CN109232386A - A kind of method of asymmetric syntheses (S)-preclamol - Google Patents
A kind of method of asymmetric syntheses (S)-preclamol Download PDFInfo
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C07B53/00—Asymmetric syntheses
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Abstract
The invention discloses a kind of asymmetric syntheses (S)-preclamol new methods.This method is using racemic alpha-halogenate glutaric acid diester as starting material, under double oxazoline chiral ligands and metallic cobalt catalysis, asymmetry Negishi cross-coupling reaction occurs with m-methoxyphenyl zinc bromide, the glutaric acid diester of m-methoxyphenyl substitution is obtained, then through LiAlH4Reduction generates (S) -2- (3- methoxyphenyl) pentanediol, and (S)-preclamol most is made through amination cyclization and demethylation afterwards.The present invention utilizes the chiral centre of asymmetric Negishi cross-coupling reaction direct construction (S)-preclamol for the first time, and synthetic route is brief, and reaction condition is mild, gross production rate 51%.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of side of new asymmetry catalysis synthesis (S)-preclamol
Method.
Background technique
(S)-preclamol (Preclamol, formula 1) is a kind of drug for treating the mental diseases such as parkinsonism, is more
Antagonist (Hacksell, the U. of bar amine receptor；Arvidsson,L.E.；Svensson,U.；Nilsson,J.L.G.；
Sanchez,D.；Wikstroem,H.；Lindberg,P.；Hjorth,S.；Carlsson,A.J.Med.Chem.1981,24,
1475.Metman,L.V.；Sethy,V.H.；Roberts,J.R.；Bravi,D.；Hoff,J.I.；Mouradian,M.M.；
Chase,T.N.Mov Disord1994,9,577.).Since (S)-preclamol has important physiological activity, many scholars
Study its synthetic method.(S) there is an asymmetric carbon atom in-preclamol structure, synthesis key is to construct the chiral centre.Mesh
Before, the method for obtaining (S)-preclamol mainly has racemic modification Split Method, chiral induction method and asymmetry catalysis method.
(1) racemic modification Split Method mainly includes dynamics of 2,2'- (1,1'- dinaphthyl) phosphonic acids to racemic preclamol
Split (Arnold, W.；Daly,J.J.；Imhof,R.；Kyburz, E.Tetrahedron Lett.1983,24,343.), with
And two paratolunitrile tartrate to the Kinetic Resolution of racemic preclamol precursor (O- methyl preclamol)
(Thorberg,S.O.；Gawell,L.；Csoeregh,I.；Nilsson, J.L.G.Tetrahedron 1985,41,129.),
(S)-preclamol can be obtained through demethylation in the latter.
(2) chiral induction method is mainly using the chirality sweet amine alcohol of benzene as the oxazolidine annulation of chiral shift reagent,
Through multistep reactions such as reduction, demethylations, (S)-preclamol (Wong, Y.-S. is made；Marazano,C.；Gnecco,D.；
Genisson,Y.；Chiaroni,A.；Das,B.C.J.Org.Chem.1997,62,729.).
(3) asymmetry catalysis method is mainly including the use of asymmetric hydrogenation (Yang, the X.-H. of the lactone of iridium catalysis；Yue,
H.-T.；Yu,N.；Li,Y.-P.；Xie,J.-H.；Zhou, Q.-L.Chem.Sci.2017,8,1811.), the allyl of iridium catalysis
Base is alkylated (Hamilton, J.Y.；Sarlah,D.；Carreira,E.M.Angew.Chem.,Int.Ed.2015,54,
And copper/palladium chtalyst asymmetric allylboration (Jia, T. 7644.)；Cao,P.；Wang,B.；Lou,Y.；Yin,X.；
Wang,M.；Liao, J.J.Am.Chem.Soc.2015,137,13760.) asymmetric catalysis such as ,-the third carat of building (S)
Asymmetric carbon atom not.
Although having some study on the synthesis about (S)-preclamol, the chiral examination for needing stoichiometry is still remained
Therefore agent, severe reaction conditions, the problems such as reaction step is cumbersome study environment amenable, simple and direct efficient asymmetry
The method for synthesizing (S)-preclamol has important theoretical value and realistic meaning.
Summary of the invention
The present invention is intended to provide a kind of new asymmetric syntheses (S)-preclamol method.The present invention is with racemic α-
Halogenated glutaric acid diester (1) is used as starting material, under double oxazoline chiral ligands and metallic cobalt catalysis, with m-methoxyphenyl
Asymmetry Negishi cross-coupling reaction occurs for zinc bromide, obtains the glutaric acid diester (2) of m-methoxyphenyl substitution, then
Through LiAlH4Reduction generates (S) -2- (3- methoxyphenyl) pentanediol (3), and (S)-most is made through amination cyclization and demethylation afterwards
Preclamol.The hand for asymmetric Negishi cross-coupling reaction direct construction (S)-preclamol that this method is catalyzed using cobalt
Property center, synthetic route is simple and direct, and reaction condition is mild, gross production rate 51%.Asymmetric syntheses (S)-preclamol of the present invention
Synthetic route is referring to formula 2.
The method that the present invention synthesizes (S)-preclamol includes the following steps.
(1) synthesis for the glutaric acid diester (2) that m-methoxyphenyl replaces
Under argon gas protection, anhydrous THF and a small amount of 3- methoxybromobenzene are sequentially added in magnesium chips.Careful heating causes anti-
It answers, the THF solution of the bromo- 3- methoxybenzene of 1- is added dropwise, (3- methoxyphenyl) magnesium bromide is made in back flow reaction.
Under argon gas protection, in ZnBr2In sequentially add anhydrous THF with from preparation (3- methoxyphenyl) magnesium bromide, room temperature
Under be stirred to react, be made (3- methoxyphenyl) zinc bromide.
Under argon gas protection, the THF solution of anhydrous THF and double oxazoline chiral ligands are added in anhydrous cobaltous iodide (II),
It is stirred to react at room temperature, alpha-halogenate glutaric acid diester is added.- 25 DEG C are cooled to, the outstanding of (3- methoxyphenyl) zinc bromide is added dropwise
Supernatant liquid continues to be stirred to react.Quenching reaction, liquid separation extract, dry, depressurize precipitation.It is purified finally by silica gel column chromatography,
Obtain the glutaric acid diester (2) of m-methoxyphenyl substitution.
(2) synthesis of (S) -2- (3- methoxyphenyl) pentanediol (3)
In LiAlH4It is middle that anhydrous THF is added, -78 DEG C are cooled to, the glutaric acid diester (2) that m-methoxyphenyl replaces is added
THF solution, be warming up to room temperature and be stirred overnight.Quenching reaction, liquid separation extract, dry, depressurize precipitation.Finally by silica gel
It is column chromatography eluting, obtain (S) -2- (3- methoxyphenyl) pentanediol (3).
(3) synthesis of (S)-preclamol
At 0 DEG C, in the CH of (S) -2- (3- methoxyphenyl) pentanediol (3)2Cl2In solution, Et is sequentially added3N with
MsCl is warming up to room temperature, continues to be stirred to react.Quenching reaction, liquid separation extract, and wash, dry, depressurize precipitation, obtain thick diformazan
Sulphonic acid ester.
At room temperature, by n-PrNH2It is added in thick bis-mesylate, is stirred to react.Reaction mixture is diluted, is washed,
Liquid separation extracts, dry, depressurizes precipitation.It is purified finally by silica gel column chromatography, obtains O- methyl preclamol.
At room temperature, under protection of argon gas, HBr is added in O- methyl preclamol, is heated to 120 DEG C, is stirred to react.
It is cooled to 0 DEG C, alkalizes, extraction, liquid separation is dry, depressurizes precipitation, purifies finally by silica gel column chromatography, obtains-the third gram of (S)
Rameau.
Specific embodiment
Embodiment 1
The synthesis for the glutaric acid diester (2) that m-methoxyphenyl replaces
Magnesium chips (1.46g, 60mmol) is placed in two mouthfuls of Schlenk flasks of the 250mL equipped with dropping funel, it is true at 80 DEG C
Sky is 1 hour dry.Be cooled to room temperature under argon gas protection, sequentially add anhydrous THF (50mL) and 3- methoxybromobenzene (1.87g,
10mmol).Careful heating initiation reaction, the THF (10mL) that the bromo- 3- methoxybenzene (7.48g, 40mmol) of 1- is added dropwise are molten
Liquid.Reaction mixture is stirred and is flowed back 2 hours, (3- methoxyphenyl) magnesium bromide is made.
By ZnBr2(10.12g, 45mmol) is placed in another 250mL Schlenk flask, is dried in vacuo at 100 DEG C
1.5 hour.It is cooled to room temperature under argon gas protection, anhydrous THF (68.8mL) is added, continue stirring 10 minutes.Self-control is added dropwise
(3- methoxyphenyl) magnesium bromide (30mmol, 0.586M THF solution, 51.2mL).Reaction mixture is continued at room temperature
It is stirred to react 2 hours, (3- methoxyphenyl) zinc bromide is made.
Anhydrous cobaltous iodide (II) (160mg, 0.50mmol) is placed in 100mL Schlenk flask, vacuum is dry at 80 DEG C
Dry 2 hours.Be cooled to room temperature under argon gas protection, be added anhydrous THF (10mL) and pair oxazoline chiral ligand L1 (330mg,
THF (5mL) solution 0.60mmol).Mixture is stirred at room temperature 2 hours, 2- bromine glutaric acid two is added by syringe
Benzyl ester (1) (1.97g, 5.0mmol).Gained mixture is cooled to -25 DEG C, (3- methoxyphenyl) zinc bromide is added dropwise
The suspension of (25mmol).It is stirred to react at -25 DEG C 24 hours, with saturation NH4Cl solution (10mL) quenching reaction.Liquid separation,
Water phase Et2O (3 × 50mL) extraction, merges organic phase.Organic phase anhydrous Na2SO4It is dry, depressurize precipitation.Finally by silicon
Rubber column gel column chromatography (petroleum ether/methylene chloride 1:2) purifying, obtains colorless oil (S) -2- (3- methoxyphenyl) glutaric acid two
Benzyl ester (2) (1.94g, yield 93%, optical purity 87%).[α]D 23=+24.6 (c 1.3, CHCl3).1H NMR(300MHz,
CDCl3) δ 7.34-7.18 (m, 11H), 6.84-6.79 (m, 3H), 5.15-5.04 (m, 4H), 3.74 (s, 3H), 3.64 (t, J=
7.4Hz, 1H), 2.45-2.33 (m, 1H), 2.31 (t, J=7.4Hz, 2H), 2.20-2.09 (m, 1H)13C NMR(75MHz,
CDCl3)δ173.0,172.6,159.8,139.5,135.87,135.80,129.7,128.5,128.4,128.2,128.1,
127.9,120.4,113.5,113.1,66.5,66.3,55.1,50.5,31.8,28.2.HRMS(ESI):calcd
forC26H27O5[M+H]+419.1853,found 419.1840.
The structure of double oxazoline chiral ligand L1 is referring to formula 3.
Embodiment 2
(S) synthesis of -2- (3- methoxyphenyl) pentanediol (3)
By LiAlH4(0.25g, 6.6mmol) is placed in 50mL Schlenk pipe, and anhydrous THF (5mL) is added.By mixed liquor
Be cooled to -78 DEG C, then by syringe be added (S) -2- (3- methoxyphenyl) glutaric acid dibenzyl ester (2) (0.46g,
THF (3mL) solution 1.1mmol).Reaction mixture is to slowly warm up to room temperature and is stirred to react overnight.Potassium tartrate is added
Solution (20mL) quenching reaction continues stirring 6 hours.Liquid separation, water phase Et2O (3 × 30mL) extraction, merges organic phase.It is organic
Mutually use anhydrous Na2SO4It is dry, depressurize precipitation.It is purified finally by silica gel column chromatography (methylene chloride/methanol 20:1), obtains nothing
Color grease (S) -2- (3- methoxyphenyl) pentanediol (3) (0.21g, yield 90%, optical purity 87%).[α]D 23=+
9.3(c 1.8,CHCl3).1H NMR(300MHz,CDCl3) δ 7.23 (t, J=7.9Hz, 1H), 6.80-6.75 (m, 3H), 3.78
(s, 3H), 3.70 (d, J=6.8Hz, 2H), 3.55 (t, J=6.3Hz, 2H), 2.78-2.69 (m, 1H), 2.09 (br s, 2H),
1.86–1.76(m,1H),1.65–1.52(m,1H),1.49–1.40(m,2H).13C NMR(75MHz,CDCl3)δ159.8,
143.9,129.6,120.3,114.0,111.6,67.3,62.5,55.1,48.3,30.3,28.1.HRMS(ESI):calcd
forC12H19O3[M+H]+211.1329,found 211.1331.
Embodiment 3
(S) synthesis of-preclamol
At 0 DEG C, (S) -2- (3- methoxyphenyl) pentanediol (3) (0.21g, 0.99mmol) is dissolved in CH2Cl2
(8mL), is added with stirring Et3MsCl (0.21mL, 2.65mmol) is then added dropwise in N (0.69mL, 4.96mmol).It will be anti-
It answers mixed liquor to be warming up to room temperature, continues to be stirred to react 12 hours.With saturation NaHCO3Solution (5mL) quenching reaction, liquid separation.Water phase
Use CH2Cl2(3 × 20mL) extraction, merges organic phase.Organic phase is washed with saturated sodium chloride solution (20mL), through anhydrous Na2SO4
Precipitation is depressurized after drying, obtains thick bis-mesylate.
At room temperature by n-PrNH2(2.4mL, 30.0mmol) is added in thick bis-mesylate, is stirred to react 24 hours.
By reaction mixture CH2Cl2(10mL) dilution, then with saturation Na2CO3Solution (20mL) washing.Liquid separation, water phase CH2Cl2
(3 × 10mL) extraction, merges organic phase.Organic phase is washed with saturated sodium-chloride water solution (30mL), anhydrous Na2SO4It is dry, subtract
Pressure-off is molten.It is purified finally by silica gel column chromatography (methylene chloride/methanol 20:1), obtains white waxy solid O- methyl-prop gram
Rameau.
At room temperature, under protection of argon gas, by 48%HBr (3mL) be added to O- methyl preclamol (0.16g,
In 0.68mmol), 120 DEG C are heated to, is stirred to react 2 hours.Reaction mixture is cooled to 0 DEG C, with saturation Na2CO3Solution
(30mL) alkalization.Gained mixture CH2Cl2(4 × 10mL) extraction, liquid separation merge organic phase.Organic phase anhydrous sodium sulfate
Precipitation is depressurized after drying, is purified finally by silica gel column chromatography (n-hexane/acetone 1:1), is obtained yellow oil (S)-the third
Carat is not (0.13g, 3 step yields are 61%, optical purity 87%).[α]D 23=-16.3 (c 2.5, CHCl3).1H NMR
(300MHz,CDCl3) δ 7.72 (br s, 1H), 7.18 (t, J=7.8Hz, 1H), 6.78-6.70 (m, 3H), 3.23 (d, J=
11.4Hz, 1H), 3.08 (d, J=11.4Hz, 1H), 2.99-2.89 (m, 1H), 2.45-2.28 (m, 2H), 2.06-1.95 (m,
3H), 1.83-1.75 (m, 2H), 1.63-1.48 (m, 3H), 0.87 (t, J=7.4Hz, 3H)13C NMR(75MHz,CDCl3)δ
156.9,145.4,129.8,117.4,114.7,114.2,61.4,61.2,54.0,41.9,30.0,25.2,19.2,
12.0.HRMS(ESI):calcdfor C14H22NO[M+H]+220.1696,found 220.1695.
Claims (6)
1. asymmetric syntheses (S)-preclamol method, it is characterised in that: be with racemic alpha-halogenate glutaric acid diester
With m-methoxyphenyl zinc bromide asymmetry Negishi occurs for beginning raw material under double oxazoline chiral ligands and metallic cobalt catalysis
Cross-coupling reaction obtains the glutaric acid diester of m-methoxyphenyl substitution, then through LiAlH4Reduction generates (S) -2- (3- first
Phenyl) pentanediol, (S)-preclamol most is made through amination cyclization and demethylation afterwards.
2. synthetic method according to claim 1, it is characterised in that double used in asymmetric Negishi cross-coupling reaction
The substituent R of oxazoline chiral ligand ' it is ethyl, isopropyl, sec-butyl, tert-butyl, phenyl and benzyl, preferred substituents R' is
Double oxazoline chiral ligands of benzyl.
3. synthetic method according to claim 1, it is characterised in that used in asymmetry catalysis Negishi cross-coupling reaction
Cobalt salt be CoCl2、CoBr2、CoI2、Co(OAc)2、Co(acac)2、Co(PPh3)Cl2、Co(dppe)Cl2With Co (acac)3,
It is preferred that CoI2。
4. synthetic method according to claim 1, it is characterised in that institute in asymmetry catalysis Negishi cross-coupling reaction
Reaction dissolvent is ether, toluene, tetrahydrofuran, methyltetrahydrofuran and methylene chloride, preferably tetrahydrofuran.
5. synthetic method according to claim 1, it is characterised in that in asymmetry catalysis Negishia cross-coupling reaction
The halogen atom of alpha-halogenate glutaric acid diester used is Cl, Br and I, preferably bromine atom.
6. synthetic method according to claim 1, it is characterised in that institute in asymmetry catalysis Negishi cross-coupling reaction
Substituent R is methyl, ethyl, sec-butyl, cyclohexyl methyl, phenyl, p-methylphenyl and benzyl in alpha-halogenate glutaric acid diester
Base, preferably benzyl.
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Cited By (3)
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| CN110483289A (en) * | 2019-07-31 | 2019-11-22 | 中国农业大学 | A kind of method of asymmetric syntheses chirality olefin(e) acid ester |
| CN111454150A (en) * | 2019-12-25 | 2020-07-28 | 南京工业大学 | Synthesis method of (S) -2-aryl propionate compound |
| CN113929577A (en) * | 2021-11-05 | 2022-01-14 | 安徽美致诚药业有限公司 | Synthetic method of 2- (4-methylphenyl) -propionate |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483289A (en) * | 2019-07-31 | 2019-11-22 | 中国农业大学 | A kind of method of asymmetric syntheses chirality olefin(e) acid ester |
| CN110483289B (en) * | 2019-07-31 | 2021-02-09 | 中国农业大学 | Method for asymmetrically synthesizing chiral olefine acid ester |
| CN111454150A (en) * | 2019-12-25 | 2020-07-28 | 南京工业大学 | Synthesis method of (S) -2-aryl propionate compound |
| CN111454150B (en) * | 2019-12-25 | 2023-03-28 | 南京工业大学 | Synthesis method of (S) -2-aryl propionate compound |
| CN113929577A (en) * | 2021-11-05 | 2022-01-14 | 安徽美致诚药业有限公司 | Synthetic method of 2- (4-methylphenyl) -propionate |
| CN113929577B (en) * | 2021-11-05 | 2023-09-29 | 安徽美致诚药业有限公司 | Synthesis method of 2- (4-methylphenyl) -propionate |
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Application publication date: 20190118 |