CN101066945B - Process of synthesizing 3-substituted lactan compound - Google Patents
Process of synthesizing 3-substituted lactan compound Download PDFInfo
- Publication number
- CN101066945B CN101066945B CN200710041247A CN200710041247A CN101066945B CN 101066945 B CN101066945 B CN 101066945B CN 200710041247 A CN200710041247 A CN 200710041247A CN 200710041247 A CN200710041247 A CN 200710041247A CN 101066945 B CN101066945 B CN 101066945B
- Authority
- CN
- China
- Prior art keywords
- compound
- substituted
- aryl
- alkyl
- synthetic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention provides process of synthesizing 3-substituted lactam compound. Compound 3-substituted lactam is synthesized in high efficiency with aldehyde group substituted small cyclic amine compound in the presence of azacyclo carbine as the catalyst. Compared with available technology, the present invention has the advantages of wide range of applicable substrates, facile catalyst, mild reaction condition, high reaction efficiency, etc. In addition, when the substrate has chiral quaternary carbon center, the reaction can transfer the chirality to the product so as to synthesize corresponding selective lactam compound with the quaternary carbon center. Furthermore, the process needs no addition of any metal salt compound, and this is favorable to the production of medicine.
Description
Technical field
The present invention relates to a kind of method of synthetic 3-substituted lactan compound, relate in particular to a kind of method that keeps to come the spirocyclic lactams compound of synthesis of optically active by quaternary carbon chiral centre chirality in the substrate.This method is the reaction by the little cyclic amine compound ring expansion of the precursor salt of N-heterocyclic carbine and the on-the-spot N-heterocyclic carbine catalysis aldehyde radical replacement that generates of alkali effect, the reaction of the little cyclic amine compound ring expansion that also can be directly replaced by N-heterocyclic carbine catalysis aldehyde radical, this reaction can be synthesized the 3-substituted lactan compound efficiently.
Background technology
In recent years, organic molecule catalysis has caused extensive concern [(a) Seayad, the J. of academia and industry member in worldwide owing to advantages such as it are easily synthetic, and structural modification is convenient, and heavy metal free is residual; List, B.Org.Biomol.Chem.2005,3,719-724. (b) Dalko, P.I.; Moisan, L.Angew.Chem.Int.Ed.2004,43,5138-5175.], be that the organic reaction of catalyst has obtained development [a) H.Stetter, Angew.Chem.1976,88,695-704 rapidly especially in recent years wherein by N-heterocyclic carbine; Angew.Chem.Int.Ed.1976,15,639-647; B) M.S.Kerr, J.Read de Alaniz, T.Rovis, J.Am.Chem.Soc.2002,124,10298-10299; C) A.E.Mattson, A.R.Bharadwaj, K.A.Scheidt, J.Am.Chem.Soc.2004,126,2314-2315; D) M.S.Kerr, T.Rovis, J.Am.Chem.Soc.2004,126,8876-8877; E) J.Read de Alaniz, T.Rovis, J.Am.Chem.Soc.2005,127,6284-6289; F) Q.Liu, T.Rovis, J.Am.Chem.Soc.2006,128,2552-2553; G) Y.Hachisu, J.W.Bode, K.Suzuki, J.Am.Chem.Soc.2003,125,8432-8433; H) D.Enders, O.Niemeier, T.Balensiefer, Angew.Chem.2006,118,1491-1495; Angew.Chem.Int.Ed.2006,45,1463-1467; I) H.Takikawa, Y.Hachisu, J.W.Bode, K.Suzuki, Angew.Chem.2006,118,3572-3574; Angew.Chem.Int.Ed.2006,45,3492-3494; J) M.He, G.J.Uc, J.W.Bode, J.Am.Chem.Soc.2006,128,15088-15089; K) G.-Q.Li, L.-X.Dai, S.-L.You, Chem.Commun.2007,852-854], in this field, our latest developments the ring expansion of the little cyclic amine compound that replaces by N-heterocyclic carbine catalysis aldehyde radical, this reaction can be synthesized the 3-substituted lactan compound expeditiously, and this compounds is present in [a) N.C.Warshakoon in the natural of a large amount of biologically actives and the non-natural product; S.Wu; A.Boyer; R.Kawamoto; J.Sheville; S.Renock; K.Xu; M.Pokross; A.G.Evdokimov; R.Walter; M.Mekel.Bioorg.Med.Chem.Lett.2006,16,5598-5601; B) J.Uddin; K.Ueda; E.Siwu; M.Kita; D.Uemura Biorg.Med.Chem., 2006,14,6954-6961; C) H.Ishikawa; G.I.Elliott; J.Velcicky; Y.Choi; D.Boger J.Am.Chem.Soc., 2006,128,10596-10612; D) Hamlyn, Richard John; Rigoreau, Laurent Jean Martin; Raynham, Tony Michael; Priestley, Rachael Elizabeth; Soudy, Christelle Nicole Marguerite; Lyko, Frank; Bruckner, Bodo; Kern, Oliver Thomas.PCT Int.Appl.2007,71; E) Jacyno, John M.; Lin, Nan-Homg; Holladay, Mark W.; Sullivan, James P.CurrentTopics in Plant Physiology (1995), 15 (Phytochemicals and Health), 294-6.f) J.A.Ferrendelli; H.J.Kupferberg Advances in Neurology 1980,27,587-96.] the synthetic report of the lactam compound that the 3-position replaced in the document at present is a lot, but wherein all there are metal participation reaction or reaction conditions harsh mostly, shortcomings such as the reaction times is very long, thereby develop a kind of easy to operate, mild condition, and the method for the high synthetic 3-substituted lactan compound of efficient is the emphasis and the difficult point of this respect.Inventor development utilize aza ring carbene precursor salt and alkali effect, the scene generates N-heterocyclic carbine or directly uses this organic micromolecule catalyst of N-heterocyclic carbine, by aldehyde radical being replaced the synthetic of lactam compound that this substrate ring expansion that conveniently is easy to get of little cyclic lactam realizes that the 3-position replaces, the synthetic of this compounds had great significance.
Summary of the invention
The present invention seeks to provide a kind of method of synthetic 3-substituted lactan compound efficiently.When especially containing the quaternary carbon chiral centre in substrate, reaction can remain into chirality in the product, can be used to the 3-substituted lactan compound of the high enantioselectivity of high-level efficiency ground synthesis of optically active.
Method of the present invention is a kind of method that is replaced the synthetic 3-position of tetra-atomic ring aminated compounds substituted lactams compound efficiently by aldehyde radical.This method is to generate N-heterocyclic carbine as catalyzer by aza ring carbene precursor salt and alkali effect scene, also can directly use N-heterocyclic carbine as catalyzer.
Method of the present invention institute synthetic 3-position substituted lactams compound molecule general formula is:
In the formula: R
1Or R
2Be selected from H arbitrarily, contain C
1-C
16Alkyl, amino, alkoxy or halogen atom etc.; R
3Be selected from the aryl or the C of various acyl groups, replacement arbitrarily
1-C
16Alkyl etc.; X be carbonyl or
N=0,1 or 2;
The lactam compound that 3-of the present invention position replaces is that the little cyclic amine compound that replaces with aldehyde radical is a raw material, in the presence of organic solvent, the N-heterocyclic carbine catalyzed reaction that generates with the effect of aza ring carbene precursor salt and alkali makes, also can directly make, can be represented by the formula with the N-heterocyclic carbine catalyzed reaction:
The structural formula of the little cyclic amine compound that aldehyde radical replaces is:
R wherein
1Or R
2Be selected from H arbitrarily, contain C
1-C
16Alkyl, amino, alkoxyl group or halogen atom etc.; R
3Be selected from the aryl or the C of acyl group, replacement arbitrarily
1-C
16Alkyl etc.; X be carbonyl or
N=0,1 or 2; When generating N-heterocyclic carbine as catalyzer with aza ring carbene precursor salt and alkali effect scene, the structural formula of the precursor salt of N-heterocyclic carbine can be the following structural formula of optically pure arbitrarily or its enantiomorph or raceme, but not limit by diagram:
When directly using N-heterocyclic carbine as catalyzer, the structural formula of N-heterocyclic carbine can be the following structural formula of optically pure arbitrarily or its enantiomorph or raceme, but not limit by diagram:
Wherein, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14, R
15, R
16Or R
17Be H, C
1-C
16Alkyl, aryl, substituted aryl; Substituting group on the aryl of described replacement is the amido of alkyl, alkoxyl group or replacement, and above-mentioned each substituting group can become key separately or become key to form C each other
5-C
7Cycloalkyl, aryl, substituted aryl, the heteroaryl that contains N, O, S or Heterocyclylalkyl; A
1, A
2, A
3, A
4Be Cl
-, Br
-, BF
4 -Or ClO
4 -
Described alkali is triethylamine, 1,8-diazabicylo [5,4,0] 11 carbon-7-alkene, 1,5-diazabicylo [4,3,0] ninth of the ten Heavenly Stems-5-alkene, cesium carbonate, potassiumphosphate, two (trimethyl silicon based) sodium amide, two (trimethyl silicon based) Lithamide, two (trimethyl silicon based) potassium amide, potassium tert.-butoxide, sodium tert-butoxide or diisopropyl ethyl amine;
The mol ratio that described aldehyde radical replaces little cyclic amine compound, aza ring carbene precursor salt or N-heterocyclic carbine, alkali is 1: 0.01-0.2: 0-0.2.
When with aza ring carbene precursor salt and alkali effect, on-the-spotly generate N-heterocyclic carbine catalysis should reaction the time, little cyclic amine compound, aza ring carbene precursor salt and the alkali of described aldehyde radical replacement mol ratio 1: 0.01-0.2: 0.01-0.2.Recommending mol ratio is 1: 0.2: 0.2.Especially the mol ratio of recommendation response is: aldehyde radical replaces little cyclic amine compound: aza ring carbene precursor salt: alkali=1: 0.01: 0.01.
When directly with N-heterocyclic carbine catalysis should reaction the time, little cyclic amine compound, N-heterocyclic carbine and the alkali that described aldehyde radical replaces mol ratio 1: 0.01-0.2: 0.Especially the mol ratio of recommendation response is: aldehyde radical replaces little cyclic amine compound: N-heterocyclic carbine: alkali=1: 0.01: 0.
Temperature of reaction is recommended as 0 ℃ to 120 ℃, and further the recommendation response temperature is: 25 ℃ to 110 ℃.Reaction times was recommended as 5 hours-48 hours.
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14, R
15, R
16And R
17Ditto described.
The alkyl of being mentioned among the present invention,-oxyl, acyl group etc., unless otherwise indicated, all recommending carbon number is 1～18 group, and further to recommend carbon number be 1～10, and especially recommending carbon number is 1～5.The cycloalkyl of being mentioned among the present invention unless otherwise indicated, refers to that all carbon number is 3～18 group, further recommending carbon number is 3～10, and especially recommending carbon number is 3～7.The aryl of being mentioned among the present invention unless otherwise indicated, all refers to phenyl, C
5～C
10The heterocyclic radical that contains N, O or S, be recommended as phenyl.The heteroaryl of mentioning among the present invention is recommended C
5～C
10The heterocyclic radical that contains N, O and S.
In the inventive method, described organic solvent can be polarity or non-polar solvent.As benzene, tetracol phenixin, sherwood oil, tetrahydrofuran (THF), dimethyl formamide, N,N-DIMETHYLACETAMIDE, ether, methylene dichloride, trichloromethane, toluene, dimethylbenzene, hexanaphthene, normal hexane, normal heptane, dioxane or acetonitrile etc.
Adopt the inventive method products therefrom can pass through recrystallization, thin-layer chromatography, methods such as column chromatography underpressure distillation are separated.As the method with recrystallization, recommending solvent is the mixed solvent of polar solvent and non-polar solvent.Recommend solvent to can be methylene dichloride-normal hexane, Virahol-sherwood oil, ethyl acetate-sherwood oil, ethyl acetate-normal hexane or Virahol-ethyl acetate-mixed solvents such as sherwood oil.With thin-layer chromatography and column chromatography method, used developping agent is the mixed solvent of polar solvent and non-polar solvent.Recommend solvent to can be Virahol-sherwood oil, ethyl acetate-sherwood oil, ethyl acetate-normal hexane or Virahol-ethyl acetate-mixed solvents such as sherwood oil, its volume ratio can be respectively: polar solvent: non-polar solvent=1: 0.1-500.For example: ethyl acetate: sherwood oil=1: 0.1-50, Virahol: sherwood oil=1: 0.1-500.
The invention provides some new 3-position substituted lactams compounds
R for example wherein
1Be H; R
2Be methyl or phenyl; R
3Be phenyl, p-methylphenyl, benzyl, alkyl.This compounds can be through the reaction of routine with R
3Remove and with reduction of amide for amino and go up amino protecting group such as carbobenzoxy-(Cbz), use thereby have widely.
The invention provides a kind of effectively by aza ring carbene precursor salt and alkali effect, the on-the-spot N-heterocyclic carbine that generates or directly use N-heterocyclic carbine as catalyzer, the method for the high efficiency synthetic 3-of the little cyclic amine compound position substituted lactams compound that replaces by aldehyde radical.Compare with existing method, this method replaces little cyclic amine compound applicable to the aldehyde radical of number of different types, and the reaction conditions gentleness is easy and simple to handle.In addition, need not in the reaction to add any metal salt compound, thereby help medicine production and processing.And the productive rate of reaction is also better, is generally 78%-99%.
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention.
Embodiment 1: the preparation of thiazoles aza ring carbene precursor salt
Under the room temperature argon shield; in an exsiccant reaction tubes with 4; 5-dimethylthiazole or 4-methyl-5-hydroxy ethylthiazole (1.0mmol) is dissolved in the 10mL exsiccant acetonitrile; under quick stirring condition; the cylite or the benzyl chlorine of (1.0mmol) are added drop-wise in the system slowly, refluxed 3 hours.Question response finishes, and naturally cools to room temperature, under stirring fast, slowly drips ethyl acetate 30mL in system, and system has a large amount of white solids to separate out, and leaves standstill.Filter, get white solid, be the precursor salt of thiazoles Cabbeen.
C1: bromination (3-benzyl-4,5-dimethylthiazole)
3-Benzyl-4，5-dimethylthiazolium?bromide
Solid, 91% productive rate.′H?NMR(300MHZ，DMSO)67.492-7.324(m，5H)，5.809(s，2H)，2.499(s，3H)，2.327(s，3H)；MS(CI)m/z(relative?intensity)204(M，13.6)，171(8)，142(10.4)，114(72.81)，91(100).
C2: bromination [3-benzyl-4-methyl-5-(beta-hydroxy ethyl) thiazole]
3-Benzyl-5-(β-ethoxyethyl)-4-methy?thiazolium?Bromide
White solid, 82% productive rate; ' H NMR (300MHz, CDCl
3) 11.51 (s, 1H), 7.35 (m, 5H), 6.12 (d, 2H, J=5.2Hz), 3.49-3.65 (m, 4H), 3.0l (t, 2H, J=5.4Hz), 2.42 (s, 3H), 1.19 (t, 3H, J=7.0Hz).
C3：2-Phenyl-6，7-dihydro-5H-pyrrolo[2，1-c][1，2，4]triazol-2-ium?chloride
Overall yield C3 (15.778g 62%) .Rf (acetone)=0.09;
1H NMR (300MHz, D2O) δ 7.61-7.79 (m, 2H), 7.50-7.59 (m, 3H), 4.38 (dd, 2H, J=7.3,7.3Hz), 3.13 (dd, 2H, J=7.3,7.3Hz), 2.77 (ddd, 2H, J=15.0,7.7,7.7Hz);
13C NMR (100MHz, D2O) δ 163.9,135.5, and 131.0,130.3,121.3,47.5,26.7,21.5; IR (NaCl, compressing tablet) 1586,1513,1426,1382,967cm-1; M.p.180-184 ℃; HRMS (fast atom bombardment(FAB)), C
11H
12N
3, calculated value 186.1031. measured value 186.1038.
C4：1，3，4-triphenyl-4H-1，2，4-triazol-1-ium?perchlorate
MS(m/z，rel.intensity)397(M
+，100)，398(22)，399(32)
C5:1,3-two (2, the 6-diisopropyl phenyl) imidazole hydrochloride
1，3-Bis(2，6-diisopropylphenyl)imidzaolium?chloride
MS(m/z，rel.intensity)397(M
+，100)，398(22)，399(32).
C6:1,3-two (mesitylene base) imidazole hydrochloride
1，3-Bis(2，4，6-trimethylphenyl)imidazolium?chicride
MS (m/z, relative intensity) 340 (M
+, 100), 341 (23), 342 (32).
C7：
2-phenyl-6，10b-dihydro-4H，5aH-5-oxa-3，10cdiaza-2-azoniacyclopenta[c]fluor--ene?tetrafluoroborate
MS (m/z, relative intensity) 337 (M
+, 100), 336 (24), 338 (20).
C8：
2-Pentafluorophenyl-6，10b-dihydro-4H，5aH-5-oxa-3，10cdiaza-2-azoniacyclopenta[c]fluorene?tetrafluoroborate
MS (m/z, relative intensity) 380 (M
+, 100), 381 (20), 382 (2).
C9：2-(2，4，6-trimethylphenyl)-6，10b-dihydro-4H，5aH-5-oxa-3，10cdiaza--2-azoniacyclopenta[c]fluorene?tetrafluoroborate
MS (m/z, relative intensity) 419 (M
+, 100), 418 (25), 420 (24).
Embodiment 2: the ring expansion of N-heterocyclic carbine catalysis aldehyde radical substituted lactams compound
Under argon shield, in an exsiccant reaction tubes, add aza ring carbene precursor salt compound (0.01mmol) successively, alkali (0.01mmol), aldehyde radical replace little cyclic amine compound (1.00mmol), and methylene dichloride 4.0mL refluxes.Reaction finishes, and removal of solvent under reduced pressure gets product with the residue column chromatography for separation.Do not add special instruction, reaction all is solvent with the methylene dichloride, and temperature of reaction refluxes.
P1:N-(p-methoxyphenyl)-3-phenyl succinimide
N-(4-methoxyphenyl)-3-phenylpyrrolidine-2，5-dione
Catalyzer is C6 (1mol%); Ethyl acetate/petroleum ether=1/4, v/v; White solid, 99% productive rate;
1HNMR (CDCl
3, 300MHz) δ 2.97 (dd, 1H, J
1=4.8Hz, J
2=18.3Hz), 3.35 (dd, 1H, J
1=9.9Hz, J
2=18.6Hz), 3.82 (s, 3H), 4.16 (dd, 1H, J
1=4.8Hz, J
2=9.9Hz), 6.98 (d, 2H, J=9.0Hz), 7.23 (d, 2H, J=9.0Hz), 7.29-7.42 (m, 5H);
13C NMR (75MHz, CDCl
3): δ 37.2,45.9, and 55.4,114.5,124.4,127.3,127.6,128.0,129.2,137.2,159.5,175.4,176.9; IR (film): v
Max(cm
-1)=3007,2953,2834,1705,1513,1250,1198,777,703,670; MS (electron-bombardment, relative intensity) 293 (M
+, 50), 161 (100); Ultimate analysis C
17H
15NO
3: calculated value: C, 72.58; H, 5.37; N, 4.98; Measured value: C, 72.42; H, 5.26; N, 4.83; M.p.161-162 ℃.
P2:N-(p-methoxyphenyl)-3-(p-methoxyphenyl) succinimide
N-(4-methoxyphenyl)-3-4-(methoxyphenyl)pyrrolidine-2，5-dione
Catalyzer is C6 (1mol%); Ethyl acetate/petroleum ether=1/3, v/v; White solid, 98% productive rate;
1HNMR (CDCl
3, 300MHz) δ 2.94 (dd, 1H, J
1=4.8Hz, J
2=18.3Hz), 3.34 (dd, 1H, J
1=9.6Hz, J
2=18.6Hz), 3.81 (s, 3H), 3.82 (s, 3H), 4.12 (dd, 1H, J
1=4.8Hz, J
2=9.6Hz), 6.92 (d, 2H, J=8.7Hz), 6.98 (d, 2H, J=9.0Hz) 7.21-7.26 (m, 4H);
13CNMR (75MHz, CDCl
3): δ 37.2,45.1, and 55.3,55.4,114.4,114.6,124.4,127.6,128.4,129.1,159.2,159.5,175.5,177.2; IR (film): v
Max(cm
-1)=2960,2839,1705,1516,1251,1200,1181,1033,833,670; MS (electron-bombardment, relative intensity) 311 (M
+, 43), 134 (100); Ultimate analysis C
18H
17NO
4: calculated value: C, 69.44; H, 5.50; N, 4.50; Measured value: C, 69.30; H, 5.79; N, 4.32; M.p.172-173 ℃.
P3:N-(p-methoxyphenyl)-3-(rubigan) succinimide
3-(4-chlorophenyl)-N-(4-methoxyphenyl)pyrrolidine-2，5-dione
Catalyzer is C6 (1mol%); Reaction solvent is 1, and the 4-dioxane refluxes; Ethyl acetate/petroleum ether=1/4, v/v; White solid, 93% productive rate;
1HNMR (CDCl
3, 300MHz) δ 2.95 (dd, 1H, J
1=5.1Hz, J
2=18.6Hz), 3.37 (dd, 1H, J
1=9.6Hz, J
2=18.3Hz), 3.83 (s, 3H), 4.17 (dd, 1H, J
1=4.8Hz, J
2=9.6Hz), 6.99 (d, 2H, J=9.0Hz), 7.21-7.27 (m, 4H), 7.38 (d, 2H, J=8.4Hz);
13C NMR (75MHz, CDCl
3): δ 36.9,45.2, and 55.5,114.5,124.3,127.6,128.8,129.4,134.0,135.4,159.6,175.0,176.4; IR (compressing tablet): v
Max(cm
-1)=3472,3072,3012,2837,1783,1706,1513,1251,1205,1167,1029,832,670; MS (electron-bombardment, m/z, relative intensity) 315 (M
+, 37), 149 (100); Ultimate analysis C
17H
14ClNO
3: calculated value: C, 64.67; H, 4.47; N, 4.44; Measured value: C, 64.63; H, 4.66; N, 4.39; M.p.197-198 ℃.
P4:N-(p-methoxyphenyl)-3-(2-thienyl) succinimide
N-(4-methoxyphenyl)-3-(thiophen-2-yl)pyrrolidine-2，5-dione
Catalyzer is C6 (1mol%); Reaction solvent is 1, the 4-dioxane; Ethyl acetate/petroleum ether=1/4, v/v; White solid, 85% productive rate;
1H NMR (CDCl
3, 300MHz) δ 3.06 (dd, 1H, J
1=5.4Hz, J
2=18.3Hz), 3.37 (dd, 1H, J
1=9.6Hz, J
2=18.6Hz), 3.80 (s, 3H), 4.39 (dd, 1H, J
1=5.4Hz, J
2=9.6Hz), and 6.94-7.06 (m, 4H), 7.17-7.29 (m, 3H);
13C NMR (75MHz, CDCl
3): δ 37.1,41.0, and 55.4,114.4,124.2,125.3,125.5,127.1,127.5,138.3,159.5,174.5,175.5; IR (compressing tablet): v
Max(cm
-1)=3105,3004,2833,1902,1779,1709,1704,1516,1405,1250,1199,1175,1030,667; MS (electron-bombardment, m/z, relative intensity) 287 (M
+, 3), 110 (100); HRMS (electron-bombardment) C
15H
13NO
3S (M
+): calculated value 287.0616 measured values: 287.0619; M.p.122-124 ℃.
P5:N-(p-methoxyphenyl)-3-methyl succinimide
N-(4-methoxyphenyl)-3-methylpyrrolidine-2，5-dione
Catalyzer is C6 (1mol%); Ethyl acetate/petroleum ether=1/5, v/v; White solid, 91% productive rate;
1HNMR (CDCl
3, 300MHz) δ 1.45 (d, 3H, J=7.2Hz), 2.49 (dd, 1H, J
1=3.6Hz, J
2=16.8Hz), 3.00-3.13 (m, 2H), 3.82 (s, 3H), 6.98 (d, 2H, J=9.3Hz), 7.19 (d, 2H, J=8.7Hz);
13C NMR (75MHz, CDCl
3): δ 16.8,34.7, and 36.5,55.4,114.4,124.5,127.6,159.4,175.7,179.8; IR (compressing tablet): v
Max(cm
-1)=3005,2943,2846,1773,1704,1511,1396,1245,1182,1166,1031,836,668; MS (electron-bombardment, m/z, relative intensity) 219 (M
+, 100); HRMS (electron-bombardment) C
12H
13NO
3(M
+): calculated value: 219.0895; Measured value: 219.0900; M.p.91-93 ℃.
P6:N-(p-methoxyphenyl)-3-n-pentyl succinimide
N-(4-methoxyphenyl)-3-pentylpyrrolidine-2，5-dione
Catalyzer is C6 (1mol%); Ethyl acetate/petroleum ether=1/5, v/v; White solid, 99% productive rate;
1HNMR (CDCl
3, 300MHz) δ 0.9l (brs, 3H), 1.33-1.44 (m, 6H), 1.55-1.68 (m, 1H), 1.93-2.04 (m, 1H), 2.53 (m, 1H), 2.88-3.03 (m, 2H), 3.81 (s, 3H), 6.97 (d, 2H, J=9.0Hz), 7.18 (d, 2H, J=9.0Hz);
13C NMR (75MHz, CDCl
3): δ 14.0,22.4, and 26.3,31.4,31.4,34.5,40.0,55.4,114.4,124.5,127.6,159.4,176.0,179.3; IR (thin film): v
Max(cm
-1)=3074,2957,2932,2856,1776,1706,1519,1394,1255,1174,1027,822,769; MS (EI, m/z, rel.intensity) 275 (M
+, 53), 205 (100); HRMS (EI) C
16H
21NO
3(M
+): calculated value 275.1521; Measured value: 275.1521; M.p.67-68 ℃.
P7:N-(p-methoxyphenyl)-3-sec.-propyl succinimide
3-isopropyl-N-(4-methoxyphenyl)pyrrolidine-2，5-dione
Catalyzer is C6 (1mol%); Ethyl acetate/petroleum ether=1/5, v/v; White solid, 93% productive rate;
1HNMR (CDCl
3, 300MHz) δ 0.96 (d, 3H, J=6.9Hz), 1.04 (d, 3H, J=7.2Hz), 2.39 (m, 1H), 2.58 (dd, 1H, J
1=4.2Hz, J
2=18.3Hz), 2.82 (dd, 1H, J
1=9.3Hz, J
2=18.3Hz), 2.93 (m, 1H), 3.80 (s, 3H), 6.96 (d, 2H, J=8.7Hz), 7.15 (d, 2H, J=9.0Hz);
13C NMR (75MHz, CDCl
3): δ 17.1,19.8, and 29.0,30.3,45.5,55.3,114.3,124.4,127.6,159.3,176.1,178.6; IR (compressing tablet): v
Max(cm
-1)=2963,2935,1709,1513,1399,1255,1200,1035,831,771,672; MS (electron-bombardment, m/z, relative intensity) 247 (M
+, 100); HRMS (electron-bombardment) C
14H
17NO
3(M
+): calculated value: 247.1208; Measured value: 247.1208; M.p.112-114 ℃.
P8:N-(p-methoxyphenyl)-3,3-dimethyl succinimide
N-(4-methoxyphenyl)-3，3-dimethylpyrrolidine-2，5-dione
Catalyzer is C6 (5mol%); Ethyl acetate/petroleum ether=1/5, v/v; White solid, 97% productive rate;
1HNMR (CDCl
3, 300MHz) δ 1.42 (s, 6H), 2.71 (s, 2H), 3.83 (s, 3H), 6.98 (d, 2H, J=9.0Hz), 7.20 (d, 2H, J=9.0Hz);
13C NMR (75MHz, CDCl
3): δ 25.7,25.7, and 40.0,43.7,55.4,114.4,124.6,127.6,159.4,175.1,182.4; IR (compressing tablet): v
Max(cm
-1)=2936,2843,1775,1710,1511,1397,1248,1148,1033,834,788; MS (electron-bombardment, m/z, relative intensity) 233 (M
+, 87), 83 (100); HRMS (electron-bombardment) C
13H
15NO
3(M
+): calculated value: 233.1052; Measured value: 233.1051;
P9:N-(p-methoxyphenyl)-3-ethyl-3-phenyl succinimide
3-ethyl-N-(4-methoxyphenyl)-3-phenylpyrrolidine-2，5-dione
Catalyzer is C6 (5mol%); Reaction solvent is 1, and the 4-dioxane refluxes ethyl acetate/petroleum ether=1/5, v/v; White solid, 97% productive rate;
1H NMR (CDCl
3, 300MHz) δ 0.97 (t, 3H, J=7.2Hz), 2.17 (dq, 2H, J
1=5.1Hz, J
2=7.2Hz), 3.06 (AB, 1H, J
AB=18.3Hz), 3.25 (AB, 1H, J
BA=18.0Hz), 3.80 (s, 3H), 6.97 (d, 2H, J=8.7Hz), 7.19 (d, 2H, J=8.7Hz), 7.27-7.51 (m, 5H);
13C NMR (75MHz, CDCl
3): δ 9.0,32.7, and 41.1,52.1,55.4,114.4,124.4,126.1,127.5,127.7,128.8,140.6,159.4,174.9,179.3; IR (compressing tablet): v
Max(cm
-1)=3474,3059,2970,2939,1779,1712,1515,1388,1253,1033,823,736,701; MS (electron-bombardment, m/z, relative intensity) 309 (M
+, 66), 149 (100); HRMS (electron-bombardment) C
19H
19NO
3(M
+): calculated value: 309.1365; Measured value: 309.1371.
P10:N-(all trimethylammoniums)-3-phenyl succinimide
N-mesityl-3-phenylpyrrolidine-2，5-dione
Catalyzer is C6 (5mol%); Ethyl acetate/petroleum ether=1/5, v/v; White solid, 78% productive rate;
1HNMR (300MHz, CDCl
3) δ 2.09 (s, 3H), 2.11 (s, 3H), 2.30 (s, 3H), 3.05 (dd, 1H, J
1=5.1Hz, J
2=18.6Hz), 3.43 (dd, 1H, J
1=9.9Hz, J
2=18.6Hz), 4.24 (dd, 1H, J
1=5.1Hz, J
2=9.9Hz), 6.97 (d, 2H, J=4.5Hz), 7.31-7.44 (m, 5H);
13C NMR (75MHz, CDCl
3) δ 17.6,17.8,21.0,37.2,46.2,127.3,127.4,127.9,129.1,129.3,129.3,135.1,135.2,137.0,139.3,175.1,176.4; IR (compressing tablet): v
Max(cm
-1)=3466,3028,2919,1773,1712,1488,1372,1184,863,785,667; MS (electron-bombardment, m/z, relative intensity) 293 (M
+, 30), 161 (100); HRMS (electron-bombardment) C
19H
19NO
2(M
+): calculated value: 293.1416 measured values: 293.1412; M.p.137-138 ℃.
P11：
Catalyzer is C6 (1mol%); Ethyl acetate/petroleum ether=1/3, v/v; White foam shape solid, 92% productive rate 99.9%ee, [chiral column AD-H, hexane/isopropyl alcohol=70/30,1.0mlmin
-1, λ=220nm, t (maximum retention time)=19.67 minute, t (minimum retention time)=15.12 minutes]; [α]
D 20=-46.5 (c1.0, CHCl
3).
1H NMR and
13There is rotational isomer in C NMR demonstration system, and its amount of substance ratio is 2: 1..
1H NMR (300MHz, CDCl
3) δ 1.90-2.18 (m, 2H), 2.78 (AB, 1H, J
AB=17.7Hz), 3.12,3.27 (AB, 1H, J
BA=18.0Hz), 3.60-3.71 (m, 2H), 3.77,3.79 (s, 3H), 5.06-5.18 (m, 2H), 6.62,6.96 (d, 2H, J=9.0Hz), 6.79,7.26 (d, 2H, J=9.0Hz), 7.24-7.34 (m, 5H);
13C NMR (75Hz, CDCl
3) δ: 23.1,23.9,38.2,40.0,41.4,42.4,47.4,48.3,55.3,55.3,64.2,65.1,67.2,68.1,114.1,114.3,123.9,124.5,127.3,127.8,127.8,128.0,128.4,128.5,128.6,128.7,135.1,135.9,153.0,154.1,159.2,159.4,173.1,173.6,177.4,177.7; IR (compressing tablet): v
Max(cm
-1)=2957,2883,2840,1718,1696,1514,1417,1253,1213,1166; MS (electron-bombardment, m/z, relative intensity) 394 (M
+, 27), 91 (100); HRMS (electron-bombardment) calculated value: C
22H
22N
2O
5(M
+): 394.1529 measured values: 394.1535; M.p.107-108 ℃.
P12:N-(p-methoxyphenyl)-4-Phenylpyrrolidine ketone
N-(4-methoxyphenyl)-4-phenylpyrrolidin-2-one
MS (m/z, relative intensity) 267 (M
+, 100), 268 (19), 269 (2).
P13:N-(p-methoxyphenyl)-4-methyl-2-pyrrolidone
N-(4-methoxyphenyl)-4-methylpyrrolidin-2-one
MS (m/z, relative intensity) 205 (M
+, 100), 206 (13)
P14:N-(p-methoxyphenyl)-4-n-pentyl pyrrolidone
N-(4-methoxyphenyl)-4-penthylpyrrolidin-2-one
MS (m/z, relative intensity) 261 (M
+, 100), 262 (18), 263 (2).
Embodiment 3: the reduction of acid amides (application example) in the product
Under argon shield, (0.5mmol is 182.0mg) with tetrahydrofuran (THF) 5mL to add P11 in dry system.After placing ice-water bath to be cooled to 0 ℃ the system, in system, slowly add LiAlH in batches
4(2.5mmol 101.3mg), stirred 30 minutes, removed ice-water bath, recovered room temperature naturally, stirred.The reaction back (TLC follows the tracks of reaction) that finishes, system is cooled to 0 ℃ after, slowly drip distilled water 0.18mL, stir after 30 minutes filtration.Wash solid with ethyl acetate, merge organic phase, dry back column chromatography.Petrol ether/ethyl acetate=3/1,3 ‰ triethylamine), get corresponding reduzate, productive rate 86%.
White solid.99.7%ee, [chiral column OD-H (15cm), hexane/isopropyl alcohol=98/2,0.7mlmin
-1, λ=230nm, t (maximum retention time)=15.71 minute, t (minimum retention time)=13.29 minutes]; [α]
D 20=-18.4 (c 0.82, CHCl
3).
1H NMR (300MHz, CDCl
3) δ 1.68-1.94 (m, 5H), 2.13-2.20 (m, 1H), 2.37 (s, 3H), 2.76-2.83 (m, 2H), 2.97 (d, 1H, J=9.3Hz), 3.21-3.29 (m, 1H), 3.35-3.44 (m, 2H), 3.76 (s, 3H), 6.52 (d, 2H, J=9.0Hz), 6.85 (d, 2H, J=9.6Hz);
13C NMR (75MHz, CDCl
3) 820.8,30.2,34.8,38.3,47.3,53.4,54.4,55.9,69.6,112.3,114.9,142.9,150.8; IR (compressing tablet): v
Max(cm
-1)=2979,2951,2828,2781,1516,1241,1042,814; MS (electron-bombardment, m/z, relative intensity) 246 (M
+, 42), 150 (100) .HRMS (electron-bombardment) C
15H
22NO (M
+): calculated value: 246.1732 measured values: 246.1736; M.p.46-48 ℃.
Claims (5)
1. the method for a synthetic 3-substituted lactan compound, it is characterized in that in the presence of organic solvent and 0 ℃～120 ℃ under, replacing little cyclic amine compound with aldehyde radical is raw material, the N-heterocyclic carbine that generates with aza ring carbene precursor salt and cesium carbonate, potassiumphosphate or alkali effect react the lactam compound that made the replacement of 3-position in 2-36 hour as catalyzer;
The mol ratio that described aldehyde radical replaces little cyclic amine compound, aza ring carbene precursor salt and cesium carbonate, potassiumphosphate or alkali is 1: 0.01-0.2: 0.01-0.2;
The structural formula that described aldehyde radical replaces little cyclic amine compound is
Described aza ring carbene precursor salt has following structural formula:
Described N-heterocyclic carbine has following structural formula:
Described alkali is triethylamine, 1,8-diazabicylo [5,4,0] 11 carbon-7-alkene, 1,5-diazabicylo [4,3,0] ninth of the ten Heavenly Stems-5-alkene, two (trimethyl silicon based) sodium amide, two (trimethyl silicon based) Lithamide, two (trimethyl silicon based) potassium amide, potassium tert.-butoxide, sodium tert-butoxide or diisopropyl ethyl amine;
R wherein
1, R
2Be selected from H, C arbitrarily
1-C
16Alkyl, C
3-C
16Cycloalkyl, amino or amido, alkoxyl group or the halogen atom that replaces; R
3Be selected from the aryl or the C of acyl group, replacement arbitrarily
1-C
16Alkyl;
X be carbonyl or
N=0 or 1;
R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14, R
15, R
16Or R
17Be H, C
1-C
16The aryl of alkyl, aryl or replacement;
Substituting group on the aryl of described replacement is alkyl, alkoxyl group; Substituting group on the amido of described replacement is C
1-C
16Alkyl, aryl or C
5～C
10The Heterocyclylalkyl that contains N, O, S; A
1, A
2, A
3Or A
4Be Cl arbitrarily
-, Br
-, BF
4 -Or ClO
4 -The carbon number of described alkyl, alkoxyl group or acyl group is 1～18; Described aryl is phenyl, C
5～C
10The heterocyclic radical that contains N, O or S.
2. the method for synthetic 3-substituted lactan compound according to claim 1 is characterized in that described 3-substituted lactan compound is an optical purity, and its structure is
Wherein * is a chiral carbon atom, R
1, R
2, R
3With X according to claim 1.
3. the method for synthetic 3-substituted lactan compound according to claim 1 is characterized in that described 3-substituted lactan compound is a raceme, and its structure is
R wherein
1, R
2, R
3With X according to claim 1.
4. the method for synthetic 3-substituted lactan compound as claimed in claim 1 is characterized in that described organic solvent is benzene, tetracol phenixin, sherwood oil, tetrahydrofuran (THF), dimethyl formamide, N,N-DIMETHYLACETAMIDE, ether, methylene dichloride, trichloromethane, toluene, dimethylbenzene, hexanaphthene, normal hexane, normal heptane, dioxane or acetonitrile.
5. the method for synthetic 3-substituted lactan compound as claimed in claim 1 is characterized in that the 3-substituted lactan compound through recrystallization, thin-layer chromatography, and column chromatography or underpressure distillation are separated.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710041247A CN101066945B (en) | 2007-05-25 | 2007-05-25 | Process of synthesizing 3-substituted lactan compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710041247A CN101066945B (en) | 2007-05-25 | 2007-05-25 | Process of synthesizing 3-substituted lactan compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101066945A CN101066945A (en) | 2007-11-07 |
| CN101066945B true CN101066945B (en) | 2010-05-19 |
Family
ID=38879665
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200710041247A Expired - Fee Related CN101066945B (en) | 2007-05-25 | 2007-05-25 | Process of synthesizing 3-substituted lactan compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101066945B (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2011003015A (en) | 2008-09-18 | 2011-11-18 | Univ Northwestern | Nmda receptor modulators and uses thereof. |
| EP2542254B1 (en) | 2010-02-11 | 2018-09-26 | Northwestern University | Nmda receptor agonists and uses thereof |
| KR101692275B1 (en) | 2010-02-11 | 2017-01-04 | 노오쓰웨스턴 유니버시티 | Secondary structure stabilized nmda receptor modulators and uses thereof |
| CN102153557B (en) * | 2011-01-21 | 2013-03-20 | 中国科学院上海有机化学研究所 | Chiral center nitrogen heterocyclic carbine precursor salt with quadrol skeleton, synthetic method and application |
| KR102410989B1 (en) | 2013-01-29 | 2022-06-17 | 앱티닉스 인크. | Spiro-lactam nmda receptor modulators and uses thereof |
| BR112015018095A2 (en) | 2013-01-29 | 2017-07-18 | Naurex Inc | Spiro-lactam nmda receptor modulators and uses thereof |
| ES2935352T3 (en) | 2013-01-29 | 2023-03-06 | Aptinyx Inc | Spiro-lactam NMDA receptor modulators and their uses |
| MX2015009773A (en) | 2013-01-29 | 2016-08-05 | Aptinyx Inc | Spiro-lactam nmda receptor modulators and uses thereof. |
| WO2014120800A1 (en) | 2013-01-29 | 2014-08-07 | Naurex, Inc. | Spiro-lactam nmda receptor modulators and uses thereof |
| WO2017201285A1 (en) | 2016-05-19 | 2017-11-23 | Aptinyx Inc. | Spiro-lactam nmda receptor modulators and uses thereof |
| WO2017201283A1 (en) | 2016-05-19 | 2017-11-23 | Aptinyx Inc. | Spiro-lactam nmda receptor modulators and uses thereof |
| CA3031534C (en) | 2016-08-01 | 2023-10-17 | Aptinyx Inc. | Spiro-lactam nmda receptor modulators and uses thereof |
| BR112019001768A2 (en) | 2016-08-01 | 2019-06-11 | Aptinyx Inc | spiro-lactam receptor modulators and their uses |
| CN109661398B (en) | 2016-08-01 | 2022-07-05 | 阿普廷伊克斯股份有限公司 | Spiro-lactam and di-spiro-lactam NMDA receptor modulators and uses thereof |
| ES2973283T3 (en) | 2016-08-01 | 2024-06-19 | Tenacia Biotechnology Hong Kong Co Ltd | Spirolactam NMDA receptor modulators and uses thereof |
| AU2017306164B2 (en) | 2016-08-01 | 2021-10-21 | Aptinyx Inc. | Spiro-lactam NMDA modulators and methods of using same |
| CN106916093B (en) * | 2017-02-23 | 2019-07-09 | 福州大学 | A kind of method that N-heterocyclic carbine catalyzes and synthesizes polysubstituted pyrrole alkane ketone compounds |
| WO2019152687A1 (en) | 2018-01-31 | 2019-08-08 | Aptinyx Inc. | Spiro-lactam nmda receptor modulators and uses thereof |
| US12012413B2 (en) | 2019-11-11 | 2024-06-18 | Tenacia Biotechnology (Hong Kong) Co., Limited | Methods of treating painful diabetic peripheral neuropathy |
-
2007
- 2007-05-25 CN CN200710041247A patent/CN101066945B/en not_active Expired - Fee Related
Non-Patent Citations (4)
| Title |
|---|
| Benito Alcaide, et al..Organocatalytic Ring Expansion of β-Lactams to γ-Lactams through a Novel N1-C4 Bond Cleavage. DirectSynthesis ofEnantiopure Succinimide Derivatives.Org. Lett.7 18.2005,7(18),3981-3984. |
| Benito Alcaide,et al..Organocatalytic Ring Expansion of β-Lactams to γ-Lactams through a Novel N1-C4 Bond Cleavage.DirectSynthesis ofEnantiopure Succinimide Derivatives.Org. Lett.7 18.2005,7(18),3981-3984. * |
| Ming He, et al..Catalytic Synthesis of γ-Lactams via Direct Annulations ofEnals and N-Sulfonylimines.Org. Lett.7 14.2005,7(14),3131-3134. |
| Ming He,et al..Catalytic Synthesis of γ-Lactams via Direct Annulations ofEnals and N-Sulfonylimines.Org. Lett.7 14.2005,7(14),3131-3134. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101066945A (en) | 2007-11-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101066945B (en) | Process of synthesizing 3-substituted lactan compound | |
| CN101125817B (en) | Method for synthesizing aldehyde substituted small ring amines compounds with high enantioselectivity and 3-substituted lactams compounds with optical activity | |
| Chen et al. | Formal [4+ 1] annulation reactions in the synthesis of carbocyclic and heterocyclic systems | |
| Ganesh et al. | Catalytic enantioselective additions of indoles to nitroalkenes | |
| Chen et al. | Copper-catalyzed N-alkynylations of sulfoximines with bromoacetylenes | |
| Yu et al. | A highly efficient asymmetric Michael addition of α, α-disubstituted aldehydes to maleimides catalyzed by primary amine thiourea salt | |
| Parmar et al. | Complete field guide to asymmetric BINOL-phosphate derived Brønsted acid and metal catalysis: history and classification by mode of activation; Brønsted acidity, hydrogen bonding, ion pairing, and metal phosphates | |
| Jiang et al. | Enantio-and diastereoselective asymmetric addition of 1, 3-dicarbonyl compounds to nitroalkenes in a doubly stereocontrolled manner catalyzed by bifunctional rosin-derived amine thiourea catalysts | |
| Liu et al. | Asymmetric Aza-Mannich Addition of Oxazolones to N-Tosyl Aldimines: Synthesis of Chiral α-Disubstituted α, β-Diamino Acids | |
| Matlock et al. | Synthesis of α-substituted vinylsulfonium salts and their application as annulation reagents in the formation of epoxide-and cyclopropane-fused heterocycles | |
| Zhang et al. | Group-assisted purification chemistry for asymmetric mannich-type reaction of chiral N-phosphonyl imines with azlactones leading to syntheses of α-quaternary α, β-diamino acid derivatives | |
| Ma et al. | Studies on Pd (II)-Catalyzed Coupling− Cyclization of α-or β-Amino Allenes with Allylic Halides | |
| Pirali et al. | Ammonium chloride promoted three-component synthesis of 5-iminooxazoline and its subsequent transformation to macrocyclodepsipeptide | |
| Yao et al. | N, N′-Dioxide/gadolinium (III)-catalyzed asymmetric conjugate addition of nitroalkanes to α, β-unsaturated pyrazolamides | |
| Li et al. | Divergent synthesis of enantioenriched β-functional amines via desymmetrization of meso-aziridines with isocyanides | |
| Ranieri et al. | Diastereo-and enantioselective catalytic vinylogous Mukaiyama-Mannich reactions of pyrrole-based silyl dienolates with alkyl-substituted aldehydes | |
| Alonso et al. | Using heteroaryl-lithium reagents as hydroxycarbonyl anion equivalents in conjugate addition reactions with (S, S)-(+)-pseudoephedrine as chiral auxiliary; enantioselective synthesis of 3-substituted pyrrolidines | |
| Bolchi et al. | One-pot racemization process of 1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline: A key intermediate for the antimuscarinic agent solifenacin | |
| Mandal et al. | Synthesis of β-lactams through alkyne–nitrone cycloadditions | |
| Hu et al. | Chiral bifunctional ferrocenylphosphine catalyzed highly enantioselective [3+ 2] cycloaddition reaction | |
| Zhou et al. | N-Heterocyclic carbene-promoted [4+ 2] annulation of α-chloro hydrazones with α-chloro aliphatic aldehydes to access enantioenriched dihydropyridazinones | |
| Sharma et al. | Direct access to the optically active VAChT inhibitor vesamicol and its analogues via the asymmetric aminolysis of meso-epoxides with secondary aliphatic amines | |
| Hou et al. | Asymmetric synthesis of oxindole-derived vicinal tetrasubstituted acyclic amino acid derivatives by the Mannich-type reaction | |
| Ooi et al. | Asymmetric Synthesis of α‐Acyl‐γ‐butyrolactones Possessing All‐Carbon Quaternary Stereocenters by Phase‐Transfer‐Catalyzed Alkylation | |
| Fan et al. | Cu (I)-catalyzed asymmetric Mannich reaction of glycine Schiff bases to ketimines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100519 Termination date: 20140525 |