CN105017181A - Carfilzomib key intermediate and preparation method of its derivative - Google Patents

Carfilzomib key intermediate and preparation method of its derivative Download PDF

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CN105017181A
CN105017181A CN201510381433.0A CN201510381433A CN105017181A CN 105017181 A CN105017181 A CN 105017181A CN 201510381433 A CN201510381433 A CN 201510381433A CN 105017181 A CN105017181 A CN 105017181A
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compd
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CN105017181B (en
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朱永强
杜晓
雷萌
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Nanjing Normal University
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Nanjing Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
    • C07D301/19—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic hydroperoxides

Abstract

The invention belongs to the technical field of compound preparation, and more specifically relates to a carfilzomib key intermediate [(1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl]-carbamate and a preparation method of its derivative. The method takes a compound E as a raw material, the compound E is dissolved by a solvent and is reacted with diisopropylethylaine and pyridine, after complete reaction, a reaction product is purified to obtain a product F; the concrete reaction processes are shown in a following specification: wherein, R1 is selected from C1-6 alkyl or C6-10 aryl C1-6 alkyl; R2 is tertbutyloxycarbonyl (Boc) or benzyloxycarbonyl (Cbz). According to the invention, operation condition for all the steps is mild, the used reagents are conventional reagents which have the advantages of low cost, high yield, and little environmental pollution, and the key intermediate is adapted to large scale industrial production.

Description

The preparation method of Ka Feizuo meter key intermediate and derivative thereof
Technical field
The invention belongs to technical field of compound preparation, be specifically related to the preparation method of a kind of Ka Feizuo meter key intermediate [(1S)-3-methyl isophthalic acid-[[(2R)-2-methyl oxirane base] carbonyl] butyl]-carbamate and derivative thereof.
Background technology
Accepting the multiple myeloma (MM) of at least two kinds of medicines (comprising Velcade and immunomodulator treatment) before Ka Feizuo meter (carfilzomib) is used for the treatment of, is the irreversible proteasome blocker of high selectivity of a new generation.Wherein in the preparation process of Ka Feizuo meter, [(1S)-3-methyl isophthalic acid-[[(2R)-2-methyl oxirane base] carbonyl] butyl]-carbamate (6) is its key intermediate.
Further further investigation finds, general formula is the compound of F, can be used for Ka Feizuo meter similar medicine and some proteolytic enzyme
The synthesis of body inhibitor, wherein R 1for C 1-6alkyl or C 6-10aryl C 1-6alkyl:
By carrying out analysis and summary to prior art, discovery general formula is that the synthetic method of the midbody compound of F mainly contains following several:
Patent US20090105156 discloses following synthetic route:
Route 1:
The L-Leu that the method is protected with Boc base, for initial compounds, through Weinreb amidation, with different allylic bromination reactive magnesium, through sodium borohydride reduction, epoxidation, reoxidizes the key intermediate obtained such as formula (6).In the method, the 2nd step uses the pseudoallyl magnesium bromide of 4 times amount to be reactant, and the pseudoallyl magnesium bromide that existing market is sold is expensive, and a large amount of raw materials not easily obtains, and cost is higher; 3rd step adopts NaBH simultaneously 4/ CeCl 3.7H 2o is by α, and beta-unsaturated carbonyl is reduced to hydroxyl, and reaction conditions is comparatively harsh, and stereoselectivity is poor; In 4th step, epoxidation principal product and proportion of by-product are 1:1, and yield is lower; Use Dess-Martin reagent to carry out oxidizing reaction in 5th step, toxicity is comparatively large, comparatively large to environmental hazard, is not suitable for suitability for industrialized production.
Route 2:
Without the reduction step of carbonyl in route 2, directly double bond is adopted pyridine/NaOCl or Ca (OCl) 2/ NMP epoxidation, shorten reactions steps, but epoxidation stereoselectivity is poor, and when adopting pyridine/NaOCl, major-minor proportion of products is 2.5:1, and principal product yield only has 27.7%; Adopt Ca (OCl) 2during/NMP, principal product yield is 43.2%, slightly improves, but overall yield is still lower, and end product needs post to be separated, and is not suitable for suitability for industrialized production.
Patent US2005256324 discloses following synthetic route:
Route 3:
In route 3, initial compounds protects L-Leu with Cbz, through Weinreb amidation, with different allylic bromination reactive magnesium obtain, after through sodium borohydride reduction, epoxidation, reoxidize the key intermediate obtained such as formula (6).Still use excessive different allylic bromination reactive magnesium to generate α in the preparation process of this route initial compounds, beta-unsaturated carbonyl, then adopts NaBH 4/ CeCl 3.7H 2o is by α, and beta-unsaturated carbonyl is reduced to hydroxyl, and cause the stereoselectivity of product poor, resultant ratio is 4.5:1, and productive rate is lower, is unsuitable for actual production.
Patent US2007293465 discloses following synthetic route:
Route 4:
In route 4, initial compounds is using Cbz as amino protecting group, through Weinreb amidation, with different allylic bromination reactive magnesium obtain, after through sodium borohydride reduction, epoxidation, reoxidize the key intermediate obtained such as formula (18).This route still uses excessive different allylic bromination reactive magnesium to generate α, beta-unsaturated carbonyl with route 3, uses NaBH 4/ CeCl 3.7H 2o reduces double bond, and also cause the stereoselectivity of product poor, resultant ratio is 5:1, and productive rate is lower; Also use Dess-Martin reagent simultaneously and carry out oxidizing reaction, toxicity is comparatively large, comparatively large to environmental hazard, is not suitable for suitability for industrialized production.
Patent WO2014003203 discloses following synthetic route:
Route 5:
Route 5 initial compounds is obtained by above-mentioned prior art, adopts R afterwards 3n.BH 3reducing carbonyl, obtains the key intermediate of formula (6) and formula (12) through double bond epoxidation, hydroxyl oxidize.In this route, the asymmetric reduction of ketone carbonyl uses expensive boranes reductive agent, and reaction conditions is comparatively harsh, and reaction process needs strict temperature control to-5 DEG C to-10 DEG C, and industrial being difficult to realizes; The N-oxy-compound that in 3rd step, the oxidation of hydroxyl adopts not easily is prepared, and cost is higher, therefore, considers this route and is not suitable for industrialized production.
Summary of the invention
In order to solve, above-mentioned stereoselectivity is poor, yield is low and high in cost of production problem, the present invention provides through experimental study that a kind of principal product stereoselectivity is high, yield is high, production cost is low, environmental pollution is little, be suitable for the preparation method of the Ka Feizuo meter key intermediate of suitability for industrialized production and derivative F thereof, and particular content is as follows:
The preparation method of a kind of Ka Feizuo meter key intermediate and derivative F thereof, it is characterized in that taking compd E as raw material, it reacted with diisopropylethylamine and pyridine. sulfur trioxide with after dissolution with solvents, obtain product F through purifying after reacting completely, concrete reaction process is as follows:
R described in all structural formulas in the present invention 1be selected from C 1-6alkyl or C 6-10aryl C 1-6alkyl;
Further, R 1be selected from C 1-6alkyl or phenyl C 1-6alkyl;
Further, R 1be selected from
Term " alkyl " refers to entirely saturated branch or unramified hydrocarbon part.The representative example of alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl etc.
Term " aryl " refers to monocycle or the bicyclic aromatic hydrocarbon radical group at loop section with 6-10 carbon atom.Term " aryl " also refers to that the group that wherein aromatic ring and cycloalkyl ring condense, the group wherein connected are positioned on aromatic ring or on the cycloalkyl ring that condenses.The representative example of aryl has phenyl, naphthyl, six hydrogen indenyls, indanyl or tetralyl.Term " C 6-10aryl " be the aromatic hydrocarbon radical that ring portion has 6 to 10 carbon atoms.
The alkyl that term " arylalkyl " is replaced by aryl.The representative example of arylalkyl is benzyl or phenyl-CH 2cH 2-.
R in all structural formulas in the present invention 2for tertbutyloxycarbonyl (Boc) or carbobenzoxy-(Cbz) (Cbz); Described solvent is DMSO, DMF, toluene, dioxane or its mixture, preferred DMSO; The mol ratio of described diisopropylethylamine, pyridine. sulfur trioxide and compd E is 1 ~ 5:1 ~ 5:1.
Compd E synthesizes by the following method: by Compound D and vanadium acetylacetonate dissolution with solvents, reacts under nitrogen protection with peroxy tert-butyl alcohol, and through extraction separatory after reacting completely, dry, concentrate to obtain product E, concrete reaction process is as follows:
Wherein the described solvent of above-mentioned reaction is tetrahydrofuran (THF), methylene dichloride, ethanol, methyl alcohol, ethyl acetate or its mixture, preferred methylene dichloride; The mol ratio of described vanadium acetylacetonate, tertbutanol peroxide and Compound D is 0.05 ~ 0.2:1 ~ 3:1.
The preparation process of Compound D is as follows: react under optimal temperature with aluminum isopropylate and Virahol after Compound C being dissolved in solvent, through extraction separatory after reacting completely, dry, concentrated generation Compound D, and concrete reaction process is as follows:
Wherein the described solvent of above-mentioned reaction is DMSO, DMF, toluene, dioxane or its mixture, preferred toluene; Described temperature is 30-60 DEG C, preferably 50 DEG C; The mol ratio of described aluminum isopropylate, Virahol and Compound C is 1 ~ 5:1-20:1, preferred 1:5-10:1.
Compound C is prepared as follows: be dissolved in by B in solvent, with acetyl piperidine salt, piperidines and formaldehyde reaction, through extraction separatory after reacting completely, dry, concentrated obtained product C, and concrete reaction process is as follows:
Wherein the described solvent of above-mentioned reaction is tetrahydrofuran (THF), methylene dichloride, ethanol, methyl alcohol, ethyl acetate or its mixture, preferred tetrahydrofuran (THF); The mol ratio of described acetyl piperidine salt, piperidines, formaldehyde and compd B is 1 ~ 10:1 ~ 10:1 ~ 20:1, preferably 2 ~ 5:1 ~ 3:5 ~ 10:1.
Compd B is prepared as follows: be dissolved in by A in solvent, with ethyl phosphonium bromide reactive magnesium under cold condition, uses 1N hydrochloric acid after reacting completely, through extraction separatory, dry, concentrated obtained product B, and concrete reaction process is as follows:
Wherein the described solvent of above-mentioned reaction is tetrahydrofuran (THF), methylene dichloride, ethanol, methyl alcohol, ethyl acetate or its mixture, preferred tetrahydrofuran (THF); Described low temperature is-20 DEG C to-30 DEG C, preferably-20 DEG C; The mol ratio of described ethylmagnesium bromide and compd A is 1 ~ 5:1, preferred 4:1.
This route is after improving, alcohol is oxidized to the lower pyridine. sulfur trioxide of the process use cost of ketone (E-F), avoid using cost in prior art higher and the reagent such as the N-oxy-compound prepared of the transition-metal catalyst that environmental pollution is large or be difficult to, not only reduce production cost, and simple to operate, be more suitable for suitability for industrialized production; In this route, the asymmetric reduction (C-D) of ketone adopts aluminum isopropylate cheap and easy to get and Virahol simultaneously, avoid using expensive boranes reductive agent, high e.e value can be ensured on the one hand, also simplify operation on the other hand, room temperature reaction, and yield can up to more than 99%; In addition, in reaction process, (A-B-C) avoids the use of expensive reagent isopropyl alkene magnesium bromide, ethylmagnesium bromide cheap and easy to get is adopted to be reaction raw materials, although compared with prior art step increases to some extent, institute in steps operational condition is gentle, and agents useful for same is conventional reagent, cost is low, yield is high, and environmental pollution is little, is more suitable for large-scale industrial production.
Embodiment
Adopt specific embodiment to set forth further the present invention below, but and do not mean that and limit the scope of the invention by any way.Embodiment 1:[(1S)-3-methyl isophthalic acid-[[(2R)-2-methyl oxirane base] carbonyl] butyl] synthesis of-t-butyl carbamate (6)
By 0.12mol [(1S, 2S)-1-hydroxy-4-methyl-1-[[(2R)-2-methyl oxirane base] penta-2-base] t-butyl carbamate (5) is dissolved in 100ml dimethyl sulfoxide (DMSO), add 0.24mol diisopropylethylamine, add 0.24mol pyridine. sulfur trioxide under ice bath in batches, rise to room temperature reaction, TLC detection reaction is to complete, be extracted with ethyl acetate after adding suitable quantity of water, use 1N dilute hydrochloric acid respectively, saturated common salt water washing 1 time, obtain 0.10mol epoxidation product (6) after organic phase drying is concentrated, yield is 83.3%.
1H NMR(400MHz,CDCl 3)δ4.86(d,J＝8.0Hz,1H),4.30(t,J＝9.6Hz,1H),3.27(d,J＝4.8Hz,1H),2.87(d,J＝4.8Hz,1H),1.83-1.64(m,1H),1.50(s,3H),1.49-1.44(m,1H),1.39(s,9H),1.21-1.11(m,1H),0.95(d,J＝6.4Hz,3H),0.92(d,J＝6.4Hz,3H).
13C NMR(100MHz,CDCl 3)δ209.68,155.73,79.83,77.48,77.16,76.84,59.10,52.44,51.53,40.55,28.44,25.22,23.53,21.43,16.90.
Embodiment 2:[(1S)-3-methyl isophthalic acid-[[(2R)-2-methyl oxirane base] carbonyl] butyl] synthesis of-t-butyl carbamate (6)
Adopt the method identical with embodiment 1, but change the amount of diisopropylethylamine and pyridine. sulfur trioxide into 0.12mol, final 0.08mol epoxidation product (6), yield is 75.5%.
Embodiment 3:[(1S, 2S) synthesis of-1-hydroxy-4-methyl-1-[[(2R)-2-methyl oxirane base] penta-2-base] t-butyl carbamate (5)
Take 0.2mol [(3R; 4S)-3-hydroxyl-2; 6-dimethyl-1-alkene-4-base] t-butyl carbamate (4); add 200ml methylene dichloride to dissolve; then 0.04mol vanadium acetylacetonate is added; under nitrogen protection; ice bath is cooled to 0 DEG C, slowly drips peroxy tert-butyl alcohol, doubles strong stirring and spends the night; TLC detects raw material and disappears; use dichloromethane extraction after adding suitable quantity of water, use saturated sodium thiosulfate respectively, saturated common salt water washing 1 time; obtain 0.12mol hydroxyl epoxidation product (5) after organic phase drying is concentrated and purified, yield is 60.8%.
1H NMR(600MHz,CDCl 3)δ4.88(d,J＝9.6Hz,1H),3.95-3.85(m,1H),3.82(d,J＝3.0Hz,1H),2.97(d,J＝4.8Hz,1H),2.61(d,J＝4.8Hz,1H),2.44(s,1H),1.69-1.57(m,1H),1.48-1.44(m,1H),1.43(s,9H),1.36(s,3H),1.11-1.04(m,1H),0.91(d,J＝6.6Hz,3H),0.90(d,J＝6.6Hz,3H).
13C NMR(150MHz,CDCl 3)δ155.78,79.38,77.37,77.16,76.95,74.13,57.65,50.31,49.97,37.97,28.52,24.50,24.08,21.59,18.54.
Embodiment 4:[(1S, 2S) synthesis of-1-hydroxy-4-methyl-1-[[(2R)-2-methyl oxirane base] penta-2-base] t-butyl carbamate (5)
Adopt the method identical with embodiment 3, but just the amount of vanadium acetylacetonate is reduced to 0.02mol, final 0.09mol hydroxyl epoxidation product (5), yield is 45.6%.
Embodiment 5:[(3R, 4S)-3-hydroxyl-2,6-dimethyl-1-alkene-4-base] synthesis of t-butyl carbamate (4)
Take the aluminum isopropylate of 0.3mol and the Virahol of 3mol, add 200ml toluene and 0.3mol (S)-4-(t-butoxycarbonyl amino)-2,6-dimethyl-1-teracrylic acid-one (3), dissolve with 100ml toluene, drip under room temperature into reaction system, drip and finish, in 50 DEG C of reactions, TLC detection reaction is to complete, be extracted with ethyl acetate after adding suitable quantity of water, use 1N dilute hydrochloric acid respectively, saturated common salt water washing 1 time, obtain 0.30mol product (4) after organic phase drying is concentrated, yield is 100%.
1H NMR(600MHz,CDCl 3)δ5.00(s,1H),4.93(dd,J＝3.0,1.2Hz,1H),4.70(d,J＝7.8Hz,1H),4.14(s,1H),3.82(t,J＝9.6Hz,1H),2.42(s,1H),1.75(s,4H),1.67-1.57(m,J＝6.0,3.6Hz,1H),1.43(s,11H),1.31-1.23(m,2H),1.20-1.14(m,1H),0.90(d,J＝6.6Hz,3H),0.88(d,J＝6.6Hz,3H).
13C NMR(150MHz,CDCl 3)δ156.28,145.07,111.45,79.48,78.05,77.37,77.16,76.95,51.27,37.43,28.54,24.78,23.90,21.67,19.55.
Embodiment 6:[(3R, 4S)-3-hydroxyl-2,6-dimethyl-1-alkene-4-base] synthesis of t-butyl carbamate (4)
Adopt the working method identical with embodiment 5, the amount of Virahol is reduced to 1.5mol, final 0.26mol product (4), yield is 89.5%.
Embodiment 7:(S) synthesis of-4-(t-butoxycarbonyl amino)-2,6-dimethyl-1-teracrylic acid-one (3)
Take 0.4mol (S)-4-t-butoxycarbonyl amino-6-methyl-3-heptanone (2), dissolve with 400ml tetrahydrofuran (THF), add 1.5mol acetyl piperidine salt and 1.0mol piperidines and 2.0mol formaldehyde, after backflow 3h, then add 2.0mol formaldehyde, TLC detection reaction is to complete, be extracted with ethyl acetate after adding suitable quantity of water, use 1N dilute hydrochloric acid respectively, saturated common salt water washing 1 time, obtain 0.31mol product (3) after organic phase drying is concentrated, yield is 78.7%.
1H NMR(600MHz,CDCl 3)δ6.07(s,1H),5.87(s,1H),5.14(d,J＝8.4Hz,1H),5.05(td,J＝9.6,3.6Hz,1H),1.89(s,3H),1.76-1.71(m,1H),1.50-1.44(m,1H),1.42(s,9H),1.32(ddd,J＝14.4,9.6,4.8Hz,1H),0.99(d,J＝6.6Hz,3H),0.89(d,J＝6.6Hz,3H).
13C NMR(150MHz,CDCl 3)δ201.76,142.47,126.15,79.70,77.37,77.16,76.95,52.73,43.31,28.48,25.11,23.50,21.90,17.96.
Embodiment 8:(S) synthesis of-4-(t-butoxycarbonyl amino)-2,6-dimethyl-1-teracrylic acid-one (3)
Adopt the working method identical with embodiment 7, but change the amount of acetyl piperidine salt into 0.8mol, the amount of piperidines is reduced to 1.2mol, and the usage quantity of twice formaldehyde is 1.0mol, and final 0.28mol product (3), yield is 70.9%.
Embodiment 9:(S) synthesis of-4-t-butoxycarbonyl amino-6-methyl-3-heptanone (2)
Take N-tertiary butyloxycarbonyl acyl group-L-Leu-N '-methoxyl group-N '-methane amide (1) 0.5mol and be placed in reaction flask; dissolve with 500ml tetrahydrofuran (THF), at-20 DEG C, drip ethylmagnesium bromide (2.0M; 750ml), Bi Shengzhi ambient temperature overnight is dripped.Slow dropping 1N dilute hydrochloric acid cancellation reaction, extraction into ethyl acetate, saturated common salt water washing, organic phase drying concentrates to obtain 0.40mol product (2), and yield is 80.6%.
1H NMR(600MHz,CDCl 3)δ5.04(d,J＝7.4Hz,1H),4.28(td,J＝9.0,3.6Hz,1H),2.59-2.38(m,2H),1.73-1.61(m,1H),1.52-1.44(m,1H),1.39(s,9H),1.34-1.25(m,1H),1.03(t,J＝7.2Hz,3H),0.92(d,J＝6.6Hz,3H),0.88(d,3H).
13C NMR(150MHz,CDCl 3)δ210.96,155.71,79.69,77.37,77.16,76.95,57.71,40.99,33.03,28.39,24.96,23.37,21.85,7.67.
Embodiment 10:(S) synthesis of-4-t-butoxycarbonyl amino-6-methyl-3-heptanone (2)
Adopt the working method identical with embodiment 9, but temperature is reduced to-30 DEG C, the amount of ethylmagnesium bromide changes into (1.0M, 325ml), and final 0.30mol product (2), yield is 60.3%.
Embodiment 11:[(1S)-1-[[(2R)-2-methyl oxirane base] carbonyl] styroyl] synthesis of-t-butyl carbamate (12)
By 0.12mol [(1S, 2S)-1-hydroxyl-2-[[(2R)-2-methyl oxirane base] styroyl] t-butyl carbamate (11) is dissolved in 100ml dimethyl sulfoxide (DMSO), add 0.24mol diisopropylethylamine, add 0.24mol pyridine. sulfur trioxide under ice bath in batches, rise to room temperature reaction, TLC detection reaction is to complete, be extracted with ethyl acetate after adding suitable quantity of water, use 1N dilute hydrochloric acid respectively, saturated common salt water washing 1 time, obtain 0.083mol epoxidation product (12) after organic phase drying is concentrated, yield is 68.7%.
1H NMR(400MHz,CDCl 3)δ7.25(m,5H),4.93(d,J＝7.7Hz,1H),4.58(dd,J＝13.2,8.0Hz,1H),3.29(d,J＝4.9Hz,1H),3.10(dd,J＝13.9,5.0Hz,1H),2.90(d,J＝4.9Hz,1H),2.73(dd,J＝13.8,7.7Hz,1H),1.50(s,3H),1.36(s,9H).
Embodiment 12:[(1S, 2S) synthesis of-1-hydroxyl-2-[[(2R)-2-methyl oxirane base] styroyl] t-butyl carbamate (11)
Take 0.2mol [(3R; 4S)-3-hydroxyl-5-phenyl-1-alkene-4-base] t-butyl carbamate (10); add 200ml methylene dichloride to dissolve; then 0.04mol vanadium acetylacetonate is added; under nitrogen protection; ice bath is cooled to 0 DEG C; slow dropping peroxy tert-butyl alcohol; double strong stirring to spend the night, TLC detects raw material and disappears, and uses dichloromethane extraction after adding suitable quantity of water; use saturated sodium thiosulfate respectively; saturated common salt water washing 1 time, obtain 0.151mol hydroxyl epoxidation product (11) after organic phase drying is concentrated and purified, yield is 75.5%.
1H NMR(600MHz,CDCl 3)δ7.25(m,5H),4.87(d,J＝9.4Hz,1H),4.12(m,1H),3.85(d,J＝2.3Hz,1H),3.01(d,J＝4.6Hz,1H),2.86(dd,J＝14.0,4.7Hz,1H),2.75(dd,J＝14.2,9.5Hz,1H),2.60(d,J＝4.6Hz,1H),2.34(s,1H),1.38(s,3H),1.32(s,9H).
Embodiment 13:[(3R, 4S)-3-hydroxyl-5-phenyl-1-alkene-4-base] synthesis of t-butyl carbamate (10)
Take the aluminum isopropylate of 0.3mol and the Virahol of 3mol, add 200ml toluene and 0.3mol (S)-4-(t-butoxycarbonyl amino)-5-phenyl-1-penten-3-one (9), dissolve with 100ml toluene, drip under room temperature into reaction system, drip and finish, in 50 DEG C of reactions, TLC detection reaction is to complete, be extracted with ethyl acetate after adding suitable quantity of water, use 1N dilute hydrochloric acid respectively, saturated common salt water washing 1 time, obtain 0.23mol product (10) after organic phase drying is concentrated, yield is 75.9%.
1H NMR(600MHz,CDCl 3)δ7.24(m,0H),7.24(m,5H),5.08(s,1H),5.00(s,1H),4.64(s,1H),4.20(s,1H),3.98(s,1H),2.89(dd,J＝14.3,3.7Hz,1H),2.70(s,1H),2.36(s,1H),1.81(s,3H),1.34(s,9H).
Embodiment 14:(S) synthesis of-4-(t-butoxycarbonyl amino)-5-phenyl-1-penten-3-one (9)
Take 0.4mol (S)-4-t-butoxycarbonyl amino-5-phenyl-propione (8), dissolve with 400ml tetrahydrofuran (THF), add 1.5mol acetyl piperidine salt and 1.0mol piperidines and 2.0mol formaldehyde, after backflow 3h, then add 2.0mol formaldehyde, TLC detection reaction is to complete, be extracted with ethyl acetate after adding suitable quantity of water, use 1N dilute hydrochloric acid respectively, saturated common salt water washing 1 time, obtain 0.1mol product (9) after organic phase drying is concentrated, yield is 54.1%.
1H NMR(600MHz,CDCl 3)δ7.26(s,5H),7.19(m,5H),6.01(s,1H),5.85(d,J＝1.2Hz,1H),5.33(m,1H),5.26(s,1H),3.10(m,1H),2.91(m,1H),1.86(s,3H),1.38(d,J＝20.7Hz,9H).
Embodiment 15:(S) synthesis of-4-t-butoxycarbonyl amino-5-phenyl-propione (8)
Take N-tertiary butyloxycarbonyl acyl group-n-phenylalanine-N '-methoxyl group-N '-methane amide (7) 0.5mol and be placed in reaction flask; dissolve with 500ml tetrahydrofuran (THF), at-20 DEG C, drip ethylmagnesium bromide (2.0M; 750ml), Bi Shengzhi ambient temperature overnight is dripped.Slow dropping 1N dilute hydrochloric acid cancellation reaction, extraction into ethyl acetate, saturated common salt water washing, organic phase drying concentrates to obtain 0.35mol product (8), and yield is 69.6%.
1H NMR(600MHz,CDCl 3)δ7.26(s,5H),7.23(m,5H),5.13(d,J＝7.4Hz,1H),4.54(dd,J＝14.0,6.9Hz,1H),3.04(dd,J＝13.8,6.9Hz,1H),2.97(dd,J＝13.9,6.3Hz,1H),2.38(m,2H),1.41(s,9H),1.00(t,J＝7.2Hz,3H).
Embodiment 16:[(1S)-3-phenyl-1-[[(2R)-2-methyl oxirane base] carbonyl] propyl group] synthesis of-t-butyl carbamate (18)
By 0.12mol [(1S, 2S)-1-hydroxy-4-phenyl-1-[[(2R)-2-methyl oxirane base] butyl] t-butyl carbamate (17) is dissolved in 100ml dimethyl sulfoxide (DMSO), add 0.24mol diisopropylethylamine, add 0.24mol pyridine. sulfur trioxide under ice bath in batches, rise to room temperature reaction, TLC detection reaction is to complete, be extracted with ethyl acetate after adding suitable quantity of water, use 1N dilute hydrochloric acid respectively, saturated common salt water washing 1 time, obtain 0.12mol epoxidation product (18) after organic phase drying is concentrated, yield is 100%.
1H NMR(400MHz,CDCl 3)δ7.24(m,5H),5.02(d,J＝7.9Hz,1H),4.35(d,J＝3.4Hz,1H),3.21(d,J＝4.8Hz,1H),2.87(d,J＝5.0Hz,1H),2.69(m,2H),2.11(m,1H),1.63(m,1H),1.49(s,3H),1.43(s,9H).
Embodiment 17:[(1S, 2S) synthesis of-1-hydroxy-4-phenyl-1-[[(2R)-2-methyl oxirane base] butyl] t-butyl carbamate (17)
Take 0.2mol [(3R; 4S)-3-hydroxyl-6-phenyl-1-alkene-4-base] t-butyl carbamate (16); add 200ml methylene dichloride to dissolve; then 0.04mol vanadium acetylacetonate is added; under nitrogen protection; ice bath is cooled to 0 DEG C; slow dropping peroxy tert-butyl alcohol; double strong stirring to spend the night, TLC detects raw material and disappears, and uses dichloromethane extraction after adding suitable quantity of water; use saturated sodium thiosulfate respectively; saturated common salt water washing 1 time, obtain 0.062mol hydroxyl epoxidation product (17) after organic phase drying is concentrated and purified, yield is 31.0%.
1H NMR(600MHz,CDCl 3)δ7.25(m,5H),4.96(d,J＝9.2Hz,1H),3.89(d,J＝10.2Hz,1H),3.85(s,1H),2.95(d,J＝4.8Hz,1H),2.77(m,1H),2.60(m,2H),2.14(s,1H),1.73(m,2H),1.47(d,J＝6.4Hz,9H),1.26(m,3H).
Embodiment 18:[(3R, 4S)-3-hydroxyl-6-phenyl-1-alkene-4-base] synthesis of t-butyl carbamate (16)
Take the aluminum isopropylate of 0.3mol and the Virahol of 3mol, add 200ml toluene and 0.3mol (S)-4-(t-butoxycarbonyl amino)-6-phenyl-1-hexene-3-one (15), dissolve with 100ml toluene, drip under room temperature into reaction system, drip and finish, in 50 DEG C of reactions, TLC detection reaction is to complete, be extracted with ethyl acetate after adding suitable quantity of water, use 1N dilute hydrochloric acid respectively, saturated common salt water washing 1 time, obtain 0.26mol product (16) after organic phase drying is concentrated, yield is 86.1%.
1H NMR(600MHz,CDCl 3)δ7.23(m,5H),5.01(s,1H),4.92(dd,J＝2.7,1.4Hz,1H),4.80(d,J＝8.8Hz,1H),4.12(dd,J＝14.3,7.2Hz,1H),3.79(s,1H),2.75(m,1H),2.59(m,1H),2.15(s,1H),1.80(m,1H),1.65(d,J＝14.0Hz,3H),1.59(s,1H),1.45(d,J＝13.7Hz,9H).
Embodiment 19:(S) synthesis of-4-(t-butoxycarbonyl amino)-6-phenyl-1-hexene-3-one (15)
Take 0.4mol (S)-4-t-butoxycarbonyl amino-6-phenyl-3-hexanone (14), dissolve with 400ml tetrahydrofuran (THF), add 1.5mol acetyl piperidine salt and 1.0mol piperidines and 2.0mol formaldehyde, after backflow 3h, then add 2.0mol formaldehyde, TLC detection reaction is to complete, be extracted with ethyl acetate after adding suitable quantity of water, use 1N dilute hydrochloric acid respectively, saturated common salt water washing 1 time, obtain 0.034mol product (15) after organic phase drying is concentrated, yield is 48.6%.
1H NMR(600MHz,CDCl 3)δ7.22(m,5H),5.90(s,1H),5.83(s,1H),5.35(m,1H),5.06(s,1H),2.64(m,2H),2.05(m,2H),1.87(s,3H),1.46(s,9H).
Embodiment 20:(S) synthesis of-4-t-butoxycarbonyl amino-6-phenyl-3-hexanone (14)
Take N-tertiary butyloxycarbonyl acyl group-hyperphenylalaninemia-N '-methoxyl group-N '-methane amide (13) 0.5mol and be placed in reaction flask; dissolve with 500ml tetrahydrofuran (THF), at-20 DEG C, drip ethylmagnesium bromide (2.0M; 750ml), Bi Shengzhi ambient temperature overnight is dripped.Slow dropping 1N dilute hydrochloric acid cancellation reaction, extraction into ethyl acetate, saturated common salt water washing, organic phase drying concentrates to obtain 0.41mol product (14), and yield is 81.1%.
1H NMR(600MHz,CDCl 3)δ7.22(m,5H),5.25(d,J＝7.4Hz,1H),4.38(d,J＝4.2Hz,1H),2.64(m,2H),2.48(m,2H),2.19(m,1H),1.81(m,1H),1.45(s,9H),1.06(t,J＝7.3Hz,3H).
Embodiment 21:[(1S)-1-[[(2R)-2-methyl oxirane base] carbonyl] amyl group] synthesis of-t-butyl carbamate (24)
By 0.12mol [(1S, 2S)-1-hydroxyl-1-[[(2R)-2-methyl oxirane base] amyl group] t-butyl carbamate (23) is dissolved in 100ml dimethyl sulfoxide (DMSO), add 0.24mol diisopropylethylamine, add 0.24mol pyridine. sulfur trioxide under ice bath in batches, rise to room temperature reaction, TLC detection reaction is to complete, be extracted with ethyl acetate after adding suitable quantity of water, use 1N dilute hydrochloric acid respectively, saturated common salt water washing 1 time, obtain 0.057mol epoxidation product (24) after organic phase drying is concentrated, yield is 47.7%.
1H NMR(400MHz,CDCl 3)δ4.92(d,J＝8.3Hz,1H),4.27(t,J＝8.0Hz,1H),3.25(d,J＝4.8Hz,1H),2.88(d,J＝5.0Hz,1H),1.75(m,1H),1.59(s,1H),1.51(s,3H),1.42(d,J＝9.5Hz,9H),1.34(d,J＝7.6Hz,2H),1.30(s,2H),0.90(-CH 3,m,3H).
Embodiment 22:[(1S, 2S) synthesis of-1-hydroxyl-1-[[(2R)-2-methyl oxirane base] amyl group] t-butyl carbamate (23)
Take 0.2mol [(3R; 4S)-3-hydroxy-2-methyl-1-alkene-4-base] t-butyl carbamate (22); add 200ml methylene dichloride to dissolve; then 0.04mol vanadium acetylacetonate is added; under nitrogen protection; ice bath is cooled to 0 DEG C; slow dropping peroxy tert-butyl alcohol; double strong stirring to spend the night, TLC detects raw material and disappears, and uses dichloromethane extraction after adding suitable quantity of water; use saturated sodium thiosulfate respectively; saturated common salt water washing 1 time, obtain 0.06mol hydroxyl epoxidation product (23) after organic phase drying is concentrated and purified, yield is 49.7%.
1H NMR(600MHz,CDCl 3)δ4.90(-CONH,d,J＝9.2Hz,1H),3.80(-CH,s,1H),3.75(-CH,s,1H),2.97(-CH 2,d,J＝4.8Hz,1H),2.62(-CH 2,d,J＝4.8Hz,1H),2.34(-OH,d,J＝10.0Hz,1H),1.44(-CH 3,s,9H),1.38(-CH 2,m,2H),1.37(-CH 3,s,3H),1.31(-CH 2,m,2H),1.23(-CH 2,ddd,J＝11.3,4.6,2.3Hz,2H),0.88(-CH 3,t,J＝6.4Hz,3H).
Embodiment 23:[(3R, 4S)-3-hydroxy-2-methyl-1-alkene-4-base] synthesis of t-butyl carbamate (22)
Take the aluminum isopropylate of 0.3mol and the Virahol of 3mol, add 200ml toluene and 0.3mol (S)-4-(t-butoxycarbonyl amino)-2-methyl isophthalic acid-octene-3-ketone (21), dissolve with 100ml toluene, drip under room temperature into reaction system, drip and finish, in 50 DEG C of reactions, TLC detection reaction is to complete, be extracted with ethyl acetate after adding suitable quantity of water, use 1N dilute hydrochloric acid respectively, saturated common salt water washing 1 time, obtain 0.24mol product (22) after organic phase drying is concentrated, yield is 78.4%.
1H NMR(600MHz,CDCl 3)δ5.01(-CH 2,s,1H),4.95(-CH 2,d,J＝1.3Hz,1H),4.65(-CONH,s,1H),4.14(-CH,s,1H),3.74(-CH,s,1H),2.23(-OH,d,J＝7.7Hz,1H),1.76(-CH 3,s,3H),1.44(-CH 3,d,J＝10.0Hz,9H),1.27(-CH 2,s,2H),0.88(-CH 3,t,J＝6.7Hz,3H).
Embodiment 24:(S) synthesis of-4-(t-butoxycarbonyl amino)-2-methyl isophthalic acid-octene-3-ketone (21)
Take 0.4mol (S)-4-t-butoxycarbonyl amino-3-octanone (20), dissolve with 400ml tetrahydrofuran (THF), add 1.5mol acetyl piperidine salt and 1.0mol piperidines and 2.0mol formaldehyde, after backflow 3h, then add 2.0mol formaldehyde, TLC detection reaction is to complete, be extracted with ethyl acetate after adding suitable quantity of water, use 1N dilute hydrochloric acid respectively, saturated common salt water washing 1 time, obtain 0.12mol product (21) after organic phase drying is concentrated, yield is 48.8%.
1H NMR(600MHz,CDCl 3)δ6.05(-CH 2,s,1H),5.88(-CH 2,d,J＝0.9Hz,1H),5.28(-CONH,d,J＝8.1Hz,1H),5.01(-CH,dt,J＝12.5,6.4Hz,1H),1.90(-CH 3,s,3H),1.76(-CH 2,m,1H),1.49(-CH 2,m,1H),1.43(-CH 3,s,9H),1.33(-CH 2,m,2H),1.25(-CH 2,d,J＝2.5Hz,2H),0.87(-CH 3,t,J＝7.0Hz,3H).
Embodiment 25:(S) synthesis of-4-t-butoxycarbonyl amino-3-octanone (20)
Take N-tertiary butyloxycarbonyl acyl group-L-nor-leucine-N '-methoxyl group-N '-methane amide (19) 0.5mol and be placed in reaction flask; dissolve with 500ml tetrahydrofuran (THF), at-20 DEG C, drip ethylmagnesium bromide (2.0M; 750ml), Bi Shengzhi ambient temperature overnight is dripped.Slow dropping 1N dilute hydrochloric acid cancellation reaction, extraction into ethyl acetate, saturated common salt water washing, organic phase drying concentrates to obtain 0.38mol product (20), and yield is 75.5%.
1H NMR(600MHz,CDCl 3)δ5.17(-CONH,d,J＝6.4Hz,1H),4.31(-CH,dd,J＝11.9,7.2Hz,1H),2.51(-CH 2,m,2H),1.81(-CH 2,m,1H),1.50(-CH 2,ddd,J＝11.5,10.6,5.9Hz,1H),1.43(-CH 3,s,9H),1.34(-CH 2,m,2H),1.25(-CH 2,m,2H),1.07(-CH 3,t,J＝7.3Hz,3H),0.88(-CH 3,t,J＝7.0Hz,3H)。

Claims (11)

1. the preparation method of Yi Zhong Ka Feizuo meter key intermediate and derivative thereof, it is characterized in that taking compd E as raw material, it reacted with diisopropylethylamine and pyridine. sulfur trioxide with after dissolution with solvents, obtain product F through purifying after reacting completely, concrete reaction process is as follows:
Wherein said R 1be selected from C 1-6alkyl or C 6-10aryl C 1-6alkyl;
R 2for tertbutyloxycarbonyl (Boc) or carbobenzoxy-(Cbz) (Cbz).
2. preparation method as claimed in claim 1, is characterized in that described R 1be selected from C 1-6alkyl or phenyl C 1-6alkyl.
3. preparation method as claimed in claim 2, is characterized in that described R 1be selected from
4. preparation method as claimed in claim 1, is characterized in that described solvent is DMSO, DMF, toluene, dioxane or its mixture; The mol ratio of described diisopropylethylamine, pyridine. sulfur trioxide and compd E is 1 ~ 5:1 ~ 5:1.
5. preparation method as claimed in claim 1, is characterized in that compd E synthesizes by the following method: by Compound D and vanadium acetylacetonate dissolution with solvents, reacts under nitrogen protection with peroxy tert-butyl alcohol; through extraction separatory after reacting completely; drying, concentrate to obtain product E, concrete reaction process is as follows:
6. preparation method as claimed in claim 5, is characterized in that described solvent is tetrahydrofuran (THF), methylene dichloride, ethanol, methyl alcohol, ethyl acetate or its mixture; The mol ratio of described vanadium acetylacetonate, tertbutanol peroxide and Compound D is 0.05 ~ 0.2:1 ~ 3:1.
7. preparation method as claimed in claim 5, it is characterized in that the preparation process of Compound D is as follows: react under optimal temperature with aluminum isopropylate and Virahol after Compound C being dissolved in solvent, through extraction separatory after reacting completely, dry, concentrated generation Compound D, concrete reaction process is as follows:
8. preparation method as claimed in claim 7, is characterized in that described solvent is DMSO, DMF, toluene, dioxane or its mixture; Described temperature is 30-60 DEG C; The mol ratio of described aluminum isopropylate, Virahol and Compound C is 1 ~ 5:1-20:1.
9. preparation method as claimed in claim 7, is characterized in that Compound C is prepared as follows: be dissolved in by B in solvent, with acetyl piperidine salt, piperidines and formaldehyde reaction, through extraction separatory after reacting completely, dry, concentrated obtained product C, and concrete reaction process is as follows:
10. preparation method as claimed in claim 9, is characterized in that described solvent is tetrahydrofuran (THF), methylene dichloride, ethanol, methyl alcohol, ethyl acetate or its mixture; The mol ratio of described acetyl piperidine salt, piperidines, formaldehyde and compd B is 1 ~ 10:1 ~ 10:1 ~ 20:1.
11. preparation methods as claimed in claim 9, is characterized in that compd B is prepared as follows: be dissolved in by A in solvent, with ethyl phosphonium bromide reactive magnesium under cold condition, 1N hydrochloric acid is used after reacting completely, through extraction separatory, dry, concentrated obtained product B, concrete reaction process is as follows:
Wherein said solvent is tetrahydrofuran (THF), methylene dichloride, ethanol, methyl alcohol, ethyl acetate or its mixture; Described low temperature is-20 DEG C to-30 DEG C; The mol ratio of described ethylmagnesium bromide and compd A is 1 ~ 5:1.
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