CN105461662A - Synthetic method for chiral epoxy compound of anti-HIV drug intermediate - Google Patents
Synthetic method for chiral epoxy compound of anti-HIV drug intermediate Download PDFInfo
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- CN105461662A CN105461662A CN201410439809.4A CN201410439809A CN105461662A CN 105461662 A CN105461662 A CN 105461662A CN 201410439809 A CN201410439809 A CN 201410439809A CN 105461662 A CN105461662 A CN 105461662A
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Abstract
The invention belongs to the field of chemical synthesis and particularly relates to a preparation method for a chiral epoxy compound of an anti-HIV drug intermediate. The method provided by the invention synthesizes the chiral epoxy compound by using a special ligand according to a route represented by the formula. L-phenylalanine used for synthesizing the anti-HIV drug intermediate is low in price and is easily available. The synthetic method is simple and feasible, the yield of the chiral epoxy compound is high, and the synthetic cost of the chiral epoxy compound is obviously lowered compared with that in an existing process.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to the preparation method of the chiral epoxy compound of inverase intermediate.
Background technology
It is reported, after discovery human immunodeficiency virus (HIV) is the inducement of acquired immune deficiency syndrome (AIDS) (AIDS), increasing correlative study concentrates on antiviral therapy.Therefore, the demand of antiviral is aobvious to be increased, and wherein, the synthesis of chiral epoxy compound also enjoys those skilled in the art to pay close attention to.It is reported, chiral epoxy compound is just playing more and more important effect in fields such as modern organic synthesis, chiral drug synthesis, its major cause is: some chiral epoxy compounds itself have important physiologically active, and many chemical conversions can be completed by chiral epoxy compound, thus some chipal compounds with physiologically active can be synthesized.
Current correlative study has: " OrganicProcess & Development2002,6,323-328 ", it is disclosed that the synthetic method of hiv protease inhibitor B MS-232632; " J.Org.Chem.1994,59,3656-3664 " which describes the research of the extensive synthesis of hiv protease inhibitor Ro31-8959, etc.But existing synthetic method is all because cost is higher, or technique is more complicated etc. is comparatively difficult to actually operating.In view of present situation, present inventor intends the synthetic method providing a kind of new chiral epoxy compound, for current urgent need.
Summary of the invention
Object of the present invention is intended to the defect overcoming prior art, provides a kind of synthetic method of new chiral epoxy compound, is specifically related to a kind of preparation method of chiral epoxy compound of inverase intermediate.The present invention proposes the synthesis that proprietary part carries out chiral epoxy compound, and obtain unusual effect, the synthesis cost of chiral epoxy compound obviously reduces compared with the prior art.
Specifically, the preparation method of the chiral epoxy compound of a kind of inverase intermediate of the present invention, is characterized in that, by following synthetic route, synthesized the chiral epoxy compound of inverase intermediate by the L-Phe of commercial cheapness, comprise the following steps:
(1) under NaOH and THF exists, formula II compound and tert-Butyl dicarbonate react production III compound,
(2) at CH
3n
2under existing with HX, formula III compound and formula IV compound, formula V compound react production VI compound,
Wherein, HX represents halogenide, comprises HCl, HBr, HI etc.;
(3) at MTBE and H
2under O exists, formula VI compound and NaBH
4production VII compound,
(4) in the presence of a base, formula VII compound of formula I compound
In step of the present invention (1), the mol ratio of formula II compound and tert-Butyl dicarbonate is 1:1 ~ 1:1.2, is preferably 1:1.1; The mol ratio of formula II compound and NaOH is 1:2 ~ 1:2.4, is preferably 1:2.2; The amount ratio of formula II compound and THF is 1g formula II compound/3mLTHF ~ 1g formula II compound/7mLTHF, is preferably 1g formula II compound/5mLTHF; Reaction times is 2 ~ 10 hours, is preferably 4 ~ 7 hours; Temperature of reaction is 10 DEG C ~ 100 DEG C, is preferably 20 DEG C ~ 50 DEG C;
In step of the present invention (2), the mol ratio of formula III compound and formula IV compound is 1:0.9 ~ 1:1.2, is preferably 1:1; The mol ratio of formula II compound and formula V compound is 1:0.9 ~ 1:1.2, is preferably 1:1; Formula II compound and CH
3n
2consumption be 1g formula II compound/3mLCH
3n
2~ 1g formula II compound/7mLCH
3n
2, be preferably 1g formula II compound/5mLCH
3n
2; Reaction times is 1 ~ 20 hour, is preferably 2 ~ 12 hours; Temperature of reaction is-40 DEG C ~ 40 DEG C, is preferably-28 DEG C ~ 20 DEG C;
In step of the present invention (3), formula VI compound and NaBH
4mol ratio be 1:1 ~ 1:5, be preferably 1:2.5; The consumption of formula VI compound and MTBE is 1g formula II compound/10mLMTBE ~ 1g formula II compound/30mLMTBE, is preferably 1g formula II compound/22mLMTBE; The consumption of formula VI compound and water is 1g formula II compound/1mL water ~ 1g formula II compound/3mL water, is preferably 1g formula II compound/2mL water; Reaction times is 10 ~ 30 hours, is preferably 15 ~ 20 hours; Temperature of reaction is-10 DEG C ~ 30 DEG C, is preferably 0 DEG C ~ 20 DEG C;
In step of the present invention (4), described alkali is preferably potassium hydroxide; The mol ratio of formula VII compound and alkali is 1:0.8 ~ 1:1, is preferably 1:0.9; Reaction times is 2 ~ 6 hours, is preferably 3 hours.
Method of the present invention, proprietary part is adopted to carry out the synthesis of chiral epoxy compound, synthesis inverase intermediate L-Phe used is cheap, be easy to get, synthetic method is simple, chiral epoxy compound productive rate is high, and the synthesis cost of chiral epoxy compound obviously reduces compared with the prior art.
Embodiment
The present invention is further illustrated below with specific embodiment.
Embodiment 1: preparation BOC-L-phenylalanine (formula III compound)
In 3L there-necked flask, add water 1060mL, under ice bath, add NaOH solid 106g, stir, temperature Tmax=52 DEG C, when temperature is down to below 30 DEG C, adds L-Phe (formula II compound) 198.4g, add THF1056mL, as T=22 DEG C, drip BoC
2o289g, 22min titration, temperature 37 DEG C now, under room temperature, reaction is spent the night, and system produces a large amount of white solid;
Next day samples TLC, and raw material has reacted complete, decompression (45 DEG C) removing THF, and residue aqueous phase is creamy white, and adds HCL wherein and regulates pH=1, use CH
2cL
2(1+1) extract 2 times, TLC aqueous phase product-free, organic phase brine500mL washs once, dried over sodium sulfate.Be spin-dried for organic phase, obtain 332g oily liquids, by adding 1.2L normal hexane in oily liquids, add be back to clearly molten, backflow 5min be placed on stirred at ambient temperature, filter, dry to obtain formula III compound 311.58g, HPLC purity 99.44%, productive rate 98.5%.
Embodiment 2: the chloro ketone compound (a kind of formula VI compound) of preparation Boc-L-phenylalanine
In 1L there-necked flask, add formula III compound 66.3g, THF500mL, is cooled to-25 DEG C, drips formula IV compound 29.15g in there-necked flask, stirs 30 minutes.Dropping formula V compound 27.18g, reacts 92 minutes, is incubated-25 to-28 DEG C, produces a large amount of white solid in dropping process.Fast filtering at-5 DEG C, filter cake THF (50+50) mL washes twice, and filtrate is transferred in 2L there-necked flask, lowers the temperature at about 0 DEG C, nitrogen replacement three times, drips CH to system
3n
2370mL, react 90 minutes, temperature maintains about 0 DEG C, and system becomes yellow-green colour from colourless, adds HCl400mL reaction and spend the night (room temperature) in system;
Next day separatory, collect organic phase, aqueous phase MTBE (200+200) mL extracts 2 times to aqueous phase TLC product-free, the saturated NaHCO of organic phase
3wash respectively once with saturated NaCl, anhydrous Na
2sO
4dry;
Be spin-dried for organic phase and obtain 695g white solid VI.Above solid is dissolved in 650mL sherwood oil, and reflux is until clearly molten, and cooling is afterwards placed in refrigerator cold-storage.Filter after 2 hours, dry to obtain 55.6g white solid, productive rate 74%, HPLC94%.
Embodiment 3: the chloro ketone compound (a kind of formula VI compound) of preparation Boc-L-phenylalanine
Formula III compound 70.4g is added in 1L there-necked flask; THF530mL, is cooled to less than-28 DEG C, drips formula IV compound 30g in there-necked flask; drip complete stirring 30 minutes; dropping formula V compound 27.5g, reacts 85 minutes, is incubated-28 DEG C to-30 DEG C systems and produces a large amount of white solid; fast filtering at-5 DEG C; filtrate is transferred in 2L there-necked flask, and nitrogen protection drips CH in system
3n
2400mL, react 50 minutes, temperature maintains about 0 DEG C, and system is in yellow, and drip HCl700mL in 1 hour backward system, room temperature reaction spends the night;
Next day separatory, collect organic phase, aqueous phase MTBE (200+200) mL to aqueous phase TLC product-free, organic phase uses saturated NaHCO respectively
3wash once with each 100mL of saturated NaCl, NaSO
4dry.；
Be spin-dried for obtain 71.3g white solid and formula VI compound, above solid is dissolved in 680mL sherwood oil, reflux is to clearly molten, and cooling crystallization, is placed in refrigerator cold-storage, within 4 hours, filters, dries to obtain 55g white solid, productive rate 70%.
Embodiment 4: the reduzate (a kind of formula VII compound) of the chloro ketone compound of preparation Boc-L-phenylalanine
Formula VI compound 55g is added, MTBE1220mL, H in 2L there-necked flask
2o96mL, is cooled to 0 DEG C, and cryosel is bathed, and magnetic agitation, adds NaBH in batches
419.4g, is no more than 0 DEG C with temperature and is advisable, and reacts 45 minutes, about adds latter 1 hour, and system produces white solid, insulation reaction.TLC after 1 hour, formula VI compound almost without residue, rises to ambient temperature overnight;
Next day, above-mentioned system is revolved and steams removing MTBE, add H
2o1L, EA2.2L, saturated NaHSO
3be adjusted to pH6-7, now system clarification, separatory, collect organic phase, aqueous phase EA (500+500) mL extracts 2 times, and to TLC aqueous phase product-free, organic phase uses H respectively
2once, NaSO4 is dry, filters, revolve steaming, obtain 54.2g white solid and formula VII compound after 2 hours, filters and dry to obtain 29.2g white solid, productive rate 52.8% after 2 hours for each 1L washing of O and Brine.
Embodiment 5: the reduzate (a kind of formula VII compound) of the chloro ketone compound of preparation Boc-L-phenylalanine
Formula VI compound 52g is added, MTBE1150mL, H in 2L there-necked flask
2o90mL, is cooled to less than 0 DEG C.During Nei Wen-4 DEG C, add NaBH to system in batches
420.5g, sampled TLC after 1.5 hours, and the reaction of formula VI compound is complete, processing reaction liquid, revolved steaming (40 DEG C) removing MTBE, added water 1L, EA2L, drip NaHSO under stirring
3saturated solution to pH=6-7, Scatter Gather organic phase afterwards, aqueous phase EA (500+500) mL extracting twice, TLC aqueous phase product-free, organic phase H
2the each 1L of O, NaCl saturated solution washes once, NaSO
4drying, is spin-dried for organic phase, obtains 51.4g white solid and formula VII compound.
Embodiment 6: synthesizing chiral epoxy compound (type I compound)
Formula VII compound 27mmol is joined in methyl alcohol (270mL) and carries out stirring into suspension and in cooled on ice, in 5 minutes, add the methanol solution that 50mL contains potassium hydroxide (30mmol) simultaneously, 3 hours are mixed under room temperature, then concentrated removal methyl alcohol, precipitation methylene dichloride (300mL) and water (2*100mL) carry out extracting and separating, and the dichloromethane solution containing extract is carried out drying (Na successively
2sO
4), filter, evaporation, obtain the white solid that fusing point is 122-125 DEG C, be type I compound (7.1g, 100%), utilize n-normal hexane to carry out recrystallize, obtain analytically pure I, fusing point 122-124.5 DEG C. [α] 20D-8.1 ° of (c=1.0%inMeOH) .1HNMR (CDCl3) δ 1.39 (s, 9H), 2.77-3.02 (m, 5H), 3.70 (bs, 1H), 7.2-7.4 (m, 5H). analyze.C
15h
21nO
3calculated value: C, 68.42; H, 8.04; N, 5.32. basic value: C, 68.42; H, 8.05; N, 5.08.MS(FAB)m/z264[M+H]
+。
Claims (9)
1. a synthetic method for the chiral epoxy compound of inverase intermediate, is characterized in that, by following step, and syntheticcompoundofformulaⅰ:
(1) under NaOH and THF exists, formula II compound and tert-Butyl dicarbonate react production III compound
(2) at CH
3n
2under existing with HX, formula III compound and formula IV compound, formula V compound react production VI compound
(3) at MTBE and H
2under O exists, formula VI compound and NaBH
4production VII compound
(4) in the presence of a base, formula VII compound of formula I compound
2. the method for claim 1, is characterized in that: in described step (1), and the mol ratio of formula II compound and tert-Butyl dicarbonate is 1:1 ~ 1:1.2; The mol ratio of formula II compound and NaOH is 1:2 ~ 1:2.4; The amount ratio of formula II compound and THF is: 1g formula II compound/3mLTHF ~ 1g formula II compound/7mLTHF; Reaction times is 2 ~ 10 hours; Temperature of reaction is 10 DEG C ~ 100 DEG C.
3. the method for claim 1, is characterized in that: in described step (1), and the mol ratio of formula II compound and tert-Butyl dicarbonate is 1:1.1; The mol ratio of formula II compound and NaOH is 1:2.2; The amount ratio of formula II compound and THF is: 1g formula II compound/5mLTHF; Reaction times is 4 ~ 7 hours; Temperature of reaction is 20 DEG C ~ 50 DEG C.
4. the method for claim 1, is characterized in that, in described step (2), the mol ratio of formula III compound and formula IV compound is 1:0.9 ~ 1:1.2; The mol ratio of formula II compound and formula V compound is 1:0.9 ~ 1:1.2; Formula II compound and CH
3n
2consumption be 1g formula II compound/3mLCH
3n
2~ 1g formula II compound/7mLCH
3n
2; Reaction times is 1 ~ 20 hour; Temperature of reaction is-40 DEG C ~ 40 DEG C.
5. the method for claim 1, is characterized in that, in described step (2), the mol ratio of formula III compound and formula IV compound is 1:1; The mol ratio of formula II compound and formula V compound is 1:1; Formula II compound and CH
3n
2consumption be 1g formula II compound/5mLCH
3n
2; Reaction times is 2 ~ 12 hours; Temperature of reaction is-28 DEG C ~ 20 DEG C.
6. the method for claim 1, is characterized in that: described in step (3), formula VI compound and NaBH
4mol ratio be 1:1 ~ 1:5; The consumption of formula VI compound and MTBE is 1g formula II compound/10mLMTBE ~ 1g formula II compound/30mLMTBE; The consumption of formula VI compound and water is 1g formula II compound/1mL water ~ 1g formula II compound/3mL water; Reaction times is 10 ~ 30 hours; Temperature of reaction is-10 DEG C ~ 30 DEG C.
7. the method for claim 1, is characterized in that: described in step (3), formula VI compound and NaBH
4mol ratio be 1:2.5; The consumption of formula VI compound and MTBE is 1g formula II compound/22mLMTBE; The consumption of formula VI compound and water is 1g formula II compound/2mL water; Reaction times is 15 ~ 20 hours; Temperature of reaction is 0 DEG C ~ 20 DEG C.
8. the method for claim 1, is characterized in that: described alkali is potassium hydroxide; The mol ratio of formula VII compound and alkali is 1:0.8 ~ 1:1; Reaction times is 2 ~ 6 hours.
9. the method for claim 1, is characterized in that: described alkali is potassium hydroxide; The mol ratio of formula VII compound and alkali is 1:0.9; Reaction times is 3 hours.
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| CN201410439809.4A CN105461662A (en) | 2014-08-31 | 2014-08-31 | Synthetic method for chiral epoxy compound of anti-HIV drug intermediate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108794352A (en) * | 2018-06-20 | 2018-11-13 | 南京肽业生物科技有限公司 | A kind of new method of Boc Amino acid synthesis |
| CN109942514A (en) * | 2019-04-20 | 2019-06-28 | 淮海工学院 | A method of preparing sulfuric acid A Zhalawei intermediate |
| CN113004227A (en) * | 2021-03-10 | 2021-06-22 | 常州吉恩药业有限公司 | Synthesis method of (2S,3S) -3- (tert-butyloxycarbonylamino) -1, 2-epoxy-4-phenylbutane |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000053172A1 (en) * | 1999-03-08 | 2000-09-14 | Smithkline Beecham Corporation | Ccr-3 receptor antagonists |
| EP1428818A2 (en) * | 1999-08-31 | 2004-06-16 | Ajinomoto Co., Inc. | Method for producing N-carbamate-protected beta-aminoepoxide and beta-aminoalcohol |
| CN102643236A (en) * | 2012-02-21 | 2012-08-22 | 浙江师范大学 | Method for preparing chiral amide imidazolium bromide ionic liquid from natural amino acid |
-
2014
- 2014-08-31 CN CN201410439809.4A patent/CN105461662A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000053172A1 (en) * | 1999-03-08 | 2000-09-14 | Smithkline Beecham Corporation | Ccr-3 receptor antagonists |
| EP1428818A2 (en) * | 1999-08-31 | 2004-06-16 | Ajinomoto Co., Inc. | Method for producing N-carbamate-protected beta-aminoepoxide and beta-aminoalcohol |
| CN102643236A (en) * | 2012-02-21 | 2012-08-22 | 浙江师范大学 | Method for preparing chiral amide imidazolium bromide ionic liquid from natural amino acid |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108794352A (en) * | 2018-06-20 | 2018-11-13 | 南京肽业生物科技有限公司 | A kind of new method of Boc Amino acid synthesis |
| CN109942514A (en) * | 2019-04-20 | 2019-06-28 | 淮海工学院 | A method of preparing sulfuric acid A Zhalawei intermediate |
| CN109942514B (en) * | 2019-04-20 | 2022-09-09 | 淮海工学院 | Method for preparing azalazavir sulfate intermediate |
| CN113004227A (en) * | 2021-03-10 | 2021-06-22 | 常州吉恩药业有限公司 | Synthesis method of (2S,3S) -3- (tert-butyloxycarbonylamino) -1, 2-epoxy-4-phenylbutane |
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