CN103694196A - Cytochrome P450 monooxygenase inhibitor intermediate, and preparation methods and application thereof - Google Patents

Cytochrome P450 monooxygenase inhibitor intermediate, and preparation methods and application thereof Download PDF

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CN103694196A
CN103694196A CN201210366903.2A CN201210366903A CN103694196A CN 103694196 A CN103694196 A CN 103694196A CN 201210366903 A CN201210366903 A CN 201210366903A CN 103694196 A CN103694196 A CN 103694196A
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compound
formula
phenyl
unsubstituted
alkyl
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李金亮
赵楠
罗光顺
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SHANGHAI DESANO PHARMACEUTICAL CO Ltd
SHANGHAI DISAINUO CHEMICAL PHARMACEUTICAL CO Ltd
Shanghai Desano Chemical Pharmaceutical Co Ltd
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SHANGHAI DESANO PHARMACEUTICAL CO Ltd
SHANGHAI DISAINUO CHEMICAL PHARMACEUTICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms

Abstract

The invention provides a cytochrome P450 monooxygenase inhibitor intermediate, and preparation methods and an application thereof. Specifically, the invention provides the intermediate compound represented by the formula IV and used for preparation of a cytochrome P450 monooxygenase inhibitor (cobicistat), wherein X represents bromine, chlorine or a sulfonate group, R represents a hydroxyl group, a substituted or unsubstituted C1-C8 straight-chain or branched-chain alkyl, a substituted or unsubstituted naphthenic group, or a substituted or unsubstituted C3-C20 aralkyl. The invention also provides the preparation methods of the intermediate, and a method for preparing cobicistat from the intermediate. The preparation methods have the advantages of simple preparation process and low cost, and are suitable for industrialized production.

Description

Cytochrome P 450 monooxygenases inhibitor intermediate and method for making thereof and purposes
Technical field
The invention belongs to the synthetic field of medicine, be specifically related to a kind of preparation method of intermediate and synthetic method and intermediate thereof of cytochrome P 450 monooxygenases inhibitor.
Background technology
The oxidative metabolism of cytochrome P 450 enzymes is one of main mechanism of drug metabolism, generally can maintain or improve the degrade blood plasma level of responsive medicine of cytochrome P 450 enzymes by giving cytochrome P 450 inhibitors, to improve the pharmacokinetics of medicine, can be used for strengthening the validity of antiretroviral drugs.Such as WO2008010921 discloses a kind of suc as formula the cytochrome P 450 monooxygenases particular compound (Cobicistat) shown in I compound:
Figure BDA00002201637100011
The synthetic method of the disclosed formula I compound of WO2008010921 has multiple, and wherein a kind of method is as shown in following route:
Figure BDA00002201637100021
The method agents useful for same is expensive, and by product is more and be difficult for removing, long reaction time, and cost is high, is unfavorable for suitability for industrialized production.
WO2010115000 improves above-mentioned route:
Figure BDA00002201637100022
In above-mentioned route, the first step ring-opening reaction reagent used is Iodotrimethylsilane, and Iodotrimethylsilane is expensive.This step ring-opening reaction of WO2010115000 report and yield of morpholine substitution reaction two steps subsequently are not high yet, only have 71%, make that only raw materials cost of Iodotrimethylsilane is just very high, are not suitable for suitability for industrialized production.
In sum, this area is in the urgent need to a kind of method of low cost, high-level efficiency, applicable suitability for industrialized production cytochrome P 450 monooxygenases inhibitor.
Summary of the invention
An object of the present invention is to provide a kind of novel midbody compound for the preparation of cytochrome P 450 monooxygenases inhibitor, and preparation method thereof.
Another object of the present invention is the synthetic method of preparing cytochrome P 450 monooxygenases inhibitor of a kind of applicable suitability for industrialized production of exploitation.
A first aspect of the present invention, provides compound shown in a kind of formula IV;
Figure BDA00002201637100031
Wherein, X is bromine, chlorine or sulfonate group;
R is the aralkyl of straight chain, branched-chain alkyl or C3～C8 cycloalkyl, replacement or the unsubstituted C3～C20 of hydrogen, replacement or unsubstituted C1～C8.
Preferably, described replacement is to have one or more substituting groups that are selected from lower group: halogen, phenyl, C1～C4 alkyl; Wherein said phenyl comprises unsubstituted phenyl or has 1～3 substituent substituted-phenyl that is selected from hydroxyl, C1～C3 alkyl, halogen.
A second aspect of the present invention, provides the preparation method of compound shown in a kind of formula IV, it is characterized in that, described method comprises step:
(a), in inert solvent, under halogenating agent exists, formula III compound reacts with formula ROH compound, forms formula IV compound;
Figure BDA00002201637100032
Above-mentioned various, X is bromine or chlorine; And R is the aralkyl of straight chain, branched-chain alkyl or C3～C8 cycloalkyl, replacement or the unsubstituted C3～C20 of hydrogen, replacement or unsubstituted C1～C8;
Preferably, described replacement is to have one or more substituting groups that are selected from lower group: halogen, phenyl, C1～C4 alkyl; Wherein said phenyl comprises unsubstituted phenyl or has 1～3 substituent substituted-phenyl that is selected from hydroxyl, C1～C3 alkyl, halogen.
Or described method comprises step:
(b) in inert solvent, formula III compound reacts with alkali MOH the intermediate that obtains open loop, and then this intermediate reacts with compound R Y and obtains formula V compound, formula V compound again with compound R 1-SO 2y reaction, forms formula IV compound;
Figure BDA00002201637100041
Above-mentioned various in,
R is the aralkyl of straight chain, branched-chain alkyl or C3～C8 cycloalkyl, replacement or the unsubstituted C3～C20 of hydrogen, replacement or unsubstituted C1～C8;
In another preference, described replacement is to have one or more substituting groups that are selected from lower group: halogen, phenyl, C1～C4 alkyl; Wherein said phenyl comprises unsubstituted phenyl or has 1 ~ 3 substituent substituted-phenyl that is selected from hydroxyl, C1～C3 alkyl, halogen.
X is sulfonate group R 1-SO 2o-;
R 1straight or branched alkyl or aryl for C1～C8; With
Y is Cl or Br or I;
M is basic metal or alkaline-earth metal, preferably sodium and potassium.
In another preference, described R 1-SO 2y comprises alkyl sulfonyl chloride or aryl sulfonyl chloride, is more preferably methane sulfonyl chloride, p-methylphenyl SULPHURYL CHLORIDE, ethyl chloride, sec.-propyl SULPHURYL CHLORIDE, or its combination.
In another preference, in step (a), described inert solvent comprises: tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO), 2-methyltetrahydrofuran, 1,3-dimethyl-2-imidazolidone or its mixture; Preferred methylene dichloride.
In another preference, in step (b), described inert solvent comprises: tetrahydrofuran (THF), methylene dichloride, chloroform, acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO), 2-methyltetrahydrofuran, 1,3-dimethyl-2-imidazolidone or its mixture; Preferred methylene dichloride.
In another preference, described halogenating agent is the Lewis acid that contains chlorine or bromine.
Preferably, described halogenating agent is selected from lower group: bromotrimethylsilane, trimethylchlorosilane, triethyl bromo-silicane, chlorotriethyl silane, triisopropyl bromo-silicane, tri isopropyl chlorosilane, hydrogen bromide, hydrogenchloride, or its combination, preferably bromotrimethylsilane or trimethylchlorosilane.
In another preference, in step (a), the mol ratio of formula III compound and bromizating agent or chlorizating agent is 1:1～1:5, preferably 1:1～1:3.
In another preference, it is characterized in that, temperature of reaction is-5～25 ℃, preferably 0～20 ℃.
In another preference, the reaction times is 0.1～24h.
A third aspect of the present invention, provides a kind of preparation method who has suc as formula the compound of structure shown in II, it is characterized in that, the method comprises the following steps:
(i) in inert solvent, formula IV compound reacts with morpholine, forms formula II compound;
Figure BDA00002201637100051
In various, X is bromine, chlorine or sulfonate group;
R is the aralkyl of straight chain, branched-chain alkyl or C3～C8 cycloalkyl, replacement or the unsubstituted C3～C20 of hydrogen, replacement or unsubstituted C1～C8.
Preferably, described replacement is to have one or more substituting groups that are selected from lower group: halogen, phenyl, C1～C4 alkyl; Wherein said phenyl comprises unsubstituted phenyl or has 1～3 substituent substituted-phenyl that is selected from hydroxyl, C1～C3 alkyl, halogen.
In another preference, in step (i), also comprise before step: with method preparation formula IV compound described in second aspect present invention.
In another preference, by the formula IV compound making, not treated, be directly used in the reaction of step (i).
In another preference, the mol ratio of formula IV compound and morpholine is 1:2～1:5, preferably 1:2.5～1:3.5.
In another preference, the temperature of reaction of step (i) is 20～60 ℃, is preferably 20～40 ℃.
In another preference, the reaction times is 0.1～24h.
A fourth aspect of the present invention, provides a kind of preparation method of formula I compound, it is characterized in that, the method comprises the following steps:
(i) in inert solvent, formula IV compound reacts with morpholine, forms formula II compound;
(ii) under alkaline condition, formula II compound is hydrolyzed, and forms formula V compound;
(iii) formula V compound and formula VI compound are carried out to condensation, form formula I compound.
Figure BDA00002201637100061
A fifth aspect of the present invention, provides a kind of as the purposes of the compound that first aspect present invention provided, and it is characterized in that, described compound is used to the cytochrome P 450 monooxygenases inhibitor shown in preparation formula I or formula II compound as intermediate.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can combining mutually between specifically described each technical characterictic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, at this, tire out and state no longer one by one.
Embodiment
The inventor, through extensive and deep research, has developed a kind of compound having as shown in the formula IV structure first, and preparation method thereof:
Wherein, X is bromine, chlorine or sulfonate group; R is the aralkyl of straight chain, branched-chain alkyl or C3-8 cycloalkyl, replacement or the unsubstituted C3～C20 of hydrogen, replacement or unsubstituted C1～C8.
Using above-claimed cpd as intermediate, can be low-cost, make efficiently suc as formula the cytochrome P 450 monooxygenases particular compound (Cobicistat) shown in I compound.On this basis, the inventor has completed the present invention.
Term
As used herein, term " formula I compound ", " cytochrome P 450 monooxygenases particular compound " and " Cobicistat " are used interchangeably, and all representative has the compound of structure shown in formula I.
Term " alkyl sulfonyl chloride " refers to the SULPHURYL CHLORIDE that a chlorine atom is replaced by alkyl.
Term " aryl sulfonyl chloride " refers to the SULPHURYL CHLORIDE that a chlorine atom is replaced by aryl.
Referring to refer to can be as the atom of electron pair receptor for term " the Lewis acid that contains chlorine or bromine ", molecule, ion or atomic group, preferably, the used Lewis acid that contains chlorine or bromine is in the present invention: bromotrimethylsilane, trimethylchlorosilane, triethyl bromo-silicane, chlorotriethyl silane, triisopropyl bromo-silicane, tri isopropyl chlorosilane, hydrogen bromide, hydrogenchloride, or its combination, preferably bromotrimethylsilane or trimethylchlorosilane.
Term " C1-C4 alkyl " refers to have the straight or branched alkyl of 1-4 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl or similar group.
Term " straight chain of C1-C8, branched-chain alkyl " refers to have the straight or branched alkyl of 1-8 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl or similar group.
Term " C3-C8 cycloalkyl " refers to have the cycloalkyl of 3-8 carbon atom, for example cyclopropane base, methyl cyclopropane base or similar group.
Term " aralkyl of C3～C20 " refers to have the straight or branched aralkyl of 1-8 carbon atom, for example benzyl, styroyl or similar group.
The preparation of formula IV compound
Formula IV compound can be prepared by following approach:
Figure BDA00002201637100081
In organic solvent, formula III compound and bromizating agent or chlorination reaction obtain formula IV compound.Or
Figure BDA00002201637100082
In inert solvent, formula III compound and alkali reaction obtain the intermediate of open loop, and then this intermediate reacts with RY and obtains formula V compound, formula V compound again with R 1-SO 2y reaction, forms formula VI compound;
Raw material formula III compound can make by ordinary method, also can obtain by purchase.
In the present invention, bromizating agent or chlorizating agent can be the Lewis acid that contains arbitrarily chlorine or bromine.Preferred bromizating agent or chlorizating agent include but not limited to: bromotrimethylsilane, trimethylchlorosilane, triethyl bromo-silicane, chlorotriethyl silane, triisopropyl bromo-silicane, tri isopropyl chlorosilane, hydrogen bromide, hydrogenchloride, or its combination, preferably, described bromizating agent or chlorizating agent are bromotrimethylsilane, trimethylchlorosilane, or its combination.
In another preference, described R 1-SO 2y comprises alkyl sulfonyl chloride or aryl sulfonyl chloride, is more preferably methane sulfonyl chloride, p-methylphenyl SULPHURYL CHLORIDE, ethyl chloride, sec.-propyl SULPHURYL CHLORIDE, or its combination.
The preparation of formula II compound
Formula II compound can be prepared by following approach:
Figure BDA00002201637100083
Formula IV compound reacts with morpholine, obtains formula II compound.
Raw material formula IV compound can make by ordinary method, preferably, can make by method provided by the invention.
The preparation of formula I compound
Formula I compound can be prepared by following approach:
Figure BDA00002201637100091
Formula IV compound reacts with morpholine and obtains formula II compound, and formula II compound is under alkaline condition, and hydrolysis obtains formula V compound, then obtains formula I compound with formula VI compound condensation.
Compared with prior art, the present invention mainly has the following advantages:
1. the intermediate formula IV compound for the preparation of formula I compound of novel structure is provided.
2. in the preparation method of formula IV compound of the present invention, open loop reagent used is bromizating agent or chlorizating agent, and such as bromotrimethylsilane or trimethylchlorosilane, the Iodotrimethylsilane of cost ratio prior art is cheaply over half.And the two step molar yields that open loop and morpholine replace have improved more than 20% than prior art, production cost is low, is applicable to suitability for industrialized production.
3. the preparation method that a kind of new formula I compound is provided, the method combines new intermediate and preparation method thereof, significantly reduces the production cost of formula I compound, is applicable to suitability for industrialized production.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and umber calculate by weight.The raw material that the present invention is used or reagent, unless otherwise noted, all make or commercially available obtaining according to a conventional method.
Preferably, raw material formula II compound, formula VI compound all can prepare with reference to WO2008010921.
The preparation of the bromo-2-of embodiment 1 (S)-4-(3-((2-sec.-propyl-4-thiazolyl) methyl)-3-methyl urea groups)-ethyl butyrate (formula IV-a compound)
By 100g (0.336mol) compound III, be dissolved in 500g methylene dichloride, add 100g dehydrated alcohol, be cooled to 0～10 ℃, drip bromotrimethylsilane 154g (1.0mol), room temperature reaction disappears to starting compound III, and TLC detects (methylene chloride/methanol=20/1 (V/V)).Be cooled to 0～10 ℃, saturated sodium bicarbonate 100g * 3 washing for reaction solution, separates organic layer, concentrated compound IV-a 120g, the purity 95.1% of obtaining.Molar yield 92%.LC-MS:M+1=406.1
The preparation of the bromo-2-of embodiment 2 (S)-4-(3-((2-sec.-propyl-4-thiazolyl) methyl)-3-methyl urea groups)-ethyl butyrate (formula IV-a compound)
By 100g (0.336mol) compound III, be dissolved in 500g methylene dichloride, add 100g dehydrated alcohol, be cooled to 10～20 ℃, drip triethyl bromo-silicane 195g (1.0mol), room temperature reaction disappears to starting compound III, and TLC detects (methylene chloride/methanol=20/1 (V/V)).Be cooled to 10～22 ℃, the washing of saturated sodium bicarbonate 100g * 3, separates organic layer, concentrated compound IV-a 112g, the purity 92.2% of obtaining.Molar yield 82%.LC-MS:M+1=406.1
The preparation of the bromo-2-of embodiment 3 (S)-4-(3-((2-sec.-propyl-4-thiazolyl) methyl)-3-methyl urea groups)-methyl-butyrate (formula IV-b compound)
Change the ethanol in embodiment 1 into methyl alcohol, other operate with embodiment 1, obtain IV-b, purity 96.2%.Molar yield 85%.LC-MS:M+1=392.1
The preparation of the bromo-2-of embodiment 4 (S)-4-(3-((2-sec.-propyl-4-thiazolyl) methyl)-3-methyl urea groups)-isopropyl butyrate (formula IV-c compound)
Change the ethanol in embodiment 1 into Virahol, other operate with embodiment 1, obtain compound IV-c.Purity 97.1%.Molar yield 83%.LC-MS:M+1=420.1
The preparation of the bromo-2-of embodiment 5 (S)-4-(3-((2-sec.-propyl-4-thiazolyl) methyl)-3-methyl urea groups)-butyric acid benzyl ester (formula IV-d compound)
Change the ethanol in embodiment 1 into benzyl alcohol, other operate with embodiment 1, obtain compound IV-d, purity 92.3%.Molar yield 73%.LC-MS:M+1=468.1
The preparation of the chloro-2-of embodiment 6 (S)-4-(3-((2-sec.-propyl-4-thiazolyl) methyl)-3-methyl urea groups)-ethyl butyrate (formula IV-e compound)
100g (0.336mol) compound III, be dissolved in 500g methylene dichloride, add 100g dehydrated alcohol, be cooled to 0～10 ℃, drip trimethylchlorosilane 162g (1.5mol), room temperature reaction disappears to starting compound III, and TLC detects (methylene chloride/methanol=20/1 (V/V)).Be cooled to 0～10 ℃, saturated sodium bicarbonate 100g * 3 washing for reaction solution, separates organic layer, concentrated compound IV-e 120g, the purity 94.6% of obtaining.Molar yield 80%.LC-MS:M+1=362.9
The preparation of the chloro-2-of embodiment 7 (S)-4-(3-((2-sec.-propyl-4-thiazolyl) methyl)-3-methyl urea groups)-methyl-butyrate (formula IV-f compound)
Change the ethanol in embodiment 6 into methyl alcohol, other operate with embodiment 6, obtain compound IV-f, purity 90.5%.Molar yield 79%.LC-MS:M+1=348.9
The preparation of the chloro-2-of embodiment 8 (S)-4-(3-((2-sec.-propyl-4-thiazolyl) methyl)-3-methyl urea groups)-isopropyl butyrate (formula IV-g compound)
Change the ethanol in embodiment 6 into Virahol, other operate with embodiment 6, obtain compound IV-g, purity 92.6%.Molar yield 83%.LC-MS:M+1＝376.9
The preparation of the chloro-2-of embodiment 9 (S)-4-(3-((2-sec.-propyl-4-thiazolyl) methyl)-3-methyl urea groups)-benzyl butyrate (formula IV-h compound)
Change the ethanol in embodiment 6 into benzyl alcohol, other operate with embodiment 6, obtain compound IV-h, purity 90.1%.Molar yield 81%.LC-MS:M+1=425.0
The preparation of the chloro-2-of embodiment 10 (S)-4-(3-((2-sec.-propyl-4-thiazolyl) methyl)-3-methyl urea groups)-ethyl butyrate (formula IV-e compound)
100g (0.336mol) compound III, be dissolved in 500g methylene dichloride, add 100g dehydrated alcohol, be cooled to 10～20 ℃, add aluminum chloride 195g (1.0mol) in batches, room temperature reaction disappears to starting compound III, and TLC detects (methylene chloride/methanol=20/1 (V/V)).Be cooled to 10～22 ℃, the washing of saturated sodium bicarbonate 100g * 3, separates organic layer, concentrated compound IV-e 112g, the purity 90.2% of obtaining.Molar yield 79%.LC-MS:M+1=362.9
The preparation of embodiment 11 (S)-4-methanesulfonyloxy group-2-(3-((2-sec.-propyl-4-thiazolyl) methyl)-3-methyl urea groups)-benzyl butyrate (formula IV-i compound)
By 100g (0.336mol) compound III, add in potassium hydroxide 45% ethanolic soln of 38g, stirring at room is until compound III disappears (TLC detection).Be evaporated to dryly, add 300mLDMF and 100g Benzyl Chloride, stirred overnight at room temperature.Concentrating under reduced pressure, residue is dispersed in 300g water and 300g methylene dichloride, separates dichloromethane layer, and with 100mL * 3 water washing, methylene dichloride is used anhydrous sodium sulfate drying mutually.In solution, drop into triethylamine (0.370mol, 37.3g), be cooled to 0～5 ℃, drip methane sulfonyl chloride (0.370mol, 43.0g), stir 1 hour at 0～5 ℃, TLC detects raw material and disappears.Add the 100mL shrend reaction of going out, separate dichloromethane layer, by dried over sodium sulfate, rotary evaporated to dryness, obtains compound IV-i.Purity 95.1%.Molar yield 82%.LC-MS:M+1=484.7
The preparation of embodiment 12 (S)-4-tolysulfonyl oxygen base-2-(3-((2-sec.-propyl-4-thiazolyl) methyl)-3-methyl urea groups)-benzyl butyrate (formula IV-j compound)
By 100g (0.336mol) compound III, add in potassium hydroxide 45% ethanolic soln of 38g, stirring at room is until compound III disappears (TLC detection).Be evaporated to dryly, add 300mLDMF and 100g Benzyl Chloride, stirred overnight at room temperature.Concentrating under reduced pressure, residue is dispersed in 300g water and 300g methylene dichloride, separates dichloromethane layer, and with 100mL * 3 water washing, methylene dichloride is used anhydrous sodium sulfate drying mutually.In solution, drop into triethylamine (0.370mol, 37.3g), be cooled to 0～5 ℃, add Tosyl chloride (0.370mol, 70.5g), stir 1 hour at 0～5 ℃, TLC detects raw material and disappears.Add the 100mL shrend reaction of going out, separate dichloromethane layer, by dried over sodium sulfate, rotary evaporated to dryness, obtains compound IV-j.Purity 94.5%.Molar yield 84.3%.LC-MS:M+1=560.2
The preparation of embodiment 13 (S)-2-(3-((2-sec.-propyl-4-thiazolyl)-methyl)-3-methyl urea groups)-4-morpholine base ethyl butyrate (formula II-a compound)
IV-a (100g, 0.246mol) is dissolved in to 500g methylene dichloride, drips morpholine (43g, 0.492mol), insulation at 25～40 ℃, TLC detection reaction (methylene chloride/methanol=20/1 (V/V)) disappears to compound IV-a.The hydrogen bromide salt that removes by filter morpholine, mother liquor washs with saturated sodium bicarbonate, is concentrated into dryly, obtains Compound I I-a.Purity is 92.1%, molar yield 78%.LC-MS:M+1＝413.6
The preparation of embodiment 14 (S)-2-(3-((2-sec.-propyl-4-thiazolyl)-methyl)-3-methyl urea groups)-4-morpholine base ethyl butyrate (formula II-a compound)
IV-e (100g, 0.277mol) is dissolved in to 500g methylene dichloride, drips morpholine (48g, 0.554mol), insulation at 25～40 ℃, TLC detection reaction (methylene chloride/methanol=20/1 (V/V)) disappears to compound IV-e.The hydrogen bromide salt that removes by filter morpholine, mother liquor washs with saturated sodium bicarbonate, is concentrated into dryly, obtains Compound I I-a.Purity is 90.3%, molar yield 74%.LC-MS:M+1＝413.6
The preparation of embodiment 15 (S)-2-(3-((2-sec.-propyl-4-thiazolyl)-methyl)-3-methyl urea groups)-4-morpholine base ethyl butyrate (formula II-a compound)
By 100g (0.336mol) compound III, be dissolved in 500g methylene dichloride, add 100g dehydrated alcohol, be cooled to 0～22 ℃, drip TMSBr 154g (1.0mol), room temperature reaction to starting compound 1 disappears.Be cooled to 0～22 ℃, drip morpholine 146g (1.68mol), be incubated 20～30 ℃ and react to compound 4 disappearances.Reacting liquid filtering, the appropriate washed with dichloromethane of solid, saturated sodium bicarbonate 100g * 3 washing for mother liquor, separates organic layer, concentrated Compound I I-a 100g, the molar yield 93% of obtaining.LC-MS:M+1＝413.6
The preparation of embodiment 16 formula I compounds
II-a (20g) is dissolved in methylene dichloride, adds 50%KOH (5.5g) aqueous solution, and in controlling, temperature is no more than 25 ℃, and TLC analyzes II-a and disappears.Be cooled to 0～10 ℃, add (2R, 5R)-5-amino-1,6-phenylbenzene-2-hexyl carboxylamine 5-thiazole methyl ester hydrochloride (14.8g), stirs 1～2 hour, add 1-hydroxy benzo triazole (5.5g), stir 1 hour, add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (15g), be incubated 5～10 hours, TLC analyzes raw material and disappears, and reaction finishes.Reaction solution aqueous acetic acid cancellation, separates dichloromethane layer, uses NaHCO 3saturated aqueous solution washing, then wash with water, concentrated dry.It is 99.1% that HPLC detects purity.Add dehydrated alcohol, distillation remove portion ethanol obtains the solution of product compound I in ethanol.Molar yield 88%, LC-MS:M+1=777.1
All documents of mentioning in the present invention are all quoted as a reference in this application, just as each piece of document, are quoted as a reference separately.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.

Claims (10)

1. compound shown in a formula IV;
Figure FDA00002201637000011
Wherein, X is bromine, chlorine or sulfonate group;
R is the aralkyl of straight chain, branched-chain alkyl or C3～C8 cycloalkyl, replacement or the unsubstituted C3～C20 of hydrogen, replacement or unsubstituted C1～C8;
Preferably, described replacement is to have one or more substituting groups that are selected from lower group: halogen, phenyl, C1～C4 alkyl; Wherein said phenyl comprises unsubstituted phenyl or has 1-3 substituent substituted-phenyl that is selected from hydroxyl, C1～C3 alkyl, halogen.
2. a preparation method for compound shown in formula IV, is characterized in that, described method comprises step:
(a), in inert solvent, under halogenating agent exists, formula III compound reacts with formula ROH compound, forms formula IV compound;
Figure FDA00002201637000012
Above-mentioned various, X is bromine or chlorine; And R is the aralkyl of straight chain, branched-chain alkyl or C3～C8 cycloalkyl, replacement or the unsubstituted C3～C20 of hydrogen, replacement or unsubstituted C1～C8;
Preferably, described replacement is to have one or more substituting groups that are selected from lower group: halogen, phenyl, C1～C4 alkyl; Wherein said phenyl comprises unsubstituted phenyl or has 1～3 substituent substituted-phenyl that is selected from hydroxyl, C1～C3 alkyl, halogen;
Or described method comprises step:
(b) in inert solvent, formula III compound reacts with alkali MOH the intermediate that obtains open loop, and then this intermediate reacts with compound R Y and obtains formula V compound, formula V compound again with compound R 1-SO 2y reaction, forms formula IV compound;
Figure FDA00002201637000021
Above-mentioned various in,
R is the aralkyl of straight chain, branched-chain alkyl or C3～C8 cycloalkyl, replacement or the unsubstituted C3～C20 of hydrogen, replacement or unsubstituted C1～C8;
Preferably, described replacement is to have one or more substituting groups that are selected from lower group: halogen, phenyl, C1～C4 alkyl; Wherein said phenyl comprises unsubstituted phenyl or has 1～3 substituent substituted-phenyl that is selected from hydroxyl, C1～C3 alkyl, halogen;
X is sulfonate group R 1-SO 2o-;
R 1straight or branched alkyl or aryl for C1～C8; With
Y is Cl, Br or I;
M is basic metal or alkaline-earth metal, preferably sodium and potassium.
3. preparation method as claimed in claim 2, is characterized in that, described halogenating agent is the Lewis acid that contains chlorine or bromine.
4. preparation method as claimed in claim 2, is characterized in that, in step (a), the mol ratio of formula III compound and bromizating agent or chlorizating agent is 1:1～1:5, preferably 1:1～1:3.
5. preparation method as claimed in claim 2, is characterized in that, temperature of reaction is-5～25 ℃, preferably 0～20 ℃.
6. have the preparation method suc as formula the compound of structure shown in II, it is characterized in that, the method comprises the following steps:
(i) in inert solvent, formula IV compound reacts with morpholine, forms formula II compound;
Figure FDA00002201637000031
In various, X is bromine, chlorine or sulfonate group;
R is the aralkyl of straight chain, branched alkoxy or C3～C8 cycloalkyl, replacement or the unsubstituted C3～C20 of hydrogen, replacement or unsubstituted C1～C8;
Preferably, described replacement is to have one or more substituting groups that are selected from lower group: halogen, phenyl, C1～C4 alkyl; Wherein said phenyl comprises unsubstituted phenyl or has 1-3 substituent substituted-phenyl that is selected from hydroxyl, C1～C3 alkyl, halogen.
7. method as claimed in claim 6, is characterized in that, the mol ratio of formula IV compound and morpholine is 1:2～1:5, preferably 1:2.5～1:3.5.
8. method as claimed in claim 6, is characterized in that, the temperature of reaction of step (i) is 20～60 ℃, is preferably 20～40 ℃.
9. a preparation method for formula I compound, is characterized in that, the method comprises the following steps:
(i) in inert solvent, formula IV compound reacts with morpholine, forms formula II compound;
(ii) under alkaline condition, formula II compound is hydrolyzed, and forms formula V compound;
(iii) formula V compound and formula VI compound are carried out to condensation, form formula I compound.
Figure FDA00002201637000032
10. a purposes for compound as claimed in claim 1, is characterized in that, described compound is used to the cytochrome P 450 monooxygenases inhibitor shown in preparation formula I or formula II compound as intermediate.
CN201210366903.2A 2012-09-27 2012-09-27 Cytochrome P450 monooxygenase inhibitor intermediate, and preparation methods and application thereof Pending CN103694196A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
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WO2008103949A1 (en) * 2007-02-23 2008-08-28 Gilead Sciences, Inc. Modulators of pharmacokinetic properties of therapeutics
US20090175820A1 (en) * 2008-01-04 2009-07-09 Gilead Sciences, Inc. Inhibitors of cytochrome p450
CN101490023A (en) * 2006-07-07 2009-07-22 吉里德科学公司 Modulators of pharmacokinetic properties of therapeutics
CN102438982A (en) * 2009-04-03 2012-05-02 吉里德科学公司 Methods and intermediates for preparing pharmaceutical agents
WO2014057498A2 (en) * 2012-10-08 2014-04-17 Mylan Laboratories Ltd. Process for the preparation of cobicistat intermediates

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101490023A (en) * 2006-07-07 2009-07-22 吉里德科学公司 Modulators of pharmacokinetic properties of therapeutics
WO2008103949A1 (en) * 2007-02-23 2008-08-28 Gilead Sciences, Inc. Modulators of pharmacokinetic properties of therapeutics
US20090175820A1 (en) * 2008-01-04 2009-07-09 Gilead Sciences, Inc. Inhibitors of cytochrome p450
CN102438982A (en) * 2009-04-03 2012-05-02 吉里德科学公司 Methods and intermediates for preparing pharmaceutical agents
WO2014057498A2 (en) * 2012-10-08 2014-04-17 Mylan Laboratories Ltd. Process for the preparation of cobicistat intermediates

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