CN109369491A - A new class of ezetimibe derivative and preparation method thereof - Google Patents

A new class of ezetimibe derivative and preparation method thereof Download PDF

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Publication number
CN109369491A
CN109369491A CN201811501676.3A CN201811501676A CN109369491A CN 109369491 A CN109369491 A CN 109369491A CN 201811501676 A CN201811501676 A CN 201811501676A CN 109369491 A CN109369491 A CN 109369491A
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new class
dissolved
ezetimibe
compound
reaction
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王庆林
王涛
王彬彬
孙益林
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WUXI FORTUNE PHARMACEUTICAL CO LTD
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WUXI FORTUNE PHARMACEUTICAL CO LTD
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D205/00Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides a new class of ezetimibe derivatives, which is characterized in that its structural formula is shown in formula I:

Description

A new class of ezetimibe derivative and preparation method thereof
Technical field
The present invention relates to field of pharmaceutical chemistry technology more particularly to a new class of ezetimibe derivative and its preparation sides Method.
Background technique
Ezetimibe is a kind of cholesterol absorption inhibitor/NPC1L1 inhibitor, can be used as homozygous sub-family diet control Adjuvant treatment in addition can be united and applied in treatment primary (heterozygosis individually or with HMG-CoA reductase inhibitor (Statins) Sub-family or non-familial) hypercholesterolemia, can reduce total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), Apolipoprotein;With Statins use in conjunction, complementary therapy (such as LDL-C blood plasma separation displacement of other lipid-lowering therapies can be used as Method), or when other lipid-lowering therapies are invalid for reducing the TC of HoFH patient and LDL-C level;Other than diet control Adjuvant treatment, it is horizontal for reducing the sitosterol and phytosterol of homozygote familial Sitosterolemia patient.
Ezetimibe lipophilicity is strong, Determination of oil-water partition coefficient logP=4.5, thus solubility in water it is extremely low (23 DEG C, 0.012mg/ml), these factors affect pharmaceutical dosage form design and existing dosage form bioavilability it is lower (35-65%).Compared with The solubility of difference causes therapeutic effect to decline with dissolution rate, and very big obstacle is caused to the clinical expansion of drug.Therefore, pass through knot Structure modification, which improves ezetimibe water solubility, has very high researching value.
Summary of the invention
It is an object of the invention to disclose a new class of ezetimibe derivative, the water solubility of ezetimibe is improved, just In the clinical expansion of drug.
To achieve the above object, the present invention provides a new class of ezetimibe derivative, structural formula is shown in formula I:
Wherein, R is selected from following table:
The present invention also provides the preparation method of a new class of ezetimibe derivative (Formulas I structural compounds), this method It is starting with (4S) -3- [(5S) -5- (4- fluorophenyl) -5- hydroxypentanoyl base] -4- phenyl -1,3- oxaza pentane -2- ketone Object, etherificate, after TBDMSCl protection, 4- [[(4- fluorophenyl) imino group] methyl] coupling of-phenol, cyclization, acid with benzyl protection Change, hydrogenation, most afterwards through being recrystallized to give target product.
Further, compound A10 is made according to the method described above, structural formula is as follows:
Further, compound A10's step 1: by (4S) -3- [(5S) -5- (4- fluorophenyl) -5- hydroxyl is prepared Valeryl] -4- phenyl -1,3- oxaza pentane -2- ketone is dissolved in DMF, sequentially adds potassium carbonate and N- hydroxyethyl morpholine, it feeds After be stirred at room temperature 2h, TLC judgement reaction terminates, and reaction solution is poured into ice water, is filtered, filter cake is dried in vacuo white solid Body, i.e. intermediate A 10-1.
Further, compound A10's step 2: by the 4- [[(4- fluorophenyl) imino group] of benzyl protection is prepared Methyl]-phenol is dissolved in DMF, sequentially adds potassium carbonate and benzyl chloride, and 2h is stirred at room temperature after charging, and TLC judgement reaction terminates, Reaction solution is poured into ice water, is filtered, filter cake is dried in vacuo to obtain white solid, i.e. intermediate A 10-2.
Further, compound A10's step 3: first by TiCl is prepared4It is dissolved in methylene chloride, 0 DEG C of dropwise addition Ti (O- i-Pr)4, insulation reaction 30min, obtained TiCl4+Ti(O-i-Pr)4Mixed solution;
Intermediate A 10-1 and intermediate A 10-2 is dissolved in methylene chloride, and -15 DEG C are successively added dropwise DIPEA and TiCl4+Ti(O- i-Pr)4Then glacial acetic acid is added dropwise, and ice bath is cooling, and reaction solution is poured into 7% winestone in mixed solution, the 2h that is added dropwise that the reaction was continued Aqueous acid stirs 1h, warms naturally to room temperature, and 20% solution of sodium bisulfite is added, and continues to stir 2h, and organic layer separates, Washing, anhydrous sodium sulfate is dry, filters, and filtrate builds industry concentration, and methanol mashing obtains white solid, i.e. intermediate A 10-3.
Further, compound A10's step 4: intermediate A 10-3 is dissolved in methylene chloride is prepared, is sequentially added 2h is stirred at room temperature in BSA and TBAF, and TLC judgement reaction end adjusts PH to 7 with acetic acid, is concentrated under reduced pressure, after ethyl acetate extraction, Ice water washing, anhydrous sodium sulfate is dry, filters, and filtrate is concentrated to give crude product, i.e. intermediate A 10-4.
Further, compound A10's step 5: intermediate A 10-4 is dissolved in ethyl acetate is prepared, is added 10% Pd/C, overnight, TLC judgement reaction terminates the reaction of room temperature atmospheric hydrogenation, filters, and filtrate decompression concentration, residue recrystallized from acetonitrile obtains White crystal, i.e. compound A10.
Compared with prior art, the beneficial effects of the present invention are: improving the water solubility of ezetimibe, it is more advantageous to drug Clinical use.
Specific embodiment
Below with reference to each embodiment, the present invention is described in detail, but it should be stated that, these embodiments are simultaneously Non- limitation of the present invention, those of ordinary skill in the art are according to these embodiments in made function, method or structure Equivalent transformation or substitution, all belong to the scope of protection of the present invention within.
The present invention provides a new class of ezetimibe derivative, structural formula is shown in formula I:
Wherein, R is selected from following table:
The present invention also provides the preparation method of a new class of ezetimibe derivative (Formulas I structural compounds), this method It is starting with (4S) -3- [(5S) -5- (4- fluorophenyl) -5- hydroxypentanoyl base] -4- phenyl -1,3- oxaza pentane -2- ketone Object, etherificate, after TBDMSCl protection, 4- [[(4- fluorophenyl) imino group] methyl] coupling of-phenol, cyclization, acid with benzyl protection Change, hydrogenation, most afterwards through being recrystallized to give target product.
Embodiment one:
Present embodiment discloses a kind of compound A1 obtained according to the method described above, structural formula is as follows:
The preparation method of compound A1:
1.1) synthesis of intermediate A 1-1
Formula EZ-1 is (4S) -3- [(5S) -5- (4- fluorophenyl) -5- hydroxyl -1- oxopentyl] -4- phenyl -2- oxazolidine The structural formula of ketone.
(4S) -3- [(5S) -5- (4- fluorophenyl) -5- hydroxyl -1- oxopentyl] -4- phenyl -2- oxazolidone (35.7g, It 0.1mol) is dissolved in 20mlDMF, potassium carbonate (27.6g, 0.2mol) and ethylene glycol (60g, 1mol) are sequentially added, after charging 2h is stirred at room temperature, TLC judgement reaction terminates, reaction solution is poured into ice water, is filtered, filter cake is dried in vacuo to obtain white solid 36.3g.
1.2) synthesis of intermediate A 1-2
By intermediate A 1-1 (41.7g, 0.1mol), imidazoles (10.2g, 0.15mol) is dissolved in 50mlDMF, is added portionwise TBDMSCl (18.1g, 0.12mol), charging, which finishes, is stirred at room temperature reaction 1h, ethyl acetate dilution, and ice water extraction is gone out, liquid separation, water layer It is washed 2 times with ethyl acetate, merges organic layer, it is dry with anhydrous sodium sulfate after washing, it filters, filtrate concentration obtains grease 45.0g。
1.3) synthesis of intermediate A 1-3
Formula EZ-2 is the structural formula of 4- [[(4- fluorophenyl) imino group] methyl]-phenol.
4- [[(4- fluorophenyl) imino group] methyl]-phenol (21.5g, 0.1mol) is dissolved in 20mlDMF, sequentially adds carbonic acid 2h is stirred at room temperature in potassium (27.6g, 0.2mol) and benzyl chloride (12.6g, 0.1mol) after charging, TLC judgement reaction terminates, will Reaction solution pours into ice water, filters, and filter cake is dried in vacuo to obtain white solid 20.3g.
1.4) synthesis of intermediate A 1-4
TiCl4+Ti(O-i-Pr)4The preparation of mixed solution: by TiCl4(21.3g, 0.112mol) is dissolved in 100ml dichloromethane Alkane, 0 DEG C of dropwise addition Ti (O-i-Pr)4(10.6g, 0037mol), insulation reaction 30min.Intermediate A 1-2 (53.4g, 0.1mol) and Intermediate A 1-3 (61.4g, 0.2mol) is dissolved in 250ml methylene chloride, -15 DEG C be successively added dropwise DIPEA (25.8g, 0.2mol) and TiCl4+Ti(O-i-Pr)4Then glacial acetic acid (30g, 0.5mol) is added dropwise, ice bath is cold in mixed solution, the 2h that is added dropwise that the reaction was continued But, reaction solution is poured into 7% aqueous tartaric acid solution, stirs 1h, warm naturally to room temperature, 20% solution of sodium bisulfite is added 100ml continues to stir 2h, and organic layer separation, washing, anhydrous sodium sulfate is dry, filters, and filtrate builds industry concentration, and 50ml methanol is beaten Slurry, white solid 62.1g.
1.5) synthesis of intermediate A 1-5
Intermediate A 1-4 (8.4g, 10mmol) is dissolved in 80ml methylene chloride, sequentially add BSA (4.1g, 20mmol) and TBAF (261mg, 1mmol), is stirred at room temperature 2h, and TLC judgement reaction end adjusts PH to 7 with acetic acid, is concentrated under reduced pressure, ethyl acetate After extraction, ice water washing, anhydrous sodium sulfate is dry, filters, and filtrate is concentrated to give crude product 5.9g.
1.6) synthesis of intermediate A 1-6
Intermediate A 1-5 (6.6g, 10mmol) is dissolved in 10ml isopropanol, 2N concentrated sulfuric acid 2ml is added, 2h is stirred at room temperature, instead It answers liquid to pour into 80ml ice water, filters, the white solid 4.9g of filter cake drying.
1.7) synthesis of compound A1
Intermediate A 1-6 (5.43g, 10mmol) is dissolved in 20ml ethyl acetate, 10%Pd/C250mg, room temperature normal pressure is added Hydrogenation reaction is stayed overnight, and TLC judgement reaction terminates, and filters, and filtrate decompression concentration, residue recrystallized from acetonitrile obtains white crystal 4.1g.
Embodiment two
Present embodiment discloses a kind of compound A10 obtained according to the method described above, structural formula is as follows:
2.1) synthesis of intermediate A 10-1
Formula EZ-1 is (4S) -3- [(5S) -5- (4- fluorophenyl) -5- hydroxyl -1- oxopentyl] -4- phenyl -2- oxazolidine The structural formula of ketone.
(4S) -3- [(5S) -5- (4- fluorophenyl) -5- hydroxyl -1- oxopentyl] -4- phenyl -2- oxazolidone (35.7g, It 0.1mol) is dissolved in 20mlDMF, sequentially adds potassium carbonate (27.6g, 0.2mol) and N- hydroxyethyl morpholine (114g, 1mol), is fed After be stirred at room temperature 2h, TLC judgement reaction terminates, and reaction solution is poured into ice water, is filtered, filter cake is dried in vacuo to obtain white solid 37.5g。
2.2) synthesis of intermediate A 10-2
Formula EZ-2 is the structural formula of 4- [[(4- fluorophenyl) imino group] methyl]-phenol.
4- [[(4- fluorophenyl) imino group] methyl]-phenol (21.5g, 0.1mol) is dissolved in 20mlDMF, sequentially adds carbonic acid 2h is stirred at room temperature in potassium (27.6g, 0.2mol) and benzyl chloride (12.6g, 0.1mol) after charging, TLC judgement reaction terminates, will Reaction solution pours into ice water, filters, and filter cake is dried in vacuo to obtain white solid 20.3g.
2.3) synthesis of intermediate A 10-3
TiCl4+Ti(O-i-Pr)4The preparation of mixed solution: by TiCl4(21.3g, 0.112mol) is dissolved in 100ml dichloromethane Alkane, 0 DEG C of dropwise addition Ti (O-i-Pr)4(10.6g, 0037mol), insulation reaction 30min.
Intermediate A 10-1 (47.1g, 0.1mol) and intermediate A 10-2 (61.4g, 0.2mol) are dissolved in 250ml dichloromethane Alkane, -15 DEG C are successively added dropwise DIPEA (25.8g, 0.2mol) and TiCl4+Ti(O-i-Pr)4It is anti-that continuation is added dropwise in mixed solution 2h to be answered, glacial acetic acid (30g, 0.5mol) then is added dropwise, ice bath is cooling, and reaction solution is poured into 7% aqueous tartaric acid solution, stirs 1h, Room temperature is warmed naturally to, 20% solution of sodium bisulfite 100ml is added, continues to stir 2h, organic layer separation, washing, anhydrous sulphur Sour sodium is dry, filters, filtrate concentration, the mashing of 50ml methanol, white solid 60.2g.
2.4) synthesis of intermediate A 10-4
Intermediate A 10-3 (7.7g, 10mmol) is dissolved in 80ml methylene chloride, sequentially add BSA (4.1g, 20mmol) and TBAF (261mg, 1mmol), is stirred at room temperature 2h, and TLC judgement reaction end adjusts PH to 7 with acetic acid, is concentrated under reduced pressure, ethyl acetate After extraction, ice water washing, anhydrous sodium sulfate is dry, filters, and filtrate is concentrated to give crude product 5.3g.
2.5) synthesis of compound A10
Intermediate A 10-4 (4.99g, 10mmol) is dissolved in 20ml ethyl acetate, 10%Pd/C250mg is added, room temperature is normal Hydrogenation reaction is pressed to stay overnight, TLC judgement reaction terminates, and filters, and filtrate decompression concentration, residue recrystallized from acetonitrile obtains white crystal 3.89g。
It is as follows that the solubility of ezetimibe and ezetimibe derivative A1 to A10 detect table:
As seen from the above table, the ezetimibe derivative synthesized according to preparation method of the present invention, solubility ratio is according to replacing Rice shellfish is much higher, wherein the water solubility with the ezetimibe derivative of A7 and A8 is more preferable.
The series of detailed descriptions listed above only for feasible embodiment of the invention specifically Protection scope bright, that they are not intended to limit the invention, it is all without departing from equivalent implementations made by technical spirit of the present invention Or change should all be included in the protection scope of the present invention.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should It considers the specification as a whole, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art The other embodiments being understood that.

Claims (8)

1. a new class of ezetimibe derivative, which is characterized in that its structural formula is shown in formula I:
Wherein, R is selected from following table:
2. the preparation method of a new class of ezetimibe derivative, which is characterized in that this method is with (4S) -3- [(5S) -5- (4- Fluorophenyl) -5- hydroxypentanoyl base] -4- phenyl -1,3- oxaza pentane -2- ketone be starting material, etherificate, TBDMSCl protection Afterwards, it with the 4- of benzyl protection [[(4- fluorophenyl) imino group] methyl] coupling of-phenol, cyclization, acidification, hydrogenation, is most tied again afterwards Crystalline substance obtains target product.
3. the preparation method of a new class of ezetimibe derivative according to claim 2, which is characterized in that according to above-mentioned Compound A10 is made in method, and structural formula is as follows:
4. the preparation method of a new class of ezetimibe derivative according to claim 3, which is characterized in that described in preparation Compound A10's step 1: by (4S) -3- [(5S) -5- (4- fluorophenyl) -5- hydroxypentanoyl base] -4- phenyl -1,3- oxygen azepine Pentamethylene -2- ketone is dissolved in DMF, sequentially adds potassium carbonate and N- hydroxyethyl morpholine, and 2h, TLC judgement are stirred at room temperature after charging Reaction terminates, and reaction solution is poured into ice water, filters, and filter cake is dried in vacuo to obtain white solid, i.e. intermediate A 10-1.
5. the preparation method of a new class of ezetimibe derivative according to claim 4, which is characterized in that described in preparation Compound A10's step 2: 4- [[(4- fluorophenyl) imino group] methyl]-phenol of benzyl protection is dissolved in DMF, sequentially adds Potassium carbonate and benzyl chloride, are stirred at room temperature 2h after charging, TLC judgement reaction terminates, reaction solution is poured into ice water, is filtered, filter cake It is dried in vacuo to obtain white solid, i.e. intermediate A 10-2.
6. the preparation method of a new class of ezetimibe derivative according to claim 5, which is characterized in that described in preparation Compound A10's step 3: first by TiCl4It is dissolved in methylene chloride, 0 DEG C of dropwise addition Ti (O-i-Pr)4, insulation reaction 30min, be made TiCl4+Ti(O-i-Pr)4Mixed solution;
Intermediate A 10-1 and intermediate A 10-2 is dissolved in methylene chloride, and -15 DEG C are successively added dropwise DIPEA and TiCl4+Ti(O-i-Pr)4 Then glacial acetic acid is added dropwise, and ice bath is cooling, and it is water-soluble that reaction solution is poured into 7% tartaric acid in mixed solution, the 2h that is added dropwise that the reaction was continued Liquid stirs 1h, warms naturally to room temperature, and 20% solution of sodium bisulfite is added, and continues to stir 2h, organic layer separation, washing, nothing Aqueous sodium persulfate is dry, filters, and filtrate builds industry concentration, and methanol mashing obtains white solid, i.e. intermediate A 10-3.
7. the preparation method of a new class of ezetimibe derivative according to claim 6, which is characterized in that described in preparation Compound A10's step 4: intermediate A 10-3 is dissolved in methylene chloride, sequentially adds BSA and TBAF, 2h, TLC is stirred at room temperature Judgement reaction end adjusts PH to 7 with acetic acid, is concentrated under reduced pressure, and after ethyl acetate extraction, ice water washing, anhydrous sodium sulfate is dry, It filters, filtrate is concentrated to give crude product, i.e. intermediate A 10-4.
8. the preparation method of a new class of ezetimibe derivative according to claim 7, which is characterized in that described in preparation Compound A10's step 5: intermediate A 10-4 is dissolved in ethyl acetate, is added 10%Pd/C, room temperature atmospheric hydrogenation reacted Night, TLC judgement reaction terminate, filter, and filtrate decompression concentration, residue recrystallized from acetonitrile obtains white crystal, i.e. compound A10.
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