removes protecting group in the presence of mineral acid (6N hydrochloric acid) or organic acid (trifluoroacetic acid), generates the intermediate II;
(2) p-bromobenzaldehyde forms acetal and 2-bromopyridine coupling posthydrolysis generation 4-(2-pyridyl)-phenyl aldehyde (IV).More particularly, be to adopt trimethyl orthoformate protection aldehyde radical, form Grignard reagent with MAGNESIUM METAL, the employing catalyzer (for example Ni[dppp] Cl
2, Ni[dppe] Cl
2, Fe (acac)
3), mineral acid (6N hydrochloric acid) and organic acid (citric acid) be for protecting group removes agent, 0～60 ℃ of temperature range internal reaction 2～12 hours, generates the intermediate IV.Reaction solvent can be selected methyl alcohol, tetrahydrofuran (THF), ether, toluene, dioxane etc. for use.
(3) the N-methoxycarbonyl-bright aminocarbonyl hydrazine hydrate of uncle L-hydrochloride II and 4-(2-pyridyl)-phenyl aldehyde IV generate N-1-[N-(methoxycarbonyl)-L-Terleu base through reduction amination]-N-2-[4-(2-pyridyl)-benzyl] the hydrazine V.More particularly, be at hydrogen or meglumine acid and catalyzer (Pd (OH) for example
2/ C, Pd/C, Raney Ni) or inorganic reducing agent (for example sodium borohydride, POTASSIUM BOROHYDRIDE, sodium triacetoxy borohydride, sodium cyanoborohydride) exist down, 20～80 ℃ of temperature range internal reactions 4～12 hours, generate the intermediate V.Reaction solvent can be selected methyl alcohol, ethanol, Virahol etc. for use, drips little acetic acid when needing.
(4) (S)-4-chloro-3-carbonyl-1-phenyl butane-2-t-butyl carbamate removes the protection back and the condensation of methoxycarbonyl Terleu generates (S)-1-((S)-4-chloro-3-carbonyl-1-phenyl butane-2-base-amino)-3,3-dimethyl-1-carbonyl butane-2-base-Urethylane VI.More particularly; be to adopt mineral acid (hydrochloric acid) or organic acid (trifluoroacetic acid) to remove agent for protecting group; adopt condensing agent (for example EDCI, HOBt, HOAt, DCC, HBTU, HATU) or active ester method (as Pentafluorophenol, p-NP, N-hydroxy-succinamide, oxine, I-hydroxybenzotriazole etc.) or mixed anhydride method (isobutyl chlorocarbonate); organic bases (for example triethylamine, diisopropyl ethyl amine or N-methylmorpholine);-40～80 ℃ of temperature range internal reactions 2～24 hours, generate the intermediate VI.Reaction solvent can be selected N for use, dinethylformamide, methyl-sulphoxide, tetrahydrofuran (THF), ether, dioxane, acetonitrile, methylene dichloride, ethylene dichloride etc.
(5) N-1-[N-(methoxycarbonyl)-L-Terleu base]-N-2-[4-(2-pyridyl)-benzyl] the hydrazine V with (S)-1-((S)-4-chloro-3-carbonyl-1-phenyl butane-2-base-amino)-3,3-dimethyl-1-carbonyl butane-2-base-Urethylane VI nucleo philic substitution reaction generates 1-[4-(2-pyridyl) phenyl]-5 (S)-2, two { [N-(methoxycarbonyl)-L-Terleu base] the amino }-4-carbonyl-6-phenyl-2-aza-hexanes of 5-(1-[4-(Pyridin-2-yl) phenyl]-5 (S)-2,5-bis{[N-(methoxycarbonyl)-L-tert-leucinyl] amino}-4-oxo-6-phenyl-2-azahexane) VII.More particularly, be to adopt mineral alkali (for example yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, hydrated barta) or organic bases (for example sodium alkoxide, triethylamine, diisopropyl ethyl amine, pyridine, 2 hydroxy pyrimidine, piperidines, N-methyl piperidine, morpholine, N-methylmorpholine) to be the disacidify agent, adopt iodide (for example sodium iodide, potassiumiodide) accelerated reaction, 0～80 ℃ of temperature range internal reaction 2～24 hours, generate the intermediate VII.In this nucleophilic substitution reaction, the mol ratio of formula V compound and formula VI compound is 0.25: 1～4: 1, is preferably 1.1: 1; Reaction solvent can be selected N for use, dinethylformamide, methyl-sulphoxide, ether, tetrahydrofuran (THF), dioxane, hexamethylphosphoramide, acetone, acetonitrile, toluene, methylene dichloride or ethylene dichloride etc.
(6) 1-[4-(2-pyridyl) phenyl]-5 (S)-2, two { [N-(methoxycarbonyl)-L-Terleu base] the amino }-4-carbonyl-6-phenyl-2-aza-hexane VII of 5-generate 1-[4-(2-pyridyl) phenyl by reduction reaction]-5 (S)-2, two { [N-(methoxycarbonyl)-L-Terleu base] amino }-4 (S)-hydroxyl-6-phenyl-2-aza-hexane VIII of 5-.More particularly, be to adopt inorganic reducing agent (for example reduction system of lithium borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE, zinc borohydride, three tert.-butoxy lithium aluminium hydride, 3-sec-butyl lithium borohydride, diisobutyl aluminium hydride, aluminium secondary butylate, aluminum isopropylate or borine and borane of chiral oxazole (oxazaborolidine) catalyst combination) reducing carbonyl,-78～60 ℃ of temperature range internal reactions 2～24 hours, generate end product Reyataz R VIII.Reaction solvent can be selected methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), dioxane, toluene, acetonitrile, ether etc. for use.
In the present invention, the preparation of wherein former material list tertbutyloxycarbonyl hydrazine hydrate is to be raw material with 85% hydrazine hydrate, under ice bath one-sided amino is carried out the tertbutyloxycarbonyl protection and obtains.
The present invention has following advantage:
1. the existing market raw material supply of (S)-4-chloro-3-carbonyl-1-phenyl butane-2-t-butyl carbamate, cheap, do not need to prepare separately.The condensation reaction condition is easy, and reagent is cheap, the easy recrystallization purifying of product, thus reduced cost.
2. the linked reaction mild condition of intermediate V and VI, raw material VI transforms thoroughly, and another raw material V of complete reaction can not remove products therefrom VII good stability with the potassium hydrogen sulfate solution washing, the purity height is guaranteed the quality of the finished product Reyataz R and yield.
3. final step reduction reaction cis-selectivity height, raw material transforms fully.Used reductive agent three tert.-butoxy lithium aluminium hydride are cheap, safe.The reaction conditions gentleness, easy and simple to handle.
4. easily-controlled reaction conditions is easy and simple to handle, is suitable for scale operation.
Embodiment
Illustrate the present invention below, these embodiment only are used to illustrate the present invention, but do not limit the present invention in any way.
Embodiment 1 N-methoxycarbonyl-L-Terleu I
(110.3g, in tetrahydrofuran (THF) 0.66mol) (1L) and the 2N aqueous sodium hydroxide solution (1.32L), (101.7mL 1.32mol) slowly added through 1.5 hours with methyl-chloroformate to be dissolved with the L-Terleu at one.Then, said mixture is warming up to 60 ℃, stirred 18 hours, be cooled to room temperature.Concentrate and remove tetrahydrofuran (THF), resistates to pH=2, is used ethyl acetate extraction three times with the 4N hcl acidifying with dichloromethane extraction twice, water.Merge organic phase, the saturated common salt washing, anhydrous sodium sulfate drying, concentrated organic phase gets white solid I (112g, yield 90%).mp：103℃.
1HNMR(300MHz，CDCl
3)δ：5.28(d，1H，J＝12.0?Hz)，4.18(d，1H，J＝9.0?Hz)，3.69(s，3H)，1.02(s，9H)。
Embodiment 2 single tertbutyloxycarbonyl hydrazine hydrates
Under the ice bath, with the dimethyl dicarbonate butyl ester (109g, tetrahydrofuran solution 0.5mol) (100mL) slowly be added dropwise to be dissolved with 85% hydrazine hydrate (117.6g, 2mol) and salt of wormwood (138g, (1L, THF: H in tetrahydrofuran aqueous solution 1mol)
2O=1: 1).Rise to room temperature gradually, continue to stir 8 hours.Decompression is spin-dried for tetrahydrofuran (THF), water dichloromethane extraction three times.Merge organic phase and use saturated common salt water washing 3 times, dry, concentrated.Crude product gets white solid list tertbutyloxycarbonyl hydrazine hydrate (48.58g, yield 73.6%) with the sherwood oil recrystallization.
1HNMR(300?MHz，CDCl
3)δ：1.46(s，9H)，3.50(br，1H)，5.98(br，1H).
The embodiment 3 N-methoxycarbonyl-bright aminocarbonyl hydrazine hydrate of uncle L-hydrochloride II
Be dissolved with I (37.8g at one, 200mmol), EDCI (42g, 220mmol), HOBt (29.7g, add N-methylmorpholine (26.5mL in ethyl acetate 220mmol) (500mL) solution, 240mmol), stirring at room added single tertbutyloxycarbonyl hydrazine hydrate (29g after 30 minutes, 220mmol), stirring at room is 16 hours.Above-mentioned reaction mixture with ethyl acetate (500mL) dilution, with saturated sodium bicarbonate aqueous solution, water, saturated common salt washing, is merged the organic phase anhydrous sodium sulfate drying successively.Concentrated organic phase gets the spumescence solid, this solid is dissolved in the mixing solutions of tetrahydrofuran (THF) (200mL) and 6N hydrochloric acid (300mL) stirring at room 2 hours.Concentrate and remove tetrahydrofuran (THF), water dichloromethane extraction three times, concentrated water gets white solid II (45.63g, yield 95.3%).
Embodiment 41-bromo-4-(dimethoxy-methyl)-benzene III
One be dissolved with p-bromobenzaldehyde (37g, add in methyl alcohol 0.2mol) (500mL) solution trimethyl orthoformate (31.8g, 0.3mol) and tosic acid (0.38g 2mmol), stirred under the room temperature 3 hours.(0.43g 8mmol), continues to stir 1 hour to add sodium methylate.Said mixture is concentrated, filter, obtain colourless oil liquid III (44.96g, yield 98%).
1HNMR(300?MHz，CDCl
3)δ：7.49(d，2H，J＝8.7?Hz)，7.33(d，2H，J＝8.7?Hz)，5.36(s，1H)，3.30(s，6H)。
Embodiment 5 4-(2-pyridyl)-phenyl aldehyde IV
(5.11g, in dry tetrahydrofuran 212mmol) (40mL) solution, slow adding is dissolved with 1-bromo-4-(dimethoxy-methyl)-benzene, and (3.45g, dry tetrahydrofuran 15mmol) (4mL) solution adds a small amount of iodine subsequently to be added with magnesium chips at one.After reaction caused, slow dropping is dissolved with 1-bromo-4-(dimethoxy-methyl)-benzene, and (41.44g in dry tetrahydrofuran 180mmol) (36mL) solution, continued under the room temperature to stir 1 hour.With the Grignard reagent of above-mentioned preparation slowly be added dropwise to be dissolved with the 2-bromopyridine (17.14mL, 177mmol) and Ni[dppp] Cl
2In dry tetrahydrofuran (1g) (60mL) solution, stirred 1.5 hours under the room temperature.Said mixture is poured in the ice (357g) that contains concentrated hydrochloric acid (54mL) and citric acid (54g).Add diatomite (36g) after stirring half an hour, continue to stir 1 hour.Filter, concentrate and remove tetrahydrofuran (THF), resistates ethyl acetate extraction three times.Water is transferred pH=10 with sodium hydroxide, ethyl acetate extraction three times.Merge organic phase, saturated common salt washing, anhydrous sodium sulfate drying.Concentrate white solid, this crude product gets white solid IV (22g, yield 68.3%) with the isopropyl ether recrystallization.Mp：52-53℃；
1HNMR(300?MHz，CDCl
3)δ：10.08(s，1H)，8.75(d，1H，J＝3.1Hz)，8.17(d，2H，J＝8.9?Hz)，8.00-7.97(m，2H)，7.82-7.79(m，2H)，7.33-7.29(m，1H)。
Embodiment 6 N-1-[N-(methoxycarbonyl)-L-Terleu base]-N-2-[4-(2-pyridyl)-benzyl] hydrazine V
Under the nitrogen protection; be dissolved with the N-methoxycarbonyl-bright aminocarbonyl hydrazine hydrate of uncle L-II hydrochloride (31.65g at one; 132.1mmol) ethanol (250mL) solution in add triethylamine (21.9mL; 158.5mmol); stirring at room 1 hour; adding is dissolved with 4-(2-pyridyl)-phenyl aldehyde, and (heating refluxed 4 hours down for 24.18g, ethanol 132.1mmol) (100mL) solution.Be cooled to room temperature, add 20% palladium hydroxide (5g), normal pressure hydrogenation 12 hours.Filter, filtrate concentrate an oily matter, this crude product gets white solid V (37g, yield 75.7%, purity 99.4%) with isopropyl ether/ethyl alcohol recrystallization.mp：134-135℃；[α]
20 D＝-22.5°(c＝0.91，CHCl
3)；
1HNMR(300?MHz，CDCl
3)δ：8.73(d，1H，J＝4.5?Hz)，7.99(d，2H，J＝8.4?Hz)，7.85-7.75(m，2H)，7.48(d，?2H，J＝8.4Hz)，7.32-7.29(m，1H)，5.38(d，1H，J＝9.6Hz)，4.05(q
AB，2H，J＝12.6Hz，16.8Hz)，3.78(d，1H，J＝9.6Hz)，3.67(s，3H)，0.97(s，9H)；
13CNMR(100MHz，CDCl
3)δ：170.3，157.1，157.0，149.6，138.6，138.2，136.7，129.2x2，126.9x2，122.1，120.4，61.1，55.5，52.3，34.5，26.4x3.MS(EI)：m/z?370(M)+；HRMS(EI)：Calcd.for?C
20H
26O
3N
4(M
+)370.2005，Found?370.2011。
Embodiment 7 (S)-1-((S)-4-chloro-3-carbonyl-1-phenyl butane-2-base-amino)-3,3-dimethyl-1-carbonyl butane-2-base-Urethylane VI
(38.2g adds 4N hydrochloric acid (100mL) in dry tetrahydrofuran 128.3mmol) (100mL) solution, be warming up to 50 ℃ and stirred 4 hours to be dissolved with (S)-4-chloro-3-carbonyl-1-phenyl butane-2-t-butyl carbamate at one.Concentrate and remove tetrahydrofuran (THF), resistates washed with dichloromethane three times, concentrated water obtains white solid.Under the ice bath with N-methylmorpholine (28mL, 256mmol) adding is dissolved with N-methoxycarbonyl-L-Terleu (26.4g, in dry tetrahydrofuran 140mmol) (350mL) solution, slowly drip isobutyl chlorocarbonate (18.44mL, 128mmol),-25 ℃ were stirred 20 minutes, and above-mentioned white solid is added reaction system.Stirred 1 hour at-20 ℃, slowly rise to room temperature, continue to stir 3 hours.Concentrate and remove tetrahydrofuran (THF), resistates dilutes with ethyl acetate, uses saturated sodium bicarbonate, water, saturated common salt water washing successively, anhydrous sodium sulfate drying.Concentrate an oily matter, this crude product gets white solid VI (33.8g, yield 71.9%) with the sherwood oil recrystallization.mp：115-116℃；[α]
20 D＝-3.9°(c＝0.92，CHCl3)；
1HNMR(300MHz，CDCl
3)δ：0.95(s，9H)，3.01-3.02(m，2H)，3.68(s，3H)，3.85-3.94(m，2H)，4.14(d，1H，J＝15.6Hz)，4.93-5.01(m，1H)，5.27(d，1H，J＝9.3Hz)，6.23(d，1H，J＝6.0Hz)，7.16(d，2H，J＝6.6Hz)，7.27-7.35(m，3H)；
13CNMR(100MHz，CDCl
3)δ：200.6，170.8，157.0，135.1，129.0x2，128.9x2，127.5，62.5，57.1，52.4，47.7，37.5，34.4，26.4x3；MS(EI)：m/z?368(M+)；HRMS(EI)：Calcd.for?C
18H
25ClN
2O
4(M
+)368.1503，Found?368.1517。
Embodiment 8 1-[4-(2-pyridyl) phenyl]-5 (S)-2, two { [N-(methoxycarbonyl)-L-Terleu base] the amino }-4-carbonyl-6-phenyl-2-aza-hexane VII of 5-
Be dissolved with (S)-1-((S)-4-chloro-3-carbonyl-1-phenyl butane-2-base-amino)-3 at one, 3-dimethyl-1-carbonyl butane-2-base-Urethylane (28g, add sodium iodide (12.4g in acetonitrile 76mmol) (250mL) solution, 83mmol), stirring at room 15 minutes, add and be dissolved with N-1-[N-(methoxycarbonyl)-L-Terleu base]-N-2-[4-(2-pyridyl)-benzyl] hydrazine (30.7g, acetonitrile 83mmol) (350mL) solution.Stirring at room add after 15 minutes sodium bicarbonate (12.7g, 152mmo1), room temperature reaction 12 hours.Concentrate and remove acetonitrile, resistates dilutes with ethyl acetate, uses saturated sal enixum, saturated common salt water washing successively, the organic phase anhydrous sodium sulfate drying.Rotary evaporation removes and desolvates, and resistates is handled with ethanol and desalt, gets a yellow solid VII (51g, productive rate 96.2%, purity 91.7%).
1HNMR(300MHz，CD
3OD)：.8.88-8.84(m，1H)，8.73-8.67(m，1H)；8.56(d，1H，J＝8.1Hz)；8.08-8.04(m，1H)；7.90(d，2H，J＝8.7Hz)；7.78(d，2H，J＝8.7Hz)，7.31-7.15(m，5H)；4.16(t，1H，J＝7.6Hz)，3.99(s，2H)，3.85(s，1H)，3.77-3.74(m，1H)，3.20-3.10(m，2H)，3.69(s，3H)，3.57(s，3H)，2.97-2.85(m，3H)，0.83(s，9H)，0.77(s，9H).
13CNMR(100MHz，CDCl
3)δ：207.6，173.1，170.8，169.8x2，157.0，149.6，138.8，137.3，136.7，135.6，129.5x2，129.0x2，128.8x2，127.2x2，126.9，122.1，120.4，62.4，61.2，60.2，59.9，57.7，52.3，36.9，34.5，34.3，26.4x3，26.3x3.MS(ESI)：m/z?703.6(M+1)
+，725.6(M+Na)
+.HRMS(ESI)：Calcd.for?C
38H
50N
6O
7Na(M+Na)
+725.3639，found?725.3615.
Embodiment 9 1-[4-(2-pyridyl) phenyl]-5 (S)-2, two { [N-(the methoxycarbonyl)-bright amino of uncle L-] amino }-4 (S)-hydroxyl-6-phenyl-2-aza-hexane VIII of 5-
Under the ice bath, be dissolved with 1-[4-(2-pyridyl) phenyl at one]-5 (S)-2,5-two { [N-(methoxycarbonyl)-L-Terleu base] amino }-4-carbonyl-6-phenyl-2-aza-hexane (24.57g, add three tert.-butoxy lithium aluminium hydride (20.83g in diethyl ether solution 35mmol), 87.5mmol), 0 ℃ of stirring added entry (2mL) after 4 hours.Concentrate and remove ether, resistates dilutes with methylene dichloride, the saturated common salt water washing.Concentrated organic phase gets a yellow solid, and this crude product is used isopropyl ether/ethanol and ethanol/water recrystallization successively, gets white solid Reyataz R VIII (39g, yield 61.9%, purity 99.8%).mp：198-200℃，[α]
D 20＝-44.3°(c＝0.9，EtOH).
1H?NMR(300?MHz，CD
3OD)：8.59(d，1H，J＝0.8?Hz)，7.89-7.79(m，4H)，7.50(d，1H，J＝8.0?Hz)，7.35-7.32(m，1H)，7.23-7.17(m，4H)，7.13-7.11(m，1H)，4.14(t，1H，J＝7.6Hz)，3.99(s，2H)，3.85(s，1H)，3.76(d，1H，J＝9.2?Hz)，3.68(s，1H)，3.63(s，3H)，3.59(s，3H)，2.96-2.83(m，3H)，2.69(d，1H，J＝11.2Hz)，0.82(s，9H)，0.71(s，9H).MS(EI)：m/z?704(M)
+。
Embodiment 10 1-[4-(2-pyridyl) phenyl]-5 (S)-2, two { [N-(methoxycarbonyl)-L-Terleu base] the amino }-4-carbonyl-6-phenyl-2-aza-hexane VII of 5-
Be dissolved with (S)-1-((S)-4-chloro-3-carbonyl-1-phenyl butane base-2-amino)-3 at one, 3-dimethyl-1-carbonyl butane-2-Urethylane (5.52g, N 15mmol), add potassiumiodide (3.39g in dinethylformamide (20mL) solution, 22.6mmol), stirring at room 15 minutes, adding is dissolved with N-1-[N-(methoxycarbonyl)-bright amino of uncle L-]-N-2-[4-(2-pyridyl)-benzyl] hydrazine (6.66g, N 18mmol), dinethylformamide (15mL) solution.Stirring at room add after 15 minutes sodium bicarbonate (2.66g, 31.6mmol), room temperature reaction 12 hours.After above-mentioned reaction system usefulness methylene dichloride (200mL) dilution, use saturated sal enixum, saturated common salt water washing successively, anhydrous sodium sulfate drying.Concentrate crude product, handle through ethanol and desalt, a yellow solid VII (7.47g, productive rate 71%).
Embodiment 11 1-[4-(2-pyridyl) phenyl]-5 (S)-2, two { [N-(methoxycarbonyl)-L-Terleu base] amino }-4 (S)-hydroxyl-6-phenyl-2-aza-hexane VIII of 5-
Under the ice bath, be dissolved with 1-[4-(2-pyridyl) phenyl at one]-5 (S)-2,5-two { [N-(methoxycarbonyl)-L-Terleu base] amino }-4-carbonyl-6-phenyl-2-aza-hexane (6.48g, 9.23mmol) dry tetrahydrofuran (60mL) solution in add three tert.-butoxy lithium aluminium hydride (2.63g, 11.08mmol), 0 ℃ of stirring added entry (2mL) after 4 hours.Concentrate to remove and desolvate, resistates dilutes with methylene dichloride, the saturated common salt water washing.Concentrated organic phase gets a yellow solid, and this crude product is used isopropyl ether/ethanol and ethanol/water recrystallization successively, gets white solid Reyataz R VIII (3.28g, yield 50.5%, purity 99.4%).
Embodiment 12 1-[4-(2-pyridyl) phenyl]-5 (S)-2, two { [N-(methoxycarbonyl)-L-Terleu base] the amino }-4-carbonyl-6-phenyl-2-aza-hexane VII of 5-
Be dissolved with (S)-1-((S)-4-chloro-3-carbonyl-1-phenyl butane base-2-amino)-3 at one, 3-dimethyl-1-carbonyl butane-2-Urethylane (5.52g, add sodium iodide (2.25g in acetone 15mmol) (20mL) solution, 15mmol), stirring at room 15 minutes, add and be dissolved with N-1-[N-(methoxycarbonyl)-bright amino of uncle L-]-N-2-[4-(2-pyridyl)-benzyl] hydrazine (1.85g, acetone 5mmol) (15mL) solution.Stirring at room add after 15 minutes sodium bicarbonate (0.84g, 10mmol), room temperature reaction 12 hours.Above-mentioned reaction system is spin-dried for, and resistates is used saturated sal enixum, saturated common salt water washing, anhydrous sodium sulfate drying after diluting with methylene dichloride (20mL) successively.Concentrate crude product, through column chromatography for separation (sherwood oil: ethyl acetate=2: 1), a white solid VII (1.79g, productive rate 51%).
Embodiment 13 1-[4-(2-pyridyl) phenyl]-5 (S)-2, two { [N-(methoxycarbonyl)-L-Terleu base] amino }-4 (S)-hydroxyl-6-phenyl-2-aza-hexane VIII of 5-
Under the ice bath, be dissolved with 1-[4-(2-pyridyl) phenyl at one]-5 (S)-2,5-two { [N-(methoxycarbonyl)-L-Terleu base] amino }-4-carbonyl-6-phenyl-2-aza-hexane (3.51g, add aluminium secondary butylate (2.6mL in dry toluene 5mmol) (30mL) solution, 10mmol), 0 ℃ of stirring added entry (2mL) after 8 hours.Concentrate to remove and desolvate, crude product is through column chromatography for separation (sherwood oil: ethyl acetate=1: 1), get white solid Reyataz R VIII (2.96g, yield 84%).
Embodiment 14 1-[4-(2-pyridyl) phenyl]-5 (S)-2, two { [N-(methoxycarbonyl)-L-Terleu base] amino }-4 (S)-hydroxyl-6-phenyl-2-aza-hexane VIII of 5-
Under drying, the nitrogen protection, to BH
3Me
2Tetrahydrofuran (THF) (the 6mL of S, 6mmol, 1M in THF) add (R)-α in the solution, and α-phenylbenzene-2-pyrrolidine carbinol (76mg, (preparation is with reference to Lyndon C.Xavier for tetrahydrofuran (THF) 0.3mmol) (5mL) solution, Julie J.Mohan, David J.Mathre etc., Organic synthesis.2006,74,50), being reflected at 45 ℃ stirred 16 hours.To be dissolved with 1-[4-(2-pyridyl) phenyl]-5 (S)-2,5-two { [N-(methoxycarbonyl)-L-Terleu base] amino }-4-carbonyl-6-phenyl-2-aza-hexane (3.51g, dry tetrahydrofuran 5mmol) (15mL) solution slowly adds in the above-mentioned system, dropwises to continue to stir 15 minutes.Be cooled to room temperature, carefully drip methyl alcohol (2mL) cancellation reaction.Concentrate to remove and desolvate, crude product is through column chromatography for separation (sherwood oil: ethyl acetate=1: 1), get white solid Reyataz R VIII (2.68g, yield 76%).
Claims (11)
1. the synthetic method of a HIV-1 protease inhibitor atazanavir is characterized in that, this method comprises:
Formula V compound N-1-[N-(methoxycarbonyl)-L-Terleu base]-N-2-[4-(2-pyridyl)-benzyl] hydrazine and formula VI compound (S)-1-((S)-4-chloro-3-carbonyl-1-phenyl butane-2-base-amino)-3,3-dimethyl-1-carbonyl butane-2-base-Urethylane nucleo philic substitution reaction production VII compound, 1-[4-(2-pyridyl) phenyl]-5 (S)-2, two { [N-(methoxycarbonyl)-L-Terleu base] the amino }-4-carbonyl-6-phenyl-2-aza-hexanes of 5-;
Formula VII compound is by reduction reaction production VIII compound Reyataz R, i.e. 1-[4-(2-pyridyl) phenyl]-5 (S)-2, two { [N-(methoxycarbonyl)-L-Terleu base] amino }-4 (S)-hydroxyl-6-phenyl-2-aza-hexane of 5-;
Reaction formula is as follows:
2. synthetic method according to claim 1, it is characterized in that, described nucleophilic substitution reaction is the disacidify agent with mineral alkali or organic bases, described mineral alkali is yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or hydrated barta, and described organic bases is sodium alkoxide, triethylamine, diisopropyl ethyl amine, pyridine, 2 hydroxy pyrimidine, piperidines, N-methyl piperidine, morpholine or N-methylmorpholine.
3. synthetic method according to claim 1 and 2 is characterized in that, in nucleophilic substitution reaction, the mol ratio of described formula V compound and formula VI compound is 0.25: 1～4: 1; Described nucleophilic substitution reaction solvent is N, dinethylformamide, methyl-sulphoxide, ether, tetrahydrofuran (THF), dioxane, hexamethylphosphoramide, acetone, acetonitrile, toluene, methylene dichloride or ethylene dichloride; Temperature of reaction is 0～80 ℃, and the reaction times is 2～24 hours.
4. synthetic method according to claim 3 is characterized in that, in nucleophilic substitution reaction, adds iodide and promotes reaction, and described iodide are sodium iodide or potassiumiodide.
5. synthetic method according to claim 1, it is characterized in that, the reductive agent of described reduction reaction is lithium borohydride, sodium borohydride, POTASSIUM BOROHYDRIDE, zinc borohydride, three tert.-butoxy lithium aluminium hydride, 3-sec-butyl lithium borohydride, diisobutyl aluminium hydride, aluminium secondary butylate or aluminum isopropylate, the perhaps reduction system of borine and borane of chiral oxazole catalyst combination.
6. synthetic method according to claim 1 or 5, it is characterized in that, described reduction reaction solvent is methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), dioxane, toluene, acetonitrile or ether, and reduction reaction temperature is-78～60 ℃, and the reaction times is 2～24 hours.
7. synthetic method according to claim 1, it is characterized in that, described formula V compound N-1-[N-(methoxycarbonyl)-L-Terleu base]-N-2-[4-(2-pyridyl)-benzyl] hydrazine obtains as follows: in methyl alcohol, ethanol or isopropanol solvent, at hydrogen or ammonium formiate and catalyst P d (OH)
2/ C, Pd/C or Raney Ni exist down, perhaps inorganic reducing agent sodium borohydride, POTASSIUM BOROHYDRIDE, sodium triacetoxy borohydride or sodium cyanoborohydride exist down, and N-methoxycarbonyl-uncle's L-bright aminocarbonyl hydrazine hydrate hydrochloride and 4-(2-pyridyl)-phenyl aldehyde generate N-1-[N-(methoxycarbonyl)-L-Terleu base through reduction amination]-N-2-[4-(2-pyridyl)-benzyl] hydrazine.
8. synthetic method according to claim 7; it is characterized in that the described N-methoxycarbonyl-bright aminocarbonyl hydrazine hydrate of uncle L-hydrochloride obtains as follows: remove protecting group after single tertbutyloxycarbonyl hydrazine hydrate and the condensation of methoxycarbonyl Terleu and generate the N-methoxycarbonyl-bright aminocarbonyl hydrazine hydrate of uncle L-hydrochloride.
9. synthetic method according to claim 8, it is characterized in that, in condensation reaction, reaction solvent is selected N for use, dinethylformamide, methyl-sulphoxide, tetrahydrofuran (THF), dioxane, hexamethylphosphoramide, acetone, acetonitrile, toluene, methylene dichloride, ethylene dichloride or ethyl acetate, adopt condensing agent EDCI, HOBt, HOAt, DCC, HBTU or HATU, in the presence of organic bases triethylamine, diisopropyl ethyl amine, pyridine, piperidines or N-methylmorpholine, 0～60 ℃ of temperature range internal reaction 2～24 hours; Then condensation product removes protecting group in the presence of hydrochloric acid, generates the N-methoxycarbonyl-bright aminocarbonyl hydrazine hydrate of uncle L-hydrochloride.
10. synthetic method according to claim 1; it is characterized in that; described formula VI compound (S)-1-((S)-4-chloro-3-carbonyl-1-phenyl butane-2-base-amino)-3,3-dimethyl-1-carbonyl butane-2-base-Urethylane obtains as follows: (S)-4-chloro-3-carbonyl-1-phenyl butane-2-t-butyl carbamate removes after the protection and methoxycarbonyl Terleu condensation production VI compound.
11. synthetic method according to claim 10 is characterized in that, described (S)-4-chloro-3-carbonyl-1-phenyl butane-2-t-butyl carbamate removes protection, and adopting mineral acid hydrochloric acid or organic acid trifluoroacetic acid is that protecting group removes agent; Described condensation, reaction solvent is N, dinethylformamide, methyl-sulphoxide, tetrahydrofuran (THF), ether, dioxane, acetonitrile, methylene dichloride or ethylene dichloride, adopt condensing agent EDCI, HOBt, HOAt, DCC, HBTU, HATU or generate mixed anhydride method or active ester method by isobutyl chlorocarbonate, in the presence of organic bases triethylamine, diisopropyl ethyl amine or N-methylmorpholine,-40～80 ℃ of temperature range internal reactions 2～24 hours, production VI compound.
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| Title |
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| Guido Bold, et al.New Aza-Dipeptide Analogues as Potent and Orally Absorbed HIV-1 Protease.J. med. chem..1998,41(18),3387-3401. * |
| Zhongmin Xu, et al.Process Research and Development for an Efficient Synthesis of the HIV.Organic Process Research & Development.2002,6(3),323-328. * |
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