CN1299819A - (R)-2[3-(2-N-phthalic amido ethyl)-4,5-dihydro-5-isoxazolyl]-acetic acid and its synthesis - Google Patents
(R)-2[3-(2-N-phthalic amido ethyl)-4,5-dihydro-5-isoxazolyl]-acetic acid and its synthesis Download PDFInfo
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Abstract
The present invention relates to a (R)-2[3-(2-N-phthalimidoethyl)-4,5-dihydro-5-isooxazolyl]-acetic acid, it is made up by using 3-N-phthalimido-propionaldehyde as raw material through the processes of ammonization, chlorization, 1,3-dipolar addition, ester hydrolysis reaction and chiral resolution reaction. It can be used for synthesizing medicine Atorvastatin for reducing blood-fat. Said invented method is moderate in reaction condition, simple and convenient, and suitable for implementing industrial production.
Description
The present invention relates to (R)-2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-acetate, its preparation method and use.
(4R-cis)-and 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate are the key precursor of preparation blood lipid-lowering medicine Atorvastatin.Atorvastatin is a kind of very effective hydroxyl first glutaryl-coenzyme A (HMG-CoA) reductase inhibitor; it can competitive inhibition body inner cholesterol biosynthesizing; thereby can reduce in the body serum lipid concentrations and regulating blood fat level comprehensively, be to go on the market recently and become the fat-reducing medicament of main flow on the international medical market just day by day.Document Tetrahedron Lett.; 1992; 33 (17); 2283～2284 and patent US5003080, US 5155251 etc. the synthetic method of Atorvastatin is disclosed, promptly with (4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-1; 3-dioxane-4-tert.-butyl acetate is as synthetic precursor; itself and 1,4-dicarbonyl compound α-isobutyryl-β-fluorobenzene acyl group-β-phenylpropionyl aniline and its is carried out annulation, dehydroxylation protection then, hydrolysis ester group obtain Atorvastatin.
Document Tetrahedron Lett., 1992,33 (17), 2279～2282 and patent US 5599954 (4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-1, several synthetic methods of 3-dioxane-4-tert.-butyl acetate are disclosed.These methods are all or part of to have related to following two kinds of reactions: one, and NaCN is to the cyano group substitution reaction of halides; Its two, do the growth carbochain reaction of alkali with lithium diisopropyl amido (LDA).Obviously, the operational danger of first kind of reaction is very big; And the anhydrous and oxygen-free condition of second kind of reaction needed strictness and needs-40～-70 ℃ extremely low temperature, is unfavorable for industrial production, and especially in China, production unit is backward relatively, industrially is difficult to satisfy exacting terms like this.Therefore, synthetic for this compound, seek safer and easily approach have great significance.
One of purpose of the present invention provides (R)-2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-acetate.
Two of purpose of the present invention provides (R)-2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-synthetic method of acetate, so that safety, synthetic and industrialized production efficiently.
Purpose of the present invention also provides (R)-2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-purposes of acetate.Promptly be used to synthesize (4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate, and then be used to prepare hypolipemic preparation Atorvastatin.
The invention provides a kind of important compound: (R)-2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-acetate, its molecular formula is
Synthetic method of the present invention is to obtain 3-N-phthalimide-based-third oxime with 3-N-phthalimide-based-propionic aldehyde through the oxyammonia reaction, take place 1 with the 3-crotonate after the chlorination, the reaction of 3-dipolar addition, obtain isoxazoline derivative 2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-acetic ester.Behind hydrolysis of ester group, obtain (R)-2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl by chiral separation]-acetate.Its chemical equation is as follows:
Wherein, R=C
nH
2n+1, n=1-5 is as CH
3, C
2H
5, CH
2(CH
3)
2Deng.1: oxyammonia reaction, 2: chlorination reaction, 3:1, the reaction of 3-dipolar addition, 4: ester hydrolysis reaction, 5: chiral separation.
Synthetic method provided by the invention can specifically describe as follows: 1. oxyammonia reaction: in polar solvent, reaction medium is neutral, acid or alkaline, and molecular formula is
3-N-phthalimide-based-propionic aldehyde and the mol ratio of oxammonium hydrochloride be 1: 0.5-5, recommending mol ratio is 1: 0.8-2.5, temperature of reaction is 0 ℃ to 80 ℃, recommended temperature is a room temperature-50 ℃, reaction times is 2～30 hours, 10-20 hour recommendation response time, reaction is after or purify without aftertreatment.Reaction raw materials 3-N-phthalimide-based-propionic aldehyde is a known compound, can be obtained through the Michael addition by propenal and phthalic imidine.2. chlorination reaction: in polar solvent, molecular formula is
3-N-phthalimide-based-third oxime and the mol ratio of chlorination reagent be 1: 0.5-4, recommending mol ratio is 1: 0.8-2, temperature of reaction is at 0-100 ℃, reaction times is 4～40 hours, 4-12 hour recommendation response time, described chlorination reagent is N-chlorosuccinimide (NCS), NaOCl or Cl
2, reaction is after or purify without aftertreatment.3.1 the reaction of 3-dipolar addition: in polarity or non-polar solvent, molecular formula is
1-chloro-3-N-phthalimide-based-third oxime, molecular formula be CH
2=CHCH
2The 3-crotonate of COOR and the mol ratio of alkali are 1 successively: 0.8-5: 0-3 is recommended as 1: 1-3: 1-3, temperature of reaction is 0 ℃ to 100 ℃, reacts described R=C 1～60 hour
nH
2n+1, n=1-5, described alkali are organic bases or mineral alkali, described organic bases is that molecular formula is R '
3The tertiary amine of N, pyridine, hexahydropyridine, tertiary butyl alcohol potassium, sodium amide or C
4～16Quaternary ammonium compound alkali etc., described mineral alkali are sodium hydroxide or potassium hydroxide etc., wherein said R=C
1～12Alkyl, reaction is after or purify without aftertreatment.4. ester hydrolysis reaction: in polar solvent, as hydrolysing agent, wherein molecular formula is with acid or alkali
2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-mol ratio of acetic ester and hydrolysing agent is 1: 1-50, recommending mol ratio is 1: 1-20, temperature of reaction is 0～80 ℃, reaction times is 1～48 hour, reaction after or purify without aftertreatment, described acid is hydrochloric acid or sulfuric acid, described alkali is the alkali of monovalence or divalent metal, as LiOH, NaOH, KOH, Ba (OH)
2Deng.5. chiral separation: in polar solvent, molecular formula is
2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-mol ratio of acetate and resolution reagent is 1: 0.8-5, recommending mol ratio is 1: 0.8-2.5, temperature of reaction is that room temperature arrives reflux temperature, reaction times is 1 minute to 5 hours, use the mineral acid acidifying after splitting salify, if acidity is crossed the decomposition that can cause product by force, can influence the productive rate that changes into product by salt a little less than acid the mistake, so regulating pH value 0.5～4 is advisable, again through or purify without aftertreatment, the product that obtains is that molecular formula is
(R)-2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-acetate, described resolution reagent is the peaceful or brucine of vauqueline, quinoline, and described mineral acid can be hydrochloric acid, sulfuric acid, phosphoric acid etc., recommends to use aqueous hydrochloric acid.
Above-mentioned polar solvent is water, acetone, C
1-C
8Alcohol, halogenated alkane, N, dinethylformamide (DMF), methyl-sulphoxide (DMSO), tetrahydrofuran (THF) or its mixed solvent.Described C
1-C
8Alcohol such as methyl alcohol, ethanol, Virahol, isooctyl alcohol etc.
That above-mentioned aftertreatment is meant is concentrated, a step or a few step in desolventizing, neutralization, crystallization, filtration, dilution, extraction, washing, recrystallization or the drying.
Compound of the present invention (R)-2-[3-(2-N-phthalimide-based ethyl)-4; 5-dihydro-5-isoxazolyl]-acetate can make (4R-cis)-6-(2-aminoethyl)-2 behind esterification, hydrogenated ring-opened, reduction, two hydroxyl protection, amino deprotection; 2-dimethyl-1; 3-dioxane-4-tert.-butyl acetate, and then be used to prepare hypolipemic preparation Atorvastatin.The route of synthesis of design is as follows:
Synthetic method will be reported in another patent.
Synthetic method provided by the present invention compared with prior art, avoided utilizing the risky operation of NaCN and utilized severe condition such as anhydrous and oxygen-free that LDA brings, low temperature, major part operates in room temperature and can finish, obviously have advantages such as operational safety, easy, mild condition, be suitable for suitability for industrialized production.
Following examples help to understand the present invention, but do not limit content of the present invention:
Embodiment 1
The preparation of 3-N-phthalimide-based-third oxime
In the 300ml dehydrated alcohol, add the 0.01mol sodium Metal 99.5, add the 0.68mol phthalic imidine again, in 1 hour, drip the 40ml ethanol solution of 0.84mol propenal then.After the stirring at room 2 hours, add the mixing solutions of 0.92mol～3mol oxammonium hydrochloride, 0.92mol NaOH and 60ml water (perhaps ethanol or Virahol), again room temperature-80 ℃ following the stirring 2 to 30 hours.The powerful stirring down in the red reaction solution impouring 1000ml water with gained, separated out a large amount of white solids.Filter, the water thorough washing, with the gained solid with 90% ethyl alcohol recrystallization, must white solid 88g, 127～129 ℃ of m.p.Yield 59%.
C
11H
10N
2O
3, calculated value: C60.55, H4.62, N12.84; Measured value: C60.34, H4.78, N12.79.
IR(KBr),v(cm
-1)：3279,1772,1715,1613,1465。
1H?NMR(CDCl
3,300?MHz),δ(ppm)：2.62(m,1H),2.81(m,1H),3.92(m,2H),6.85(t,0.5H),7.45(br,1H),7.49(t,0.5H),7.75(m,2H),7.87(m,2H)。
MS(EI),m/e(％)：219(M
++1,6)。
Embodiment 2
The preparation of 1-chloro-3-N-phthalimide-based-third oxime
At 200ml DMF (perhaps CH
2Cl
2, water or methyl alcohol) in, add 0.2～0.25mol 3-N-phthalimide-based-third oxime and 0.23mol NCS (or NaOCl).Stirring at room, solid fades away.After 4 to 36 hours, in reaction solution impouring 800ml water, separate out white solid.Stir half an hour, filter, wash with water, drying gets product 47.6g, 163～165 ℃ of m.p.Yield 86%.Purity is measured as 95.5% with high pressure liquid chromatography (HPLC).
1H?NMR(CDCl
3,300?MHz),δ(ppm)：2.71(m,1H),2.93(m,1H),4.16(m,2H),7.59(br,1H),7.75(m,2H),7.87(m,2H)。
Embodiment 3
2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-preparation of methyl acetate
With 0.09～0.15mol1-chloro-3-N-phthalimide-based-third oxime and 0～0.20mol (or 0.5mol) 3-M Cr or 3-butenoic acid isopropyl ester, and 100ml CHCl
3(or mixed solvent of ether, DMF) adds in the 250ml there-necked flask, stirs during room temperature to 50 ℃, adds 0.14mol triethylamine (perhaps pyridine, tertiary butyl alcohol potassium, sodium amide or sodium hydroxide) and 40 ml CHCl
3Solution, reflux 1 to 10 hour.Cooling, reaction solution is used hydrochloric acid and the water washing of 1N, drying successively.Remove most of solvent, surplus about 30ml volume adds 30ml ethanol, leaves standstill, and separates out white solid.Filter, drying obtains product, is that example obtains product 22g, 94～95 ℃ of m.p with the 3-M Cr.Yield 80%.
C
16H
16N
2O
5, calculated value: C60.76, H5.10, N8.86; Measured value: C60.87, H5.35, N8.68.
1H?NMR(CDCl
3,300?MHz),δ(ppm)：2.56～2.91(m,5H),3.27(q,1H),3.70(s,3H),3.95(t,2H),4.95(m,1H),7.73(m,2H),7.83(m,2H)。
13C?NMR(CDCl
3,300?MHz),δ(ppm)：27.16,34.53,39.44,41.94,51.80,123.33,131.90,134.07,155.80,168.02,170.66。
MS(EI),m/e(％)：316(M
+,81)。
Embodiment 4
2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-preparation of acetate
With 15.8 mmol2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-methyl acetate or isopropyl ester be added in the 30ml methyl alcohol (perhaps water or THF), add 15ml～50ml concentrated hydrochloric acid (perhaps sulfuric acid, LiOH or KOH), stirred 5～20 hours room temperature～80 ℃, shows to TLC to react completely.The decompression separating methanol adds the dilution of 20ml water, with ethyl acetate extraction (20ml * 3).Merge oil phase, drying, desolventizing gets white solid 4.1g.Yield 85%.
C
15H
14N
2O
5, calculated value: C59.60, H4.67, N9.27; Measured value: C59.41, H4.50, N9.52.
1H?NMR(CDCl
3,300?MHz),δ(ppm)：2.61～2.96(m,5H),3.42(q,1H),3.87(t,2H),4.99(m,1H),7.75(m,2H),7.88(m,2H),12.36(br,1H)。
MS(EI),m/e(％)：285(M
+-17,31)。
Embodiment 5
(R)-and 2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-preparation of acetate
With 13.2mmol 2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-acetate, be dissolved in respectively in 60ml acetone and 30ml trichloromethane, water or the ethanol with 10～40mmol brucine (or vauqueline, quinoline peaceful), mix and stir, refluxed several minutes to 5 hours, then with solution concentration to about 40ml volume, insert refrigerator, slowly separate out colourless transparent crystal.Filter, vacuum-drying forms salt, is example with the brucine, obtains 2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-the salt 4.0g of acetate and the formation of above-mentioned alkali.This salt is dissolved in the 30ml methylene dichloride, adds the ammoniacal liquor of 30ml10%, stir half an hour, divide water-yielding stratum, purify with twice back of dichloromethane extraction, with its acidifying, the pH value is neutralized to 0.5～4 with mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid.Use ethyl acetate extraction (40ml * 4) then, merge organic layer, through anhydrous Na
2SO
4After the drying, remove solvent, vacuum-drying obtains white solid 0.8g.Yield 40%.
[α]
D 20=-7.12°(c=1，DMSO)。
ee％=93.8％。(with its with diazomethane esterification after, split with chirality HPLC and to measure.)
Claims (6)
1. a compound (R)-2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-acetate, its molecular formula is
2. a compound as claimed in claim 1 (R)-2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-synthetic method of acetate, it is characterized in that comprising the steps:
1) oxyammonia reaction: with 0 ℃ to 80 ℃, molecular formula is in polar solvent
3-N-phthalimide-based-propionic aldehyde and the mol ratio of oxammonium hydrochloride be 1: 0.5-5, reacted 2～30 hours, reaction medium is neutral, acid or alkaline;
2) chlorination reaction: in polar solvent and 0-100 ℃ the time, molecular formula is
3-N-phthalimide-based-third oxime and the mol ratio of chlorination reagent be 1: 0.5-4, reacted 4～40 hours, described chlorination reagent is N-chlorosuccinimide, NaOCl or Cl
2
3) 1,3-dipolar addition reaction: in polarity or non-polar solvent and 0 ℃ to 100 ℃ the time, molecular formula is
1-chloro-3-N-phthalimide-based-third oxime, molecular formula be CH
2=CHCH
2The 3-crotonate of COOR and the mol ratio of alkali are 1 successively: 0.8-5: 0-3, reacted described R=C 1～60 hour
nH2
N+1, n=1-5, described alkali are organic bases or mineral alkali, described organic bases is that molecular formula is R'
3The tertiary amine of N, pyridine, hexahydropyridine, tertiary butyl alcohol potassium or sodium amide, described mineral alkali are sodium hydroxide or potassium hydroxide, wherein said R '=C
1～12Alkyl;
4) ester hydrolysis reaction: in polar solvent and 0～80 ℃ the time, molecular formula is
2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-mol ratio of acetic ester and hydrolysing agent is 1: 1-50, reacted 1～48 hour, and described hydrolysing agent is acid or alkali, described acid is hydrochloric acid or sulfuric acid, and described alkali is the alkali of monovalence or divalent metal;
5) chiral separation: in polar solvent and room temperature when the reflux temperature, molecular formula is
2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-mol ratio of acetate and resolution reagent is 1: 0.8-5, reacted 1 minute to 5 hours, the reaction salify is after the mineral acid acidifying, the product that obtains is that molecular formula is
(R)-2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-acetate, described resolution reagent is the peaceful or brucine of vauqueline, quinoline.
3. a compound as claimed in claim 2 (R)-2-[3-(2-N-phthalimide-based ethyl)-4,5-two-hydrogen-5-isoxazolyl]-synthetic method of acetate, it is characterized in that described polar solvent is water, acetone, C
1-C
8Alcohol, halogenated alkane, N, dinethylformamide, methyl-sulphoxide, tetrahydrofuran (THF) or its mixed solvent.
4. a compound as claimed in claim 2 (R)-2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-synthetic method of acetate, it is characterized in that step 1), 2), 3), 4) or 5) product through concentrate, a step or a few step in desolventizing, neutralization, crystallization, filtration, dilution, extraction, washing, recrystallization or the drying handle.
5. a compound as claimed in claim 1 (R)-2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-purposes of acetate, it is characterized in that being used to synthesize (4R-cis)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate.
6. a compound as claimed in claim 1 (R)-2-[3-(2-N-phthalimide-based ethyl)-4,5-dihydro-5-isoxazolyl]-purposes of acetate, it is characterized in that being used to prepare medicine Atorvastatin.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103360394A (en) * | 2013-07-29 | 2013-10-23 | 上海万巷制药有限公司 | 8-chlorotheophylline preparation method |
| CN103384659A (en) * | 2011-02-21 | 2013-11-06 | 公益财团法人微生物化学研究会 | Thioamide compound, method for producing thioamide compound, method for producing [(4r,6r)-6-aminoethyl-1,3-dioxane-4-yl]acetate derivative, and method for producing atorvastatin |
-
2000
- 2000-12-08 CN CN 00127841 patent/CN1127503C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103384659A (en) * | 2011-02-21 | 2013-11-06 | 公益财团法人微生物化学研究会 | Thioamide compound, method for producing thioamide compound, method for producing [(4r,6r)-6-aminoethyl-1,3-dioxane-4-yl]acetate derivative, and method for producing atorvastatin |
| CN103384659B (en) * | 2011-02-21 | 2015-11-25 | 公益财团法人微生物化学研究会 | Thioamide compound and produce the method for this compound, [(4R, 6R)-6-aminoethyl-1,3-dioxane-4-yl] acetic ester derivative and atorvastatin |
| CN103360394A (en) * | 2013-07-29 | 2013-10-23 | 上海万巷制药有限公司 | 8-chlorotheophylline preparation method |
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