CN1931838A - Azetidinone derivative and synthetic method thereof - Google Patents
Azetidinone derivative and synthetic method thereof Download PDFInfo
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- CN1931838A CN1931838A CN200610150638.9A CN200610150638A CN1931838A CN 1931838 A CN1931838 A CN 1931838A CN 200610150638 A CN200610150638 A CN 200610150638A CN 1931838 A CN1931838 A CN 1931838A
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Abstract
A compound having the general structural formula shown in formula wherein: r is H atom or a phenolic hydroxyl protecting group; the relative configuration of the substituents at the 3-, 4-positions in the azetidinone structures is transMolding; and their use in the preparation of azetidinone compounds of the general formula wherein R1Represents H atom, halogen atom (such as F, Cl and Br atoms), and the reaction is carried out in an organic inert solvent at the temperature of-55 ℃ to 100 ℃. The ezetimibe (ezetimibe, II) and analogues thereof can be prepared by reducing the ketocarbonyl group to hydroxyl group with different reduction methods for the compound of formula (I).
Description
Technical field
The invention belongs to pharmaceutical chemistry and organic chemistry filed, particularly, the present invention relates to a kind of general structure, and be raw material, prepare the method for structure suc as formula compound shown in (I) with this compound suc as formula the compound shown in (VI) and synthetic; This method is particularly suitable for the preparation of Zetia (II).
In the said structure formula,
R is H atom or phenolic hydroxyl group protecting group; Wherein, the protecting group of phenolic hydroxyl group can be silica-based protecting group, ether protecting group, ester group protecting group, and is trimethyl silicon based as benzyl, ester group etc.; R
1Represent hydrogen atom, halogen atom (as Cl, F, Br) etc.;
In the azetidinone structure, 3-, substituent configuration on the 4-position is selected from any one in the following configuration: single enantiomer (3R, 4S), single enantiomer (3S, 4R), (3R is 4S) with (3S, 4R) mixture of two kinds of enantiomorphs, (3R, 4S) with (3S, 4R) racemic mixture of two kinds of enantiomorphs.
Background technology
Zetia (ezetimibe) is a kind of cholesterol absorption inhibitor, is used for the treatment of atherosclerosis and high TC mass formed by blood stasis.Its chemical name is: 1-(4-fluorophenyl)-3 (R)-[3-(4-fluorophenyl)-3 (S)-hydroxypropyls]-4 (S)-(4-hydroxyphenyl)-2-azetidinone, and chemical structural formula is shown in (II):
Formula is one of key intermediate of synthetic Zetia suc as formula the compound shown in (I):
In the formula: R
1Represent H atom, halogen atom (as F, Cl, Br atom); R is H atom or phenolic hydroxyl group protecting group; Wherein, the protecting group of phenolic hydroxyl group can be silica-based protecting group, ether protecting group, ester group protecting group, and is trimethyl silicon based as benzyl, ester group etc.; 3-on the azetidinone, the substituent relative configuration on the 4-position is trans.
Particularly, compound (I) (R
1=4-fluoro-) slough blocking group on the phenolic hydroxyl group after, Stereoselective reduction ketone carbonyl can obtain Zetia (II) again, shown in reaction formula 1:
Reaction formula 1
U.S. Pat 5,767,115 and J.Med.Chem.1998,41 (6), on the 973-980, reported from compound (III), prepare the method for compound (I) through ester hydrolysis, acidifying, chloride, palladium catalyzed coupling reaction, shown in reaction formula 2:
Reaction formula 2
In the above-mentioned synthetic method, the linked reaction of chloride compounds (IV) and organic zinc reagent (V) is to finish under the catalyst action that contains transition metal Pd.Commonly used catalyzer is as four-(triphenylphosphine) palladium [Pd (PPh
3)
4], catalyst consumption is 10～20% (weight ratios) of compound (IV).
U.S. Pat 5,767 in 115 disclosed methods, needs with comparatively expensive transition-metal catalyst, and large usage quantity, is unsuitable for industrial production.
Summary of the invention
The purpose of this invention is to provide the compound shown in a kind of formula (VI),
R is H atom or phenolic hydroxyl group protecting group in the formula (VI); Wherein, the protecting group of phenolic hydroxyl group can be silica-based protecting group, ether protecting group, ester group protecting group, and is trimethyl silicon based as benzyl, ester group etc., preferred benzyl protecting group; 3-on the azetidinone, the substituent relative configuration on the 4-position is trans, absolute configuration is not done concrete restriction.
According to the present invention, described general structure is characterized in that in the described azetidinone structure suc as formula the compound shown in (VI), 3-, and the substituent configuration on the 4-position is selected from any one in the following configuration:
Single enantiomer (3R, 4S), single enantiomer (3S, 4R), (3R, 4S) and (3S, 4R) mixture of two kinds of enantiomorphs, (3R, 4S) and (3S, 4R) racemic mixture of two kinds of enantiomorphs.
Another object of the present invention is that disclosing a kind of is raw material with general structure suc as formula the compound shown in (VI), the method for the azetidinone of preparation structure shown in general formula (I), and this method avoids using four-(triphenylphosphine) palladium [Pd (PPh
3)
4] wait metal catalyst.
According to the present invention, it is characterized in that formula (I) compound is to be undertaken by following reaction:
With general structure suc as formula the compound shown in (VI),
With Grignard reagent (VII) reaction,
Formula (VII) is R wherein
1For hydrogen atom, halogen atom (as Cl, F, Br) etc., X represents halogen atom;
Obtain compound shown in the formula (I),
R in the formula (I), R
1, and 3-on the azetidinone, the definition of the substituent configuration of 4-position is as mentioned above.
Among the present invention, compound shown in the above-mentioned formula (VI), can be with reference to the synthetic method of Weinreb acid amides (Weinreb amides), as: J.Org.Chem.2001,66,2534-2537, Tetrahedron:Asymmetry 1998,9,3039, Eur.J.Org.Chem.2001,3615-3624 etc. are described, and (the III) is preparation similarly from compound.
Wherein the definition of R as mentioned above.
Formula among the present invention (III) compound can adopt document J.Med.Chem.1998, and 41 (6), the 973-980 disclosed method is prepared.
According to the present invention, it is characterized in that the formula of being addressed (IV) compound when having blocking group on the phenolic hydroxyl group, if desired, can be sloughed the protecting group (R) on the phenolic hydroxyl group, obtains the compound shown in the formula (I-a),
R wherein
1, 3-on the azetidinone, the substituent configuration definition of 4-is as mentioned above.
According to the present invention, the phenolic hydroxyl group of being addressed is sloughed the reaction of protecting group, according to the difference of protecting group, can adopt general method to carry out similarly.For example, when R is the benzyl of benzyl or replacement, can slough blocking group by the method for shortening.
In more detail, the preparation of formula of the present invention (1) compound can be undertaken by the step shown in the reaction formula 3.
Reaction formula 3
In the above-mentioned reaction formula, compound (I) is to obtain by compound (VI) and Grignard reagent (VII) reaction.In compound (I), when having blocking group on the phenolic hydroxyl group, if desired,, adopt general method can slough blocking group and obtain compound (I-a) according to the structure of blocking group.
In the above-mentioned reaction formula:
R is H atom or phenolic hydroxyl group protecting group; Wherein, the protecting group of phenolic hydroxyl group can be silica-based protecting group, ether protecting group, ester group protecting group, and is trimethyl silicon based as benzyl, ester group etc., preferred benzyl protecting group;
R
1For hydrogen atom, halogen atom (as Cl, F, Br) etc.;
X represents halogen atom, is preferably chlorine atom, bromine atoms;
In the described azetidinone structure, 3-, the substituent configuration on the 4-position is selected from any one in the following configuration:
Single enantiomer (3R, 4S), single enantiomer (3S, 4R), (3R, 4S) and (3S, 4R) mixture of two kinds of enantiomorphs, (3R, 4S) and (3S, 4R) racemic mixture of two kinds of enantiomorphs.
In the above-mentioned reaction formula:
Compound (VI) carries out in inert organic solvents with the reaction of Grignard reagent (VII).Reaction solvent has no particular limits the character of solvent for use, as long as reaction or agents useful for same are free from side effects, and can dissolve, and dissolves agents useful for same at least to a certain extent.Preferred inert organic solvents is an ether solvent, as tetrahydrofuran (THF), ether, methyl tertiary butyl ether, glycol dimethyl ether etc.;
The consumption of Grignard reagent (VII) is 1 to 10 times (mol ratio) of compound (VI), and optimum condition is 1 to 4 times.
The temperature of reaction of above-mentioned reaction can be generally-35 ℃ to 50 ℃ in the scope of certain width, preferred-10 ℃ to 30 ℃.Reaction times is different because of solvent and temperature of reaction, is preferably 2 to 10 hours usually.
After reaction was finished, desired formula (I) compound can reclaim with ordinary method, as the reaction solution neutralization, added water, the organic solvent extraction washing, and drying is removed and is desolvated, and obtains product.
In above-mentioned reaction formula:
In the compound (I), the reaction of sloughing the blocking group on the phenolic hydroxyl group can be sloughed according to a conventional method according to the structure of blocking group.
When blocking group is benzyl, can be in organic solvent, metal catalyst exists down, and hydrogenation is removed.Metal catalyst can be selected palladium carbon for use, and Raney's nickel etc., hydrogen pressure are at 1atm to 8atm, preferred 1atm to 3atm.Reaction times is different because of catalyzer and reaction pressure, is preferably 2 to 10 hours usually.
According to the present invention, the compound shown in the formula (VI) can be used chloride compounds (IV) and N, and O-dimethyl hydroxylamine hydrochloride or the reaction of its free alkali obtain, shown in reaction formula 4,
Reaction formula 4
Among the present invention, chloride compounds (IV) but reference J.Med.Chem.1998,41 (6), the preparation of the method for 973-980.
Chloride compounds (IV) carries out in inert solvent according to a conventional method with the amidate action of N-methyl-N-methoxy amine hydrochlorate or its free alkali;
Above-mentioned reaction is generally finished under alkaline condition.
According to the present invention, reference J.Org.Chem.2001,66, the method of 2534-2537, also available carboxylic acid of the compound shown in the formula (VI) (VIII) and 2-chloro-4,6-dimethoxy-[1,3,5] triazine (CDMT) condensation gets compound (IX), then with N-methyl-N-methoxy amine hydrochlorate or its free alkali prepared in reaction, shown in reaction formula 5:
Reaction formula 5
From formula (I) compound of gained of the present invention, can select different method of reducing reductone carbonyls for use is hydroxyl, and the preparation Zetia (ezetimibe, II) and analogue.
Embodiment
Below each embodiment further specify the present invention, but do not impose any restrictions.
Reference example 1:
Trans-3-[2-(4-benzyl oxy phenyl)-1-(4-fluorophenyl)-4-oxo-azetidine-3-yl]-methyl propionate (III-1) synthetic
(1) N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine is synthetic
In thermometer, constant pressure funnel, water trap and churned mechanically 1000ml four-hole bottle are housed, and adding 4-benzyloxy phenyl aldehyde (42.4g, 0.2mol), toluene (500mL); After the stirring and dissolving, slowly add para-fluoroaniline (22.3g, 0.20mol), reflux 4h removes the water that dereaction produces with water trap, spends the night, evaporate to dryness gets the yellow-green colour solid.The gained crude product gets N-(4-fluorophenyl)-4 benzyloxy benzene methylene amine 55.9g with the crystallization of ethyl acetate/petroleum ether solution weight, and yield is 91.6%, fusing point: 134-135 ℃ (literature value: 134-135 ℃).
(2) trans-3-[2-(4-benzyl oxy phenyl)-1-(4-fluorophenyl)-4-oxo-azetidine-3-yl]-methyl propionate (III-1) synthetic
Under nitrogen protection; with N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine (6.1g; 20mmol) join tributylamine (8.2g; in dry toluene 44mmol) (200ml) solution; be heated to 100 ℃; (3.6g, toluene solution 22mmol) adds in the 1h to drip 4-(chloroformyl) methyl-butyrate.Thin layer chromatography (TLC) is followed the tracks of reaction to terminal, is cooled to room temperature, adds 15ml hydrochloric acid (1mol/L), stirs 15min, dilutes with ethyl acetate.Organic layer is used hydrochloric acid, saturated sodium carbonate, water, the saturated common salt water washing of 1mol/L, anhydrous magnesium sulfate drying, concentrating under reduced pressure successively.The resistates that obtains is eluent through purification by silica gel column chromatography with 1: 9 ethyl acetate/petroleum ether mixed solvent, gets 4.7g title compound (III-1), yield 55%.
1H?NMR(300MHz，CD
3Cl)δ7.25(m，11H)，6.93(d，2H)，5.03(s，2H)，4.61(d，J＝2.1Hz，1H)，3.64(s，3H)，3.11(m，1H)，2.53(m，2H)，2.20(q，2H)ppm；MS(EI)：433(M
+)。
Reference example 2:
Trans-3-[(2S)-(4-benzyl oxy phenyl)-1-(4-fluorophenyl)-4-oxo-azetidine-3-yl]-methyl propionate (III-2) synthetic
(1) (S)-5-oxo-5-[2-oxo-4-phenyl-oxazoline-3-yl]-methyl valerate (III-2-1) synthetic
N
2Under the protection, in thermometer, constant pressure funnel and churned mechanically 500ml there-necked flask are housed, adding (S)-4-phenyl-2-oxazoline ketone (32.6g, 0.2mol), anhydrous triethylamine (24.2g, 0.24mol), and the 250mL methylene dichloride, stirring and dissolving; Under the ice-water bath cooling, (35.8g 0.22mmol), after dripping, continues stirring reaction 8-16h to drip 4-(chloroformyl) methyl-butyrate.Thin layer chromatography (TLC) is followed the tracks of reaction to terminal, with the methylene dichloride dilution, use dilute hydrochloric acid, saturated sodium carbonate, water, saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrating under reduced pressure gets title compound (III-2-1), and it is synthetic that this product can be directly used in down the step.
(2) (5S)-(4-benzyl oxy phenyl)-5-(4-fluoro-anilino)-(4R)-[2 '-oxo-(4 ' S)-phenyl-oxazoline-3 '-carbonyl]-methyl valerate (VI-2-2) synthetic
N
2Protection down, in thermometer, constant pressure funnel and churned mechanically 500ml there-necked flask are housed, step product (III-2-1) addings in (14.6g, 50mmol) and the 200mL methylene dichloride, after the stirring and dissolving, under the ice-water bath cooling, adding TiCl
4(5.6mL), after dripping, continue to stir 0.5 hour.Subsequently, the CH that adds diisopropylethylamine (15.3mL)
2Cl
2Solution (20ml), after dripping, reaction is 1 hour under this temperature; After reaction mixture being cooled to-25 ℃, (30.5g 0.1mol), under this temperature, continues reaction 3-5 hour to add N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine.Thin layer chromatography (TLC) is followed the tracks of reaction to terminal, adds acetate (18mL), rises to room temperature after the stirring; Add H again
2SO
4(2mol/L 170ml), stirred 1 hour.Organic phase is with saturated aqueous common salt and water washing, anhydrous sodium sulfate drying, decolorizing with activated carbon, concentrate title compound (III-2-2).The crude product of gained, the mixed solvent recrystallization of ethyl acetate/normal hexane gets the pure product of 17.9g, yield 60.5%.
(3) trans-3-[(2S)-(4-benzyl oxy phenyl)-1-(4-fluorophenyl)-4-oxo-azetidine-3-yl]-methyl propionate (III-2) synthetic
N
2Protection down; in thermometer, constant pressure funnel and churned mechanically 500ml there-necked flask are housed; step product (III-2-2) (29.8g in the adding; 50mmol) and 350mL toluene; after the stirring and dissolving, heat temperature raising to 50 ℃ adds two-(trimethyl silicon based)-ethanamide (24.8mL); after dripping, stirred 1 hour.Subsequently, (0.13g 0.5mmol), continues to stir 3-5 hour to add tetrabutyl fluoride amine.Thin layer chromatography (TLC) is followed the tracks of reaction to terminal, uses dilute hydrochloric acid successively, and saturated sodium bicarbonate aqueous solution with saturated aqueous common salt and deionized water wash, anhydrous sodium sulfate drying, decolorizing with activated carbon, concentrates, and the gained crude product is 25.2g, and amounting to pure product yield is 93.1%.Take a morsel product through purification by silica gel column chromatography, is eluent with 1: 4 ethyl acetate/petroleum ether mixed solvent, gets the compound analysis standard substance,
1H NMR (400MHz, CD
3Cl) δ 7.25 (m, 11H), 6.93 (d, 2H), 5.03 (s, 2H), 4.61 (d, J=2.1Hz, 1H), 3.64 (s, 3H), 3.11 (m, 1H), 2.53 (m, 2H), 2.20 (q, 2H) ppm; MS (EI): 433 (M
+).
Reference example 3:
Trans-N-methyl-N-methoxyl group-3-[2-(4-benzyl oxy phenyl)-1-(4-fluorophenyl)-4-oxo-azetidine-3-yl]-propionic acid amide (VI-1) synthetic
(1) trans-3-[2-(4-benzyl oxy phenyl)-1-(4-fluorophenyl)-4-oxo-azetidine-3-yl]-propionic acid (VI-1-1) synthetic
Reference example 1 gained compound (III-1) (21.7g 50mmol) is dissolved in the methyl alcohol (30mL), and the adding lithium hydroxide monohydrate (2.1g, 50mmol), stirring at room 1 hour; (1.0g 25mmol), continues to stir 1 hour to add lithium hydroxide monohydrate again.After hydrolysis reaction finishes, add hydrochloric acid (1mol/L) and ethyl acetate, tell organic phase, drying, concentrate title compound (VI-1-1) 19.9g, yield 95%.This product can be directly used in down the step building-up reactions.
(2) trans-N-methyl-N-methoxyl group-3-[2-(4-benzyl oxy phenyl)-1-(4-fluorophenyl)-4-oxo-azetidine-3-yl]-propionic acid amide (VI-1) synthetic
N
2Protection down, on go on foot product (VI-1-1) (15.5g 37mmol) is dissolved in the anhydrous methylene chloride (100mL), add oxalyl chloride (4.9mL, 56mmol), the stirring at room reaction.After 16-24 hour, reaction solution concentrates; Add anhydrous methylene chloride in the resistates, continue to concentrate, repeat twice, get oily matter.In this oily matter, add anhydrous methylene chloride (100mL) and N, and the O-dimethyl hydroxylamine hydrochloride (4.3g, 44mmol).Under the ice-water bath cooling, and the adding pyridine (6.7g, 85mml).After dripping, continue reaction 2 hours; Slowly rise to room temperature, continue stirring reaction 8h, reaction solution is with dilute hydrochloric acid, saturated aqueous common salt, deionized water wash, anhydrous sodium sulfate drying.Concentrating under reduced pressure, resistates are eluent through purification by silica gel column chromatography with 1: 1 ethyl acetate/petroleum ether mixed solvent, get title compound (VI-1) 15.6g, yield 91%.
1H?NMR(400MHz，CD
3Cl)δ7.25(m，11H)，6.93(d，2H)，5.03(s，2H)，4.61(d，J＝2.1Hz，1H)，3.64(s，3H)，3.11(m，1H)，2.53(m，2H)，2.20(q，2H)ppm；MS(EI)：433(M
+)。
Reference example 4:
Trans-N-methyl-N-methoxyl group-3-[(2S)-(4-benzyl oxy phenyl)-1-(4-fluorophenyl)-4-oxo-azetidine-3-yl]-propionic acid amide (VI-2) synthetic
According to the operation steps of reference example 3, (10.8g 25mmol) sets out, and can get title compound (VI-2) 9.3g, yield 81% from the compound (III-2) of reference example 2 gained.
Reference example 5:
Trans-N-methyl-N-methoxyl group-3-[2-(4-benzyl oxy phenyl)-1-(4-fluorophenyl)-4-oxo-azetidine-3-yl]-propionic acid amide (VI-1) synthetic
N
2Protection down; reference example 3 gained compound (VI-1-1) (15.5g; 37mmol) be dissolved in the anhydrous tetrahydro furan (110mL); add 2-chloro-4,6-dimethoxy-[1,3; 5] triazine (CDMT) (7.4g; 44mmol) and N-methylmorpholine (12mL, 0.11mol), stirring at room reaction 1 hour.Add N, (3.6g, 37mmol), reaction mixture stirs and spends the night the O-dimethyl hydroxylamine hydrochloride.Add the 150mL deionized water, with twice of ether extracting; The organic phase that merges is used saturated sodium carbonate successively, dilute hydrochloric acid, saturated brine washing, anhydrous sodium sulfate drying.Concentrating under reduced pressure gets title compound (VI-1) 14.5g, yield 85%.
Reference example 6:
Trans-N-methyl-N-methoxyl group-3-[(2S)-(4-benzyl oxy phenyl)-1-(4-fluorophenyl)-4-oxo-azetidine-3-yl]-propionic acid amide (VI-2) synthetic
Operation steps according to reference example 5, with trans-3-[(2S)-(4-benzyl oxy phenyl)-1-(4-fluorophenyl)-4-oxo-azetidine-3-yl]-propionic acid (VI-2-1) (20.9g, 50mmol) the compound (VI-1-1) in the replacement reference example 5, can get title compound (VI-2) 19.2g, yield 83%.
Reference example 7:
Anti-form-1-(4-fluorophenyl)-3-[3-oxo-3-(4-fluorophenyl) propyl group]-4-(4-benzyl oxy phenyl)-2-azetidinone (I-1) synthetic
N
2Protection down, in thermometer, constant pressure funnel and churned mechanically 500ml there-necked flask are housed, add reference example 5 gained compound (VI-1) (18.5g, 40mmol) and anhydrous tetrahydro furan (270mL), be cooled to about-15 ℃, slowly add p-Fluoro bromo benzene Grignard reagent (29.3mL, 1.5mol/L, 44mmol), added in 1 hour, under this temperature, continue reaction 1 hour; Reaction solution slowly rises to room temperature, and thin layer chromatography (TLC) is followed the tracks of reaction to terminal, adds dilute hydrochloric acid (100mL, 1mol/L) termination reaction.Reaction mixture is told organic layer, water layer methylene dichloride extracting with methylene dichloride (500mL) dilution; Merge organic phase, with saturated brine, deionized water wash, drying.Concentrating under reduced pressure, resistates are eluent through purification by silica gel column chromatography with 1: 1 ethyl acetate/petroleum ether mixed solvent, get title compound (I-1) 16.9g, yield 85%.
1H?NMR(300MHz，CD
3Cl)δ8.0(2d，2H，Ar)，7.4-7.1(m，11H)，6.95(2d，4H)，5.1(s，2H)，4.70(d，1H，J＝2.2Hz)，3.3(m，1H)，3.2(m，2H)，2.4-2.2(m，2H)。
Reference example 8:
Synthesizing of 1-(4-fluorophenyl)-(3R)-[3-oxo-3-(4-fluorophenyl) propyl group]-(4S)-(4-benzyl oxy phenyl)-2-azetidinone (I-2)
Operation steps according to reference example 7, with trans-N-methyl-N-methoxyl group-3-[(2S)-(4-benzyl oxy phenyl)-1-(4-fluorophenyl)-4-oxo-azetidine-3-yl]-propionic acid amide (VI-2) (11.1g, 24mmol), replace the compound (VI-1) in the reference example 5, can get title compound (I-2) 10.8g, yield 90%.
Reference example 9:
Anti-form-1-(4-fluorophenyl)-3-[3-oxo-3-(4-fluorophenyl) propyl group]-4-(4-benzyl oxy phenyl)-2-azetidinone (I-1) synthetic
According to reference example 7, about 0 ℃, slowly (44mmol), other condition and method are identical for 40mL, 1.1mol/L, get title compound (I-1) 15.9g, yield 80% to the fluorochlorobenzene Grignard reagent in adding.
Reference example 10:
Anti-form-1-(4-fluorophenyl)-3-[3-oxo-3-(4-fluorophenyl) propyl group]-4-phenyl-2-azetidinone (I-a-1) synthetic
Under the room temperature, in the 1L hydrogenation still, adding reference example 7 gained compounds (I-1) (20g, 40mmol), ethanol (400mL), 10% palladium carbon (1.5g), hydrogenation is sloughed benzyl under 4atm.After 10 hours, sampling, thin layer chromatography (TLC) is followed the tracks of reaction to terminal.Reacting liquid filtering, the filter residue washing with alcohol, merging filtrate and washings, concentrating under reduced pressure get title compound (I-a-1) 15.0g, yield 92%.
Reference example 11:
1-(4-fluorophenyl)-(3R)-[3-oxo-3-(4-fluorophenyl) propyl group]-(4S)-4-phenyl)-2-azetidinone (I-a-2) synthetic
According to reference example 10, with 1-(4-fluorophenyl)-(3R)-[3-oxo-3-(4-fluorophenyl) propyl group]-(4S)-(4-benzyl oxy phenyl)-2-azetidinone (I-2) (20g, 40mmol), replace the compound (I-1) in the reference example 10, can get title compound (I-a-2) 14.8g, yield 88%.Fusing point: 59-61 ℃ (literature value: 60-62 ℃).
1H?NMR(400MHz，CD
3Cl)δ7.4-6.8(m，12H，Ar)，6.05(br?s，1H)，4.65(d，J＝2.1Hz，1H)，3.26(m，1H)，2.33(d，1H)，2.25(m，1H)。
Reference example 12:1-(4-fluorophenyl)-(3R)-[3-hydroxyl-3-(4-fluorophenyl) propyl group]-(4S)-4-phenyl)-2-azetidinone (II and II-1) synthetic
N
2Protection down; 1-(4-fluorophenyl)-(3R)-[3-oxo-3-(4-fluorophenyl) propyl group]-(4S)-4-phenyl)-2-azetidinone (I-a-2) (0.47g; in anhydrous tetrahydro furan 1mmol) (5mL) solution; tetrahydrofuran solution (the 2mol/L that adds the borine dimethyl sulphide; 0.6mL; 1.2mmol), stirring at room reaction 4 hours.After reaction finishes, add the methyl alcohol termination reaction, the reaction solution diatomite filtration, filtrate concentrated title compound (1: 1 mixture of II and II-1) 0.43g.
High pressure liquid chromatography (chiral column model C hiracel OD) is separated said mixture, and moving phase is normal hexane/Virahol (9: 1), gets compound (II, Zetia) 0.2g.
1H?NMR：(400MHz，DMSO-d
6)δ9.54(s，1H)，7.32(dd，J＝8.3，5.7Hz，2H)，7.21(m，H)，7.35(m，4H)，6.77(d，J＝8.3Hz，2H)，5.3(d，J＝4.6Hz，1H)，4.82(d，J＝2.1Hz，1H)，4.50(m，1H)，3.10(m，1H)，1.70-1.90(m，4H)。
Claims (7)
1. a general structure is suc as formula the compound shown in (VI),
In the formula: R is H atom or phenolic hydroxyl group protecting group;
The protecting group of the phenolic hydroxyl group here is selected from any one in silica-based protecting group, ether protecting group, the ester group protecting group; In preferably trimethyl silicon based, benzyl, the ester group protecting group any one; Further preferred benzyl protecting group;
In the azetidinone structure, 3-, the substituent relative configuration on the 4-position is transconfiguration.
2. general structure according to claim 1 is characterized in that in the described azetidinone structure suc as formula the compound shown in (VI), 3-, and the substituent configuration on the 4-position is selected from any one in the following configuration:
Single enantiomer (3R, 4S), single enantiomer (3S, 4R), (3R, 4S) and (3S, 4R) mixture of two kinds of enantiomorphs, (3R, 4S) and (3S, 4R) racemic mixture of two kinds of enantiomorphs.
3. general structure according to claim 1 and 2 is suc as formula the application of the compound shown in (VI) in the preparation azetidinone compounds of structure shown in general formula (I),
The R here
1Represent H atom, halogen atom (as F, Cl, Br atom).
4. general structure according to claim 3 is characterized in that suc as formula the application of the compound shown in (VI) in the azetidinone compounds of preparation structure shown in general formula (I) general structure suc as formula the reactions steps of the azetidinone compounds of the compound structure shown in (VI) shown in general formula (I) is:
With the compound shown in the formula (VI), with compound (VII) reaction,
In the formula: R
1Be hydrogen atom, halogen atom; X represents halogen atom; Obtain formula (I) compound.
5. general structure according to claim 4 is suc as formula the application of the compound shown in (VI) in the azetidinone compounds of preparation structure shown in general formula (I), it is characterized in that this reaction is to carry out in organic inert solvent, the preferred ether solvent of described organic inert solvent;
The ether solvent here is selected from any one in tetrahydrofuran (THF), ether, methyl tertiary butyl ether, the glycol dimethyl ether.
6. general structure according to claim 4 is suc as formula the application of the compound shown in (VI) in the azetidinone compounds of preparation structure shown in general formula (I), it is characterized in that general structure is 1 to 10 times suc as formula the compound shown in (VII) and general structure suc as formula the mol ratio of the compound shown in (VI), preferred 1 to 4 times.
7. general structure according to claim 4 is characterized in that temperature of reaction is-55 ℃ to 100 ℃, preferred-30 ℃ to 50 ℃ suc as formula the application of the compound shown in (VI) in the azetidinone compounds of preparation structure shown in general formula (I).
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| CN102531985A (en) * | 2011-04-25 | 2012-07-04 | 开原亨泰制药股份有限公司 | Novel method for preparing ezetimibe key intermediate |
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| US5631365A (en) * | 1993-09-21 | 1997-05-20 | Schering Corporation | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
| WO1997016424A1 (en) * | 1995-11-02 | 1997-05-09 | Schering Corporation | Process for preparing 1-(4-fluorophenyl)-3(r)-(3(s)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(s)-(4-hydroxyphenyl)-2-azetidinone |
| US5886171A (en) * | 1996-05-31 | 1999-03-23 | Schering Corporation | 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones |
| WO2000034240A1 (en) * | 1998-12-07 | 2000-06-15 | Schering Corporation | Process for the synthesis of azetidinones |
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| CN103435525B (en) * | 2013-07-25 | 2015-11-18 | 凯莱英医药集团（天津）股份有限公司 | A kind of method preparing Ezetimibe |
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