CN109384700A - A new class of Ezetimibe analog and preparation method thereof - Google Patents

A new class of Ezetimibe analog and preparation method thereof Download PDF

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Publication number
CN109384700A
CN109384700A CN201811501678.2A CN201811501678A CN109384700A CN 109384700 A CN109384700 A CN 109384700A CN 201811501678 A CN201811501678 A CN 201811501678A CN 109384700 A CN109384700 A CN 109384700A
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dissolved
new class
compound
room temperature
ezetimibe
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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

Abstract

The present invention provides a new class of Ezetimibe analog, structural formula is shown in formula I:

Description

A new class of Ezetimibe analog and preparation method thereof
Technical field
The present invention relates to field of pharmaceutical chemistry technology more particularly to a new class of Ezetimibe analog and its preparation sides Method.
Background technique
Ezetimibe is a kind of novel cholesterol absorption inhibitor/NPC1L1 inhibitor.In October, 2002, Ezetimibe It is approved by the FDA in the United States listing, the treatment for primary hypercholesterolemia;At the same time, it is listed in Germany;In April, 2003, Britain ratifies it and is used to treat homozygote familial hypercholesterolemia;In June, 2006, FDA in addition have approved Ezetimibe with Fenofibrate is combined for reducing patient's total cholesterol and low-density lipoprotein combined hyperlipidemia familial;In June, 2007, the product It is released in Japan;In June, 2008, FDA ratify it and are used for childhood idiopathic hypercholesterolemia.
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 analog, 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 analog, structural formula is shown in formula I:
Wherein, R1And R2The identical group in position or different groups, R1And R2Selected from following table:
The invention also discloses the preparation methods of a new class of Ezetimibe analog, and 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;Benzyl protection after 4- [[(4- fluorophenyl) imino group] methyl]-phenol etherificate;Two intermediate couplings, cyclization, acidification are de- TBDMS protection, hydro-reduction debenzylation, most afterwards through being recrystallized to give target product.
Further, compound C1 is made according to the method described above, structural formula is as follows:
Further, compound C1's step 1: 4- [[(4- fluorophenyl) imino group] methyl]-phenol is molten is prepared In DMF, potassium carbonate and ethylene glycol are sequentially added, 2h is stirred at room temperature after charging, TLC judgement reaction terminates, reaction solution is fallen Enter ice water, filter, filter cake is dried in vacuo to obtain white solid, i.e. intermediate C1-1.
Further, prepare compound C1's step 2: intermediate C1-1 is dissolved in acetone, sequentially add potassium carbonate and 2h is stirred at room temperature in benzyl chloride after charging, TLC judgement reaction terminates, reaction solution is poured into ice water, is filtered, filter cake vacuum drying Obtain white solid, i.e. intermediate C1-2.
Further, compound C1's step 3: by (4S) -3- [(5S) -5- (4- fluorophenyl) -5- hydroxyl-is prepared 1- oxopentyl] -4- phenyl -2- oxazolidone is dissolved in DMF, sequentially add potassium carbonate and and ethylene glycol, room temperature after charging 2h is stirred, 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 C1-3。
Further, compound C1's step 4: intermediate C1-3, imidazoles are dissolved in DMF is prepared, is added portionwise TBDMSCl, charging, which finishes, is stirred at room temperature reaction 1h, ethyl acetate dilution, and ice water extraction is gone out, liquid separation, aqueous layer with ethyl acetate washing 2 It is secondary, merge organic layer, it is dry with anhydrous sodium sulfate after washing, it filters, filtrate concentration obtains grease, i.e. intermediate C1-4.
Further, compound C1's step 5: TiCl4 is dissolved in methylene chloride, 0 DEG C of dropwise addition Ti (O-i- is prepared Pr 4 mixed solution of TiCl4+Ti (O-i-Pr) is made in) 4, insulation reaction 30min;
Intermediate C1-4 and intermediate C1-2 is dissolved in methylene chloride, and -15 DEG C are successively added dropwise DIPEA and TiCl4+Ti (O-i- Pr then glacial acetic acid is added dropwise, and ice bath is cooling, and reaction solution is poured into 7% tartaric acid in) 4 mixed solution, the 2h that is added dropwise that the reaction was continued Aqueous solution stirs 1h, warms naturally to room temperature, and 20% solution of sodium bisulfite is added, and continues to stir 2h, organic layer separation, water It washes, anhydrous sodium sulfate is dry, filters, filtrate concentration, and methanol mashing obtains white solid, i.e. intermediate C1-5.
Further, compound C1's step 6: intermediate C1-5 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 C1-6;
Intermediate C1-6 is dissolved in isopropanol, the 2N concentrated sulfuric acid is added, 2h is stirred at room temperature, reaction solution pours into ice water, filters, filter The white solid of cake drying, i.e. intermediate C1-7.
Further, compound C1's step 7: intermediate C1-7 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 C1.
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 analog, structural formula is shown in formula I:
Wherein, R1And R2The identical group in position or different groups, R1And R2Selected from following table:
The present invention also provides the preparation method of a new class of Ezetimibe analog (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, TBDMSCl protection;Benzyl protection after 4- [[(4- fluorophenyl) imino group] methyl]-phenol etherificate;Two intermediates Coupling, cyclization are acidified de- TBDMS protection, hydro-reduction debenzylation, most afterwards through being recrystallized to give target product.
Embodiment one:
Present embodiment discloses a kind of compound C1 obtained according to the method described above, structural formula is as follows:
The preparation method of compound C1:
1.1) synthesis of intermediate C1-1
Formula EZ-1 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 ethylene glycol (62g, 1mol) after charging, TLC judgement reaction terminates, will be anti- It answers liquid to pour into ice water, filters, filter cake is dried in vacuo to obtain white solid 23.5g.
1.2) synthesis of intermediate C1-2
Intermediate C1-1 (27.7g, 0.1mol) is dissolved in 50ml acetone, sequentially adds potassium carbonate (27.6g, 0.2mol) and chlorine 2h is stirred at room temperature in benzyl (12.6g, 0.1mol) after charging, TLC judgement reaction terminates, reaction solution is poured into ice water, is filtered, Filter cake is dried in vacuo to obtain white solid 34.2g.
1.3) synthesis of intermediate C1-3
Formula EZ-2 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, 0.1mol) be dissolved in 20mlDMF, sequentially add potassium carbonate (27.6g, 0.2mol) and with ethylene glycol (62g, 1mol), charging finishes 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 39.1g。
1.4) synthesis of intermediate C1-4
By intermediate C1-3 (41.9g, 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 45.8g。
1.5) synthesis of intermediate C1-5
The preparation of 4 mixed solution of TiCl4+Ti (O-i-Pr): TiCl4 (21.3g, 0.112mol) is dissolved in 100ml dichloro Methane, 0 DEG C of dropwise addition Ti (O-i-Pr) 4 (10.6g, 0037mol), insulation reaction 30min.
Intermediate C1-4 (73.0g, 0.2mol) and intermediate C1-2 (53.4g, 0.1mol) are dissolved in 250ml methylene chloride ,- 15 DEG C are successively added dropwise DIPEA (25.8g, 0.2mol) and 4 mixed solution of TiCl4+Ti (O-i-Pr), are added dropwise that the reaction was continued Then glacial acetic acid (30g, 0.5mol) is added dropwise in 2h, ice bath is cooling, and reaction solution is poured into 7% aqueous tartaric acid solution, stirs 1h, from It is so warming up to room temperature, 20% solution of sodium bisulfite 100ml is added, continues to stir 2h, organic layer separation, washing, anhydrous slufuric acid Sodium is dry, filters, and filtrate builds industry concentration, the mashing of 50ml methanol, white solid 70.4g.
1.6) synthesis of intermediate C1-6
Intermediate C1-5 (9.4g, 10mmol) is dissolved in 30ml 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 7.6g.
1.7) synthesis of intermediate C1-7
Intermediate C1-6 (6.7g, 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 4.8g of filter cake drying.
1.7) synthesis of compound C1
Intermediate C1-7 (5.6g, 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 3.6g.
Embodiment two
Present embodiment discloses a kind of compound C10 obtained according to the method described above, structural formula is as follows:
The preparation of compound C10:
2.1) synthesis of intermediate C10-1
Formula EZ-1 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, TLC judgement reaction knot is stirred at room temperature in potassium (27.6g, 0.2mol) and N- hydroxyethyl morpholine (135g, 1mol) after charging Reaction solution is poured into ice water by beam, is filtered, and filter cake is dried in vacuo to obtain white solid 28.3g.
2.2) synthesis of intermediate C10-2
Formula EZ-2 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 (135g, 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 37.2g。
2.3) synthesis of intermediate C10-3
The preparation of 4 mixed solution of TiCl4+Ti (O-i-Pr): TiCl4 (21.3g, 0.112mol) is dissolved in 100ml dichloro Methane, 0 DEG C of dropwise addition Ti (O-i-Pr) 4 (10.6g, 0037mol), insulation reaction 30min.
Intermediate C10-1 (65.8g, 0.2mol) and intermediate C10-2 (47.1g, 0.1mol) are dissolved in 250ml dichloromethane Alkane, -15 DEG C are successively added dropwise DIPEA (25.8g, 0.2mol) and 4 mixed solution of TiCl4+Ti (O-i-Pr), and it is anti-that continuation is added dropwise 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, and filtrate builds industry concentration, the mashing of 50ml methanol, white solid 81.3g.
2.4) synthesis of compound C10
Intermediate C1-3 (8.7g, 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 5.9g.
It is as follows that the solubility of Ezetimibe and Ezetimibe analog C1 to C10 detect table:
As seen from the above table, the Ezetimibe analog synthesized according to preparation method of the present invention, solubility ratio is according to folding Wheat cloth is much higher, wherein the water solubility with the Ezetimibe analog of C3 and C7 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 (10)

1. a new class of Ezetimibe analog, which is characterized in that its structural formula is shown in formula I:
Wherein, R1And R2The identical group in position or different groups, R1And R2Selected from following table:
2. the preparation method of a new class of Ezetimibe analog, 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; Benzyl protection after 4- [[(4- fluorophenyl) imino group] methyl]-phenol etherificate;Two intermediate couplings, cyclization are acidified de- TBDMS Protection, hydro-reduction debenzylation, most afterwards through being recrystallized to give target product.
3. the preparation method of a new class of Ezetimibe analog according to claim 2, which is characterized in that according to above-mentioned Compound C1 is made in method, and structural formula is as follows:
4. the preparation method of a new class of Ezetimibe analog according to claim 3, which is characterized in that described in preparation Compound C1's step 1: 4- [[(4- fluorophenyl) imino group] methyl]-phenol is dissolved in DMF, sequentially adds potassium carbonate and second 2h is stirred at room temperature in glycol after charging, TLC judgement reaction terminates, reaction solution is poured into ice water, is filtered, filter cake vacuum drying Obtain white solid, i.e. intermediate C1-1.
5. the preparation method of a new class of Ezetimibe analog according to claim 4, which is characterized in that described in preparation Compound C1's step 2: intermediate C1-1 is dissolved in acetone, sequentially adds potassium carbonate and benzyl chloride, is stirred at room temperature after charging 2h, TLC judgement reaction terminate, and reaction solution is poured into ice water, is filtered, filter cake is dried in vacuo to obtain white solid, i.e. intermediate C1-2.
6. the preparation method of a new class of Ezetimibe analog according to claim 5, which is characterized in that described in preparation Compound C1's step 3: by (4S) -3- [(5S) -5- (4- fluorophenyl) -5- hydroxyl -1- oxopentyl] -4- phenyl -2- oxazole Alkanone is dissolved in DMF, sequentially add potassium carbonate and and ethylene glycol, be stirred at room temperature 2h 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, i.e. intermediate C1-3.
7. the preparation method of a new class of Ezetimibe analog according to claim 6, which is characterized in that described in preparation Compound C1's step 4: intermediate C1-3, imidazoles are dissolved in DMF, is added portionwise TBDMSCl, charging finish is stirred at room temperature it is anti- 1h, ethyl acetate dilution are answered, ice water extraction is gone out, and liquid separation, aqueous layer with ethyl acetate washs 2 times, merges organic layer, with anhydrous after washing Sodium sulphate is dry, filters, and filtrate concentration obtains grease, i.e. intermediate C1-4.
8. the preparation method of a new class of Ezetimibe analog according to claim 7, which is characterized in that described in preparation Compound C1's step 5: TiCl4 is dissolved in methylene chloride, 0 DEG C of dropwise addition Ti (O-i-Pr) 4, insulation reaction 30min is made 4 mixed solution of TiCl4+Ti (O-i-Pr);
Intermediate C1-4 and intermediate C1-2 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, filtrate concentration, and methanol mashing obtains white solid, i.e. intermediate C1-5.
9. the preparation method of a new class of Ezetimibe analog according to claim 8, which is characterized in that described in preparation Compound C1's step 6: intermediate C1-5 is dissolved in methylene chloride, sequentially adds BSA and TBAF, 2h is stirred at room temperature, TLC sentences Disconnected 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, takes out Filter, filtrate are concentrated to give crude product, i.e. intermediate C1-6;
Intermediate C1-6 is dissolved in isopropanol, the 2N concentrated sulfuric acid is added, 2h is stirred at room temperature, reaction solution pours into ice water, filters, and filter cake dries Dry white solid, i.e. intermediate C1-7.
10. the preparation method of a new class of Ezetimibe analog according to claim 9, which is characterized in that preparation institute Compound C1's step 7: intermediate C1-7 is dissolved in ethyl acetate is stated, 10%Pd/C is added, 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 C1.
CN201811501678.2A 2018-12-10 2018-12-10 A new class of Ezetimibe analog and preparation method thereof Pending CN109384700A (en)

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