CN107344944A - A kind of method for preparing DRV intermediate - Google Patents
A kind of method for preparing DRV intermediate Download PDFInfo
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- CN107344944A CN107344944A CN201610299132.8A CN201610299132A CN107344944A CN 107344944 A CN107344944 A CN 107344944A CN 201610299132 A CN201610299132 A CN 201610299132A CN 107344944 A CN107344944 A CN 107344944A
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- YEJRWHAVMIAJKC-UHFFFAOYSA-N O=C1OCCC1 Chemical compound O=C1OCCC1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/60—Two oxygen atoms, e.g. succinic anhydride
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a kind of method for preparing DRV intermediate, and in particular to the preparation method of compound of formula I.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to the preparation method of AIDS-treating medicine DRV intermediate.
Background technology
DRV（Darunavir）It is a kind of medicine for being used to treat AIDS of drugmaker of Johnson ＆ Johnson of U.S. exploitation,
DRV ethanolates (Darunavir Ethanolate) listed in America ＆ Canada first in 2006.
DRV English name：
[(3R,3AS,6AR)-2,3,3A,4,5,6A-HEXAHYDROFURO[5,4-B]FURAN-3-YL]N-[(2S,3R)-4-
[(4-AMINOPHENYL)SULFONYL-(2-METHYLPROPYL)AMINO]-3-HYDROXY-1-PHENYLBUTAN-2-YL]
CARBAMATE
Molecular formula: C27H37N3O7S
Molecular weight: 547.66
DRV, which is that a kind of new non-peptides for treating AIDS are degeneration-resistant, turns hiv protease inhibitor, by Johnson ＆ Johnson's pharmacy
Branch company of Iceland Tibotec researches and develops success first, be current 6 kinds of protease inhibitors (inverase, Ritonavir, indenes ground that
Wei, NELFINAVIR, An Ruinawei and ABT378/r) in bioavilability highest, by blocking from infected host cell
The forming process of surface release new, ripe virion, suppress the protease of virus and work.When prolonged application this product
When, the inhibition of HIV carrier in blood can be generally reduced, increases the counting of cd4 cell, reduces the chance of aids infection, improves life
Bioplasm amount, extending life.Suitable for infected AIDS virus but take existing antiretroviral drugs have no curative effect into
Year people, the medicine must be used in combination with the Ritonavir of low dosage or other degeneration-resistant virus formulations that turn, to improve drug effect.Pass through
Its extracorporeal antivirus effect can be evaluated in the lymphocyte resisted in acute and chronic infected lymphoblast and peripheral-system blood
Activity, its IC50 are 0.012~0.08 mmol/ L to acute infection cell, are 0.41 mmol/L to chronic infection cell.Mouthful
Medicine is taken, 1 1200mg of recommended dose, twice a day, the patient of mild to moderate hepatic disfunction and the bad person of renal function should be reduced.
The adverse reaction of DRV is mainly that gastrointestinal reaction, flush, itch and perioral numbness sense, depression, emotionally disturbed, the sense of taste are disorderly
Disorderly etc..In do not recommend this product to the patient of severe hepatic disfunction.Due to containing sulfanilamide (SN) group in this component, therefore to sulphur
Amine allergy sufferers and any component allergy sufferers in this product prescription are disabled.
DRV ethanolates (Darunavir Ethanolate) listed in America ＆ Canada first in 2006,
Trade name PREZISTA, afterwards successively in multiple country's listings such as Australia, Japan.DRV ethanolates with
Cobicistat compound PREZCOBIX also listed in 2014.
Formulation：Oral suspension, 100mg/ml；Tablet, 75mg, 150mg, 600mg, 800mg.
Usage and dosage：General patient, 800mg DRVs ethanolates and 100mg Ritonavirs are taken simultaneously with food,
Once a day.There are the patient of conflict, 600mg DRVs ethanolates and 100mg Ritonavirs and food to DRV
Take simultaneously, twice a day.Children's dosage must not exceed adult's dosage, specifically follow the doctor's advice.
DRV is sold：
2012 14.14 hundred million dollars；2013 16.73 hundred million dollars；2014 18.31 hundred million dollars（Compound containing PREZCOBIX)；
13.21 hundred million dollars of the first three quarters in 2015（Compound containing PREZCOBIX).
(3R, 3aS, 6aR)-hydroxyl hexahydro furyl simultaneously ［ 2,3-b ］ furan-3-ol be DRV key intermediate.
Document J Med Chem, 1996,39:3278-3290 report using D-malic acid diethylester as initiation material
Synthesize the method for the intermediate and split the method synthesized among this by enzyme using dihydrofuran as raw material, reaction scheme is as follows
It is shown：
This method cost of material is high, and partial reaction condition requires higher and is unfavorable for amplification production and control.
Hereafter, document Org Process Res. Dev., 2007,11:972-980 and Org. Lett., 2008,
10:1103-1106 reports the method related as the Material synthesis intermediate using dihydrofuran and dimerization glycollic aldehyde respectively,
Reaction scheme is as follows：
The method chiral induction effect is undesirable, it is necessary to which the method further split with enzyme could obtain optically pure product.
Patent WO03022853A1 discloses more structurally sound synthetic method, and the method is using cheap using different Vc to rise
Beginning raw material is as follows by multistep reaction synthesis DRV intermediate, reaction scheme：
But the synthetic method Atom economy is poor, due to needing to use price higher periodic acid and lithium borohydride, cause to produce
The cost of material of product is higher.
The content of the invention
The present invention prepares DRV intermediate (3R, 3aS, 6aR)-hydroxyl hexahydro furyl simultaneously ［ 2,3 for prior art
- b ］ furan-3-ol the defects of, disclose a kind of simple, economic preparation method.
The specific content of the invention is as follows：
1. the present invention relates to a kind of preparation method of compound of formula I, comprise the following steps：
（1）Compound II is prepared in formula III compound；
（2）Compound I is prepared in Formula II compound.
2. the method as described in 1, wherein step（1）Asymmetric catalysis is carried out under catalyst existence condition, is prepared
Obtain compound II, wherein described catalyst be [(S)-BINAP] RuCl2, [(S)-BINAP] Ru (OAc) 2, [(S)-
SEGPHOS] one or more kinds of mixed catalysts in Ru (OAc) 2 or (S)-Ru (H8-BINAP) (OAC) 2.
3. the method as described in 1, wherein step（2）Compound I is prepared under the conditions of existing for reducing agent, wherein
Described reducing agent is red aluminum, LiAlH (OtBu)3, one or more kinds of mixing reducing agents in DIBAL-H.
4. the method as described in 1, its compound of formula III can be prepared by the following method,
In the presence of a base, formula III compound is prepared in reaction for formula IV compound and GBL, wherein described alkali is just
One or more kinds of mixed bases in butyl lithium, diisopropyl ammonia lithium, double (trimethyl silicon substrate) lithium amides (LHMDS).Formula
It is prepared by the method that IV compounds are referred to report in document J.Org.Chem.1993,58,7768.
5. the invention further relates to Formula II, compound shown in formula III, the nuclear magnetic spectrum and mass spectrum of formula III compound are shown in explanation
Book accompanying drawing（Accompanying drawing 1, accompanying drawing 2, accompanying drawing 3）.
Brief description of the drawings
Fig. 1 is that the nuclear-magnetism C of formula III compound composes schematic diagram；
Fig. 2 is that the nuclear-magnetism H of formula III compound composes schematic diagram；
Fig. 3 is the mass spectrogram of formula III compound.
Embodiment
The present invention is further illustrated by following nonlimiting examples.
The synthesis of formula III compound
Embodiment one
Under nitrogen protection, the hexane solution of 270mL1.6mol/L n-BuLi is added into 500mL flasks, be cooled to-
78 DEG C, 34.4g (2.0eq) GBL is added dropwise.After being added dropwise, insulated and stirred 2 hours, 31.2g is then added dropwise
(1.0eq, 0.2mol) 1,4- dioxo spiros [4,5] decyl- 2- ketone（Formula IV compound）Tetrahydrofuran solution.Insulation reaction 16h
Afterwards, reaction is quenched with saturated ammonium chloride solution, is warming up to room temperature, be layered, aqueous phase is extracted with ethyl acetate, and merges organic phase, dense
Product, yield 38% are obtained after contracting.
1 HNMR (CD3OD, 400MHz):δ4.64 (s, 2H), 3.72(t, J=6.3Hz, 2H), 2.42(t, J=
6.3Hz, 2H)
13 CNMR(CD3OD, 400MHz): δ178.77, 177.02, 98.39, 68.48,61.21, 26.00
HRMS: M-1=143.0352
Fusing point: 115-117℃.
Embodiment two
Under nitrogen protection, 160mL 2.0mol/L diisopropyl ammonia lithium solution is added into 250mL flasks, is cooled to -78
DEG C, 21.5g (2.5eq) GBL is added dropwise.After being added dropwise, insulated and stirred 2 hours, 15.6g is then added dropwise
(1.0eq, 0.1mol) 1,4- dioxo spiros [4,5] decyl- 2- ketone（Formula IV compound）Tetrahydrofuran solution.Insulation reaction 8h
Afterwards, reaction is quenched with saturated ammonium chloride solution, is warming up to room temperature, be layered, aqueous phase is extracted with ethyl acetate, and merges organic phase, dense
Product, yield 40% are obtained after contracting.
Embodiment three
Under nitrogen protection, 220mL 1.0mol/L double (trimethyl silicon substrate) lithium amides (LHMDS) are added into 250mL flasks
Solution, -78 DEG C are cooled to, 17.2g (2.0eq) GBL is added dropwise.After being added dropwise, insulated and stirred 2 hours, then
15.6g (1.0eq, 0.1mol) 1,4- dioxo spiros [4,5] decyl- 2- ketone is added dropwise（Formula IV compound）Tetrahydrofuran solution.
After insulation reaction 12h, reaction is quenched with saturated ammonium chloride solution, is warming up to room temperature, be layered, aqueous phase is extracted with ethyl acetate, and closes
And organic phase, product, yield 35% are obtained after concentration.
The synthesis of Formula II compound
Embodiment one
5.04g (0.035mol) compound III is added in 100mL autoclaves, adds 50mL methanol, stirring and dissolving.With
Air three times, then under nitrogen protection, 1.4g (0.05eq) [(S)-BINAP] is added into kettle in high pure nitrogen conversion kettle
RuCl2, gas is flushed with hydrogen to 6.0MPa, 80-90 DEG C is heated to and reacts 24 hours with air in high-purity hydrogen displacement kettle three times.Cooling
It is careful to discharge air in kettle to room temperature, reaction solution is taken out, compound II is obtained after concentration, product II is directly entered without separation
React in next step.
Embodiment two
5.76g (0.04mol) compound III is added in 100mL autoclaves, adds 60mL ethanol, stirring and dissolving.With
High pure nitrogen conversion kettle in air three times, then under nitrogen protection, into kettle add 0.17g (0.005eq) [(S)-
BINAP]Ru(OAc)2, gas is flushed with hydrogen to 6.0MPa, is heated to 60-70 DEG C of reaction 60 with air in high-purity hydrogen displacement kettle three times
Hour.Be cooled to room temperature, it is careful to discharge air in kettle, take out reaction solution, after concentration compound II, product II without separation,
It is directly entered and reacts in next step.
Embodiment three
5.76g (0.04mol) compound III is added in 100mL autoclaves, adds 60mL ethyl acetate, stirring is molten
Solution.With high pure nitrogen conversion kettle in air three times, then under nitrogen protection, into kettle add 0.34g (0.01eq) [(S)-
SEGPHOS]Ru(OAc)2, gas is flushed with hydrogen to 4.0MPa, is heated to 50-60 DEG C of reaction with air in high-purity hydrogen displacement kettle three times
72 hours.Room temperature is cooled to, it is careful to discharge air in kettle, reaction solution is taken out, compound II is obtained after concentration, product II is without dividing
From, be directly entered in next step react.
Example IV
5.76g (0.04mol) compound III is added in 100mL autoclaves, adds 60mL methanol, stirring and dissolving.With
Air three times, then under nitrogen protection, 0.17g (0.005eq) (S)-Ru (H is added into kettle in high pure nitrogen conversion kettle8-
BINAP)(OAC)2, gas is flushed with hydrogen to 2.5MPa, it is small to be heated to 30-40 DEG C of reaction 72 with air in high-purity hydrogen displacement kettle three times
When.Room temperature is cooled to, it is careful to discharge air in kettle, reaction solution is taken out, compound II is obtained after concentration, product II is without separating, directly
Tap into and reacted into next step.
The synthesis of compound of formula I：
Embodiment one
Under nitrogen protection, 120.0g (4.47eq) 68% red aluminum solution is added into 500mL four-hole bottles, adds 228.0 g
Toluene, 40.5g is added dropwise after being cooled to -10 ~ -20 DEG C（1.49eq）Trifluoroethanol, 20-30 DEG C of reaction is warming up to after being added dropwise
1-2 hours.The 100mL tetrahydrofuran solutions containing 13.1g (1.00eq) compounds II are added, control temperature is at -10 ~ 0 DEG C
Reaction to raw material II disappears.Control temperature to be added to reaction solution in 200.0g 20% sulfuric acid at -20-15 DEG C, stir 20h
Stratification afterwards, collects organic phase, and aqueous phase is extracted with 100g toluene, combining methylbenzene layer, washed with 5% sodium acid carbonate, then use water
Washing, organic phase are concentrated under reduced pressure, and obtain product 29.5g, yield 84.5%.
Embodiment two
Under nitrogen protection, the 300mL toluene of 14g (1.00eq) compound II sums is added into four-hole bottle, is stirred, be cooled to-
20 ~ -15 DEG C, add 76.5g (3.15eq) LiAlH (O in batchestBu)3, insulation reaction to raw material II disappearance.Reaction solution is added
Into 120.0g 16% hydrochloric acid, 30 DEG C of stirring reactions stratification after 30 hours is warming up to, collects organic phase, aqueous phase 100g
Toluene extracts, and combining methylbenzene layer, is washed with 5% sodium acid carbonate, is washed with water and washs, organic phase is concentrated under reduced pressure, and obtains crude product
33.1g, 94.6%。
Embodiment three
Under nitrogen protection, the 260mL toluene of 24.3g (1.00eq) compound II sums is added into four-hole bottle, is stirred, cooling
To -50 ~ -40 DEG C, 315g (3.3eq) DIBAL-H 25% toluene solution is added dropwise, insulation reaction to raw material II disappears.Will be anti-
Answer liquid to be added in 200.0g 16% hydrochloric acid, be heated to 60 DEG C and react 16 hours, stratification collects organic phase, and aqueous phase is used
150g toluene extracts, and combining methylbenzene layer, is washed with 5% sodium acid carbonate, is washed with water and washs, be layered after standing, and organic phase decompression is dense
Contracting, obtains product 61.7g, yield 95%.
Claims (10)
1. a kind of preparation method of compound of formula I,
It is characterised in that it includes following steps：
（1）Compound II is prepared in formula III compound；
（2）Compound I is prepared in Formula II compound,
。
2. the method according to claim 11, wherein step（1）It is anti-that asymmetry catalysis are carried out under catalyst existence condition
Should, compound II is prepared.
3. according to the method for claim 2, wherein described catalyst is [(S)-BINAP] RuCl2、[(S)-BINAP]Ru
(OAc)2、[(S)-SEGPHOS]Ru(OAc)2Or (S)-Ru (H8-BINAP) (OAC)2In one or more kinds of mixing
Catalyst.
4. the method according to claim 11, wherein step（2）Compound I is prepared under the conditions of existing for reducing agent.
5. according to the method for claim 4, wherein described reducing agent is red aluminum, LiAlH (OtBu)3, in DIBAL-H
One or more kinds of mixing reducing agents.
6. according to the method for claim 1, the preparation method of its compound of formula III is：
Formula IV compound and 1,4- butyrolactone react to obtain formula III compound.
7. according to the method for claim 6, in the presence of a base, formula is prepared in reaction for formula IV compound and GBL
III compounds.
8. according to the method for claim 6, wherein described alkali is：N-BuLi, diisopropyl ammonia lithium, double (trimethyls
Silicon substrate) one or more kinds of mixed bases in lithium amide (LHMDS).
9. Formula II compound
。
10. formula III compound
。
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| CN202110230463.7A CN113307783B (en) | 2016-05-07 | 2016-05-07 | Method for preparing darunavir intermediate |
| CN201610299132.8A CN107344944B (en) | 2016-05-07 | 2016-05-07 | Method for preparing darunavir intermediate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106496263A (en) * | 2015-09-08 | 2017-03-15 | 浙江九洲药业股份有限公司 | The preparation method of hexahydro furyl furan 01 derivatives, its intermediate and preparation method thereof |
| CN109627251A (en) * | 2018-12-29 | 2019-04-16 | 常州吉恩药业有限公司 | A kind of industrialized preparing process of high-purity darunavir intermediate |
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| CN107043385A (en) * | 2016-02-05 | 2017-08-15 | 成都博腾药业有限公司 | A kind of method for preparing DRV intermediate |
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| WO2011092687A1 (en) * | 2010-01-28 | 2011-08-04 | Mapi Pharma Hk Limited | Process for the preparation of darunavir and darunavir intermediates |
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| CN106496263A (en) * | 2015-09-08 | 2017-03-15 | 浙江九洲药业股份有限公司 | The preparation method of hexahydro furyl furan 01 derivatives, its intermediate and preparation method thereof |
| CN106496263B (en) * | 2015-09-08 | 2020-10-30 | 浙江九洲药业股份有限公司 | Process for producing hexahydrofurofuranol derivative, intermediate therefor, and process for producing the intermediate |
| CN109627251A (en) * | 2018-12-29 | 2019-04-16 | 常州吉恩药业有限公司 | A kind of industrialized preparing process of high-purity darunavir intermediate |
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| CN113307783A (en) | 2021-08-27 |
| CN113307783B (en) | 2023-04-07 |
| CN107344944B (en) | 2021-03-05 |
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