CN104649993A - Method for preparing cholesteryl ester transfer protein (CETP) inhibitor - Google Patents

Method for preparing cholesteryl ester transfer protein (CETP) inhibitor Download PDF

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CN104649993A
CN104649993A CN201410777914.9A CN201410777914A CN104649993A CN 104649993 A CN104649993 A CN 104649993A CN 201410777914 A CN201410777914 A CN 201410777914A CN 104649993 A CN104649993 A CN 104649993A
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formula
compound
solvent
certain embodiments
nucleophilic substitution
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雷正
李海德
杨相海
黎利军
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Guangdong HEC Pharmaceutical
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • 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
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The application relates to a method for preparing a cholesteryl ester transfer protein (CETP) inhibitor, in particular to a method for preparing a compound with a formula (1a) shown in the description. The method comprises the following steps: step (1), performing a condensation reaction on a compound with a formula (2a) shown in the description and a condensing agent capable of providing one carbonyl group, wherein the compound with the formula (2a) shown in the description in the step (1) is prepared by performing a nucleophilic substitution reaction on a compound with a formula (3) shown in the description and a compound with a formula (4) shown in the description, wherein X represents Cl, Br or I. The method for preparing the CETP inhibitor has the advantages that operation requirements are low, anhydrous and anaerobic conditions are not needed, and reactive reagents are mild.

Description

A kind of method preparing CETP inhibitor
Technical field
The application relates to medicinal chemistry art, is specifically related to the method for synthesizing the compound suppressing cholesteryl ester transfer protein (CETP).
Background technology
Chinese patent application CN 200580022618.7 discloses a series of cholestery ester transfer protein inhibitors (CETP), wherein bent of Ansai, high-density lipoprotein (HDL) (HDL) cholesterol and Apolipoprotein A1 can be increased, and reduce low-density lipoprotein (LDL) cholesterol and apolipoprotein B, can potential treatment hyperlipemia prevention of arterial is atherosis.Bent its chemical name in Ansai is (4S, 5R)-5-[3, two (trifluoromethyl) phenyl of 5-]-3-{ [4 '-fluoro-5 '-sec.-propyl-2 '-methoxyl group-4-(trifluoromethyl) xenyl-2-base] methyl }-4-methyl isophthalic acid, 3-oxazolidine-2-ketone, its chemical structure is such as formula shown in (1a):
Chinese patent application CN 201210011961 reports and reacts obtained compound (1a) by compound (5) and compound (4a), need to adopt high bp polar solvent to comprise N, dinethylformamide (DMF), N,N-DIMETHYLACETAMIDE (DMAC), HMPA (HMPA), methyl-sulphoxide (DMSO) or its mixture, and adopt highly basic as sodium amide, potassium amide, NaHMDS, KHMDS, n-Butyl Lithium or tert-butyl lithium
These highly basic are high to system moisture requirement, the strict hierarchy of control is needed to be water-less environment, and polar solvent DMF, DMAC, HMPA, DMSO that it adopts very easily absorb water, need before use strictly to dewater, highly basic and the requirement of large polar solvent to technique high, repeatable poor, limit its application in the industrial production.
Term definition
Term " optionally " refers to that an optional substituted radical can replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.
Hereinafter, (the R in formula (1), formula (2), formula (3) or formula (4) 2) a represents a R 2, same (R 4) b represents b R 4, (R 5) c represents c R 5.
The temperature in term " room temperature " finger ring border, is typically about 20 DEG C to about 30 DEG C.
Summary of the invention
Summary of the invention
First aspect present invention provides the preparation method of compound shown in a kind of formula (1),
It comprises: by formula (2) with the condensing agent of a carbonyl can be provided to carry out condensation reaction,
In the compound of formula (1) and formula (2):
Phenyl ring is optionally by (R 2) a, (R 4) b, (R 5) c replacement;
R 1for H or C1-C4 alkyl, it is optionally replaced by 1-5 F;
R 2, R 4and R 5each independent selected from halo, C1-C4 alkyl and-OC1-C4 alkyl, wherein C1-C4 alkyl and-OC1-C4 alkyl are optionally replaced by 1-5 halogen atom;
R 3be selected from H, halogen, C1-C4 alkyl and-OC1-C4 alkyl, wherein C1-C4 alkyl and-OC1-C4 alkyl are optionally replaced by 1-5 halogen atom;
The each integer independently selected from 1-4 of a and b;
C is the integer of 0-2;
In certain embodiments, R 1for H or optionally by the C1-C3 alkyl of 1-5 F replacement.R in other embodiments 1for optionally by C1-C2 alkyl that 1-3 F replaces.R in preferred embodiments 1for CH 3.
In certain embodiments, R 2, R 4and R 5each independently selected from F, optionally by the C1-C3 alkyl that 1-5 F replaces, or optionally by the-OC1-C3 alkyl of 1-5 F replacement.In other embodiments, R 2, R 4and R 5each independently selected from F, optionally by the C1-C3 alkyl that 1-5 F replaces, or optionally by the-OC1-C2 alkyl of 1-5 F replacement.In other embodiments, R 2, R 4and R 5each independently selected from C1-C3 alkyl, CF 3,-OCH 3,-OCF 3and F.
In some embodiments, each R 2for CH 3or CF 3.
In some embodiments, R 2for CF 3.
In some embodiments, R 3for C1-C3 alkyl ,-OC1-C3 alkyl or F, wherein C1-C3 alkyl and-OC1-C3 alkyl are optionally replaced by 1-5 F.
In some embodiments, R 3for CH 3, CF 3or F.
In some embodiments, R 3for-CF 3.
In certain embodiments, a is 1 or 2, and in certain embodiments, a is 2.
In certain embodiments, b is 1-3.In some embodiments, b is 2 or 3.In some embodiments, b is 3.
In certain embodiments, c is 0 or 1.In some embodiments, c is 0.
Except as otherwise noted, alkyl can be straight or branched.
Second aspect present invention provides the method for a kind of preparation formula (2),
It comprises: carry out nucleophilic substitution reaction by compound formula (3) Suo Shi and formula (4) compound,
Wherein, formula (3) and the middle R of formula (4) 1, R 2, R 3, R 4, R 5, a, b or c be identical with the definition of formula (2) with formula (1); Y is leavings group.The example of leavings group includes but not limited to-OSO 2cH 3,-OSO 2ph ,-OSO 2ph-Me, Br, Cl, I, C1-C3 alkane carboxylicesters (such as acetic ester), trifluoro-acetate and triflate.
Detailed Description Of The Invention
First aspect present invention provides the preparation method of compound shown in a kind of formula (1),
It comprises: by formula (2) with the condensing agent of a carbonyl can be provided to carry out condensation reaction,
In the compound of formula (1) and formula (2):
Phenyl ring is optionally by (R 2) a, (R 4) b, (R 5) c replacement;
R 1for H or C1-C4 alkyl, it is optionally replaced by 1-5 F;
R 2, R 4and R 5each independent selected from halo, C1-C4 alkyl and-OC1-C4 alkyl, wherein C1-C4 alkyl and-OC1-C4 alkyl are optionally replaced by 1-5 halogen atom;
R 3be selected from H, halogen, C1-C4 alkyl and-OC1-C4 alkyl, wherein C1-C4 alkyl and-OC1-C4 alkyl are optionally replaced by 1-5 halogen atom;
The each integer independently selected from 1-4 of a and b;
C is the integer of 0-2;
In certain embodiments, R 1for H or optionally by the C1-C3 alkyl of 1-5 F replacement.R in other embodiments 1for optionally by C1-C2 alkyl that 1-3 F replaces.R in preferred embodiments 1for CH 3.
In certain embodiments, R 2, R 4and R 5each independently selected from F, optionally by the C1-C3 alkyl that 1-5 F replaces, or optionally by the-OC1-C3 alkyl of 1-5 F replacement.In other embodiments, R 2, R 4and R 5each independently selected from F, optionally by the C1-C3 alkyl that 1-5 F replaces, or optionally by the-OC1-C2 alkyl of 1-5 F replacement.In other embodiments, R 2, R 4and R 5each independently selected from C1-C3 alkyl, CF 3,-OCH 3,-OCF 3and F.
In some embodiments, each R 2for CH 3or CF 3.
In some embodiments, R 2for CF 3.
In some embodiments, R 3for C1-C3 alkyl ,-OC1-C3 alkyl or F, wherein C1-C3 alkyl and-OC1-C3 alkyl are optionally replaced by 1-5 F.
In some embodiments, R 3for CH 3, CF 3or F.
In some embodiments, R 3for-CF 3.
In certain embodiments, a is 1 or 2, and in certain embodiments, a is 2.
In certain embodiments, b is 1-3.In some embodiments, b is 2 or 3.In some embodiments, b is 3.
In certain embodiments, c is 0 or 1.In some embodiments, c is 0.
Except as otherwise noted, alkyl can be straight or branched.
In one embodiment, compound shown in formula (1) is compound shown in formula (1a), and compound shown in formula (2) is compound shown in formula (2a):
In one embodiment, the preparation method of compound shown in formula (Ia), it comprises: by formula (2a) with can provide the condensing agent of a carbonyl capable condensation reaction,
In certain embodiments, described condensing agent is 1,1'-carbonyl dimidazoles (CDI), two (trichloromethyl) carbonic ether or superpalite.
Relative to compound formula (2) Suo Shi, described condensing agent is more than 1.0 molar equivalents, as 1.5 molar equivalent to 5 molar equivalents.
In certain embodiments, the solvent that described condensation reaction uses, for being polar solvent or non-polar solvent, is selected from one or more in ether solvents, ketones solvent, esters solvent, alkane solvents, aromatic hydrocarbon solvent, nitrile solvents.Wherein, described ether solvents is selected from such as tetrahydrofuran (THF), methyl tertiary butyl ether, 1, one or more in 4-dioxane, described ketones solvent is selected from such as acetone, methylethylketone, one or more in 4-methyl-2 pentanone, described esters solvent is selected from such as ethyl acetate, isopropyl acetate, n-butyl acetate, one or more in tert.-butyl acetate, described alkane solvents is selected from such as methylene dichloride, chloroform, normal hexane, hexanaphthene, pentane, one or more in normal heptane, described aromatic hydrocarbon solvent is selected from such as benzene, in toluene or dimethylbenzene one or more etc., described nitrile solvents is selected from one or more in such as acetonitrile, propane dinitrile.In certain embodiments, the solvent that described condensation reaction uses is methylene dichloride, one or more in 1,2-ethylene dichloride, toluene, chloroform.
In certain embodiments, described condensation reaction can be carried out in the presence of a base, also can not need alkali.In certain embodiments, described alkali is selected from one or more in lithium hydroxide, sodium hydroxide, potassium hydroxide.In certain embodiments, described alkali is selected from one or more in the alkali of salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus or shares activity.In certain embodiments, described alkali is selected from one or more in potassium hydride KH, sodium hydride, lithium hydride, hydrolith, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium isopropylate, lithium hydroxide, sodium hydroxide, potassium hydroxide, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus.In certain embodiments, described alkali is selected from trimethylamine, such as triethylamine, diisopropylethylamine, DBU (1,8-diazabicyclo [5,4,0] undecylene).In one embodiment, described alkali is triethylamine, and in another embodiment, described alkali is salt of wormwood or sodium hydroxide.
In certain embodiments, described condensation is at room temperature carried out.
Second aspect present invention provides the method for a kind of preparation formula (2),
It comprises: carry out nucleophilic substitution reaction by compound formula (3) Suo Shi and formula (4) compound,
Wherein, formula (3) and the middle R of formula (4) 1, R 2, R 3, R 4, R 5, a, b or c be identical with the definition of formula (2) with formula (1); Y is leavings group.The example of leavings group includes but not limited to-OSO 2cH 3,-OSO 2ph ,-OSO 2ph-Me, Br, Cl, I, C1-C3 alkane carboxylicesters (such as acetic ester), trifluoro-acetate and triflate.
In one embodiment, the preparation method of compound shown in formula (2a),
It comprises: carry out nucleophilic substitution reaction by compound formula (3) Suo Shi and formula (4) compound,
In certain embodiments, the alkali that described nucleophilic substitution reaction uses is selected from one or more in potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium isopropylate, shares activity alkali.In certain embodiments, described alkali is selected from one or more in lithium hydroxide, sodium hydroxide, potassium hydroxide.In certain embodiments, described alkali is selected from one or more in potassium hydride KH, sodium hydride, lithium hydride, hydrolith, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium isopropylate, lithium hydroxide, sodium hydroxide, potassium hydroxide.In certain embodiments, described alkali is selected from trimethylamine, such as triethylamine, diisopropylethylamine, DBU (1,8-diazabicyclo [5,4,0] undecylene), and in one embodiment, described alkali is selected from triethylamine or diisopropylethylamine.
In certain embodiments, the solvent that described nucleophilic substitution reaction uses is polar solvent or non-polar solvent, is selected from one or more in dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE, ether solvents, ketones solvent, esters solvent, alkane solvents, aromatic hydrocarbon solvent, nitrile solvents.Wherein, described alcoholic solvent is selected from methyl alcohol, ethanol or 1, ammediol, 1, 2-propylene glycol, one or more in trichloro-butyl alcohol, described ether solvents is selected from such as tetrahydrofuran (THF), methyl tertiary butyl ether, 1, one or more in 4-dioxane, described ketones solvent is selected from such as acetone, butanone or methylethylketone, one or more in 4-methyl-2 pentanone, described esters solvent is selected from such as ethyl acetate, isopropyl acetate, n-butyl acetate, one or more in tert.-butyl acetate, described alkane solvents is selected from such as methylene dichloride, chloroform, normal hexane, hexanaphthene, pentane, one or more in normal heptane, described aromatic hydrocarbon solvent is selected from such as benzene, toluene etc., described nitrile solvents is selected from one or more in such as acetonitrile, propane dinitrile.In one embodiment, the solvent that described nucleophilic substitution reaction uses is methylene dichloride.
In certain embodiments, described nucleophilic substitution reaction can carry out to inert solvent reflux temperature for-30 DEG C.In certain embodiments temperature of reaction be-10 DEG C to inert solvent reflux temperature.Temperature of reaction is room temperature in certain embodiments.
In certain embodiments, shown in formula (4), the amount of compound can be equivalent or excessive relative to compound formula (3) Suo Shi, is 1 to 3 equivalents in certain embodiments.Be 1.1 to 2 equivalents in certain embodiments.
In certain embodiments, the amount of described nucleophilic substitution reaction alkali used can be equivalent (mole) or excessive (mole) relative to compound formula (3) Suo Shi, is 1 to 5 equivalents in certain embodiments.Be 1.2 to 3.0 molar equivalents in certain embodiments.Be 1.5 equivalents in further embodiments.
In one embodiment, the preparation method of compound shown in formula (1a), it comprises:
Step 1) by formula (2a) and the condensing agent generation condensation reaction that can provide a carbonyl,
Step 2) step 1) in formula (2a) shown in compound shown in formula (3) and formula (4) compound carry out nucleophilic substitution reaction and prepare,
Wherein, X is Cl, Br or I.
In certain embodiments, step 1) described in condensing agent be 1,1'-carbonyl dimidazoles (CDI), two (trichloromethyl) carbonic ether or superpalite.
Relative to compound formula (2) Suo Shi, described condensing agent is more than 1.0 equivalents, as 1.5 molar equivalent to 5 equivalents.
In certain embodiments, the solvent that described condensation reaction uses, for being polar solvent or non-polar solvent, is selected from one or more in ether solvents, ketones solvent, esters solvent, alkane solvents, aromatic hydrocarbon solvent, nitrile solvents.Wherein, described ether solvents is selected from such as tetrahydrofuran (THF), methyl tertiary butyl ether, 1, one or more in 4-dioxane, described ketones solvent is selected from one or more in such as acetone, butanone, methylethylketone, 4-methyl-2 pentanone, described esters solvent is selected from one or more in such as ethyl acetate, isopropyl acetate, n-butyl acetate, tert.-butyl acetate, described alkane solvents is selected from one or more in such as methylene dichloride, chloroform, normal hexane, hexanaphthene, pentane, normal heptane, and described aromatic hydrocarbon solvent is selected from such as benzene, toluene etc.; Described nitrile solvents is selected from one or more in such as acetonitrile, propane dinitrile.In certain embodiments, the solvent that described condensation reaction uses is methylene dichloride, one or more in 1,2-ethylene dichloride, toluene, chloroform.
In certain embodiments, described condensation reaction can be carried out in the presence of a base, also can not need alkali.Described alkali is selected from one or more in potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium isopropylate or shares activity alkali.In certain embodiments, described alkali is selected from one or more in lithium hydroxide, sodium hydroxide, potassium hydroxide.In certain embodiments, described alkali is selected from one or more in the alkali of salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus or shares activity.In certain embodiments, described alkali is selected from one or more in potassium hydride KH, sodium hydride, lithium hydride, hydrolith, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium isopropylate, lithium hydroxide, sodium hydroxide, potassium hydroxide, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus.In certain embodiments, described alkali is selected from trimethylamine, such as triethylamine, diisopropylethylamine, DBU (1,8-diazabicyclo [5,4,0] undecylene).In one embodiment, described alkali is triethylamine, and in another embodiment, described alkali is salt of wormwood or sodium hydroxide.
In certain embodiments, described condensation reaction is at room temperature carried out.
In certain embodiments, step 2) alkali that uses of described nucleophilic substitution reaction be selected from potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium isopropylate or shares activity alkali one or more.In certain embodiments, described alkali is selected from one or more in lithium hydroxide, sodium hydroxide, potassium hydroxide.In certain embodiments, described alkali is selected from one or more in potassium hydride KH, sodium hydride, lithium hydride, hydrolith, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium isopropylate, lithium hydroxide, sodium hydroxide, potassium hydroxide.In certain embodiments, described alkali is selected from trimethylamine, such as triethylamine, diisopropylethylamine, DBU (1,8-diazabicyclo [5,4,0] undecylene), and in one embodiment, described alkali is selected from potassium tert.-butoxide.
In certain embodiments, the solvent that described nucleophilic substitution reaction uses is polar solvent or non-polar solvent, is selected from one or more in ether solvents, ketones solvent, esters solvent, alkane solvents, aromatic hydrocarbon solvent or nitrile solvents.Wherein, described ether solvents is selected from such as tetrahydrofuran (THF), methyl tertiary butyl ether or 1, one or more in 4-dioxane, described ketones solvent is selected from one or more in such as acetone, butanone or methylethylketone or 4-methyl-2 pentanone, described esters solvent is selected from one or more in such as ethyl acetate, isopropyl acetate, n-butyl acetate or tert.-butyl acetate, described alkane solvents is selected from one or more in such as methylene dichloride, chloroform, normal hexane, hexanaphthene or pentane or normal heptane, and described aromatic hydrocarbon solvent is selected from such as benzene, toluene etc.; Described nitrile solvents is selected from one or more in such as acetonitrile, propane dinitrile.In one embodiment, the solvent that described nucleophilic substitution reaction uses is methylene dichloride.
In certain embodiments, described nucleophilic substitution reaction can carry out to inert solvent reflux temperature for-30 DEG C.In certain embodiments temperature of reaction be-10 DEG C to room temperature.In certain embodiments, described nucleophilic substitution reaction temperature is 5 DEG C.
In certain embodiments, shown in formula (4), the amount of compound can be equivalent or excessive relative to compound formula (3) Suo Shi, is 1 to 3 equivalents in certain embodiments.Be 1.1 to 2 equivalents in certain embodiments.
In certain embodiments, the amount of described nucleophilic substitution reaction alkali used can be equivalent (mole) or excessive (mole) relative to compound formula (3) Suo Shi, is 1 to 5 equivalents in certain embodiments.Be 1.2 to 3.0 equivalents in certain embodiments.Be 1.5 equivalents in further embodiments.
The invention provides the method for compound shown in compound shown in Formula shown in compound shown in a kind of preparation formula (1) or formula (1a) or (2) or (2a), described method, lower to the requirement of operation, without the need to anhydrous and oxygen-free condition; Reaction reagent is gentle, in compound (2a), prepares the overall yield of compound shown in end product formula (1a) more than 40%.
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation, prepares such as formula compound method disclosed in WO 2006014357 shown in compound (3a) Suo Shi and formula (5).
In the present invention, min represents minute, and h represents hour, and g represents gram, and ml represents milliliter.
Compound shown in embodiment 1 preparation formula (4a)
Shown in formula (5), compound (6.3g) is dissolved in DMF (31.5ml), nitrogen replacement three times; Above-mentioned solution is cooled to 25 DEG C, drips SOCl 2(2.1ml); Dropwise, insulated and stirred 4 ~ 5h, HPLC monitoring, to reacting completely, adds 4.6ml water, stirs 0.5 ~ 2h; Slowly drip 11.2ml water, stirring is spent the night.Filter, filter cake 36ml DMF:H 2o (V:V) washes once for 1:1, and 36ml washes 3 times; Filter cake 40 DEG C of drying under reduced pressure 24h (productive rates: 96%).
Compound shown in embodiment 2 preparation formula (2a)
Room temperature, under nitrogen protection, compound formula (3a) Suo Shi (WO 2006014357) (6.3), potassium tert.-butoxide (3.5g) and tetrahydrofuran (THF) (79ml) are mixed, after stirred at ambient temperature 20min, system is cooled to 5 DEG C, compound (6.3g) shown in formula (4a) is added in above-mentioned turbid solution, under nitrogen protection, stir 18h; Add the dilute hydrochloric acid cancellation reaction of 10%wt., organic phase washing twice, concentrated, cross column separating purification, productive rate 84%.
Compound shown in embodiment 3 preparation formula (1a)
Room temperature, is dissolved in methylene dichloride (1ml) by compound (0.1g) formula (2a) Suo Shi, 1,1'-carbonyl dimidazoles (40mg) under nitrogen protection; Stirring at room temperature 16h under nitrogen protection; Add water cancellation, and organic phases washed with water is once, concentrated, crosses column purification, PE:EA (10:1 → 4:1) wash-out; Mother liquor concentrations to most of solvent is distilled out of (later stage very easily bubble bumping), adds 7 ~ 8ml normal heptane and takes away residual solvent; Add 8ml Skellysolve A in residue, rise to 40 ~ 50 DEG C of dissolvings, be more slowly down to-20 DEG C of stirrings and spend the night; Low temperature fast filtering; 40 DEG C of drying under reduced pressure 21h, productive rate 69%.
Compound shown in embodiment 4 preparation formula (1a)
Room temperature, is dissolved in tetrahydrochysene fluorine and mutters in (15ml) and form mixture by compound (1.0g) formula (2a) Suo Shi, 1,1'-carbonyl dimidazoles (0.4g) under nitrogen protection; Add sodium carbonate (40mg) nitrogen protection in mixture under, stirring at room temperature is to reacting complete; Add water cancellation, and organic phases washed with water is once, concentrated, crosses column purification, PE:EA (10:1 → 4:1) wash-out; Mother liquor concentrations to most of solvent is distilled out of (later stage very easily bubble bumping), adds 7 ~ 8ml normal heptane and takes away residual solvent; Add 8ml Skellysolve A in residue, rise to 40 ~ 50 DEG C of dissolvings, be more slowly down to-20 DEG C of stirrings and spend the night; Low temperature fast filtering; 40 DEG C of drying under reduced pressure 21h, productive rate 79%.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.

Claims (8)

1. a preparation method for compound shown in formula (1a), it comprises:
Step 1) by formula (2a) and the condensing agent generation condensation reaction that can provide a carbonyl,
Step 2) step 1) in formula (2a) shown in compound shown in formula (3a) and formula (4a) compound carry out nucleophilic substitution reaction and prepare,
Wherein, X is Cl, Br or I.
2. the method for claim 1, step 1) described in condensing agent be 1,1'-carbonyl dimidazoles (CDI), two (trichloromethyl) carbonic ether or superpalite.
3. the method for claim 1, the solvent that described condensation reaction uses is methylene dichloride, one or more in 1,2-ethylene dichloride, toluene, chloroform.
4. the method for claim 1, the alkali that described nucleophilic substitution reaction uses is selected from one or more in potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium isopropylate, shares activity alkali.
5. the method for claim 1, the solvent of described nucleophilic substitution reaction is selected from one or more in dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), methyl tertiary butyl ether, Isosorbide-5-Nitrae-dioxane.
6. the method for claim 1, described nucleophilic substitution reaction temperature be-10 DEG C to room temperature.
7. method as claimed in claim 6, described nucleophilic substitution reaction temperature is 5 DEG C.
8. the method for claim 1, it comprises: step 1) room temperature, under nitrogen protection, compound (0.1g) formula (2a) Suo Shi, 1,1'-carbonyl dimidazoles (40mg) are dissolved in methylene dichloride (1ml); Stirring at room temperature 16h under nitrogen protection; Add water cancellation, and organic phases washed with water is once, concentrated, crosses column purification, sherwood oil: ethyl acetate (V:V is 10:1 → 4:1) wash-out; Mother liquor concentrations to most of solvent is distilled out of, and adds 7 ~ 8ml normal heptane and takes away residual solvent; Add 8ml Skellysolve A in residue, rise to 40 ~ 50 DEG C of dissolvings, be more slowly down to-20 DEG C of stirrings and spend the night; Low temperature fast filtering; 40 DEG C of drying under reduced pressure 21h;
Step 2) room temperature, under nitrogen protection, compound (6.3) formula (3a) Suo Shi, potassium tert.-butoxide (3.5g) and tetrahydrofuran (THF) (79ml) are mixed, after stirred at ambient temperature 20min, system is cooled to 5 DEG C, compound (6.3g) shown in formula (4a) is added in above-mentioned turbid solution, under nitrogen protection, stir 18h; Add the dilute hydrochloric acid cancellation reaction of 10%wt., organic phase washing twice, concentrated.
CN201410777914.9A 2014-06-12 2014-12-15 Method for preparing cholesteryl ester transfer protein (CETP) inhibitor Pending CN104649993A (en)

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Cited By (2)

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CN106032362A (en) * 2015-03-10 2016-10-19 湖南千金湘江药业股份有限公司 Preparation method of Anacetrapib
WO2018016743A1 (en) * 2016-07-19 2018-01-25 재단법인 대구경북첨단의료산업진흥재단 Oxazolidinone derivative compound as cetp inhibitor

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WO2014111953A1 (en) * 2013-01-17 2014-07-24 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for preparation of anacetrapib and intermediates thereof

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106032362A (en) * 2015-03-10 2016-10-19 湖南千金湘江药业股份有限公司 Preparation method of Anacetrapib
CN106032362B (en) * 2015-03-10 2018-06-19 湖南千金湘江药业股份有限公司 The preparation method of Ansai Qu
WO2018016743A1 (en) * 2016-07-19 2018-01-25 재단법인 대구경북첨단의료산업진흥재단 Oxazolidinone derivative compound as cetp inhibitor

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