CN1950370B - Enantiomer-pure hexahydro- pyrrolocyclopenta- pyridine derivatives - Google Patents
Enantiomer-pure hexahydro- pyrrolocyclopenta- pyridine derivatives Download PDFInfo
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- CN1950370B CN1950370B CN2005800135347A CN200580013534A CN1950370B CN 1950370 B CN1950370 B CN 1950370B CN 2005800135347 A CN2005800135347 A CN 2005800135347A CN 200580013534 A CN200580013534 A CN 200580013534A CN 1950370 B CN1950370 B CN 1950370B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to the novel therapeutically valuable enantiomer-pure [3aalpha,8balpha]-1,2,3,3a,4,8b-hexahydropyrrolocyclopentapyridine derivatives of the general formula (I), wherein Z is a single bond or CH2, R1 represents hydrogen or a straight-chain or branched, optionally unsaturated lower alkyl group which may be perfluorated, R2 and R3 independently represent hydrogen, a straight-chain or branched, optionally unsaturated lower alkyl group which may be perfluorated, lower alkoxy, lower alkylthio or halogen, and X and Y alternately represent CH or N. The invention also relates to the pharmaceutical salts thereof, to a method for their production and to their use.
Description
The present invention relates to [3a α, the 8b α]-1,2,3 of the new enantiomer-pure that therapeutic value is arranged of following general formula, 3a, 4,8b-hexahydro-pyrrolocyclopenta-pyridine-derivative and their pharmacologically acceptable salt:
Wherein:
Z represents singly-bound or CH
2,
R1 represents hydrogen or straight chain or ramose, optional undersaturated low alkyl group, and described low alkyl group also can be by perfluorination,
R2 and R3 represent hydrogen independently of one another, straight chain or ramose, and optional undersaturated low alkyl group, described low alkyl group also can be by perfluorination, lower alkoxy, lower alkylthio or halogen,
X and Y select a ground and represent CH or N.
Has surprising positive performance according to the compound of enantiomer-pure of the present invention or preparation with respect to the mixture of enantiomers or the racemoid of these compounds, especially aspect its biological activity, particularly in central nervous system (ZNS) field.The fact shows that various enantiomorphs have strong difference between the effects, shown in embodiment 9.
The invention still further relates to a kind of method for preparing general formula (I) compound, it is characterized in that, make the compound of following general formula
Wherein R2, R3, X and Y have above definition, are converted into to reductibility general formula (I) compound of Z=singly-bound wherein and R1=hydrogen, and its optional 1-phenylethyl isocyanate reaction with enantiomer-pure is the compound of following general formula,
Obtain the diastereomer of indissoluble by crystallization by the non-enantiomer mixture that obtains like this, the general formula of the diastereisomericallypure pure that obtains like this (III) compound under conditions suitable, be split as enantiomer-pure, general formula (I) compound of Z=singly-bound and R1=hydrogen wherein, it is chosen wantonly, and reaction obtains wherein Z=CH under alkylation conditions
2General formula (I) compound, and randomly with general formula (I) but compound is converted into the salt of its drug use.
More than the term " low alkyl group " of Shi Yonging represents to have the straight chain or the ramose alkyl of 1-4 carbon atom, for example methyl, ethyl, n-propyl and sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl.
More than the term " lower alkoxy " of Shi Yonging represents to have the straight chain or the ramose alkoxyl group of 1-4 carbon atom, methoxyl group for example, oxyethyl group, positive propoxy and isopropoxy, n-butoxy, isobutoxy and tert.-butoxy.
More than the term " lower alkylthio " of Shi Yonging represents to have the straight chain or the ramose alkylthio of 1-4 carbon atom, for example methyl sulphur, ethyl sulphur, n-propyl sulphur and sec.-propyl sulphur, normal-butyl sulphur, isobutyl-sulphur and tertiary butyl sulphur.
More than the term " halogen " of Shi Yonging represents fluorine, chlorine, bromine or iodine.
Preferably carry out like this according to reaction of the present invention, general formula (II) compound is dissolved in polar solvent such as ethyl acetate, diox, ethanol or the methyl alcohol, mix with 1-5 equivalent appropriate catalyst such as W2-Raney Ni or blue Buddhist nun's cobalt etc., 40~70 ℃ of following hydrogenations, up to absorbing stoichiometric hydrogen.
For enantiomer separation, be dissolved in the Z=singly-bound that inert solvent obtains and general formula (I) racemic compound of R1=hydrogen and become general formula (III) compound as in tetrahydrofuran (THF), diox or the acetone, and from the non-enantiomer mixture that obtains like this, obtain the diastereomer of indissoluble by crystallization with 1 equivalent (+) or (-) 1-phenylethyl isocyanate reaction.In order to split, the diastereisomericallypure pure compound of the general formula (III) that obtains like this is dissolved in high-boiling point alcohol such as propyl alcohol, butanols, amylalcohol, ethylene glycol etc. or their aqueous mixture, is heated to boil with 5-20 normal alkali such as sodium propylate, sodium butylate, amylalcohol sodium or sodium hydroxide and reaches 1-24 hour.
The enantiopure compound of the general formula (I) of z=singly-bound that obtains like this and R1=hydrogen optional is dissolved in inert solvent such as tetrahydrofuran (THF), two alkane, acetonitrile or the dimethyl formamide etc. in order to carry out alkylation, with the compound of foretelling 20 equivalent following formulas
R1 one CHO (IV),
Wherein R1 has above definition and 1.5-4 equivalent reductive agents, for example mixing such as sodium cyanoborohydride, and one 20 ℃~100 ℃ reactions 1 to 24 hour.
General formula (I) compound that obtains in this reaction is a kind of basic cpd, can be converted into the compatible salt of its medicine with inorganic or organic acid in a usual manner.
Salt formation for example can followingly carry out, formula (I) compound is dissolved among suitable solvent such as water, rudimentary aliphatic alcohol, THF, two mouthfuls of oxanes, benzene, diethyl ether, DMF or the DMSO, adds the desirable acid of monovalent, well uniform mixing, after forming the salt end, vacuum extracts solvent.Choose wantonly and salt is being separated laggard capable recrystallization.
The spendable salt of medicine is the salt of strong inorganic acid example hydrochloric acid, Hydrogen bromide, sulfuric acid etc., also can be the salt of those organic acids such as fumaric acid, citric acid, sebacic acid etc.
The general formula of x=N and Y=CH (i i) compound for example can obtain (similar E.Schr according to flow process 1
Le r M.Lehrmann and I.B
T tcher, Eur.J.Med.Chem.1979,14 (4), 309-15, J.Hurst and D.G.W i bberly, J.Chem.Soc.1962,119).Therefore, wherein R4 represents optional 2 monomethyls, the one 3 one nicotine acid esters that replaced by R2 and R3 of the logical formula V of low alkyl group, carry out the free radical bromination with 1.05 equivalent NBS in the ebullient tetracol phenixin, crude product, replaces in the N dimethyl formamide at N with 1.O equivalent sodium malonate.The wherein R5 that obtains represents three esters of the general formula (VI) of low alkyl group, under the effect of 1.O5 equivalent sodium hydride, in the ebullient tetrahydrofuran (THF), carry out the Dieckmann ester condensation, by carrying out cancellation with aqueous ammonium chloride solution, single saponification and decarboxylation turn to D one ketone ester (VII).At N, carry out alkylation with the sodium hydride deprotonation and with iodomethyl cyanide in N-. two-methylformamide after, saponification and decarboxylation turn to the compound of general formula (II) by heating in 2n hydrochloric acid.
Flow process 1
The general formula of X=CH and Y=N (II) compound for example can be according to flow process 2, and the nicotine acid esters of the optional general formula (VIII) that is replaced by R2 and R3 of representing low alkyl group from R4 wherein obtains.With 1.0 equivalent carbonochloridic acid esters it is activated, and in tetrahydrofuran (THF), be reacted into 1 with the zinc-copper-organism base (0rgany1) of 3-iodo propionic ester, the 4-dihydropyridine, in ebullient dimethylbenzene, it is oxidized to pyridine (the similar M.J.Sh iao that R5 wherein represents the general formula (IX) of low alkyl group with sulphur, W.L.Chia, C.J.Peng and C.C.Shen, J.Org.Chem.1933,58,3162-4).Its under 1.3 equivalent sodium methylate effects, in ebullient methyl alcohol, in Di eckmann ester condensation cyclisation be 'beta '-ketoester (X) (similar D.Binder, MonatsheftefurChemie1974,105,196-202).At N, carry out alkylation with the sodium hydride deprotonation and with iodomethyl cyanide in the dinethylformamide after, saponification and decarboxylation turn to the compound of general formula (II) by heating in 2n hydrochloric acid.
Flow process 2
General formula (IV), (V) and compound (V) are that document is disclosed, perhaps can similarly be prepared according to routine and method that the technician knows.
According to general formula of the present invention (I) compound and salt thereof is the agonist of maincenter nicotine-acceptor-hypotype; therefore be applicable to treatment maincenter stimulus-transmitting system system disease especially well; for example old and feeble dementia, Alzheimer's disease, parkinsonism, Tourette's syndrome, dyskinesia, anxiety disorder, depression, fear, psychosis, Bulimia nerovsa, the apocleisis that causes; and, be used to improve consciousness and attention and be used for smoking alternative medicine etc. as pain killer, nociception agent, neuroprotective.
Because these pharmacology character; described new compound can be used for the treatment of disease with conventional Galenic formula form as medicine separately or with other active substances with mixing; cure or palliate a disease by the system that activates subtypes of central nicotinic receptor; perhaps as pain killer, nociception agent, neuroprotective; be used to improve consciousness and attention, and be used for the smoking alternative medicine.
The invention still further relates to the medicament that for example uses with pharmaceutical dosage forms, it contains with good grounds general formula of the present invention (I) compound and salt thereof, also mix oral to be fit to, through the organic or inorganic solid support material of the medicine of intestines, parenteral and topical such as water, gelatin, gum arabic, lactose, starch, Magnesium Stearate, talcum, vegetables oil, polyalkylene glycol, Vaseline etc.
This pharmaceutical preparation can exist with solid form, for example as tablet, diaphragm agent, sugar-pill, suppository, capsule, micro-capsule, perhaps exist with liquid form, for example as solution, injection liquid, suspension or emulsion, perhaps the composition that delays to discharge with active substance exists.
Described preparation is optional to be sterilized and/or to contain auxiliary agent such as sanitas, stablizer or emulsifying agent, is used to change the salt or the damping fluid of osmotic pressure.
Pharmaceutical preparation particularly has the associating of the material of therapeutic value according to compound of the present invention and other.Compound of the present invention can be mixed with combined preparation with above listed auxiliary agent and/or carrier substance with them.
This new compound amount with every agreement that contracts a film or TV play to an actor or actress 1-200mg in pharmaceutical composition according to the present invention exists, and remaining is the compatible filler of medicine.
Dosage about 1-200mg/kg every day that described new compound is suitable, but can consider other dosage according to treatment patient's situation.Described new compound can be with multiple doses more and with oral administration.
Following examples are explained the present invention in more detail, and are not to limit the invention to this:
Embodiment 1
(+)-[3a α, 8b α]-1,2,3,3a, 4, the 8b-hexahydropyrrolo is [2 ', 3 ': 3,4] ring penta also
[1,2-b] pyridine-dihydrochloride
6.68g (278mmo l) sodium hydride is mixed with the anhydrous amylalcohol of 280m l down at 0 ℃, and at room temperature stirred 30 minutes.(17.4mmol) 5.34g (-)-[1 (S), 3a α, 8b α]-1,2,3,3a, 4,8b-six hydrogen-N-(1-phenylethyl)-pyrrolo-[2 ', 3 ': 3,4] rings penta [1,2-b] pyridine-1-carboxylic acid amide with solid form at N
2-countercurrent purge adds next time, and the reaction mixture of existing side by side soon is heated to and boils two hours.
Extract solvent out under 60 ℃/0.1 millibar, and use methyl alcohol: ammoniacal liquor=100: 2 filters residue fast through 400g silica gel.Extract solvent out, crude product carried out column chromatography, by the gradient elution purifying (400g silica gel, methylene dichloride: methyl alcohol=1: 1-〉methyl alcohol-methyl alcohol: ammoniacal liquor=100: 2).
Products therefrom is absorbed in the 20ml methylene dichloride, through sodium sulfate/gac drying, filters and distilling off solvent.
Productive rate: 2.23g oldlace crystal (82% theoretical yield)
DC: methyl alcohol: ammoniacal liquor=100: 2; R
f=0.5
With the hydrochloric acid alcoholic solution this product is converted into its dihydrochloride, acetone extraction is filtered and uses in crystallization in ethanol.The clear crystal of gained is hygroscopic by force.
[α]
D 20:+14.4 ± 1.1 ° (c=0.22/ methyl alcohol)
Trace element analysis: RW5 C (%) H (%) N (%)
Total molecular formula: calculated value: 51.52 6.05 12.02
C
10H
14Cl
2N
2Experimental value: 51.52 6.10 11.81
1H-NMR?(D
2O):
δ(ppm)=8.73(d,1H,Pcp-H6);8.69(d,1H,Pcp-H8);7.94(dd,1H,Pcp-H7);5.54(d,1H,Pcp-H8b);3.80-3.20(m,5H,Pcp-H2,3a,4A,4B);2.58-2.36(m,1H,Pcp-H3A);2.09-1.90(m,1H,Pcp-H3B)
13C-NMR(D
2O):
δ(ppm)=156.2(s,Pcp-C4a);142.5(d,Pcp-C6);139.7(d,Pcp-C8);133.3(s,Pcp-C8a);123.1(d,Pcp-C7);62.2(d,Pcp-C8b);43.5(t,Pcp-C2);36.6(d,Pcp-C3a);33.1(t,Pcp-C4);28.3(t,Pcp-C3)
Embodiment 2
(-)-[3a α, 8b α]-1,2,3,3a, 4, the 8b-hexahydropyrrolo is [2 ', 3 ': 3,4] ring penta also
[1,2-b] pyridine-dihydrochloride
Be similar to embodiment 1, by 9.10g (30.0mMo1) (+) [1 (R), 3a α, 8b α]-1,2,3,3a, 4,8b-six hydrogen-N-(1-phenylethyl)-pyrrolo-[2 ', 3 ': 3,4] ring penta [1,2-b] pyridine-1-carboxylic acid amide preparation (72% theoretical yield, clear crystal).
[α]
D 20:-13.9+1.0 ° (c=0.24/ methyl alcohol)
Trace element analysis: RW7 C (%) H (%) N (%)
Total molecular formula: calculated value: 51.16 6.09 11.93
C
10H
14Cl
2N
2* 0.09H
2O experimental value: 51.22 6.24 11.80
1H-NMR(D
2O):
δ(ppm)=8.73(d,1H,Pcp-H6);8.69(d,1H,Pcp-H8);7.94(dd,1H,Pcp-H7);5.54(d,1H,Pcp-H8b);3.80-3.20(m,5H,Pcp-H2,3a,4A,4B);2.58-2.36(m,1H,Pcp-H3A);2.09-1.90(m,1H,Pcp-H3B)
13C-NMR(D
2O):
δ(ppm)=156.2(s,Pcp-C4a);142.5(d,Pcp-C6);139.7(d,Pcp-C8);133.3(s,Pcp-C8a);123.1(d,Pcp-C7);62.2(d,Pcp-C8b);43.5(t,Pcp-C2);36.6(d,Pcp-C3a);33.1(t,Pcp-C4);28.3(t,Pcp-C3)
Raw material can followingly make:
2-[2,2-pair-(methoxycarbonyl)]-ethyl-3-pyridine-3-carboxylic acid methyl ester
219.0g (1.45mol) 2-methyl-3-pyridine carboxylic acid methyl ester is heated to boil with 271.0g (1.52mol) N-bromo-succinimide and 13.0g dibenzoyl superoxide in 3.5 liters of anhydrous tetrachloromethanes and spends the night.
With solid filtering, solvent is extracted out, and residue is dissolved in the 250m l anhydrous dimethyl formamide, and is splashing into 223.3g (1.45mo l) dimethyl malonic acid sodium under 10 ℃ in the suspension of 1.2 liters of anhydrous dimethyl formamides, and at room temperature stirs 18 hours.
Extract solvent out under high vacuum, residue is distributed between 2.5 premium on currency and the 1.5 liters of diethyl ether, and water at every turn with the extraction of 800ml diethyl ether repeatedly.The organic phase 200ml water washing that merges through sodium sulfate/gac drying, is filtered, with the solvent extraction, and with 200m1 diethyl ether lixiviate (digeriert) residue.
Productive rate: 138.5g clear crystal (34% theoretical yield)
DC: ethyl acetate; R
f=0.6
Fp.:59-62 ℃ (diethyl ether, lixiviate)
Trace element analysis: HK29 C (%) H (%) N (%)
Total molecular formula: calculated value: 55.51 5.38 4.98
C
10H
14Cl
2N
2Experimental value: 55.71 5.26 4.92
1H-NMR(CDCl
3):
δ(ppm)=8.55(dd,1H,Py-H6);8.18(dd,1H,Py-H4);7.20(dd,1H,Py-H5);4.22(t,1H,CH);3.90(s,3H,OCH
3);3.80(d,2H,CH2);3.70(s,6H,OCH
3)
13C-NMR(CDCl
3):
δ(ppm)=169.7(s,2C,C
COOCH
3);166.2(s,
COOCH
3);158.4(s,Py-C2);151.3(d,Py-C6);138.3(d,Py-C4);125.0(s,Py-C3);121.2(d,Py-C5);52.2(q,2C,OCH
3);52.1(q,OCH
3);49.6(d,CH);34.9(t,CH
2)
6,7-dihydro-5-oxygen-5H-1-pyridine-6-carboxylic acid methyl ester
In the suspension of 800ml ebullient anhydrous tetrahydro furan, slowly being added in 93.5g (332mmol) 2-[2 in the anhydrous tetrahydro furan of 600ml heat to 8.40g (350mmol) sodium hydride, 2-is two-(methoxycarbonyl)]-ethyl-3-pyridine carboxylic acid methyl ester.Heating reflux reaction solution finishes up to producing gas, thereby separates out product.
Refrigerative suspension is poured in 1.5 liters of saturated ammonium chloride solutions, stirred 30 minutes, and filtering precipitate.Solid is with 250ml flooding three times, with the lixiviate of 250ml methyl alcohol once, and under 70 ℃/20 millibars through five phosphorus oxide dryings.
Productive rate: 55.4g clear crystal (87% theoretical yield)
DC: ethyl acetate: R
f=0.4
Fp.:92-96 ℃ (ethyl acetate)
Trace element analysis: C (%) H (%) N (%)
Total molecular formula: calculated value: 62.824.747.32
C
10H
9NO
3Experimental value: 63.024.797.32
1H-NMR(CDCl
3):
The ketone form:δ (ppm)=8.82 (dd.1H.Pn-H2): 8.02 (dd.1H.Pn-H4): 7.35 (dd.1H.Pn-H3); 3.79 (dd, 1H, Pn-H6); 3.78 (s, 3H, OCH
3); 3.72-3.40 (m, 2H, Pn-H7A, B)
The enol form:δ (ppm)=8.58 (dd, 1H, Pn-H2): 7.87 (dd, 1H, Pn-H4); 7.27 (dd, 1H, Pn-H3); 3.86 (s, 3H, OCH
3); 3.61 (s, 2H, Pn-H7)
13C-NMR(CDCl
3):
The ketone form:δ (ppm)=197.6 (s.Pn-C5); 172.7 (s,
COOCH
3); 168.8 (s, Pn-C7a); 156.3 (d, Pn-C2); 132.7 (d, Pn-C4); 128.5 (s, Pn-C4a); 122.8 (d, Pn-C3); 52.8 (d, Pn-C6); 52.7 (q, OCH
3);
32.9(t,Pn-C7)
The enol form:δ (ppmn)=169.3 (s.
COOCH
3); 167.1 (s, Pn-C5)
*163.5 (s, Pn-C7a)
*149.8 (d, Pn-C2); 131.9 (s, Pn-C4a)
*128.1 (d, Pn-C4); 121.7 (d, Pn-C3); 102.0 (s, Pn-C6); 51.3 (q, OCH
3); 34.8 (t, Pn-C7)
6-(cyano methyl)-6,7-dihydro-5-oxygen-5H-1-pyridine-6-carboxylic acid methyl ester
Under 5 ℃, in the suspension of 400ml anhydrous dimethyl formamide, add 55.4g (290mmol) 6 to 7.66g (319mmol) sodium hydride, 7-dihydro-5-oxygen-5H-1-pyridine-6-carboxylic acid methyl ester, and stir up to producing gas and finish.After being added in 55.7g (333mmol) iodomethyl cyanide in the 200ml anhydrous dimethyl formamide, at first stirred 30 minutes down, at room temperature stirred then 18 hours at 5 ℃.
Regulating pH with acetate is 5, and meticulous vacuum (Finevakuum) is extracted dimethyl formamide out, and residue is absorbed in the 900ml water, uses 600ml dichloromethane extraction twice at every turn, uses the 300ml dichloromethane extraction three times at every turn.Organic phase is filtered and distilling off solvent through sodium sulfate/gac drying.Crude product filters (1.2kg silica gel KG60, ethyl acetate) back recrystallization from the 200ml ethyl acetate at Startfleck.
Productive rate: 35.6g clear crystal (53% theoretical yield)
DC: ethyl acetate; R
f=0.6
Fp.:99-101 ℃ (ethyl acetate)
Trace element analysis: FG1C (%) H (%) N (%)
Total molecular formula: calculated value: 62.614.3812.17
C
12H
10N
2O 3 experimental values: 62.454.2712.16
1H-NMR(CDCl
3):
δ(ppm)=8.90(dd,1H,Pn-H2);8.09(dd,1H,Pn-H4);7.44(dd,1H,Pn-H3);3.87(d,1H,Pn-H7A);3.71(s,3H,OCH
3);3.42(d,1H,Pn-H7B);3.20(d,1H,CHAHB-CN);2.98(d,IH,CHA
HB-CN)
13C-NMR(CDCl
3):
δ(ppm)=197.4(s,Pn-C5);171.6(s,COOCH
3);168.6(s,Pn-C7a);157.1(d,Pn-C2);133.4(d,Pn-C4);127.5(s,Pn-C4a);123.4(d,Pn-C3);116.0(s,CN);56.6(s,Pn-C6);53.6(q,OCH
3);39.4(t,Pn-C7);22.1(t,
CH
2CN)
6,7-dihydro-5-oxygen-5H-1-pyridine-6-carboxylic acid nitriles
(35.6g 155mmo l) 6-(cyano methyl)-6,7-dihydro-5-oxygen-1-pyridine-6-carboxylic acid methyl is heated in 400ml2n hydrochloric acid boils 90 minutes.
With solid sodium carbonate reaction soln is adjusted to pH=9, uses 200ml dichloromethane extraction twice at every turn, use the 100ml dichloromethane extraction three times at every turn.Organic phase is filtered through sodium sulfate/gac drying, and distilling off solvent.
Productive rate: 24.0g clear crystal (90% theoretical yield)
DC: ethyl acetate; R
f=0.5
Fp.:95-97 ℃ (methylene dichloride)
Trace element analysis: FG2C (%) H (%) N (%)
Total molecular formula: calculated value: 69.764.6816.27
C
10H
8N
2O experimental value: 69.544.7616.20
1H-NMR(CDCl
3):
δ(ppm)=8.87(dd,1H,Pn-H2);8.06(dd,1H,Pn-H4);7.37(dd,1H,Pn-H3);3.66(dd,1H,Pn-H7A):3.22-2.92(m.3H.Pn-H7B.Pn-H6.C
HAHB-CN):273(dd.1
13C-NMR(CDCl
3):
δ(ppm)=202.2(s,Pn-C5);171.7(s,Pn-C7a);156.5(d,Pn-C2);132.4(d,Pn-C4);128.9(s,Pn-C4a);123.0(d,Pn-C3);117.2(s,CN);42.7(d,Pn-C6);34.5(t,Pn-C7);18.3(t,
CH
2CN)
(±)-[3a α, 8 α]-1,2,3,3a, 4, the 8b-hexahydropyrrolo is [2 ', 3 ': 3,4] ring penta also
[1,2-b] pyridine
4.0g (23.23mmol) 6,7-dihydro-5-oxygen-5H-1-pyridine-6-acetate nitrile is dissolved in the 80ml anhydrous methanol, stirs and filter with gac.The blue Buddhist nun's cobalt catalyst of solution and 16g mixes, and hydrogenation under 50 ℃ and 90psi hydrogen pressure in Parr-equipment, absorbs the hydrogen end up to theory.
Catalyzer filters through Hyflo, distills out the solvent of filtrate, and residue filters by Startfleck, through 400g silica gel, uses methyl alcohol: ammoniacal liquor=100: 2 carries out purifying.Distilling off solvent, residue are absorbed in the methylene dichloride, through sodium sulfate/gac drying, filter and extract out solvent.
Productive rate: 2.61g colorless oil (70% theoretical yield)
DC: methyl alcohol: ammoniacal liquor=100: 2; R
f=0.5
1H-NMR(CDCl
3):
δ(ppm)=8.42(dd,1H,Pcp-H6);7.62(dd,1H,Pcp-H8);7.09(dd,1H,Pcp-H7);4.74(d,1H,Pcp-H8b);3.30(dd,1H,Pcp-H4A);3.12-2.61(m,4H,Pcp-H4B,2,3a);2.15-1.94(m,1H,Pcp-H3A);1.68-1.49(m,1H,Pcp-H3B)
13C-NMR(CDCl
3):
δ(ppm)=164.0(s,Pcp-C4a);149.3(d,Pcp-C6);137.4(s,Pcp-C8a);133.1(d,Pcp-C8);121.7(d,Pcp-C7);66.5(d,Pcp-C8b);46.6(t,Pcp-C2);40.2(d,Pcp-C3a);39.3(t,Pcp-C4);35.7(t,Pcp-C3)
(-)-[1 (S), 3a α, 8b α]-1,2,3,3a, 4,8b-six hydrogen-N-(1-phenylethyl)-
Pyrrolo-[2 ', 3 ': 3,4]-ring penta [1,2-b] pyridine-1-carboxylic acid amide
2.50g in the 30ml anhydrous propanone (15.6mmol) (±)-[3a α, 8b α]-1,2,3,3a, 4, the 8b-hexahydropyrrolo is [2 ' also, 3 ': 3,4] ring penta [1,2-b] pyridine and 2.30g (15.6mmol) in the 25ml anhydrous propanone (S)-(-)-1-phenylethyl isocyanic ester mixes, stirring is 60 minutes under the room temperature, for complete crystallization, place refrigerator overnight.
Filter crystal, and with cold anhydrous propanone lixiviate.
Productive rate: 2.04g clear crystal (85% theoretical yield)
DC: methylene dichloride: methyl alcohol=95: 5; R
f=0.5
Fp.:187-189 ℃ (acetone)
[α]
D 20:-229.5 ± 0.5 ° (c=1.00/ methylene dichloride)
Trace element analysis: GD28C (%) H (%) N (%)
Total molecular formula: calculated value: 74.246.8913.67
C
19H
21N
3O experimental value: 74.247.1013.53
1H-NMR(CDCl
3):
δ(ppm)=8.39(d,1H,Pcp-H6);8.03(d,1H,Pcp-H8);7.34-7.21(m,5H,Bz-H2-4);7.06(dd,1H,Pcp-H7);5.36(d,1H,Pcp-H8b);5.05(m,1H,C
H);4.63(d,1H;NH);3.36-3.29(m,2H,Pcp-H2);3.18(dd,1H,Pcp-H4A);3.10-2.90(m,1H,Pcp-H3a);2.83(dd,1H,Pcp-H4B);2.29-2.14(m,1H,Pcp-H3A);1.79-1.60(m,1H,Pcp-H3B);1.48(d,3H,CH
3)
13C-NMR(CDCl
3):
δ(ppm)=161.9(s,Pcp-C4a);156.3(s,CO);149.0(d,Pcp-C6);144.4(s,Bz-Cl);137.3(s,Pcp-C8a);135.6(d,Pcp-C8);128.4(d,2C,Bz-C3);126.9(d,Bz-C4);125.9(d,2C,Bz-C2);121.9(d,Pcp-C7);64.5(d,Pcp-C8b);49.7(d,CH);45.7(t,Pcp-C2);39.0(d,Pcp-C3a);37.8(t,Pcp-C4);31.3(t,Pcp-C3);22.5(q,CH
3)
(+)-[1 (R), 3a α, 8b α]-1,2,3,3a, 4,8b-six hydrogen-N-(1-phenylethyl)-
Pyrrolo-[2 ', 3 ': 3,4]-ring penta [1,2-b] pyridine-1-carboxylic acid amide
By 5.12g (31.9mmol) (±)-[3a α, 8b α]-1,2,3,3a, 4, the 8b-hexahydropyrrolo also [2 ', 3 ': 3,4] ring penta-[1,2-b] pyridine and 4.47g (30.3mmol) (R)-(+)-1-phenylethyl isocyanic ester.Be similar to (-)-[1 (S), 3a α, 8b α]-1,2,3,3a, 4,8b-six hydrogen-N-(1-phenylethyl)-pyrrolo-[2 ', 3 ': 3,4]-ring penta [1,2-b] pyridine-1-carboxylic acid amide is prepared
Productive rate: 4.19g clear crystal (85% theoretical yield)
DC: methylene dichloride: methyl alcohol=95: 5; R
f=0.5
Fp.:184-186 ℃ (acetone)
[α]
D 20:+230.4 ± 0.5 ° (c=0.19/ methylene dichloride)
Trace element analysis: RWl C (%) H (%) N (%)
Total molecular formula: calculated value: 74.246.8913.67
C
19H
21N
3O experimental value: 74.267.0413.56
1H-NMR(CDCl
3):
δ(ppm)=8.39(d,1H,Pcp-H6);8.03(d,1H,Pcp-H8);7.34-7.21(m,5H,Bz-H2-4);7.06(dd,1H,Pcp-H7);5.36(d,1H,Pcp-H8b);5.05(mn,1H,C
H);4.63(d,1H;NH);3.36-3.29(m,2H,Pcp-H2);3.18(dd,1H,Pcp-H4A);3.10-2.90(m,1H,Pcp-H3a);2.83(dd,1H,pcp-H4B);2.29-2.14(m,1H,Pcp-H3A);1.79-1.60(m,1H,Pcp-H3B);1.48(d,3H,CH
3)
13C-NMR(CDCl
3):
δ(ppm)=161.9(s,Pcp-C4a);156.3(s,Co);149.0(d,Pcp-C6);144.4(s,Bz-Cl);137.3(s,Pcp-
C8a);135.6(d,Pcp-C8);128.4(d,2C,Bz-C3);126.9(d,Bz-C4);125.9(d,2C,Bz-C2);
121.9(d,Pcp-C7);64.5(d,Pcp-C8b);49.7(d,CH);45.7(t,Pcp-C2);39.0(d,Pcp-
C3a);37.8(t,Pcp-C4);31.3(t,Pcp-C3);22.5(q,CH
3)
Embodiment 3
(-)-[3a α, 8b α]-1,2,3,3a, 4,8b-six hydrogen-1-methyl-pyrrolo-[2 ', 3 ':
3,4] ring penta [1,2-b] pyridine-dihydrochloride
1.15g in 60m l acetonitrile (7.17mmo l) [3a α, 8b α]-1,2,3,3a, 4, the 8b-hexahydropyrrolo is [2 ' also, 3 ': 3,4] ring penta-[1,2-b] pyridine (embodiment 1) is with 5.42ml35% formaldehyde solution and mix with 1.04g (16.5mmol) sodium cyanoborohydride in batches subsequently.Reaction mixture at room temperature stirred 30 minutes.
Regulate pH=1 with 2n hydrochloric acid now, use twice of 30ml dichloromethane extraction at every turn.Make water reach pH by adding the 2n sodium hydroxide solution〉11, use the 30ml dichloromethane extraction six times at every turn.Organic phase is filtered and distilling off solvent through sodium sulfate/gac drying.
Productive rate: 1.13g yellow oil (90% theoretical yield)
DC: methyl alcohol: ammoniacal liquor=100: 2; R
f=0.8
Methylene dichloride: methyl alcohol=10: 1; R
f=0.5
With the hydrochloric acid alcoholic solution this product is converted into its dihydrochloride, acetone extraction is filtered and uses in crystallization in ethanol.The gained clear crystal is hygroscopic by force.
[α]
D 20:-29.6 ± 1.0 ° (c=0.44/ methyl alcohol)
Trace element analysis: RW 16C (%) H (%) N (%)
Total molecular formula: calculated value: 48.836.9310.35
C
11H
16N
2Cl
2* 1.30H
2O experimental value: 48.846.7910.22
1H-NMR(D
2O):
δ(ppm)=8.78(d,1H,Pcp-H6);8.75(d,1H,Pcp-H8);7.96(dd,1H,Pcp-H7);5.28(d,1H,Pcp-H8b);3.85-3.50(m,3H,Pcp-H2,4A);3.19(s,3H,CH
3);3.50-3.00(m,2H,Pcp-H4B,3a);2.80-2.50(m,1H,Pcp-H3A);2.05-1.80(m,1H,Pcp-H3B)
13C-NMR(D
2O):
δ(ppm)=161.5(s,Pcp-C4a);146.8(d,Pcp-C6);145.5(d,Pcp-C8);137.2(s,Pcp-C8a);128.2(d,Pcp-C7);76.7(d,Pcp-C8b);59.4(t,Pcp-C2);43.1(d,Pcp-C3a);41.9(q,CH
3);38.4(t,Pcp-C4);32.9(t,Pcp-C3)
Embodiment 4
(+)-[3a α, 8b α]-1,2,3,3a, 4,8b-six hydrogen-1-methyl-pyrrolo-[2 ', 3 ':
3,4] ring penta [1,2-b] pyridine-dihydrochloride
Be similar to embodiment 3, by 1.13g (7.17mMol) [3a α, 8b α]-1,2,3,3a, 4, the 8b-hexahydropyrrolo is [2 ' also, 3 ': 3,4] ring penta-[1,2-b] pyridine (embodiment 2), 5.42m l 35% formaldehyde solution and 1.04g (16.5mMol) sodium cyanoborohydride are prepared (86% theoretical yield, clear crystal).
[α]
D 20+ 27.5 ± 0.5 ° (c=0.42/ methyl alcohol)
Trace element analysis: RW8C (%) H (%) N (%)
Total molecular formula: calculated value: 48.966.9210.38
C
11H
16N
2Cl
2* 1.26H
2O experimental value: 48.926.6410.48
1H-NMR(D
2O):
δ(ppm)=8.78(d,1H,Pcp-H6);8.75(d,1H,Pcp-H8);7.96(dd,1H,Pcp-H7);5.28(d,1H,Pcp-H8b);3.85-3.50(m,3H,pcp-H2,4A);3.19(s,3H,CH
3);3.50-3.00(m,2H,pcp-H4B,3a);2.80-2.50(m,1H,Pcp-H3A);2.05-1.80(m,1H,Pcp-H3B)
13C-NMR(D
2O):
δ(ppm)=161.5(s,Pcp-C4a);146.8(d,Pcp-C6);145.5(d,Pcp-C8);137.2(s,Pcp-C8a);128.2(d,Pcp-C7);76.7(d,Pcp-C8b);59.4(t,Pcp-C2);43.1(d,Pcp-C3a);41.9(q,CH
3);38.4(t,Pcp-C4);32.9(t,pcp-C3)
Embodiment 5
(+)-[3a S-(3a α, 8b α)]-1,2,3,3a, 4, the 8b-hexahydropyrrolo also [3 ', 2 ':
4,5]-ring penta [1,
2-c] pyridine-dihydrochloride
6.00g (250mMol) sodium hydride mixes with the anhydrous amylalcohol of 240ml down at 0 ℃, and stirs 30 minutes.(15.6mMol) 4.80g [1S-[1R* (R*), 2 (R*)]]-1,2,3,3a, 4,8b-six hydrogen-N-(1-phenylethyl) pyrrolo-[3 ', 2 ': 4,5] ring penta [1,2-c] pyridine-1-acid amides once adds with solid form, and the reacting by heating mixture is to boiling two hours.
Under 60 ℃/0.1 millibar, extract solvent out, and with residue through 500g silica gel KG60 (methyl alcohol: ammoniacal liquor=100: 2) filter fast.Crude product column chromatography purification (250g silica gel KG 60; Methyl alcohol: ammoniacal liquor=100: 2).
Products therefrom is absorbed in the 20ml methylene dichloride, through sodium sulfate/gac drying, filters and distilling off solvent.
Productive rate: 1.93g beige crystals (77% theoretical yield)
DC: methyl alcohol: ammoniacal liquor=100: 2; R
f=0.25
With the hydrochloric acid alcoholic solution product is converted into its dihydrochloride, acetone extraction is filtered and uses in crystallization in ethanol.The gained clear crystal is hygroscopic by force.
[α]
D 20:+37.9 ° (c=0.12/ methyl alcohol)
Trace element analysis: HA42C (%) H (%) N (%)
Total molecular formula: calculated value: 50.506.1511.78
C
10H
14Cl
2N
2* 0.26H
2O experimental value: 50.646.0811.55
1H-NMR(D
2O):
δ(ppm)=8.97(s,lH,Pcp-H8);8.72(d,1H,Pcp-H6);8.03(d,1H,Pcp-H5);5.58(d,1H,Pcp-H8b);3.78-3.40(m,3H,Pcp-H3a,4A,B);3.38-3.18(m,2H,Pcp-H2A,B);2.54-2.30(m,1H,Pcp-H3A);2.04-1.87(m,1H,Pcp-H3B)
13C-NMR(D
2O):
δ(ppm)=168.8(s,Pcp-C4a);143.3(d,Pcp-C8);141.1(d.Pcp-C6);138.0(s,Pcp-C8a);126.1(d,Pcp-C5);67.0(d,Pcp-C8b);47.8(t,Pcp-C2);42.6(d,Pcp-C3a);40.2(t,Pcp-C4);32.6(t,Pcp-C3)
Embodiment 6
(-)-[3aR-(3a α, 8b α)]-1,2,3,3a, 4, the 8b-hexahydropyrrolo also [3 ', 2 ':
4,5]-ring penta [1,2-c]-pyridine-dihydrochloride
Be similar to embodiment 5, by 1.00g (3.26mMo l) [1R-[1R* (R*), 2 (S*)]]-1,2,3,3a, 4,8b-six hydrogen-N-(1-phenylethyl) pyrrolo-[3 ', 2 ': 4,5] ring penta [1,2-c] pyridine-1-acid amides is prepared (83% theoretical yield, clear crystal)
[α]
D 20:-36.8 ° (c=0.11/ methyl alcohol)
Trace element analysis: HA43C (%) H (%) N (%)
Total molecular formula: calculated value: 50.586.1511.80
C
10H
14Cl
2N
2* 0.25H
2O experimental value: 50.646.0411.55
1H-NMR(D
2O):
δ(ppm)=8.97(s,1H,Pcp-H8);8.72(d,1H,Pcp-H6);8.03(d,lH,Pcp-H5);5.58(d,1H,Pcp-H8b);3.78-3.40(m,3H,Pcp-H3a,4A,B);3.38-3.18(m,2H,Pcp-H2A,B);2.54-2.30(m,1H,Pcp-H3A);2.04-1.87(m,1H,Pcp-H3B)
13C-NMR(D
2O):
δ(ppm)=168.7(s,Pcp-C4a);143.3(d,Pcp-C8);141.1(d,Pcp-C6);137.9(s,Pcp-C8a);126.0(d,Pcp-C5);67.0(d,Pcp-C8b);47.8(t,Pcp-C2);42.6(d,Pcp-C3a);40.2(t,Pcp-C4);32.5(t,Pcp-C3)
Raw material is prepared as follows:
6-cyano methyl-5,6-dihydro-7-oxygen-7H-2-pyridine-6-carboxylic acid methyl ester
Under 0 ℃, in the suspension of 500ml anhydrous dimethyl formamide, add 30.00g (157mMo l) 5 to 4.51g (188mmol) sodium hydride, 6-dihydro-7-oxygen-7H-2-pyridine-6-carboxylic acid methyl ester in batches.The suspension of Xing Chenging at room temperature stirred two hours thus, added 31.40g (188mMol) iodomethyl cyanide down at 0 ℃, and mixture at room temperature stirs and spends the night.
Under 60 ℃/0.1 millibar, extract solvent out, and residue is distributed in 500ml water and altogether between 4 liters of diethyl ether.Extraction agent is filtered and extracted out to the organic phase that merges through sodium sulfate/gac drying.Crude product is recrystallization from 250ml ethanol.
The orange crystal of productive rate: 23.50g (65% theoretical yield)
DC:EE;R
f=0.35
Fp.:102-103 ℃ (ethanol)
Trace element analysis: HA 32C (%) H (%) N (%)
Total molecular formula: calculated value: 62.614.4812.17
C
12H
10N
2O
3Experimental value: 62.394.3312.14
1H-NMR(CDCl
3):
δ(ppm)=9.08(s,1H,Pn-HI);8.82(d,1H,Pn-H3);7.53(dd,1H,Pn-H4);3.72(s,3H,OC
H 3);3.833.36(AB,1H,Pn-H5A);3.212.29(AB,1H,C
H AH
BCN?)
13C-NMR(CDCl
3):
δ(ppm)=197.6(s,
C=O);168.3(s,
COOCH
3);160.1(s,Pn-C4a);154.9(d,Pn-Cl);147.7(d,Pn-C3);129.8(s,Pn-C7a);121.7(d,Pn-C4);116.1(s,
CN);56.6(s,Pn-C6);53.6(q,O
CH
3);36.7(t,Pn-C5);22.1(t,
CH
2CN)
5,6-dihydro-7-oxygen-7H-2-pyridine-6-acetate nitrile
11.6g (50.4mMol) 6-cyano methyl-5,6-dihydro-7-oxygen-7H-2-pyridine-6-carboxylic acid methyl ester is heated in 180ml2n hydrochloric acid boils 4 hours, is adjusted to pH=9 with solid sodium bicarbonate then, uses the 100ml ethyl acetate extraction seven times at every turn.Solvent is filtered and extracted out to the organic phase 100ml water washing that merges through sodium sulfate/gac drying.With diethyl ether extracted many times product.
Productive rate: 7.20g sap green crystal (83% theoretical yield)
DC:EE;R
f=0.2
Fp.:94-95 ℃ (diethyl ether)
Trace element analysis: HA33C (%) H (%) N (%)
Total molecular formula: calculated value: 69.254.7316.15
C
10H
8N
2O*0.07H
2O experimental value: 69.264.8616.00
1H-NMR(CDCl
3):
δ(ppm)=9.01(s,1H,Pn-H1);8.75(d,lH,Pn-H3);7.49(dd,1H,Pn-H4);3.72-3.40(m,1H,Pn-H6);3.14-2.89(mn,3H,Pn-H5A,B,C
H AH
BCN);2.77-2.60(m,1H,CH
A H BCN)
13C-NMR(CDCl
3):
δ(ppm)=202.2(s,
C=O);160.0(s,Pn-C4a);153.9(d,Pn-Cl);146.2(d,Pn-C3);130.9(s,Pn-C7a);121.6(d,Pn-C4);117.0(s,
CN);42.3(d,Pn-C6);31.3(t,Pn-C5);17.7(t,
CH
2CN)
(+)-[3a α-α 8b α]-1,2,3,3a, 4, the 8b-hexahydropyrrolo is [3 ', 2 ': 4,5] ring penta also
[1,2-c] pyridine
3.45g (20.0mMol) 5,6-dihydro-7-oxygen-7H-2-pyridine-6-acetate nitrile is dissolved in the 110ml anhydrous methanol, stirs with gac, filter, mix as blue Buddhist nun's cobalt of catalyzer with 12g, and hydrogenation under 50 ℃ and 90psi in Parr-equipment, absorb hydrogen up to theory and finish.
Blue Buddhist nun's cobalt filters through Hyflo, distills out the solvent of filtrate, and residue carries out purifying (135g silica gel KG60 with column chromatography; Methyl alcohol: ammoniacal liquor=100: 2).
Productive rate: 2.00g brown crystal (62% theoretical yield)
DC: methyl alcohol: ammoniacal liquor=100: 2; R
f=0.25.
Trace element analysis: HA34A C (%) H (%) N (%)
Total molecular formula: calculated value: 74.977.5517.48
C
10H
12N
2Experimental value: 74.717.5717.39
1H-NMR(CDCl
3):
δ(ppm)=8.56(s,1H,Pcp-H8);8.38(d,1H,Pcp-H6);7.09(d,lH,Pcp-H5);4.85(d,1H,Pcp-H8b);3.28-3.13(m,1H,Pcp-H3a);3.13-2.90(m,2H,Pcp-H4A,B);2.80-2.62(m,2H,Pcp-H2A,B);2.34(S
brcit,1H,N
H);2.10-1.95(m,1H,Pcp-H3A);1.63-1.47(m,1H,Pcp-H3B)
13C-NMR(CDCl
3):
δ(ppm)=152.6(s,Pcp-C4a);148.3(d,Pcp-C8);147.2(d,Pcp-C6);140.6(s,Pcp-C8a);119.9(d,Pcp-C5);67.0(d,Pcp-C8b);46.8(t,Pcp-C2);41.4(d,Pcp-C3a);38.5(t,Pcp-C4);35.6(t,Pcp-C3)
[1S-[1R* (R*), 2 (R) *]]-1,2,3,3a, 4,8b-six hydrogen-N-(1-phenylethyl)
Pyrrolo--[3 ', 2 ': 4,5] encircle penta [1,2-c] pyridine-1-acid amides
10.15g in the 230ml anhydrous propanone (63.4mMol) (±)-(3a α, 8b α]-1,2,3,3a, 4, the 8b-hexahydropyrrolo also [3 ', 2 ': 4,5] ring penta [1,2-c]-pyridine and 9.32g (63.4mMol) in the 20ml anhydrous propanone (S)-(-)-Alpha-Methyl phenylmethane isocyanic ester mixes, at room temperature stirred 30 minutes, and extracted solvent then out.
Crude product is dissolved in the 500ml ebullient ethyl acetate, stirs 5 minutes and filters through gac.Filtrate is mixed with crystal seed, leaves standstill to carry out crystallization in 3 hours under-20 ℃.Filter the crystal of being separated out, use twice of the ice-cold ethyl acetate lixiviate of 5ml at every turn.
Productive rate: 5.00g beige crystals (52% theoretical yield)
DC:EE∶MeOH=8∶1;0.3
Fp.:163-164 ℃ (ethyl acetate)
[α]
D 20:-218.3 ° (c=0.12/ methylene dichloride)
Trace element analysis: HA35C (%) H (%) N (%)
Total molecular formula: calculated value: 73.386.9413.51
C
19H
21N
3O*0.2H
2O experimental value: 73.506.8813.51
1H-NMR(CDCl
3):
δ(Ppm)=8.93(s,1H,Pcp-H8);8.44(d,1H,Pcp-H6);7.43-7.20(m,5H,Ph-H2,3,4,5,6);7.13(d,1H,Pcp-H5);5.46(d,1H,Pcp-H8b);5.10(dq,1H,C
H);4.55(d,1H,N
H,
3J
H,CH=7.7Hz);3.42-3.26(m,2H,Pcp-H2A,B);3.18-2.96(m,2H,Pcp-H3a,4A);2.75(d,1H,Pcp-H4B);2.31-2.11(m,1H,Pcp-H3A);1.75-1.57(m,1H,Pcp-H3B);1.40(d,3H,C
H 3)
13C-NMR(CDCl
3):
δ(ppm)=156.1(s,
C=O);150.4(s,Pcp-C4a);148.8(d,Pcp-C8);148.4(d,Pcp-C6);144.3(s,Ph-Cl);140.1(s,Pcp-C8a);128.5(d,2C,Ph-C3,5);127.0(d,Ph-C4);126.0(d,2C,Ph-C2,6);120.2(d,Pcp-C5);65.0(d,Pcp-C8b);49.8(d,
CH);45.8(t,Pcp-C2);40.9(d,Pcp-C3a);35.8(t,Pcp-C4);31.1(t,Pcp-C3);22.5(q,
CH
3)
[1R-[11R* (R*), 2 (S*)]]-1,2,3,3a, 4,8b-six hydrogen-N-(1-phenylethyl)-
Pyrrolo--[3 ', 2 ': 4,5] encircle penta [1,2-c] pyridine-1-acid amides
The mother liquor of above product is concentrated and is 300ml, chooses the temperature dissolving at boiling point wantonly, mixes with crystal seed, and carries out crystallization in 5 hours-20 ℃ of placements.The crystal that filtration is separated out is used twice of the ice-cold ethyl acetate lixiviate of 2ml at every turn.
Productive rate: 1.20g clear crystal (12% theoretical yield)
DC:EE∶MeOH=8∶1∶0.3
Fp.:154-155 ℃ (ethyl acetate)
[α]
D 20:+185.6 ° (c=0.13/ methylene dichloride)
Trace element analysis: HA36C (%) H (%) N (%)
Total molecular formula: calculated value: 72.966.9613.43
C
19H
21N
3O*0.3H
2O experimental value: 73.056.8813.34
1H-NMR(CDCl
3):
δ(ppm)=8.88(s,1H,Pcp-H8);8.44(d,1H,Pcp-H6);7.42-7.20(m,5H,Ph-H2,3,4,5,6);7.13(d,1H,Pcp-H5);5.40(d,1H,Pcp-H8b,
3J
H,H3a=7.4Hz);5.12(dq,1H,C
H);4.55(d,1H,N
H);3.45-3.25(m,2H,Pcp-H2A,B);3.19-3.00(m,2H,Pcp-H3a,4A);2.75(d,1H,Pcp-H4B);2.31-2.15(m,1H,Pcp-H3A);1.70-1.59(m,1H,Pcp-H3B);1.57(d,3H,C
H 3)
13C-NMR(CDCl
3):
δ(ppm)=156.3(s,
C=O);150.5(s,Pcp-C4a);148.9(d,Pcp-C8);148.6(d,Pcp-C6);144.2(s,Ph-Cl);140.2(s,Pcp-C8a);128.6(d,2C,Ph-C3,5);127.2(d,Ph-C4);126.1(d,2C,Ph-C2,6);120.5(d,Pcp-C5);65.1(d,Pcp-C8b);49.8(d,
CH);46.0(t,Pcp-C2);41.1(d,Pcp-C3a);35.9(t,Pcp-C4);31.3(t,Pcp-C3);22.5(q,
CH
3)
Embodiment 7
(+)-[3a S-(3a α, 8b α)]-1,2,3,3a, 4,8b-six hydrogen-1-methylpyrrole also-
[3 ', 2 ': 4,5] encircle penta [1,2-c] pyridine-dihydrochloride
650mg in the 30ml anhydrous acetonitrile (4.06mMo l) [3a S-(3a α, 8b α)]-1,2,3,3a, 4, the 8b-hexahydropyrrolo is [3 ', 2 ': 4 also, 5]-and ring penta [1,2-c] pyridine and 3.1m l35% formaldehyde solution, mix with 586mg (9.33mMol) sodium cyanoborohydride distributively then.Reaction mixture at room temperature stirred 30 minutes.
Now be adjusted to pH=1, use twice of 30ml dichloromethane extraction at every turn with 2n hydrochloric acid.Make water reach pH=10 by adding the 2n sodium hydroxide solution, use 50m l dichloromethane extraction five times at every turn.Through the dry organic phase of sodium sulfate/gac, filter and distilling off solvent.
Productive rate: 650mg yellow oil (92% theoretical yield)
DC: methylene dichloride: methyl alcohol=8: 1; R
f=0.25
With the hydrochloric acid alcoholic solution this product is converted into its dihydrochloride, acetone extraction is filtered and uses in crystallization in ethanol.The gained clear crystal is hygroscopic by force.
[α]
D 20:+13.2 ° (c=0.11/ methyl alcohol)
Trace element analysis: HA46C (%) H (%) N (%)
Total molecular formula: calculated value: 52.206.6311.07
C
11H
16Cl
2N
2* 0.33H
2O experimental value: 52.256.7110.88
1H-NMR(D
2O):
δ(ppm)=9.08(s,1H,Pcp-H8);8.76(d,1H,Pcp-H6);8.05(d,1H,Pcp-H5);5.50-5.26(m,1H,Pcp-H8b);3.86-3.20(m,5H,Pcp-H2A,B,3a,4A,B);3.15(s,3H,C
H 3);2.76-2.48(m,1H,Pcp-H3A);2.10-1.81(m,1H,Pcp-H3B)
13C-NMR(D
2O):
δ(ppm)=168.8(s,Pcp-C4a);143.9(d,Pcp-C8);140.8(d,Pcp-C6);136.5(s,Pcp-C8a);126.3(d,Pcp-C5);76.5(d,Pcp-C8b);58.6(t,Pcp-C2);42.8(q,
CH
3);42.0(d,Pcp-C3a);40.6(t,Pcp-C4);31.9(t,Pcp-C3)
Embodiment 8
(-)-[3aR-(3a α, 8b α)]-1,2,3,3a, 4,8b-six hydrogen-1-methylpyrrole also-
[3 ', 2 ': 4,5] encircle penta [1,2-c] pyridine-dihydrochloride
Be similar to embodiment 7, by 580mg (3.62mMol) [3aR-(3a α, 8b α)]-1,2,3,3a, 4, the 8b-hexahydropyrrolo is [3 ', 2 ': 4,5]-ring penta [1 also, 2-c] pyridine, 2.74m l35% formaldehyde solution and 523mg (8.33mMol) sodium cyanoborohydride be prepared (90% theoretical yield, clear crystal)
[α]
D 20:-14.0 ° (c=0.14/ methyl alcohol)
Trace element analysis: HA47C (%) H (%) N (%)
Total molecular formula: calculated value: 52.426.6111.11
C
11H
16Cl
2N
2* 0.27H
2O experimental value: 52.476.8010.94
1H-NMR(D
2O):
δ(ppm)=9.08(s,1H,Pcp-H8);8.76(d,1H,Pcp-H6);8.05(d,1H,Pcp-H5);5.50-5.26(m,1H,Pcp-H8b);3.86-3.20(m,5H,Pcp-H2A,B,3a,4A,B);3.15(s,3H,C
H 3);2.76-2.48(m,1H,Pcp-H3A);2.10-1.81(m,1H,Pcp-H3B)
13C-NMR?(D
2O):
δ(ppm)=168.8(s,Pcp-C4a);143.8(d,Pcp-C8);140.8(d,Pcp-C6);136.7(s,Pcp-C8a);126.3(d,Pcp-C5);76.5(d,Pcp-C8b);58.7(t,Pcp-C2);42.8(q,
CH
3);42.1(d,Pcp-C3a);40.6(t,Pcp-C4);31.9(t,Pcp-C3)
Embodiment 9
The radioligand test
Variation by people such as Pabreza (Pabreza, L.A., Dhawan, S., Kella r, K.J., Mo l.Pha rma co l.1991,39,9-12) measure in the rat brain film on the α 4 β 2-hypotypes [
3H] Cy tisin combination:
The rat brain that does not contain cerebellum is rich in the part of film, and (ABSInc.Wilmington DE) slowly floods at 4 ℃, wash, and resuspending is in 30 parts of BS S-Tris-damping fluids (120mMNaCl, 5mM KC1,2mM CaCl
2, 2mM MgCl
2And 50mMTris-Cl, pH7.4,4 ℃) in.The diluent (10 of test compounds
-5To 10
-11M), contain 100-200 μ g protein and 0.75nM[
3H] Cytisin (30Ci/mmol; PerkinElmerNEN, Boston, MA), in final volume 500 μ l, at 4 ℃ of following incubations 75 minutes (each 2 kinds of sample).Measure the combination of nonspecific property with 10 μ M (-)-nicotine.By measure described incubation thing through the vacuum filtration of WhatmanGF/C-strainer, strainer uses 0.5% polyaziridine wetting in advance.Be collected in many sieve plates of micropore FB with the Packard cell harvester and go up relevant radioactivity, and measure with PackardTopc ount microplate β counter.Measure IC by non-linear regression
50-value, and thus by Cheng-Prusoff equation calculating K
i-value, wherein K
i=IC
50/ 1+[part]/K
DMean value by at least three independent measurements obtains average K
i-value.
Claims (15)
1. (-)-[3a α, 8b α]-1,2,3 that the enantiomer-pure of therapeutic value is arranged, 3a, 4,8b-six hydrogen-1-methyl-pyrrolo-[2 ', 3 ': 3,4]-ring penta [1,2-b] pyridine, (-)-[3aR-(3a α, 8b α)]-1,2,3,3a, 4,8b-six hydrogen-pyrrolo-[3 ', 2 ': 4,5]-ring penta [1,2-c] pyridine or (-)-[3aR-(3a α, 8b α)]-1,2,3,3a, 4,8b-six hydrogen-1-methyl-pyrrolo-[3 ', 2 ': 4,5]-penta [1,2-c] encircled but the salt of pyridine or their drug use.
2. (-)-[3a α, 8b α]-1,2,3,3a, 4,8b-six hydrogen-1-methyl-pyrrolo-[2 ', 3 ': 3,4]-ring penta [1,2-b] pyridine-dihydrochloride.
3. (-)-[3aR-(3a α, 8b α)]-1,2,3,3a, 4,8b-six hydrogen-pyrrolo-[3 ', 2 ': 4,5]-ring penta [1,2-c] pyridine-dihydrochloride.
4. (-)-[3aR-(3a α, 8b α)]-1,2,3,3a, 4,8b-six hydrogen-1-methyl-pyrrolo-[3 ', 2 ': 4,5]-ring penta [1,2-c] pyridine-dihydrochloride.
5. the method for each compound among the preparation claim 1-4 is characterized in that, makes general formula compound
Wherein R2, R3 are hydrogen, and X and Y be CH or N independently, are converted into to reductibility general formula (I) compound of Z=singly-bound wherein and R1=hydrogen,
Its optional 1-phenylethyl isocyanate reaction with enantiomer-pure is the compound of following general formula
Obtain the diastereomer of indissoluble by crystallization by the non-enantiomer mixture that obtains like this, the general formula of the diastereisomericallypure pure that obtains like this (III) compound under conditions suitable, be split as enantiomer-pure, general formula (I) compound of Z=singly-bound and R1=hydrogen wherein, it is chosen wantonly, and reaction obtains wherein Z=CH under alkylation conditions
2General formula (I) compound, and randomly with general formula (I) but compound is converted into the salt of its drug use.
6. pharmaceutical preparation, it comprises each compound and salt and the conventional lid human relations auxiliary agent and/or the combination of carrier substance according to claim 1-4.
7. according to the pharmaceutical preparation of claim 6, itself and other compound and the auxiliary agent and/or the carrier substance combination of therapeutic value arranged.
8. according to the purposes of compound in the preparation medicine of claim 1, described medicine is used for the treatment of the disease of maincenter stimulus-transmitting system system.
9. purposes according to Claim 8, described disease is old and feeble dementia or the Alzheimer's disease that causes.
10. according to the purposes of compound in the preparation medicine of claim 1, described medicine is used for the treatment of the disease of maincenter stimulus-transmitting system system.
11. according to the purposes of claim 10, described disease is parkinsonism, Tourette's syndrome or dyskinesia.
12. according to the purposes of compound in the preparation medicine of claim 1, described medicine is used for the treatment of the disease of maincenter stimulus-transmitting system system.
13. according to the purposes of claim 12, described disease is anxiety disorder, depression, fear, psychosis, Bulimia nerovsa or apocleisis.
14. according to the purposes of compound in the preparation medicine of claim 1, described medicine is used for the treatment of the disease of maincenter stimulus-transmitting system system.
15. according to the purposes of claim 14, described medicine is used to improve consciousness and attention as pain killer, nociception agent, neuroprotective, and is used for the smoking alternative medicine.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT0074704A AT414305B (en) | 2004-04-29 | 2004-04-29 | New enantiomerically pure hexahydro-pyrrolo-cyclopenta-pyridine derivatives, useful as central nicotine receptor subtype agonists for e.g. treating Alzheimer's or Parkinson's disease, anxiety and depresssion |
ATA747/2004 | 2004-04-29 | ||
AT7462004A AT501007A1 (en) | 2004-04-29 | 2004-04-29 | NEW (3A ALPHA, 8B ALPHA) -1,2,3,3A, 4,8B-HEXAHYDROPYRROLO (3 ', 2': 4,5) CYCLOPENTA (1,2-C) PYRIDINE DERIVATIVES, METHOD CLOSED YOUR MANUFACTURE AND ITS USE |
ATA746/2004 | 2004-04-29 | ||
PCT/EP2005/051921 WO2005105800A1 (en) | 2004-04-29 | 2005-04-28 | Enantiomer-pure hexahydro- pyrrolocyclopenta- pyridine derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1950370A CN1950370A (en) | 2007-04-18 |
CN1950370B true CN1950370B (en) | 2010-11-03 |
Family
ID=36178261
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2005800135347A Expired - Fee Related CN1950370B (en) | 2004-04-29 | 2005-04-28 | Enantiomer-pure hexahydro- pyrrolocyclopenta- pyridine derivatives |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN1950370B (en) |
AT (1) | AT414305B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103059029B (en) * | 2012-12-28 | 2014-12-10 | 塔里木大学 | Hexahydro-pyrrole[2,3]indole compound and its preparation method and use in bactericidal activity |
-
2004
- 2004-04-29 AT AT0074704A patent/AT414305B/en not_active IP Right Cessation
-
2005
- 2005-04-28 CN CN2005800135347A patent/CN1950370B/en not_active Expired - Fee Related
Non-Patent Citations (4)
Title |
---|
Hongbin Zhai et al..A Facile Synthesis ofCis-1-Methyl-1,2,3,3a,4,8b-hexahydropyrrolo[3,2-f]pyrindine,anAnnulated Nicotine Analog.ORGANIC LETTERS4 25.2002,4(25),4385-4386. |
Hongbin Zhai et al..A Facile Synthesis ofCis-1-Methyl-1,2,3,3a,4,8b-hexahydropyrrolo[3,2-f]pyrindine,anAnnulated Nicotine Analog.ORGANIC LETTERS4 25.2002,4(25),4385-4386. * |
ULLRICH T ET AL.Conformationally constrained nicotines: polycyclic,bridged,andspiro-annulated analogues as novel ligands for the nicotinicacetylcholine receptor.JOURNAL OF MEDICAL CHEMISTRY45.2002,454047-4054. * |
WO 0100626 A,全文. |
Also Published As
Publication number | Publication date |
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CN1950370A (en) | 2007-04-18 |
ATA7472004A (en) | 2006-04-15 |
AT414305B (en) | 2006-12-15 |
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