CN105884628A - Preparation method of 2,4-ditertbutyl-5-aminophenol - Google Patents

Preparation method of 2,4-ditertbutyl-5-aminophenol Download PDF

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CN105884628A
CN105884628A CN201610394376.4A CN201610394376A CN105884628A CN 105884628 A CN105884628 A CN 105884628A CN 201610394376 A CN201610394376 A CN 201610394376A CN 105884628 A CN105884628 A CN 105884628A
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butyl
acetamide
hydroxy phenyl
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acid
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CN105884628B (en
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江锣斌
茆勇军
朱春平
朱国庆
陈天昀
王晗
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SHANGHAI FAMO BIOTECHNOLOGY Co.,Ltd.
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Shanghai University of Engineering Science
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to the technical field of organic synthesis and bulk pharmaceutical chemical intermediate preparation, in particular to a preparation method of cystic fibrosis treatment new drug ivacaftor key intermediate 2,4-ditertbutyl-5-aminophenol. The method comprises the steps of 1, acetylation, wherein (A) m-aminophenol or (B) acetic anhydride or acetyl chloride is used as a raw material, and a reaction is carried out to prepare N-(3-hydroxyphenyl)acetamide; 2, tertiary butyl substituting, wherein N-(3-hydroxyphenyl) acetamide and tert butyl alcohol are catalyzed by concentrated sulfuric acid to prepare N-(2,4-ditertbutyl-5-hydroxy phenyl)acetamide; 3, deacetylation, wherein the N-(2,4-ditertbutyl-5-hydroxy phenyl)acetamide is hydrolyzed by acid or alkali to obtain 2,4-ditertbutyl-5-aminophenol. According to the synthesis process, raw materials are easy to obtain, reaction conditions are mold, postprocessing is easy and convenient, amplified preparation is promoted, and the yield is high.

Description

The preparation method of 2,4-di-t-butyl-5-amino phenols
Technical field
The invention belongs to organic synthesis and the preparing technical field of crude drug intermediate, fine particularly to seed capsules Dimensionization treatment new drug is according to the preparation of the key intermediate 2,4-di-t-butyl-5-amino phenols cutting down Kato (ivacaftor) Method.
Background technology
According to cut down Kato (ivacaftor) be by Vertex company of the U.S. research and development for treating rare type capsule fiber The medicine changed, in approval listing in Nikkei FDA Food and Drug Administration January 31 in 2012 (FDA), commodity Entitled Kalydeco.This medicine is used for treating a kind of cystic fibrosis transmembrance regulator (CFTR) gene The rare type cystic fibrosis (CF) that G551D sudden change causes, is suitable for the age 6 years old and above patient use.Its Chemical name structure is shown in formula I:
2,4-di-t-butyl-5-amino phenols are that preparation depends on the key intermediate raw material cutting down Kato, its chemical constitution such as formula Shown in II.The at present preparation of 2,4-di-t-butyl-5-amino phenols mainly includes two kinds of methods:
Method one (WO2011072241；WO2007134279；US20100184739；J.Med.Chem., 2014,57 (23), 9776-9795), synthetic route is as shown in formula III.The method with 2,4-DI-tert-butylphenol compounds is Initiation material, chloro-formate reaction protection hydroxyl, prepare compound 4 and 5, wherein product 4 through nitrification Needing through column chromatography for separation, yield about 29%, subsequent reactions includes sloughing protection group and catalytic hydrogen reduction obtains Compound 1.The low selectivity of nitration reaction, low yield in this route, need the method using column chromatography to divide From purified product, column chromatography need to use the silica gel of 20～100 times of product qualities and substantial amounts of eluting solvent, becomes This substantially increases, and limits it and amplify preparation.
Method two (IP.com Journal, 2013,13 (5B), 1-3), synthetic route is as shown in formula IV.Its scheme For: with 2,4-DTBP as raw material, protect hydroxyl, then through nitrification through bromo, chloro-formate reaction Prepare compound 10, after prepare target compound 1 through the catalytic hydrogen reduction of alkalescence condition.
The method that this reaction is taked is, is beginning to use bromine occupy-place, the most again nitrification, and this can partly be avoided nitre The selective problems of base.But first step bromo-reaction yield is unsatisfactory, about 66%, and column chromatography need to be used Method isolated and purified；Additionally, final step hydrogenation reaction also needs to carry out under pressure, have certain Danger；And route needs introduce 2 blocking groups, cause Atom economy relatively low.
Accordingly, it would be desirable to for the defect in the presence of prior art, prior art is improved, it is provided that a kind of Raw material is easy to get, concise in technology, easy to operate, the higher preparation method of yield, to reduce cost.
Summary of the invention
It is desirable to provide a kind of 2, the preparation method of 4-di-t-butyl-5-amino phenols, for of the prior art Defect, it is provided that a kind of have raw material be easy to get, concise in technology, easy to operate, yield is high, the 2,4-of low cost The preparation method of di-t-butyl-5-amino phenols.
Technical solution of the present invention is, the preparation method of 2,4-di-t-butyl-5-amino phenols, and step includes:
(1) acetylation: with (A) meta-aminophenol, (B) acetic anhydride or chloroacetic chloride as raw material, reaction system For obtaining N-(3-hydroxy phenyl) acetamide；
(2) tert-butyl group replaces: N-(3-hydroxy phenyl) acetamide and the tert-butyl alcohol are through sulphuric acid catalysis, system For obtaining N-(2,4-di-t-butyl-5-hydroxy phenyl acetamide；
(3) acid of deacetylation: N-(2,4-di-t-butyl-5-hydroxy phenyl) acetamide or basic hydrolysis obtain 2,4-di-t-butyl-5-amino phenols.
The route of synthesis is shown as a formula V.
Step (1) is particularly as follows: meta-aminophenol is mixed by a. with solvent I, at 0～100 DEG C of temperature, stirring bar Drip acetic anhydride or chloroacetic chloride under part, react 0.5～6hr；Preferably, reaction temperature is 40～80 DEG C；
Meta-aminophenol is 1:1～20 with the mol ratio of acetic anhydride or chloroacetic chloride, more preferably 1:1～2；
Organic solvent I is selected from acetic acid, dimethylformamide (DMF), ethyl acetate, acetonitrile, dimethyl second Amide (DMAC) or dimethyl sulfoxide (DMSO)；Meta-aminophenol is 1mol with the amount ratio of solvent I: 0.3～2L；
Preferably, the time for adding of chloroacetic chloride or acetic anhydride is 1～15min；
B., during reaction mixture cooling is fallen back, continue stirring reaction 6～24hr, take solid and obtain N-(3- Hydroxy phenyl) acetamide.
Step (2) is: is dissolved in solvent II, and adds the tert-butyl alcohol by N-(3-hydroxy phenyl) acetamide； Dropping concentrated sulphuric acid, reacts 10～60hr at 0～50 DEG C；Preferably react at 10～30 DEG C.
Preferably, solvent II selected from dichloromethane, chloroform, toluene, ethyl acetate, oxolane or Acetonitrile.N-(3-hydroxy phenyl) acetamide is 1mol:2～5L with the amount ratio of solvent II；
Preferably, N-(3-hydroxy phenyl) acetamide, the tert-butyl alcohol and concentrated sulphuric acid mol ratio be 1:2～20:1～ 30, preferably 1:2～5:1～3, more preferably 1:2.5～3.5:1.2～2.5；The concentration of concentrated sulphuric acid is 95wt%～99.9wt%；Preferably, concentrated sulphuric acid time for adding is 1～60min.
In step (3), N-(2,4-di-t-butyl-5-hydroxy phenyl) acetamide is mixed by (i) with solvent II I Close, be added thereto to acid or alkali, back flow reaction 1～18hr；(ii) reactant mixture adds frozen water stirring, Take precipitation regulation pH and wash to neutral, and recrystallization purifying.
Preferably, in step (i), after reaction, 1/4～2/3 solvent is removed in decompression distillation, then residue is reacted Thing is poured in frozen water and is stirred, and takes solid, obtains 2,4-di-t-butyl-5-amino phenols crude product.
Preferably, in step (ii), by ethyl acetate and petroleum ether mixed liquor recrystallization purifying (ethyl acetate It is 1:2～2:1 with petroleum ether volume ratio).
Preferably, N-(2,4-di-t-butyl-5-hydroxy phenyl) acetamide and acid or the mol ratio of alkali be 1:1～ 20, preferably 5～10；Preferably, step (i) reflux time is 8～20 hours.
Preferably, solvent II I is selected from methanol or the second that ethanol, methanol, water, volumetric concentration are 50%～90% Alcohol-water solution, oxolane or acetonitrile.N-(2,4-di-t-butyl-5-hydroxy phenyl) acetamide and solvent II I Amount ratio be 1mol:3～8L, preferably 1mol:3.5～6L.
Preferably, described acid is concentration 2mol/L～saturated hydrochloric acid or hydrobromic acid, or concentration 15wt%～ 50% sulphuric acid；Described alkali is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or cesium carbonate, preferably For concentration 1mol/L～saturated solution.
This method is with meta-aminophenol as raw material, and through acetylation, the tert-butyl group replaces, deacetylation obtains target chemical combination Thing 2,4-di-t-butyl-5-amino phenols, total recovery is more than 60%.Relative to prior art, the advantage of this method It is:
(1) with relatively conventional meta-aminophenol and acetic anhydride or chloroacetic chloride as initiation material, intermediate steps uses The tert-butyl group and inorganic acid or alkali, have the advantage that raw material is easy to get.
(2) concise in technology of this method, reactions steps is few, and reaction condition is gentle, operates more convenient；After Processing method is simple and convenient, is suitable for amplifying preparation.
(3) need not introduce too much blocking group, Atom economy is good.
(4) yield and the total recovery of each step of this method are high (total recovery can be more than 60%), reaction condition Simple with raw material, it is possible to decrease cost.Target compound can be as cystic fibrosis therapies new drug according to cutting down Kato (ivacaftor) key intermediate raw material, so being conducive to the industrialized production of this crude drug, promotes economy The development of technology, has good application prospect.
Detailed description of the invention
Below in conjunction with specific embodiment, technical scheme is illustrated.
The preparation (1) of embodiment 1 N-(3-hydroxy phenyl) acetamide
0.1mol meta-aminophenol (10.9g) is mixed with 60mL acetic acid, stirs at 60 DEG C；Inhale with needle tubing Take 0.12mol acetic anhydride (12.2g, 11.34mL), under stirring at 60 DEG C, in 15min, acetic anhydride is dripped Add in mixed liquor.
After reacting 2 hours, reactant liquor is cooled to room temperature, pours into while stirring in 300mL water, is finished down follow-up , there is white solid in continuous stirring.It is stirred overnight (8～12hr), sucking filtration, dries and obtain 13.8g white solid, Yield 91%.
1H NMR(400MHz,DMSO-d6):δ2.01(s,3H),6.42(m,1H),6.92(m,1H), 7.04(m,1H),7.18(m,1H),9.33(s,1H),9.78(s,1H).ESI-MS(m/z)152.2[M+H]+。
The preparation (1) of embodiment 2 N-(2,4-di-t-butyl-5-hydroxy phenyl) acetamide
Weigh the N-prepared by embodiment 1 (3-hydroxy phenyl) acetamide (12.5g, 0.083mol) and be placed in eggplant In shape bottle, add 300mL toluene, stirring and dissolving；Add the tert-butyl alcohol (23.1mL, 17.9g, 0.25mol), And in 10min, under stirring condition, drip 99.8wt% concentrated sulphuric acid (16.3g, 9.0mL, 0.166mmol).
Room temperature (10～30 DEG C) continues stirring reaction 12h, generates pale solid, sucking filtration.This solid is added Enter in 200mL water, add saturated NaHCO3Solution regulation pH to 6, sucking filtration, it is washed with water to neutrality (pH=6.8～7.2), obtains white solid, dries to obtain solid 17.0g, yield 78%.
1H NMR(400MHz,DMSO-d6):δ1.25(s,9H),1.33(s,9H),1.99(s,3H),6.45( s,1H),7.11(s,1H),9.00(s,1H),9.16(s,1H).ESI-MS(m/z)264.3[M+H]+,527.4 [2M+H]+,549.4[2M+Na]+。
The preparation (1) of embodiment 3 2,4-di-t-butyl-5-amino phenols
0.038mol N-(2,4-di-t-butyl-5-hydroxy phenyl) acetamide (10.0g) is joined volume dense In the ethanol-water solution (150mL) of degree 80%, stirring, in reactant liquor, add the hydrochloric acid 20.6mL of 9.7mol/L (0.2mol), then back flow reaction 12h.Partial solvent (about 80mL) is removed in decompression distillation, by anti-for residue Thing is answered to pour in 100mL frozen water, stirring, generate pale solid, sucking filtration, dry.Solid and 80mL Water mixes, stirring, the sodium hydroxide adding 20% regulation pH to 6, generates pale solid, sucking filtration, dries. Crude product 70mL ethyl acetate/petroleum ether mixed liquor (ethyl acetate and petroleum ether volume ratio 1:1) recrystallization Purification, obtains white solid product 7.4g, yield 88%.
1H NMR(400MHz,DMSO-d6):δ1.32(s,9H),1.34(s,9H),6.79(s,1H),7.19(s, 1H),9.78(brs,2H).ESI-MS(m/z)222.3[M+H]+。
HPLC: post: InertSustain C18 (250mm × 4.6mm × 5 μm)；Detection: 220nm；Flow velocity: 0.8 mL/min；Temperature: 30 DEG C；Injection volume: 1 μ L；Solvent: methanol；Concentration: 0.2mg/mL；The operation time: 15min；Mobile phase A: water；Mobile phase B: methanol/acetic acid=100:0.1；Gradient elution: mobile phase A/stream Dynamic phase B=10/90:tR=5.404min, purity: 98.24%.
From embodiment 1～3, overall yield of reaction reaches 62.5%.
The preparation (2) of embodiment 4 N-(3-hydroxy phenyl) acetamide
1mol meta-aminophenol (109.1g) is mixed with 500mL DMF, stirs at 60 DEG C；Take 1.15mol Chloroacetic chloride (90.3g), under stirring at 60 DEG C, is added dropwise to chloroacetic chloride in mixed liquor in 15min.
After 60 DEG C of stirring reactions 5 hours, reactant liquor is cooled to room temperature, pours 2000mL water while stirring into In, continue stirring after being finished down, white solid occurs.It is stirred overnight (8～12hr), sucking filtration, dries and obtain 127.0g White solid, yield 84%.Spectrogram testing result is with embodiment 1.
The preparation (2) of embodiment 5 N-(2,4-di-t-butyl-5-hydroxy phenyl) acetamide
Weigh N-(3-hydroxy phenyl) acetamide 0.75mol, add 1500mL oxolane, stirring and dissolving； Add the 2.4mol tert-butyl alcohol, and in 60min, drip 1.2mol 99.8% concentrated sulphuric acid.
Room temperature (10～25 DEG C) stirring reaction 24h, generates pale solid, sucking filtration.This solid is joined In 1500mL water, add saturated NaHCO3Solution regulation liquid is to pH 6.5.Sucking filtration, solids washed with water To neutral, obtain white solid, dry to obtain pale solid 146.1g, yield 74%.
Spectrogram testing result is with embodiment 2.
Embodiment 6 2,4-di-t-butyl-5-amino phenols (2)
0.3mol N-(2,4-di-t-butyl-5-hydroxy phenyl) acetamide is joined oxolane (1500mL) In, stirring, in reactant liquor, add 500mL 4mol/L sodium hydroxide solution (2mol), be then refluxed for reaction 15h.Partial solvent (about 1000mL) is removed in decompression distillation, is poured into by residual reactant in 400mL frozen water, Stirring, generates pale solid, sucking filtration, dries.Solid mixes with 400mL water, stirring, adds 3mol/L Salt acid for adjusting pH to 6, generate pale solid, sucking filtration, dry.Crude product 600mL ethyl acetate/ Petroleum ether mixed liquor (ethyl acetate and petroleum ether volume ratio 1:1) recrystallization purifying, white solid product 57.7g, Yield 87%.
Spectrogram testing result is with embodiment 3.
The preparation (3) of embodiment 7 N-(2,4-di-t-butyl-5-hydroxy phenyl) acetamide
Weigh N-(3-hydroxy phenyl) acetamide (30.2g, 0.2mol), add 500mL dichloromethane, Stirring and dissolving；Add the tert-butyl alcohol (44.5g, 0.6mol), drip 99.8% concentrated sulphuric acid the most under agitation (29.5g, 0.3mol), time for adding is 30min.
Room temperature (10～30 DEG C) stirring reaction 48h, generates pale solid, sucking filtration.This solid is joined In 500mL water, add saturated NaHCO3Solution regulation liquid is to pH=6.Sucking filtration, solids washed with water is extremely Neutrality, obtains white solid, dries to obtain pale solid 38.0g, yield 72%.
Spectrogram testing result is with embodiment 2.
The preparation (4) of embodiment 8 N-(2,4-di-t-butyl-5-hydroxy phenyl) acetamide
Weigh N-(3-hydroxy phenyl) acetamide (30.2g, 0.2mol), add 800mL acetonitrile, stirring Dissolve；Add the tert-butyl alcohol (44.5g, 0.6mol), then drip 99.8% concentrated sulphuric acid (29.5g, 0.3mol), Time for adding is 30min.
Room temperature (10～30 DEG C) stirring reaction 48h, generates pale solid, concentrates～500mL solvent second Nitrile, gained solid sucking filtration.This solid is joined in 500mL water, adds saturated NaHCO3Solution regulates Liquid pH to 6.Sucking filtration, solids washed with water, to neutral, obtain white solid, dries to obtain pale solid 37.4g, yield 71%.Spectrogram testing result is with embodiment 2.
It is pointed out that above-described embodiment is only technology design and the feature of the explanation present invention, its object is to Allow the personage being familiar with this Project Technical will appreciate that present disclosure and to implement according to this, can not be limited this with this The protection domain of invention.All equivalence changes made according to spirit of the invention or modification, all should contain at this Within the protection domain of invention.

Claims (10)

  1. The preparation method of 1.2,4-di-t-butyl-5-amino phenols, it is characterised in that preparation process includes:
    (1) with (A) meta-aminophenol, (B) acetic anhydride or chloroacetic chloride as raw material, reaction prepares N- (3-hydroxy phenyl) acetamide；
    (2) N-(3-hydroxy phenyl) acetamide and the tert-butyl alcohol are through sulphuric acid catalysis, prepare N-(2,4- Di-t-butyl-5-hydroxy phenyl acetamide；
    (3) acid of N-(2,4-di-t-butyl-5-hydroxy phenyl) acetamide or basic hydrolysis obtain the tertiary fourth of 2,4-bis- Base-5-amino phenols.
  2. The preparation method of the most according to claim 12,4-di-t-butyl-5-amino phenols, it is characterised in that Step (1) is:
    A. meta-aminophenol is mixed with solvent I, under 0～100 DEG C of temperature, stirring condition drip acetic anhydride or Chloroacetic chloride, reacts 0.5～6hr；Described meta-aminophenol is 1:1～20 with the mol ratio of acetic anhydride or chloroacetic chloride； Organic solvent I is selected from acetic acid, dimethylformamide, ethyl acetate, acetonitrile, dimethyl acetylamide or dimethyl Sulfoxide；
    B., during reaction mixture cooling is fallen back, continue stirring reaction 6～24hr, take solid and obtain N-(3- Hydroxy phenyl) acetamide.
  3. The preparation method of the most according to claim 12,4-di-t-butyl-5-amino phenols, it is characterised in that Step (2) is: is dissolved in solvent II, and adds the tert-butyl alcohol by N-(3-hydroxy phenyl) acetamide；Dropping Concentrated sulphuric acid, reacts 1～60hr at 0～50 DEG C；Taking solid to mix with water, regulation pH also washs to neutral；
    Described solvent II is selected from dichloromethane, chloroform, toluene, ethyl acetate, oxolane or second Nitrile；N-(3-hydroxy phenyl) acetamide, the tert-butyl alcohol and concentrated sulphuric acid mol ratio are 1:1～20:1～30；Dense The concentration of sulphuric acid is 95wt%～99.9wt%.
  4. The preparation method of the most according to claim 12,4-di-t-butyl-5-amino phenols, it is characterised in that Step (3) is:
    I N-(2,4-di-t-butyl-5-hydroxy phenyl) acetamide is mixed with solvent II I, is added thereto to by () Acid or alkali, back flow reaction 1～18hr；
    (ii) reactant mixture adds frozen water stirring, takes precipitation regulation pH and washs to neutral, and recrystallization is pure Change；
    Solvent II I selected from the methanol that ethanol, methanol, water, volumetric concentration are 50%～90% or ethanol water, Oxolane or acetonitrile；
    N-(2,4-di-t-butyl-5-hydroxy phenyl) acetamide is 1:1～20 with the mol ratio of acid or alkali；Described Acid be hydrochloric acid, hydrobromic acid or sulphuric acid；Described alkali is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, carbonic acid Sodium or cesium carbonate.
  5. The preparation method of the most according to claim 22,4-di-t-butyl-5-amino phenols, it is characterised in that In step a, meta-aminophenol is 1mol:0.3～2L with the amount ratio of solvent I；Meta-aminophenol and acetic anhydride or The mol ratio of chloroacetic chloride is 1:1～2；The time for adding of chloroacetic chloride or acetic anhydride is 1～15min, reaction temperature It it is 40～80 DEG C.
  6. The preparation method of the most according to claim 32,4-di-t-butyl-5-amino phenols, it is characterised in that N-(3-hydroxy phenyl) acetamide, the tert-butyl alcohol and concentrated sulphuric acid mol ratio are 1:2～5:1～3, at 10～30 DEG C Lower reaction；The concentration of concentrated sulphuric acid is 95%～99.9%, and time for adding is 1～60min.
  7. The preparation method of the most according to claim 32,4-di-t-butyl-5-amino phenols, it is characterised in that N-(3-hydroxy phenyl) acetamide is 1mol:2～5L with the amount ratio of solvent II.
  8. The preparation method of the most according to claim 42,4-di-t-butyl-5-amino phenols, it is characterised in that After the reaction that step (i) is obtained, 1/4～2/3 solvent is removed in decompression distillation, then pours residual reactant into ice Water stirs, takes solid, obtain 2,4-di-t-butyl-5-amino phenols crude product；
    With volume ratio 1:2～the ethyl acetate of 2:1 and petroleum ether mixed liquor recrystallization purifying in step (ii).
  9. The preparation method of the most according to claim 42,4-di-t-butyl-5-amino phenols, it is characterised in that N-(2,4-di-t-butyl-5-hydroxy phenyl) acetamide is 1:5～10 with the mol ratio of acid or alkali, described acid For concentration 2mol/L～saturated hydrochloric acid or hydrobromic acid, or concentration 15wt%～50% sulphuric acid；Described alkali is 1mol/L～saturated sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or cesium carbonate solution.
  10. The preparation method of the most according to claim 42,4-di-t-butyl-5-amino phenols, its feature exists In, N-(2,4-di-t-butyl-5-hydroxy phenyl) acetamide is 1mol:3～8L with the amount ratio of solvent II I.
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US9670163B2 (en) 2005-12-28 2017-06-06 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US9931334B2 (en) 2005-12-28 2018-04-03 Vertex Pharmaceuticals Incorporated Solid forms of N[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US10537565B2 (en) 2005-12-28 2020-01-21 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US11291662B2 (en) 2005-12-28 2022-04-05 Vertex Pharmaceuticals Incorporated Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US10646481B2 (en) 2008-08-13 2020-05-12 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US11564916B2 (en) 2008-08-13 2023-01-31 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US9751839B2 (en) 2009-03-20 2017-09-05 Vertex Pharmaceuticals Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
US10272046B2 (en) 2012-02-27 2019-04-30 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US11147770B2 (en) 2012-02-27 2021-10-19 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US11752106B2 (en) 2012-02-27 2023-09-12 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
CN107098822A (en) * 2017-06-07 2017-08-29 上海微巨实业有限公司 A kind of preparation method for preparing the hydroxy acetophenone of 3 amino of Pranlukast key intermediate 2
CN107098822B (en) * 2017-06-07 2021-05-28 上海微巨实业有限公司 Preparation method for pranlukast key intermediate 3-amino-2-hydroxyacetophenone

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