CN101979378A - Method for synthesizing chiral gamma-lactam compounds - Google Patents
Method for synthesizing chiral gamma-lactam compounds Download PDFInfo
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Abstract
The invention discloses a method for synthesizing chiral gamma-lactam compounds by using rhodium catalyzed asymmetric addition reaction technology. The method comprises that: a compound 1, an organic boric acid compound, a chiral olefin ligand, a rhodium catalyst precursor and an additive undergo asymmetric catalyzed addition reaction for 0.5 to 48 hours at the temperature of between 40 and 90 DEG C in a mixed solvent consisting of organic solvent and water, wherein the reaction has the following general formula. The method for synthesizing a series of gamma-lactam compounds with high optical activity in one step by using the rhodium catalyzed asymmetric addition reaction technology has the advantages of short reaction step, high yield and good selectivity; and the reaction products can be synthesized into a series of medicinal intermediates with important bioactivity by simple transformation.
Description
Technical field
The present invention relates to the synthetic method of the gamma-lactam compound of a series of high-optical-purities, specifically, relate to a kind of method of utilizing the gamma-lactam compound of the catalytic asymmetric reduction reaction technology of rhodium synthesis of chiral.
Background technology
Gamma-lactam is compared with the beta-lactam structure, seldom exists at occurring in nature, but but is the important structure fragment of many drug molecules or bioactive molecules.As rolipram (rolipram) is the inhibitor of phosphodiesterase IN (PDE IV), can be used for dysthymia disorders, its antidepressant effect and tolerance all are better than tricyclic antidepressant, and do not have anticholinergic and imitate, and severe, slight or atypia patients with depression are all had better curative effect and security.Meanwhile, gamma-lactam is again the important as precursors of synthetic γ-An Jidingsuan.It is to study comparatively deep a kind of important inhibitory nerve mediator at present that γ-An Jidingsuan (GABA) is distributed widely in the animal and plant body, participate in multiple Metabolic activity, have very high physiologically active, many γ-An Jidingsuan compounds all are important drug molecules.Reflection current potential as between root behind baclofen (Baclofen) reduction spinal cord list cynapse or multisynaptic reflection current potential and the spinal cord and back root produces the skeletal muscle relaxation effect, is important clinically skeletal muscle relaxation medicine.Therefore, for synthesizing of gamma-lactam compound, especially chirality is synthetic, enjoys chemists' concern all the time.
Organometallic reagent is the methods of synthesizing the gamma-lactam of 4 replacements of a class very effectively to the addition of unsaturated five membered lactams, can efficiently synthesize as important drug molecules such as rolipram and baclofens.But above-mentioned research just reported that by people such as He employing chiral phosphine ligand rhodium complex has carried out corresponding research up to 2006, but the productive rate and the selectivity all not ideal enough (WO 2006081562A2) of reaction.This may be because five membered lactams structure-activities are lower, and usually pentacyclic addition reaction is obtained high enantioselectivity relatively due to the difficulty.In recent years, the appearance of chirality diene ligand, in many transition-metal catalysis, embodied special advantages, especially in the catalytic asymmetric reaction of some rhodiums, have higher reactive behavior and selectivity than conventional chiral phosphine ligand, but utilize this novel chiral part synthesis of chiral gamma-lactam compound, do not see relevant report so far.
Summary of the invention
The purpose of this invention is to provide a kind of method of utilizing the catalytic asymmetric reduction reaction technology of rhodium synthesis of chiral gamma-lactam compound, to obtain the gamma-lactam compound of a series of high optical activities, satisfy the preparation demand of the key intermediate of a series of chiral drugs.
The synthetic method of chirality gamma-lactam compound provided by the invention, be by compound 1 and organic boronic compound, chiral olefin part, rhodium catalyst precursor and additive, in the mixed solvent of organic solvent and water composition, carried out the asymmetry catalysis addition reaction 0.5～48 hour at 40～90 ℃, its reaction expression is as follows:
Described organic boronic compound is selected from down a kind of in the array structure:
Described chiral olefin part has following structure:
Described rhodium catalyst precursor is the monovalence rhodium complex;
Described additive is organic bases, mineral alkali or mineral acid;
Described organic solvent is halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent, ketones solvent or alcoholic solvent;
Wherein:
R
1=C
1-6Alkyl, C
3-6Cycloalkyl, R
3Or R
4The phenyl, the R that replace
5The thiazolinyl that replaces, heteroaryl, phenyl ring are by R
6The benzyl, C (O) R that replace
7Perhaps C (O) OR
8
R
2=R
3Or R
4The phenyl, heteroaryl, 1-naphthyl or the 2-naphthyl that replace;
R
3Or R
4=H, C
1-6Alkyl, C
1-6Alkoxyl group, trifluoromethyl, nitro, cyano group or halogen;
R
5=C
1-6Alkyl or benzyl;
R
6=H, C
1-6Alkyl or C
1-6Alkoxyl group;
R
7Or R
8=C
1-6Alkyl, C
3-6Cycloalkyl or phenyl ring are by R
6The benzyl that replaces;
R
9=R
10Or R
11The phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, benzyl, perfluorinated sulfonic acid base or the diarylphosphino that replace;
R
10Or R
11=H, C
1-6Alkyl, C
1-6Alkoxyl group, trifluoromethyl, nitro, cyano group or halogen.
The preferred monovalence monoolefine of described rhodium catalyst precursor rhodium complex, monoolefine wherein is preferably ethene, cyclopentenes, tetrahydrobenzene or cyclooctene, for example: [RhCl (C
2H
4)
2]
2, [Rh (OH) (C
2H
4)
2]
2Perhaps [Rh (CH
3COO) (C
2H
4)
2]
2Deng.
The preferred triethylamine of described organic bases (TEA), nitrogen methylmorpholine (NMP), diisopropyl ethyl amine or pyridine.
The preferred sodium hydride of described mineral alkali, sodium hydroxide, potassium hydroxide, Potassium monofluoride or potassiumphosphate.
The preferred fluorine potassium cyanide of described mineral acid.
Described organic solvent is preferably methylene dichloride, 1,2-ethylene dichloride chloroform, toluene, tetrahydrofuran (THF), 1,4-dioxane or acetone.
Described mixed solvent is 0～1 by organic solvent and water by volume: 1 forms.
The preferred F of described halogen, Cl or Br.
The preferred furyl of described heteroaryl, thienyl or pyridyl.
Preferred 50～60 ℃ of the temperature of described asymmetry catalysis addition reaction, preferred 5～10 hours of reaction times.
Mol ratio between described compound 1 and organic boronic compound, rhodium catalyst precursor, chiral olefin part and additive is preferably 1: 1.5～and 3: 0.01～0.05: 0.01～0.05: 0.5～3.
The structural formula of described chirality gamma-lactam compound is:
Compared with prior art, the beneficial effect that has of the present invention is as follows:
Realized utilizing the catalytic asymmetric reduction reaction technology of rhodium first, one-step synthesis obtains the gamma-lactam compound of a series of high optical activities, reactions steps is short, the productive rate height, selectivity is good, and reaction product just can be used for synthetic a series of active medicine intermediates of important biomolecule that have by simple conversion.
Specific implementation method
Below by embodiment in detail the present invention is described in detail, but the present invention is not limited to following embodiment.
Embodiment 1～4
Under argon shield, add R
1The compound 1 (0.2mmol) of=Boc (tertbutyloxycarbonyl), phenyl-boron dihydroxide (0.4mmol), 1.2mg rhodium catalyst precursor [RhCl (C
2H
4)
2]
2(0.0045mmol), 1.6mg chiral olefin ligand L 1*, 2ml toluene stirs 15min under the room temperature; Add the KHF that the 0.2ml volumetric molar concentration is 4mol/L again
2The aqueous solution carries out stirring reaction by the temperature shown in the table 1; When TLC monitoring [developping agent: ethyl acetate/petroleum ether=1/4; The colour developing mode: iodine dyes] after reaction finished, with ethyl acetate extraction three times, organic phase was washed with saturated nacl aqueous solution, the anhydrous sodium sulphate solid drying; At 40 ℃ of concentrating under reduced pressure, column chromatography (PE/EA=6/1, wash-out), the white solid that obtains are chirality gamma-lactam compound-(R)-1-tertbutyloxycarbonyl-4-phenyl-2-Pyrrolidone (2a):
[α]
D 27-5.6(c?0.83CHCl
3)for?98.2％ee；
1H?NMR(400MHz，CDCl
3)：δ1.54(s，9H)，2.72(dd，J＝10Hz，17.6Hz，1H)，2.90(dd，J＝8.4Hz，17.2Hz，1H)，3.49-3.58(m，1H)，3.69(dd，J＝8.4Hz，10.0Hz，1H)，4.16(dd，J＝8.4Hz，10.4Hz，1H)，7.24-7.30(m，3H)，7.34-7.38(m，2H)；
13C?NMR(100MHz，CDCl
3)：628.00，36.38，40.27，53.08，83.01，126.72，127.40，128，96，140.57，149.88，172.94；
EI-MS?m/z(％)：261(2.62，M
+)，206(51.68)，188(22.00)，162(23.42)，161(33.19)，104(100)，103(20.69)，57(84.60)，41(24.69)；
HRMS(EI)calcd?for?C
15H
19NO
3261.1365，found?261.1369；
HPLC：Chiracel?OJ-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝80/20；flow＝0.7mL/min；Retention?time：10.7min(S)，12.3min(R)。
Annotate:
Used R
1The synthetic method of the compound 1 of=Boc (tertbutyloxycarbonyl) is illustrated in [Tetrahedron-Asymmetry] 1992,3,1035;
Used phenyl-boron dihydroxide and rhodium catalyst precursor [RhCl (C
2H
4)
2]
2Be to buy and get from Aldrich company;
The structural formula of used chiral olefin ligand L 1* is as follows:
Table 1 differential responses temperature is to the influence of the method for the invention
| Embodiment | Temperature of reaction (℃) | Reaction times (hour) | Productive rate (%) | Ee value (%) |
| 1 | 60 | 6 | 99 | 97 |
| 2 | 50 | 10 | 99 | 97 |
| 3 | 40 | 24 | 52 | 97 |
| 4 | Room temperature | 24 | ＜10 | 97 |
By table 1 result as seen: when temperature of reaction was 50～60 ℃, the reaction times only needed 6～10 hours, can make productive rate reach 99%, and the ee value reaches 97%.
Embodiment 5～9
Organic solvent-toluene among the embodiment 1 is replaced with the organic solvent shown in the table 2, and all the other contents are investigated the influence of different organic solvents to the method for the invention with embodiment 1.
Table 2 different organic solvents is to the influence of the method for the invention
| Embodiment | Organic solvent | Reaction times (hour) | Productive rate (%) | Ee value (%) |
| 1 | Toluene | 6 | 99 | 97 |
| 5 | Tetrahydrofuran (THF) | 10 | 99 | 98 |
| 6 | 1, the 4-dioxane | 8 | 99 | 98 |
| 7 | Methylene dichloride | 24 | 81 | 96 |
| 8 | 1, the 2-ethylene dichloride | 24 | 87 | 96 |
| 9 | Acetone | 24 | 79 | 97 |
By table 2 result as seen: when organic solvent is toluene, tetrahydrofuran (THF) or 1, during the 4-dioxane, the reaction times only needs 6～10 hours, can make productive rate reach 99%, and the ee value reaches 97%～98%.
Embodiment 10～14
With the additive-KHF among the embodiment 1
2Replace with the additive shown in the table 3, all the other contents are investigated the influence of different additive to the method for the invention with embodiment 1.
Table 3 different additive is to the influence of the method for the invention
| Embodiment | Additive | Reaction times (hour) | Productive rate (%) | Ee value (%) |
| 1 | KHF 2 | 6 | 99 | 97 |
| 10 | K 3PO 4 | 24 | 65 | 81 |
| 11 | KOH | 24 | 58 | 71 |
| 12 | KF | 6 | 98 | 95 |
| 13 | Et 3N | 6 | 99 | 98 |
| 14 | DIPEA | 8 | 98 | 98 |
By table 3 result as seen: when additive is KHF
2, KF, Et
3When N or DIPEA, the reaction times only needs 6～8 hours, can make productive rate reach 98%～99%, and the ee value reaches 95%～98%.
Embodiment 15～24
With the chiral olefin ligand L 1 among the embodiment 1
*Replace with the chiral olefin part shown in the table 4, all the other contents are investigated the influence of different chiral olefin parts to the method for the invention with embodiment 1.
The different chiral olefin parts of table 4 are to the influence of the method for the invention
| Embodiment | The chiral olefin part | Reaction times (hour) | Productive rate (%) | Ee value (%) |
| 1 | L1 * | 6 | 99 | 97 |
| 15 | L2 * | 5 | 99 | 69 |
| 16 | L3 * | 5 | 99 | 96 |
| 17 | L4 * | 5 | 99 | 94 |
| 18 | L5 * | 6 | 99 | 96 |
| 19 | L6 * | 24 | 40 | 94 |
| 20 | L7 * | 8 | 99 | 88 |
| 21 | L8 * | 6 | 98 | 96 |
By table 4 result as seen: when the chiral olefin part is L1
*, L3
*, L4
*, L5
*Or L8
*The time, the reaction times only needs 5～6 hours, can make productive rate reach 98%～99%, and the ee value reaches 94%～97%.
Used chiral olefin ligand L
*Structural formula as follows:
Annotate: the synthetic method of above-mentioned chiral olefin part is illustrated in [J.Am.Chem.Soc] 2007,129,5336.
Embodiment 25～40
The phenyl of the phenyl-boron dihydroxide among the embodiment 1 is replaced with the substituting group shown in the table 5, and all the other contents are investigated the influence of different organic boronic compounds to the method for the invention with reference to embodiment 1.
The different organic boronic compounds of table 5 are to the influence of the method for the invention
I wherein is:
Annotate: the synthetic method of above-mentioned organic boronic compound is illustrated in [Tetrahedron] 2006,62,4907.
(R)-1-tertbutyloxycarbonyl-4-p-methoxyphenyl-2-Pyrrolidone (2b):
[α]
D 27-0.4(c?0.89CHCl
3)for?98.0％ee；
1H?NMR(400MHz，CDCl
3)：δ1.53(s，9H)，2.67(dd，J＝10.4Hz，17.2Hz，1H)，2.87(dd，J＝8Hz，16.8Hz，1H)，3.44-3.53(m，1H)，3.64(dd，J＝8.8Hz，10.4Hz，1H)，3.8(s，3H)，4.13(dd，J＝8Hz，10.4Hz，1H)，6.89(d，J＝8.8Hz，2H)，7.16(d，J＝8.4Hz，2H)；
13C?NMR(100MHz，CDCl
3)：δ27.94，35.66，40.40，53.27，55.23，82.87，114.27，127.68，132.44，149.84，158.79，173.05；
EI-MS?m/z(％)：291(3.70，M
+)，191(35.73)，134(100)，57(28.09)；
HRMS(EI)calcd?for?C
16H
21NO
4291.1471，found?291.1465；
HPLC：Chiracel?OJ-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝80/20；flow＝0.7mL/min；Retention?time：17.4min(S)，20.5min(R)。
(R)-1-tertbutyloxycarbonyl-4-p-methylphenyl-2-Pyrrolidone (2c):
[α]
D 27-1.3(c?0.95CHCl
3)for?98.3％ee；
1H?NMR(400MHz，CDCl
3)：δ1.53(s，9H)，2.34(s，3H)，2.69(dd，J＝10.0Hz，17.6Hz，1H)，2.87(dd，J＝8.8Hz，17.6Hz，1H)，3.45-3.54(m，1H)，3.66(dd，J＝8.8Hz，10.4Hz，1H)，4.13(dd，J＝8.4Hz，10.8Hz，1H)，7.12-7.18(m，4H)；
13C?NMR(100MHz，CDCl
3)：δ20.91，27.95，36.01，40.32，53.18，82.89，126.56，129.55，137.04，137.48，149.85，173.06；
EI-MS?m/z(％)：275(12.98，M
+)，175(43.17)，118(100)，117(39.81)，57(48.02)；
HRMS(EI)calcd?for?C
16H
21NO
3275.1521，found?275.1523；
HPLC：Chiracel?OD-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝90/10；flow＝0.7mL/min；Retention?time：17.3min(R)，19.5min(S)。
(R)-1-tertbutyloxycarbonyl-4-m-methoxyphenyl-2-Pyrrolidone (2d):
[α]
D 27-3.5(c?0.91CHCl
3)for?97.8％ee；
1H?NMR(400MHz，CDCl
3)：δ1.54(s，9H)，2.71(dd，J＝10Hz，17.2Hz，1H)，2.88(dd，J＝8.8Hz，17.6Hz，1H)，3.46-3.55(m，1H)，3.68(dd，J＝8.8Hz，10.4Hz，1H)，3.81(s，3H)，4.15(dd，J＝8.4Hz，10.8Hz，1H)，6.77-6.84(m，3H)，7.26-7.30(m，1H)；
13C?NMR(100MHz，CDCl
3)：δ27.93，36.29，40.12，52.91，55.15，82.92，112.27，112.88，118.84，129.96，142.11，149.78，159.94，172.85；
EI-MS?m/z(％)：291(30.69，M
+)，191(56.99)，134(100)，57(49.23)；
HRMS(EI)calcd?for?C
16H
21NO
4291.1471，found?291.1470；
HPLC：Chiracel?OJ-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝80/20；
flow＝0.7mL/min；Retention?time：14.1min(S)，16.5min(R)。
(R)-1-tertbutyloxycarbonyl-4-between aminomethyl phenyl-2-Pyrrolidone (2e):
[α]
D 27-4.8(c?0.90CHCl
3)for?98.2％ee；
1HNMR(400MHz，CDCl
3)：δ1.54(s，9H)，2.36(s，3H)，2.71(dd，J＝10Hz，17.2Hz，1H)，2.88(dd，J＝8.4Hz，17.2Hz，1H)，3.45-3.54(m，1H)，3.68(dd，J＝8.4Hz，10.4Hz，1H)，4.14(dd，J＝8.0Hz，10.8Hz，1H)，7.03-7.11(m，3H)，7.23-7.26(m，1H)；
13C?NMR(100MHz，CDCl
3)：δ21.31，27.92，36.22，40.20，53.06，82.86，123.66，127.40，128.04，128.76，138.57，140.46，149.80，173.00；
EI-MS?m/z(％)：275(11.97，M
+)，175(44.15)，118(100)，117(37.35)，57(56.05)；
HRMS(EI)calcd?for?C
16H
21NO
3275.1521，found?275.1523；
HPLC：Chiracel?OJ-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝80/20；flow＝0.7mL/min；Retention?time：8.8min(S)，9.6min(R)。
(R)-1-tertbutyloxycarbonyl-4-o-methoxyphenyl-2-Pyrrolidone (2f):
[α]
D 27-25.0(c?0.85CHCl
3)for?99.1％ee；
1H?NMR(400MHz，CDCl
3)：δ1.53(s，9H)，2.80-2.83(m，2H)，3.69-3.77(m，2H)，3.84(s，3H)，4.08-4.12(m，1H)，6.89-6.96(m，2H)，7.15-7.17(m，1H)，7.25-7.29(m，1H)；
13C?NMR(100MHz，CDCl
3)：δ27.99，31.63，38.60，51.71，55.21，82.71，110.73，120.67，127.39，128.45，128.55，150.11，157.37，173.81；
EI-MS?m/z(％)：291(12.20，M
+)，219(21.97)，134(56.00)，118(62.77)，117(42.48)，91(38.70)，57(100)；
HRMS(EI)calcd?for?C
16H
21NO
4291.1471，found?291.1476；
HPLC：Chiracel?OJ-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝80/20；flow＝0.7mL/min；Retention?time：10.0min(S)，11.9min(R)。
(R)-1-tertbutyloxycarbonyl-4-o-methyl-phenyl--2-Pyrrolidone (2g):
[α]
D 27-16.7(c?0.88CHCl
3)for?99.2％ee；
1H?NMR(400MHz，CDCl
3)：δ1.54(s，9H)，2.36(s，3H)，2.69(dd，J＝8.8Hz，17.2Hz，1H)，2.88(dd，J＝8.0Hz，17.2Hz，1H)，3.68-3.78(m，2H)，4.10(dd，J＝7.2Hz，10.0Hz，1H)，7.18-7.24(m，4H)；
13C?NMR(100MHz，CDCl
3)：δ19.51，27.90，32.11，39.71，52.33，82.88，124.83，126.61，127.04，130.69，135.77，138.71，149.83，172.99；
EI-MS?m/z(％)：275(0.32，M
+)，219(44.24)，118(82.85)，117(49.99)，57(100)；
HRMS(EI)calcd?for?C
16H
21NO
3275.1521，found?275.1527；
HPLC：Chiracel?OD-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝90/10；flow＝0.7mL/min；Retention?time：16.3min(S)，17.9min(R)。
(R)-1-tertbutyloxycarbonyl-4-(1-naphthyl)-2-Pyrrolidone (2h):
[α]
D 27-76.2(c?0.88CHCl
3)?for?99.4％ee；
1H?NMR(400MHz，CDCl
3)：δ1.53(s，9H)，2.90(dd，J＝7.2Hz，17.2Hz，1H)，3.05(dd，J＝8.8Hz，17.6Hz，1H)，3.83-3.89(m，1H)，4.27-4.33(m，2H)，7.40-7.59(m，4H)，7.80(d，J＝8.4Hz，1H)，7.90(d，J＝8.0Hz，1H)，7.99(d，J＝8.4Hz，1H)；
13C?NMR(100MHz，CDCl
3)：δ28.07，31.92，39.70，52.53，83.18，122.59，125.55，125.98，126.64，128.09，129.29，131.36，134.13，136.35，150.07，173.04；
EI-MS?m/z(％)：311(20.86，M
+)，211(45.60)，154(100)，153(56.17)，152(28.85)，134(22.02)，57(29.37)；
HRMS(EI)calcd?for?C
19H
21NO
3311.1521，found?311.1528；
HPLC：Chiracel?OJ-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝80/20；flow＝0.7mL/min；Retention?time：17.4min(S)，18.4min(R)。
(R)-1-tertbutyloxycarbonyl-4-(2-naphthyl)-2-Pyrrolidone (2i):
[α]
D 26+4.6(c?0.89CHCl
3)for?97.8％ee；
1H?NMR(400MHz，CDCl
3)：δ1.55(s，9H)，2.83(dd，J＝9.6Hz，17.2Hz，1H)，2.98(dd，J＝8.4Hz，17.2Hz，1H)，3.68-3.74(m，1H)，3.80(dd，J＝8.0Hz，10.0Hz，1H)，4.23(dd，J＝8.4Hz，10.4Hz，1H)，7.35-7.37(m，1H)，7.46-7.52(m，2H)，7.67(s，1H)，7.79-7.86(m，3H)；
13C?NMR(100MHz，CDCl
3)：δ28.00，36.42，40.18，52.99，83.05，124.68，125.36，126.04，126.50，127.63，128.87，128.87，132.57，133.36，137.90，149.91，172.92；
EI-MS?m/z(％)：311(21.66，M
+)，211(42.60)，154(100)，153(25.57)；
HRMS(EI)calcd?for?C
19H
21NO
3311.1521，found?311.1516；
HPLC：Chiracel?OJ-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝80/20；flow＝0.7mL/min；Retention?time：28.7min(S)，33.5min(R)。
(R)-1-tertbutyloxycarbonyl-4-(3-cyclopentyloxy-4 p-methoxy-phenyl)-2-Pyrrolidone (2j):
[α]
D 26-3.6(c?0.89CHCl
3)for?97.4％ee，After?recrystallization，[α]
D 26-4.1(c?1.00CHCl
3)for99.3％ee，[lit.：[α]
D 25-4.6(c?1.00，CHCl
3)for?98％ee?in?the?R-isomer；J.Am.Chem.Soc.2002，13394.]；
1H?NMR(400MHz，CDCl
3)：δ1.54(s，9H)，1.57-1.63(m，2H)，1.81-1.96(m，6H)，2.67(dd，J＝9.6Hz，17.2Hz，1H)，2.87(dd，J＝8.4Hz，172Hz，1H)，3.41-3.49(m，1H)，3.65(dd，J＝8.8Hz，10.8Hz，1H)，3.83(s，3H)，4.12(dd，J＝8.0Hz，10.4Hz，1H)，4.74-4.77(m，1H)，6.74-6.77(m，2H)，6.83-6.85(m，1H)；
13C?NMR(100MHz，CDCl
3)：δ23.89，27.93，32.70，35.98，40.46，53.28，56.06，80.57，82.91，112.29，113.73，118.71，132.96，147.93，149.36，149.86，173.05；
EI-MS?m/z(％)：375(5.23，M
+)，207(86.59)，150(100)，134(30.30)，124(59.34)，109(27.13)，57(31.72)，41(40.25)；
HRMS(EI)calcd?for?C
21H
29NO
5375.2046，found?375.2045；
HPLC：Chiracel?OD-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝80/20；flow＝0.7mL/min；Retention?time：19.5min(R)，26.0min(S)。
(R)-1-tertbutyloxycarbonyl-4-p-trifluoromethyl phenyl-2-Pyrrolidone (2k):
[α]
D 26-1.1(c?0.93CHCl
3)for?97.2％ee；
1H?NMR(400MHz，CDCl
3)：δ1.54(s，9H)，2.71(dd，J＝9.6Hz，17.6Hz，1H)，2.94(dd，J＝8.8Hz，17.6Hz，1H)，3.56-3.65(m，1H)，3.71(dd，J＝8.0Hz，10.8Hz，1H)，4.19(dd，J＝8.0Hz，10.4Hz，1H)，7.37(d，J＝8.0Hz，2H)，7.62(d，J＝8.4Hz，2H)；
13C?NMR(100MHz，CDCl
3)：δ28.03，36.20，40.06，52.69，83.36，122.62，125.33，126.02，127.21，129.90，144.78，149.82，172.23；
ESI-MS：352.0[M+Na]
+；
HRMS(ESI)calcd?for?C
16H
18F
3NO
3Na
+，352.1131，found?352.1128；
HPLC：Chiracel?OJ-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝80/20；flow＝0.7mL/min；Retention?time：10.2min(S)，13.2min(R)。
(R)-1-tertbutyloxycarbonyl-4-is to fluorophenyl-2-Pyrrolidone (2l):
[α]
D 26-5.7(c?0.95CHCl
3)for?96.8％ee；
1H?NMR(400MHz，CDCl
3)：δ1.54(s，9H)，2.67(dd，J＝10.0Hz，17.6Hz，1H)，2.89(dd，J＝8.4Hz，17.2Hz，1H)，3.48-3.57(m，1H)，3.65(dd，J＝8.4Hz，10.8Hz，1H)，4.15(dd，J＝8.0Hz，10.8Hz，1H)，7.03-7.07(m，2H)，7.19-7.23(m，2H)；
13C?NMR(100MHz，CDCl
3)：δ27.96，35.69，40.33，53.07，83.08，115.67，115.88，128.21，128.29，136.27，149.79，161.95，172.65；
EI-MS?m/z(％)：279(2.85，M
+)，195(32.90)，179(43.87)，138(87.39)，135(96.21)，122(100)，95(39.92)，91(40.93)；
HRMS(EI)calcd?for?C
15H
18FNO
3279.1271，found?279.1264；
HPLC：Chiracel?OJ-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝80/20；flow＝0.7mL/min；Retention?time：12.8min(S)，14.9min(R)。
(R)-1-tertbutyloxycarbonyl-4-rubigan-2-Pyrrolidone (2m):
[α]
D 27+1.2(c?0.94CHCl
3)for?97.0％ee；After?recrystallization，[α]
D 26+1.7(c?1.00CHCl
3)for?99.4％ee；
1H?NMR(400MHz，CDCl
3)：δ1.54(s，9H)，2.66(dd，J＝10.0Hz，17.6Hz，1H)，2.89(dd，J＝8.4Hz，17.2Hz，1H)，3.47-3.56(m，1H)，3.65(dd，J＝8.4Hz，10.8Hz，1H)，4.15(dd，J＝8.0Hz，10.8Hz，1H)，7.18(d，J＝8.4Hz，2H)，7.33(d，J＝8.4Hz，2H)；
13C?NMR(100MHz，CDCl
3)：δ28.02，35.83，40.20，52.92，83.22，128.11，129.14，133.27，139.11，149.83，172.54；
EI-MS?m/z(％)：295(6.23，M
+)，240(20.02)，195(39.35)，138(91.43)，103(24.85)，57(100)，41(28.20)；
HRMS(EI)calcd?for?C
15H
18C1NO
3295.0975，found?295.0977；
HPLC：Chiracel?OJ-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝80/20；flow＝0.7mL/min；Retention?time：15.2min(S)，18.9min(R)。
(R)-1-tertbutyloxycarbonyl-4-is to bromophenyl-2-Pyrrolidone (2n):
[α]
D 26+3.2(c?0.92CHCl
3)for?97.2％ee；
1H?NMR(400MHz，CDCl
3)：δ1.54(s，9H)，2.66(dd，J＝9.6Hz，17.2Hz，1H)，2.89(dd，J＝8.4Hz，17.2Hz，1H)，3.46-3.54(m，1H)，3.65(dd，J＝8.4Hz，10.8Hz，1H)，4.15(dd，J＝8.0Hz，10.8Hz，1H)，7.12(d，J＝8.4Hz，2H)，7.48(d，J＝8.4Hz，2H)；
13C?NMR(100MHz，CDCl
3)：δ27.99，35.86，40.11，52.81，83.19，121.24，128.45，132.07，139.64，149.79，172.49；
EI-MS?m/z(％)：339(9.61，M
+)，258(36.38)，241(38.23)，239(38.09)，184(74.08)，182(74.08)，103(32.40)，57(100)，41(34.08)；
HRMS(EI)calcd?for?C
15H
18BrNO
3339.0470，found?339.0468；
HPLC：Chiracel?OJ-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝80/20；flow＝0.7mL/min；Retention?time：17.4min(S)，23.0min(R)。
(R)-1-tertbutyloxycarbonyl-4-between chloro-phenyl--2-Pyrrolidone (2o):
[α]
D 27-2.9(c?0.94CHCl
3)for?93.2％ee；
1H?NMR(400MHz，CDCl
3)：δ1.54(s，9H)，2.68(dd，J＝9.6Hz，17.2Hz，1H)，2.90(dd，J＝8.4Hz，17.2Hz，1H)，3.47-3.56(m，1H)，3.68(dd，J＝8.4Hz，10.4Hz，1H)，4.16(dd，J＝8.4Hz，10.8Hz，1H)，7.12-7.14(m，1H)，7.23-7.32(m，3H)；
13C?NMR(100MHz，CDCl
3)：δ28.00，36.06，40.04，52.73，83.23，124.89，127.08，127.64，130.28，134.82，142.64，149.77，172.41；
EI-MS?m/z(％)：295(2.65，M
+)，195(48.50)，140(29.98)，138(100)，135(57.24)，103(32.23)，77(23.47)，41(28.21)；
HRMS(EI)calcd?for?C
15H
18ClNO
3295.0975，found?295.0978；
HPLC：Chiracel?OJ-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝80/20；flow＝0.7mL/min；Retention?time：12.3min(S)，14.7min(R)。
(R, E)-1-tertbutyloxycarbonyl-4-(2-phenyl vinyl)-2-Pyrrolidone (2p):
1H?NMR(400MHz，CDCl
3)：δ1.54(s，9H)，2.49(dd，J＝8.8Hz，16.8Hz，1H)，2.73(dd，J＝8.4Hz，17.6Hz，1H)，3.08-3.18(m，1H)，3.54(dd，J＝8.0Hz，10.8Hz，1H)，3.98(dd，J＝7.6Hz，16.0Hz，1H)，6.49(d，J＝16.0Hz，1H)，7.25-7.36(m，5H)；
13C?NMR(100MHz，CDCl
3)：δ28.02，34.67，39.38，51.63，83.02，126.25，127.84，128.61，128.65，131.86，136.36，149.94，173.04；
EI-MS?m/z(％)：287(18.50，M
+)，187(32.32)，130(100)，128(32.68)，115(35.17)，57(56.49)，41(25.59)；
ESI-MS：310.1[M+Na]
+，597.4[2M+Na]
+；
HRMS(ESI)calcd?for?C
17H
21NO
3Na
+，310.1414，found?310.1416；
HPLC：Chiracel?OJ-H?Column(250mm)；detected?at?254nm；n-hexane/i-propanol＝80/20；flow＝0.7mL/min；Retention?time：18.3min(S)，21.0min(R)。
(R, E)-(R)-1-tertbutyloxycarbonyl-4-(2-hexyl vinyl)-2-Pyrrolidone (2q):
1H?NMR(400MHz，CDCl
3)：δ0.87-0.90(m，3H)，1.27-1.36(m，8H)，1.52(s，9H)，1.98-2.03(m，2H)，2.35(dd，J＝9.6Hz，17.2Hz，1H)，2.61(dd，J＝8.0Hz，17.2Hz，1H)，2.85-2.95(m，1H)，3.40(dd，J＝8..8Hz，10.8Hz，1H)，3.87(dd，J＝8.0Hz，10.4Hz，1H)，5.36(dd，J＝7.6Hz，15.2Hz，1H)，5.52-5.58(m，1H)；
13C?NMR(100MHz，CDCl
3)：δ14.04，22.57，28.03，28.75，29.12，31.65，32.35，34.30，39.57，51.88，82.83，128.83，133.10，150.05，173.43；
ESI-MS：318.2[M+Na]
+；
HRMS(ESI)calcd?for?C
17H
29NO
3Na
+，318.2040，found?318.2042；
HPLC：Chiracel?OD-H?Column(250mm)；detected?at?214nm；n-hexane/i-propanol＝90/10；flow＝0.7mL/min；Retention?time：8.7min(R)，9.7min(S)。
Above-mentioned product can be used as important medicine intermediate and uses.For example: compound 2m transformed through several steps can obtain drug molecule baclofen [(a) Eur.J.Pharmacol.1978,52,133; B) J.Med.Chem.1991,34,2557; (c) Med.Res.Rev.1992,72,593.]; Compound 2j then can be converted into the drug molecule rolipram [(a) DrugsFuture 1998,23,108; (b) J.Med.Chem.1993,36,3274; (c) Nat.Med.1995,7,244.].
Embodiment 41: drug molecule (R)-(-)-baclofen is synthetic
Compound 2m ethyl acetate petroleum ether recrystallization, the recrystallized product selectivity is promoted to more than the 99%ee, then 2m (0.16mmol) is dissolved in the CH of 1ml
2Cl
2In, room temperature condition drips TFA (10eq) down, and TLC shows no raw material residue behind the stirring 0.5h, adds KOH solution and regulates PH to alkaline, uses CH again
2Cl
2Extraction, anhydrous Na
2SO
4Drying concentrates column chromatography (EA/2%Et
3N) get white solid with quantitative yield.In 100 ℃ of following back flow reaction 14h, reaction finishes direct the concentrating in back and obtains white solid (R)-(-)-baclofen products therefrom in 6N HCl, yield 94%, and reaction formula is as follows:
Wherein:
(R)-4-rubigan-2-Pyrrolidone
[α]
D 26-38.6(c?1.00EtOH)，[lit.：[α]
D 25-39(c?1.00，EtOH)for?99％ee?in?the?R-isomer；J.Am.Chem.Soc.2005，119.]；
1H?NMR(400MHz，CDCl
3)：δ2.45(dd，J＝8.8Hz，16.8Hz，1H)，2.74(dd，J＝8.8Hz，16.8Hz，1H)，3.36-3.40(m，1H)，3.63-3.72(m，1H)，3.77-3.81(m，1H)，6.44(br?s，1H)，7.18-7.20(m，2H)，7.31-7.33(m，2H)；
13C?NMR(100MHz，CDCl
3)：δ37.88，39.67，49.42，128.13，129.02，132.92，140.66，177.55.EI-MS?m/z(％)：195(44.89，M
+)，139(11.18)，138(100)，103(20.85)；
HRMS(EI)calcd?for?C
10H
10ClNO?195.0451，found?195.0449。
(R)-(-)-baclofen
[α]
D 27-3.9(c?0.64，H
2O)，[lit.：[α]
D 25-3.79(c?0.65，H
2O)for?99％ee?in?the?R-isomer；J.Am.Chem.Soc.2005，119.]；
1H?NMR(400MHz，DMSO-d
6)：δ2.57(dd，J＝9.2Hz，16.4Hz，1H)，2.86(dd，J＝5.2Hz，16.4Hz，1H)，2.96-2.98(m，1H)，3.09-3.12(m，1H)，7.35-7.41(m，4H)，8.11(s，3H)，12.24(br?s，1H)；
13C?NMR(100MHz，DMSO-d
6)：δ37.79，39.02，43.15，128.50，128.90，131.78，139.38，172.24；
ESI-MS：214.1[M+H]
+；
HRMS(ESI)calcd?for?C
10H
13ClNO
2 +，214.0629，found?214.0630。
Embodiment 42: drug molecule (R)-(-)-rolipram is synthetic
Compound 2j ethyl acetate petroleum ether recrystallization, the recrystallized product selectivity is promoted to more than the 99%ee, then 2j (0.16mmol) is dissolved in the CH of 1ml
2Cl
2In, room temperature condition drips TFA (10eq) down, and TLC shows no raw material residue behind the stirring 0.5h, adds KOH solution and regulates PH to alkaline, uses CH again
2Cl
2Extraction, anhydrous Na
2SO
4Drying concentrates column chromatography (EA/2%Et
3N) obtain white solid with quantitative yield.
(R)-rolipram
[α]
D 27-33.0(c?1.00MeOH)，[lit.：[α]
D 25-33.9(c?1.09，MeOH)for?99％ee?in?the?R-isomer；J.Am.Chem.Soc.2002，13394.]；
1H?NMR(400MHz，CDCl
3)：δ1.59-1.63(m，2H)，1.81-1.94(m，6H)，2.47(dd，J＝8.8Hz，16.8Hz，1H)，2.71(dd，J＝8.8Hz，16.8Hz，1H)，3.38(dd，J＝7.6Hz，8.8Hz，1H)，3.58-3.66(m，1H)，3.73-3.77(m，1H)，3.83(s，3H)，4.75-4.78(m，1H)，6.56(br?s，1H)，6.76-6.84(m，3H)；
13C?NMR(100MHz，CDCl
3)：δ23.96，32.76，38.18，39.92，49.79，56.12，80.61，112.29，113.92，118.80，134.62，147.90，149.18，177.96；
EI-MS?m/z(％)：275(14.69，M
+)，207(68.55)，150(100)，135(17.75)；
HRMS(EI)calcd?for?C
16H
21NO
3275.1521，found?275.1522。
Claims (14)
1. the synthetic method of a chirality gamma-lactam compound, it is characterized in that, described method is by compound 1 and organic boronic compound, chiral olefin part, rhodium catalyst precursor and additive, in the mixed solvent of organic solvent and water composition, carried out the asymmetry catalysis addition reaction 0.5～48 hour at 40～90 ℃, its reaction expression is as follows:
Described organic boronic compound is selected from down a kind of in the array structure:
Described chiral olefin part has following structure:
Described rhodium catalyst precursor is the monovalence rhodium complex;
Described additive is organic bases, mineral alkali or mineral acid;
Described organic solvent is halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ether solvent, ketones solvent or alcoholic solvent;
Wherein:
R
1=C
1-6Alkyl, C
3-6Cycloalkyl, R
3Or R
4The phenyl, the R that replace
5The thiazolinyl that replaces, heteroaryl, phenyl ring are by R
6The benzyl, C (O) R that replace
7Perhaps C (O) OR
8
R
2=R
3Or R
4The phenyl, heteroaryl, 1-naphthyl or the 2-naphthyl that replace;
R
3Or R
4=H, C
1-6Alkyl, C
1-6Alkoxyl group, trifluoromethyl, nitro, cyano group or halogen;
R
5=C
1-6Alkyl or benzyl;
R
6=H, C
1-6Alkyl or C
1-6Alkoxyl group;
R
7Or R
8=C
1-6Alkyl, C
3-6Cycloalkyl or phenyl ring are by R
6The benzyl that replaces;
R
9=R
10Or R
11The phenyl, 1-naphthyl, 2-naphthyl, heteroaryl, benzyl, perfluorinated sulfonic acid base or the diarylphosphino that replace;
R
10Or R
11=H, C
1-6Alkyl, C
1-6Alkoxyl group, trifluoromethyl, nitro, cyano group or halogen.
2. the synthetic method of chirality gamma-lactam compound according to claim 1 is characterized in that: described rhodium catalyst precursor is a monovalence monoolefine rhodium complex.
3. the synthetic method of chirality gamma-lactam compound according to claim 2 is characterized in that: described monoolefine is ethene, cyclopentenes, tetrahydrobenzene or cyclooctene.
4. the synthetic method of chirality gamma-lactam compound according to claim 3 is characterized in that: described rhodium catalyst precursor is [RhCl (C
2H
4)
2]
2, [Rh (OH) (C
2H
4)
2]
2Perhaps [Rh (CH
3COO) (C
2H
4)
2]
2
5. the synthetic method of chirality gamma-lactam compound according to claim 1 is characterized in that: described organic bases is triethylamine (TEA), nitrogen methylmorpholine (NMP), diisopropyl ethyl amine or pyridine.
6. the synthetic method of chirality gamma-lactam compound according to claim 1 is characterized in that: described mineral alkali is sodium hydride, sodium hydroxide, potassium hydroxide, Potassium monofluoride or potassiumphosphate.
7. the synthetic method of chirality gamma-lactam compound according to claim 1 is characterized in that: described mineral acid is a fluorine potassium cyanide.
8. the synthetic method of chirality gamma-lactam compound according to claim 1 is characterized in that: described organic solvent is a methylene dichloride, 1,2-ethylene dichloride chloroform, toluene, tetrahydrofuran (THF), 1,4-dioxane or acetone.
9. the synthetic method of chirality gamma-lactam compound according to claim 1 is characterized in that: described mixed solvent is 0～1 by organic solvent and water by volume: 1 forms.
10. the synthetic method of chirality gamma-lactam compound according to claim 1 is characterized in that: described halogen is F, Cl or Br.
11. the synthetic method of chirality gamma-lactam compound according to claim 1 is characterized in that: described heteroaryl is furyl, thienyl or pyridyl.
12. the synthetic method of chirality gamma-lactam compound according to claim 1 is characterized in that: the temperature of described asymmetry catalysis addition reaction is 50～60 ℃, and the reaction times is 5～10 hours.
13. the synthetic method of chirality gamma-lactam compound according to claim 1 is characterized in that: the mol ratio between described compound 1 and organic boronic compound, rhodium catalyst precursor, chiral olefin part and additive is 1: 1.5～3: 0.01～0.05: 0.01～0.05: 0.5～3.
14. the synthetic method of chirality gamma-lactam compound according to claim 1 is characterized in that: the structural formula of described chirality gamma-lactam compound is:
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103373948A (en) * | 2012-04-27 | 2013-10-30 | 中国科学院上海有机化学研究所 | Preparation method for natural product (-)-kainic acid |
| JP2018035148A (en) * | 2011-11-21 | 2018-03-08 | ネオンク テクノロジーズ インク． | Pharmaceutical composition containing deuterium reinforced perillyl alcohol, isoperillyl alcohol and derivative thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994002443A2 (en) * | 1992-07-23 | 1994-02-03 | Claus Herdeis | PROCESS FOR PREPARING ENANTIOMER-PURE β-SUBSTITUTED η-AMINOBUTYRIC ACID DERIVATES, NEW ENANTIOMER-PURE INTERMEDIATE STAGES OF SAID PROCESS AND THEIR USE |
| CN101012187A (en) * | 2007-02-13 | 2007-08-08 | 中国科学院上海有机化学研究所 | Chiral diene ligand, synthesis method and its application in asymmetric reaction |
| CN101111246A (en) * | 2005-01-28 | 2008-01-23 | Irm责任有限公司 | Synthesis of aryl pyrrolidones |
| CN101115481A (en) * | 2005-01-28 | 2008-01-30 | Irm责任有限公司 | Phenyl-substituted pyrrolidones |
-
2010
- 2010-10-13 CN CN2010105054870A patent/CN101979378B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994002443A2 (en) * | 1992-07-23 | 1994-02-03 | Claus Herdeis | PROCESS FOR PREPARING ENANTIOMER-PURE β-SUBSTITUTED η-AMINOBUTYRIC ACID DERIVATES, NEW ENANTIOMER-PURE INTERMEDIATE STAGES OF SAID PROCESS AND THEIR USE |
| CN101111246A (en) * | 2005-01-28 | 2008-01-23 | Irm责任有限公司 | Synthesis of aryl pyrrolidones |
| CN101115481A (en) * | 2005-01-28 | 2008-01-30 | Irm责任有限公司 | Phenyl-substituted pyrrolidones |
| CN101012187A (en) * | 2007-02-13 | 2007-08-08 | 中国科学院上海有机化学研究所 | Chiral diene ligand, synthesis method and its application in asymmetric reaction |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018035148A (en) * | 2011-11-21 | 2018-03-08 | ネオンク テクノロジーズ インク． | Pharmaceutical composition containing deuterium reinforced perillyl alcohol, isoperillyl alcohol and derivative thereof |
| CN103373948A (en) * | 2012-04-27 | 2013-10-30 | 中国科学院上海有机化学研究所 | Preparation method for natural product (-)-kainic acid |
| CN103373948B (en) * | 2012-04-27 | 2015-07-08 | 中国科学院上海有机化学研究所 | Preparation method for natural product (-)-kainic acid |
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